Search results

Title: Temperature Influences Chorda Tympani Nerve Responses to Sweet, Salty, Sour, Umami, and Bitter Stimuli in Mice.
Creator: Lu, Bo, Breza, Joseph M, Contreras, Robert J
Abstract/Description: Temperature profoundly affects the perceived intensity of taste, yet we know little of the extent of temperature's effect on taste in the peripheral nervous system. Accordingly, we investigated the influence of temperature from 23 °C to 43 °C in 4 °C intervals on the integrated responses of the chorda tympani (CT) nerve to a large series of chemical stimuli representing sweet, salty, sour, bitter, and umami tastes in C57BL/J6 mice. We also measured neural responses to NaCl, Na-gluconate, Na...
Show moreTemperature profoundly affects the perceived intensity of taste, yet we know little of the extent of temperature's effect on taste in the peripheral nervous system. Accordingly, we investigated the influence of temperature from 23 °C to 43 °C in 4 °C intervals on the integrated responses of the chorda tympani (CT) nerve to a large series of chemical stimuli representing sweet, salty, sour, bitter, and umami tastes in C57BL/J6 mice. We also measured neural responses to NaCl, Na-gluconate, Na-acetate, Na-sulfate, and MSG with and without 5 µM benzamil, an epithelial sodium channel (ENaC) antagonist, to assess the influence of temperature on ENaC-dependent and ENaC-independent response components. Our results showed that for most stimuli (0.5M sucrose, glucose, fructose, and maltose; 0.02M saccharin and sucralose; 0.5M NaCl, Na-gluconate, Na-acetate, Na-sulfate, KCl, K-gluconate, K-acetate, and K-sulfate; 0.05M citric acid, acetic acid, and HCl; 0.1M MSG and 0.05M quinine hydrochloride: QHCl), CT response magnitudes were maximal between 35 °C and 39 °C and progressively smaller at cooler or warmer temperatures. In contrast, the weakest responses to NHCl, (NH)SO4, and K-sulfate were at the lowest temperature, with response magnitude increasing monotonically with increasing temperature, while the largest responses to acetic acid were at the lowest temperature, with response magnitude decreasing with increasing temperature. The response to sweet and umami stimuli across temperatures were similar reflecting the involvement of TRPM5 activity, in contrast to bitter stimuli, which were weakly affected by temperature. Temperature-modulated responses to salts and acids most likely operate through mechanisms independent of ENaC and TRPM5.
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Date Issued: 2016-08-06
Identifier: FSU_pmch_27497433, 10.1093/chemse/bjw082, PMC5070488, 27497433, 27497433, bjw082
Format: Citation

Title: The ties that bond: neurochemistry of attachment in voles..
Creator: Gobrogge, Kyle, Wang, Zuoxin
Abstract/Description: In socially monogamous prairie voles (Microtus ochrogaster), mating induces three primary types of behavior; namely, partner preference, selective aggression toward conspecific strangers, and bi-parental care, making this rodent an ideal model system to study sociality and underlying neurochemical mechanisms associated with monogamous mating strategies. Here, we highlight species differences in neurochemical receptor distributions associated with mating experience leading to the establishment...
Show moreIn socially monogamous prairie voles (Microtus ochrogaster), mating induces three primary types of behavior; namely, partner preference, selective aggression toward conspecific strangers, and bi-parental care, making this rodent an ideal model system to study sociality and underlying neurochemical mechanisms associated with monogamous mating strategies. Here, we highlight species differences in neurochemical receptor distributions associated with mating experience leading to the establishment of stable pair-bonds. Specifically, we illustrate the role of nucleus accumbens dopamine in programming the formation and maintenance of monogamous bonds and describe the role of anterior hypothalamic vasopressin in the regulation of selective aggression. We conclude by discussing recent molecular work in voles and emphasize the importance of this rodent for future research in the behavioral neurobiology field.
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Date Issued: 2016-06-01
Identifier: FSU_pmch_27131991, 10.1016/j.conb.2016.04.011, PMC4921794, 27131991, 27131991, S0959-4388(16)30046-0
Format: Citation

Title: Neurochemical Mediation of Affiliation and Aggression Associated With Pair-Bonding.
Creator: Gobrogge, Kyle L, Jia, Xixi, Liu, Yan, Wang, Zuoxin
Abstract/Description: The neuropeptides vasopressin and corticotropin-releasing factor facilitate, while serotonin inhibits, aggression. How the brain is wired to coordinate interactions between these functionally opposed neurotransmitters to control behavioral states is poorly understood. Pair-bonded male prairie voles (Microtus ochrogaster) were infused with a retrograde tracer, Fluoro-Gold, and tested for affiliation and aggression toward a female partner or novel female subject. Subsequent immunocytochemical...
Show moreThe neuropeptides vasopressin and corticotropin-releasing factor facilitate, while serotonin inhibits, aggression. How the brain is wired to coordinate interactions between these functionally opposed neurotransmitters to control behavioral states is poorly understood. Pair-bonded male prairie voles (Microtus ochrogaster) were infused with a retrograde tracer, Fluoro-Gold, and tested for affiliation and aggression toward a female partner or novel female subject. Subsequent immunocytochemical experiments examined neuronal activation using Fos and neurochemical/neuroreceptor profiles on brain areas involved in these social behaviors. Finally, a series of behavioral pharmacologic and real-time in vivo brain microdialysis experiments were performed on male prairie voles displaying affiliation or aggression. We localized a subpopulation of excitatory vasopressin neurons in the anterior hypothalamus that may gate corticotropin-releasing factor output from the amygdala to the anterior hypothalamus and then the lateral septum to modulate aggression associated with mate guarding. Conversely, we identified a subset of inhibitory serotonergic projection neurons in the dorsal raphe that project to the anterior hypothalamus and may mediate the spatiotemporal release of neuropeptides and their interactions in modulating aggression and affiliation. Together, this study establishes the medial extended amygdala as a major neural substrate regulating the switch between positive and negative affective states, wherein several neurochemicals converge and interact to coordinate divergent social behaviors.
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Date Issued: 2017-02-01
Identifier: FSU_pmch_27129413, 10.1016/j.biopsych.2016.02.013, PMC4992658, 27129413, 27129413, S0006-3223(16)00100-1
Format: Citation

Title: Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine.
Creator: Duclot, Florian, Perez-Taboada, Iara, Wright, Katherine N, Kabbaj, Mohamed
Abstract/Description: Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear...
Show moreOnly a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-d-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory.
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Date Issued: 2016-10-01
Identifier: FSU_pmch_27343386, 10.1016/j.neuropharm.2016.06.022, PMC5017153, 27343386, 27343386, S0028-3908(16)30275-1
Format: Citation

Title: GABAergic mechanisms contributing to categorical amygdala responses to chemosensory signals.
Creator: Westberry, Jenne M, Meredith, Michael
Abstract/Description: Chemosensory stimuli from conspecific and heterospecific animals, elicit categorically different immediate-early gene response-patterns in medial amygdala in male hamsters and mice. We previously showed that conspecific signals activate posterior (MeP) as well as anterior medial amygdala (MeA), and especially relevant heterospecific signals such as chemosensory stimuli from potential predators also activate MeP in mice. Other heterospecific chemosignals activate MeA, but not MeP. Here we show...
Show moreChemosensory stimuli from conspecific and heterospecific animals, elicit categorically different immediate-early gene response-patterns in medial amygdala in male hamsters and mice. We previously showed that conspecific signals activate posterior (MeP) as well as anterior medial amygdala (MeA), and especially relevant heterospecific signals such as chemosensory stimuli from potential predators also activate MeP in mice. Other heterospecific chemosignals activate MeA, but not MeP. Here we show that male hamster amygdala responds significantly differentially to different conspecific signals, by activating different proportions of cells of different phenotype, possibly leading to differential activation of downstream circuits. Heterospecific signals that fail to activate MeP do activate GABA-immunoreactive cells in the adjacent caudal main intercalated nucleus (mICNc) and elicit selective suppression of MeP cells bearing GABA-Receptors, suggesting GABA inhibition in MeP by GABAergic cells in mICNc. Overall, work presented here suggests that medial amygdala may discriminate between important conspecific social signals, distinguish them from the social signals of other species and convey that information to brain circuits eliciting appropriate social behavior.
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Date Issued: 2016-09-07
Identifier: FSU_pmch_27329335, 10.1016/j.neuroscience.2016.06.020, PMC4955787, 27329335, 27329335, S0306-4522(16)30250-0
Format: Citation

Title: The neurobiology of pair bond formation, bond disruption, and social buffering.
Creator: Lieberwirth, Claudia, Wang, Zuoxin
Abstract/Description: Enduring social bonds play an essential role in human society. These bonds positively affect psychological, physiological, and behavioral functions. Here, we review the recent literature on the neurobiology, particularly the role of oxytocin and dopamine, of pair bond formation, bond disruption, and social buffering effects on stress responses, from studies utilizing the socially monogamous prairie vole (Microtus ochrogaster).
Date Issued: 2016-10-01
Identifier: FSU_pmch_27290660, 10.1016/j.conb.2016.05.006, PMC5072360, 27290660, 27290660, S0959-4388(16)30065-4
Format: Citation

Title: Postsynaptic Fmrp Regulates Synaptogenesis In Vivo In The Developing Cochlear Nucleus.
Creator: Wang, Xiaoyu, Zorio, Diego A. R., Schecterson, Leslayann, Lu, Yong, Wang, Yuan
Abstract/Description: A global loss of the fragile X mental retardation protein (FMRP; encoded by the Fmr1 gene) leads to sensory dysfunction and intellectual disabilities. One underlying mechanism of these phenotypes is structural and functional deficits in synapses. Here, we determined the autonomous function of postsynaptic FMRP in circuit formation, synaptogenesis, and synaptic maturation. In normal cochlea nucleus, presynaptic auditory axons form large axosomatic endbulb synapses on cell bodies of...
Show moreA global loss of the fragile X mental retardation protein (FMRP; encoded by the Fmr1 gene) leads to sensory dysfunction and intellectual disabilities. One underlying mechanism of these phenotypes is structural and functional deficits in synapses. Here, we determined the autonomous function of postsynaptic FMRP in circuit formation, synaptogenesis, and synaptic maturation. In normal cochlea nucleus, presynaptic auditory axons form large axosomatic endbulb synapses on cell bodies of postsynaptic bushy neurons. In ovo electroporation of drug-inducible Fmr1-shRNA constructs produced a mosaicism of FMRP expression in chicken (either sex) bushy neurons, leading to reduced FMRP levels in transfected, but not neighboring nontransfected, neurons. Structural analyses revealed that postsynaptic FMRP reduction led to smaller size and abnormal morphology of individual presynaptic endbulbs at both early and later developmental stages. We further examined whether FMRP reduction affects dendritic development, as a potential mechanism underlying defective endbulb formation. Normally, chicken bushy neurons grow extensive dendrites at early stages and retract these dendrites when endbulbs begin to form. Neurons transfected with Fmr1 shRNA exhibited a remarkable delay in branch retraction, failing to provide necessary somatic surface for timely formation and growth of large endbulbs. Patch-clamp recording verified functional consequences of dendritic and synaptic deficits on neurotransmission, showing smaller amplitudes and slower kinetics of spontaneous and evoked EPSCs. Together, these data demonstrate that proper levels of postsynaptic FMRP are required for timely maturation of somatodendritic morphology, a delay of which may affect synaptogenesis and thus contribute to long-lasting deficits of excitatory synapses.
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Date Issued: 2018-07-18
Identifier: FSU_libsubv1_wos_000439698400004, 10.1523/JNEUROSCI.0665-18.2018
Format: Citation

Title: The role of ΔfosB in the medial preoptic area: Differential effects of mating and cocaine history..
Creator: McHenry, Jenna A, Robison, Christopher L, Bell, Genevieve A, Vialou, Vincent V, Bolaños-Guzmán, Carlos A, Nestler, Eric J, Hull, Elaine M
Abstract/Description: The transcription factor deltaFosB (ΔFosB) is induced in the nucleus accumbens (NAc) by repeated exposure to drugs of abuse and natural rewards. Less is known about its role in other brain areas. Here, we compared the effects of mating versus cocaine history on induction of ΔFosB in the medial preoptic area (MPOA), an integral site for reproductive behavior, and in the NAc. ΔFosB immunoreactivity (ir) was increased in the MPOA of previously naïve and experienced male rats that mated the day...
Show moreThe transcription factor deltaFosB (ΔFosB) is induced in the nucleus accumbens (NAc) by repeated exposure to drugs of abuse and natural rewards. Less is known about its role in other brain areas. Here, we compared the effects of mating versus cocaine history on induction of ΔFosB in the medial preoptic area (MPOA), an integral site for reproductive behavior, and in the NAc. ΔFosB immunoreactivity (ir) was increased in the MPOA of previously naïve and experienced male rats that mated the day before euthanasia, compared to unmated controls and experienced males with recent mating abstinence. Western immunoblots confirmed that the 35-37-kDa isoform of ΔFosB was increased more in recently mated males. Conversely, previous plus recent cocaine did not increase ΔFosB-ir in the MPOA, despite an increase in the NAc. Next, a viral vector expressing ΔFosB, its dominant negative antagonist ΔJunD, or green fluorescent protein (GFP) control, were microinjected bilaterally into the MPOA. ΔFosB overexpression impaired copulation and promoted female-directed aggression, compared to ΔJunD and control males. These data suggest that ΔFosB in the mPOA is expressed in an experience-dependent manner and affects systems that coordinate mating and aggression. (PsycINFO Database Record
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Date Issued: 2016-10-01
Identifier: FSU_pmch_27657309, 10.1037/bne0000160, PMC5201202, 27657309, 27657309, 2016-45747-001
Format: Citation

Title: Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory in .
Creator: Krishnan, Harini C, Gandour, Catherine E, Ramos, Joshua L, Wrinkle, Mariah C, Sanchez-Pacheco, Joseph J, Lyons, Lisa C
Abstract/Description: Insufficient sleep in individuals appears increasingly common due to the demands of modern work schedules and technology use. Consequently, there is a growing need to understand the interactions between sleep deprivation and memory. The current study determined the effects of acute sleep deprivation on short and long-term associative memory using the marine mollusk , a relatively simple model system well known for studies of learning and memory. were sleep deprived for 9 hours using context...
Show moreInsufficient sleep in individuals appears increasingly common due to the demands of modern work schedules and technology use. Consequently, there is a growing need to understand the interactions between sleep deprivation and memory. The current study determined the effects of acute sleep deprivation on short and long-term associative memory using the marine mollusk , a relatively simple model system well known for studies of learning and memory. were sleep deprived for 9 hours using context changes and tactile stimulation either prior to or after training for the operant learning paradigm, learning that food is inedible (LFI). The effects of sleep deprivation on short-term (STM) and long-term memory (LTM) were assessed. Acute sleep deprivation prior to LFI training impaired the induction of STM and LTM with persistent effects lasting at least 24 h. Sleep deprivation immediately after training blocked the consolidation of LTM. However, sleep deprivation following the period of molecular consolidation did not affect memory recall. Memory impairments were independent of handling-induced stress, as daytime handled control animals demonstrated no memory deficits. Additional training immediately after sleep deprivation failed to rescue the induction of memory, but additional training alleviated the persistent impairment in memory induction when training occurred 24 h following sleep deprivation. Acute sleep deprivation inhibited the induction and consolidation, but not the recall of memory. These behavioral studies establish as an effective model system for studying the interactions between sleep and memory formation.
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Date Issued: 2016-12-01
Identifier: FSU_pmch_27748243, 10.5665/sleep.6320, PMC5103805, 27748243, 27748243, sp-00313-16
Format: Citation

Title: Alteration Of Neuronal Excitability And Short-term Synaptic Plasticity In The Prefrontal Cortex Of A Mouse Model Of Mental Illness.
Creator: Crabtree, Gregg W., Sun, Ziyi, Kvajo, Mirna, Broek, Jantine A. C., Fenelon, Karine, McKellar, Heather, Xiao, Lan, Xu, Bin, Bahn, Sabine, O'Donnell, James M., Gogos, Joseph A.
Abstract/Description: Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced...
Show moreUsing a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltagedependent potassium channel subunit K(v)1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of K(v)1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.
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Date Issued: 2017-04-12
Identifier: FSU_libsubv1_wos_000399440400015, 10.1523/JNEUROSCI.4345-15.2017
Format: Citation

Title: Activation of Metabotropic Glutamate Receptors Regulates Ribosomes of Cochlear Nucleus Neurons.
Creator: Hyson, Richard, Carzoli, Kathryn
Abstract/Description: The brain stem auditory system of the chick is an advantageous model for examining changes that occur as a result of deafness. Elimination of acoustic input through cochlear ablation results in the eventual death of approximately 30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). One early change following deafness is an alteration in NM ribosomes, evidenced both by a decrease in protein synthesis and reduction in antigenicity for Y10B, a monoclonal antibody that...
Show moreThe brain stem auditory system of the chick is an advantageous model for examining changes that occur as a result of deafness. Elimination of acoustic input through cochlear ablation results in the eventual death of approximately 30% of neurons in the chick cochlear nucleus, nucleus magnocellularis (NM). One early change following deafness is an alteration in NM ribosomes, evidenced both by a decrease in protein synthesis and reduction in antigenicity for Y10B, a monoclonal antibody that recognizes a ribosomal epitope. Previous studies have shown that mGluR activation is necessary to maintain Y10B antigenicity and NM viability. What is still unclear, however, is whether or not mGluR activation is sufficient to prevent deafness-induced changes in these neurons, or if other activity-dependent factors are also necessary. The current study investigated the ability of mGluR activation to regulate cochlear nucleus ribosomes in the absence of auditory nerve input. In vitro methods were employed to periodically pressure eject glutamate or mGluR agonists over neurons on one side of a slice preparation leaving the opposite side of the same slice untreated. Immunohistochemistry was then performed using Y10B in order to assess ribosomal changes. Application of glutamate and both group I and II selective mGluR agonists effectively rescued ribosomal antigenicity on the treated side of the slice in comparison to ribosomes on the untreated side. These findings suggest that administration of mGluR agonists is sufficient to reduce the early interruption of normal ribosomal integrity that is typically seen following loss of auditory nerve activity.
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Date Issued: 2014-10-21
Identifier: FSU_libsubv1_scholarship_submission_1475086818, 10.1371/journal.pone.0111243
Format: Citation

Title: Dual Detection System for Simultaneous Measurement of Intracellular Fluorescent Markers and Cellular Secretion.
Creator: Yi, Lian, Bandak, Basel, Wang, Xue, Bertram, Richard, Roper, Michael G
Abstract/Description: Glucose-stimulated insulin secretion from pancreatic β-cells within islets of Langerhans plays a critical role in maintaining glucose homeostasis. Although this process is essential for maintaining euglycemia, the underlying intracellular mechanisms that control it are still unclear. To allow simultaneous correlation between intracellular signal transduction events and extracellular secretion, an analytical system was developed that integrates fluorescence imaging of intracellular probes with...
Show moreGlucose-stimulated insulin secretion from pancreatic β-cells within islets of Langerhans plays a critical role in maintaining glucose homeostasis. Although this process is essential for maintaining euglycemia, the underlying intracellular mechanisms that control it are still unclear. To allow simultaneous correlation between intracellular signal transduction events and extracellular secretion, an analytical system was developed that integrates fluorescence imaging of intracellular probes with high-speed automated insulin immunoassays. As a demonstration of the system, intracellular [Ca] ([Ca]) was measured by imaging Fura-2 fluorescence simultaneously with insulin secretion from islets exposed to elevated glucose levels. Both [Ca] and insulin were oscillatory during application of 10 mM glucose with temporal and quantitative profiles similar to what has been observed elsewhere. In previous work, sinusoidal glucose levels have been used to test the entrainment of islets while monitoring either [Ca] or insulin levels; using this newly developed system, we show unambiguously that oscillations of both [Ca] and insulin release are entrained to oscillatory glucose levels and that the temporal correlation of these are maintained throughout the experiment. It is expected that the developed analytical system can be expanded to investigate a number of other intracellular messengers in islets or other stimulus-secretion pathways in different cells.
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Date Issued: 2016-11-01
Identifier: FSU_pmch_27712062, 10.1021/acs.analchem.6b02404, PMC5089909, 27712062, 27712062
Format: Citation

Title: Glucose Oscillations Can Activate an Endogenous Oscillator in Pancreatic Islets.
Creator: McKenna, Joseph P, Dhumpa, Raghuram, Mukhitov, Nikita, Roper, Michael G, Bertram, Richard
Abstract/Description: Pancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in β-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with...
Show morePancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in β-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with mathematical modeling that the sinusoidal glucose signal's ability to recover islet oscillations depends on its amplitude and period, and we confirm our predictions by conducting experiments with islets using a microfluidics platform. Our results suggest a mechanism whereby oscillatory blood glucose levels recruit non-oscillating islets to enhance pulsatile insulin output from the pancreas. Our results also provide support for the main hypothesis of the Dual Oscillator Model, that a glycolytic oscillator endogenous to islet β-cells drives pulsatile insulin secretion.
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Date Issued: 2016-10-27
Identifier: FSU_pmch_27788129, 10.1371/journal.pcbi.1005143, PMC5082885, 27788129, 27788129, PCOMPBIOL-D-16-00306
Format: Citation

Title: Genetic Dissection of Dual Roles for the Transcription Factor six7 in Photoreceptor Development and Patterning in Zebrafish.
Creator: Sotolongo-Lopez, Mailin, Alvarez-Delfin, Karen, Saade, Carole Jean, Vera, Daniel L, Fadool, James M
Abstract/Description: The visual system of a particular species is highly adapted to convey detailed ecological and behavioral information essential for survival. The consequences of structural mutations of opsins upon spectral sensitivity and environmental adaptation have been studied in great detail, but lacking is knowledge of the potential influence of alterations in gene regulatory networks upon the diversity of cone subtypes and the variation in the ratio of rods and cones observed in numerous diurnal and...
Show moreThe visual system of a particular species is highly adapted to convey detailed ecological and behavioral information essential for survival. The consequences of structural mutations of opsins upon spectral sensitivity and environmental adaptation have been studied in great detail, but lacking is knowledge of the potential influence of alterations in gene regulatory networks upon the diversity of cone subtypes and the variation in the ratio of rods and cones observed in numerous diurnal and nocturnal species. Exploiting photoreceptor patterning in cone-dominated zebrafish, we uncovered two independent mechanisms by which the sine oculis homeobox homolog 7 (six7) regulates photoreceptor development. In a genetic screen, we isolated the lots-of-rods-junior (ljrp23ahub) mutation that resulted in an increased number and uniform distribution of rods in otherwise normal appearing larvae. Sequence analysis, genome editing using TALENs and knockdown strategies confirm ljrp23ahub as a hypomorphic allele of six7, a teleost orthologue of six3, with known roles in forebrain patterning and expression of opsins. Based on the lack of predicted protein-coding changes and a deletion of a conserved element upstream of the transcription start site, a cis-regulatory mutation is proposed as the basis of the reduced expression of six7 in ljrp23ahub. Comparison of the phenotypes of the hypomorphic and knock-out alleles provides evidence of two independent roles in photoreceptor development. EdU and PH3 labeling show that the increase in rod number is associated with extended mitosis of photoreceptor progenitors, and TUNEL suggests that the lack of green-sensitive cones is the result of cell death of the cone precursor. These data add six7 to the small but growing list of essential genes for specification and patterning of photoreceptors in non-mammalian vertebrates, and highlight alterations in transcriptional regulation as a potential source of photoreceptor variation across species.
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Date Issued: 2016-04-08
Identifier: FSU_libsubv1_scholarship_submission_1475614578, 10.1371/journal.pgen.1005968
Format: Citation

Title: Genetic Dissection of Dual Roles for the Transcription Factor six7 in Photoreceptor Development and Patterning in Zebrafish.
Creator: Sotolongo-Lopez, Mailin, Alvarez-Delfin, Karen, Saade, Carole J., Vera, Daniel L., Fadool, James M.
Abstract/Description: The visual system of a particular species is highly adapted to convey detailed ecological and behavioral information essential for survival. The consequences of structural mutations of opsins upon spectral sensitivity and environmental adaptation have been studied in great detail, but lacking is knowledge of the potential influence of alterations in gene regulatory networks upon the diversity of cone subtypes and the variation in the ratio of rods and cones observed in numerous diurnal and...
Show moreThe visual system of a particular species is highly adapted to convey detailed ecological and behavioral information essential for survival. The consequences of structural mutations of opsins upon spectral sensitivity and environmental adaptation have been studied in great detail, but lacking is knowledge of the potential influence of alterations in gene regulatory networks upon the diversity of cone subtypes and the variation in the ratio of rods and cones observed in numerous diurnal and nocturnal species. Exploiting photoreceptor patterning in cone-dominated zebrafish, we uncovered two independent mechanisms by which the sine oculis homeobox homolog 7 (six7) regulates photoreceptor development. In a genetic screen, we isolated the lots-of-rods-junior (ljr(p23ahub)) mutation that resulted in an increased number and uniform distribution of rods in otherwise normal appearing larvae. Sequence analysis, genome editing using TALENs and knockdown strategies confirm ljr(p23ahub) as a hypomorphic allele of six7, a teleost orthologue of six3, with known roles in forebrain patterning and expression of opsins. Based on the lack of predicted protein-coding changes and a deletion of a conserved element upstream of the transcription start site, a cis-regulatory mutation is proposed as the basis of the reduced expression of six7 in ljr(p23ahub). Comparison of the phenotypes of the hypomorphic and knock-out alleles provides evidence of two independent roles in photoreceptor development. EdU and PH3 labeling show that the increase in rod number is associated with extended mitosis of photoreceptor progenitors, and TUNEL suggests that the lack of green-sensitive cones is the result of cell death of the cone precursor. These data add six7 to the small but growing list of essential genes for specification and patterning of photoreceptors in non-mammalian vertebrates, and highlight alterations in transcriptional regulation as a potential source of photoreceptor variation across species.
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Date Issued: 2016-04
Identifier: FSU_libsubv1_wos_000375231900020, 10.1371/journal.pgen.1005968
Format: Citation

Title: Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner.
Creator: Saland, Samantha K., Schoepfer, Kristin J., Kabbaj, Mohamed
Abstract/Description: We recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex-and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and...
Show moreWe recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex-and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and progesterone on initiation and maintenance of hedonic response to low-dose ketamine (2.5 mg/kg) in intact and gonadectomized male and female rats. Ketamine induced a sustained increase in sucrose preference of female, but not male, rats in an E2P4-dependent manner. Whereas testosterone failed to alter male treatment response, concurrent administration of P4 alone in intact males enhanced hedonic response low-dose ketamine. Treatment responsiveness in female rats only was associated with greater hippocampal BDNF levels, but not activation of key downstream signaling effectors. We provide novel evidence supporting activational roles for ovarian-, but not testicular-, derived hormones in mediating hedonic sensitivity to low-dose ketamine in female and male rats, respectively. Organizational differences may, in part, account for the persistence of sex differences following gonadectomy and selective involvement of BDNF in treatment response.
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Date Issued: 2016-02-18
Identifier: FSU_libsubv1_wos_000370371700002, 10.1038/srep21322
Format: Citation

Title: Mitochondrial Ultrastructure And Glucose Signaling Pathways Attributed To The Kv1.3 Ion Channel.
Creator: Kovach, Christopher P., Al Koborssy, Dolly, Huang, Zhenbo, Chelette, Brandon M., Fadool, James M., Fadool, Debra A.
Abstract/Description: Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3(-/-)) results in "Super-smeller" mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, G(olf). Kv1.3(-/-) mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity,...
Show moreGene-targeted deletion of the potassium channel Kv1.3 (Kv1.3(-/-)) results in "Super-smeller" mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, G(olf). Kv1.3(-/-) mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3(-/-) male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3(-/-) mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3(-/-) mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB.
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Date Issued: 2016-05-19
Identifier: FSU_libsubv1_wos_000376059000001, 10.3389/fphys.2016.00178
Format: Citation

Title: Behavioral Evidence for More than One Taste Signaling Pathway for Sugars in Rats.
Creator: Schier, Lindsey A., Spector, Alan C.
Abstract/Description: By conventional behavioral measures, rodents respond to natural sugars, such as glucose and fructose, as though they elicit an identical perceptual taste quality. Beyond that, the metabolic and sensory effects of these two sugars are quite different. Considering the capacity to immediately respond to the more metabolically expedient sugar, glucose, would seem advantageous for energy intake, the present experiment assessed whether experience consuming these two sugars would modify taste-guided...
Show moreBy conventional behavioral measures, rodents respond to natural sugars, such as glucose and fructose, as though they elicit an identical perceptual taste quality. Beyond that, the metabolic and sensory effects of these two sugars are quite different. Considering the capacity to immediately respond to the more metabolically expedient sugar, glucose, would seem advantageous for energy intake, the present experiment assessed whether experience consuming these two sugars would modify taste-guided ingestive responses to their yet unknown distinguishing orosensory properties. One group (GvF) had randomized access to three concentrations of glucose and fructose (0.316, 0.56, 1.1 M) in separate 30-min single access training sessions, whereas control groups received equivalent exposure to the three glucose or fructose concentrations only, or remained sugar naive. Comparison of the microstructural licking patterns for the two sugars revealed that GvF responded more positively to glucose (increased total intake, increased burst size, decreased number of pauses), relative to fructose, across training. As training progressed, GvF rats began to respond more positively to glucose in the first minute of the session when intake is principally taste-driven. During post-training brief-access taste tests, GvF rats licked more for glucose than for fructose, whereas the other training groups did not respond differentially to the two sugars. Additional brief access testing showed that this did not generalize to Na-saccharin or galactose. Thus, in addition to eliciting a common taste signal, glucose and fructose produce distinct signals that are apparently rendered behaviorally relevant and hedonically distinct through experience. The taste pathway(s) underlying this remain to be identified.
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Date Issued: 2016-01-06
Identifier: FSU_libsubv1_wos_000368348100014, 10.1523/JNEUROSCI.3356-15.2016
Format: Citation

Title: Nutrient Sensing: Another Chemosensitivity Of The Olfactory System.
Creator: Julliard, A.-Karyn, Al Koborssy, Dolly, Fadool, Debra A., Palouzier-Paulignan, Brigitte
Abstract/Description: Olfaction is a major sensory modality involved in real time perception of the chemical composition of the external environment. Olfaction favors anticipation and rapid adaptation of behavioral responses necessary for animal survival. Furthermore, recent studies have demonstrated that there is a direct action of metabolic peptides on the olfactory network. Orexigenic peptides such as ghrelin and orexin increase olfactory sensitivity, which in turn, is decreased by anorexigenic hormones such as...
Show moreOlfaction is a major sensory modality involved in real time perception of the chemical composition of the external environment. Olfaction favors anticipation and rapid adaptation of behavioral responses necessary for animal survival. Furthermore, recent studies have demonstrated that there is a direct action of metabolic peptides on the olfactory network. Orexigenic peptides such as ghrelin and orexin increase olfactory sensitivity, which in turn, is decreased by anorexigenic hormones such as insulin and leptin. In addition to peptides, nutrients can play a key role on neuronal activity. Very little is known about nutrient sensing in olfactory areas. Nutrients, such as carbohydrates, amino acids, and lipids, could play a key role in modulating olfactory sensitivity to adjust feeding behavior according to metabolic need. Here we summarize recent findings on nutrient-sensing neurons in olfactory areas and delineate the limits of our knowledge on this topic. The present review opens new lines of investigations on the relationship between olfaction and food intake, which could contribute to determining the etiology of metabolic disorders.
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Date Issued: 2017-07-12
Identifier: FSU_libsubv1_wos_000405365400001, 10.3389/fphys.2017.00468
Format: Citation

Title: Oxytocin receptor binding sites in the periphery of the neonatal mouse.
Creator: Greenwood, Maria A, Hammock, Elizabeth A D
Abstract/Description: Oxytocin (OXT) is a pleiotropic regulator of physiology and behavior. An emerging body of evidence demonstrates a role for OXT in the transition to postnatal life of the infant. To identify potential sites of OXT action via the OXT receptor (OXTR) in the newborn mouse, we performed receptor autoradiography on 20 μm sagittal sections of whole postnatal day 0 male and female mice on a C57BL/6J background using the 125iodinated ornithine vasotocin analog ([125I]-OVTA) radioligand. A competitive...
Show moreOxytocin (OXT) is a pleiotropic regulator of physiology and behavior. An emerging body of evidence demonstrates a role for OXT in the transition to postnatal life of the infant. To identify potential sites of OXT action via the OXT receptor (OXTR) in the newborn mouse, we performed receptor autoradiography on 20 μm sagittal sections of whole postnatal day 0 male and female mice on a C57BL/6J background using the 125iodinated ornithine vasotocin analog ([125I]-OVTA) radioligand. A competitive binding assay on both wild-type (WT) and OXTR knockout (OXTR KO) tissue was used to assess the selectivity of [125I]-OVTA for neonatal OXTR. Radioactive ligand (0.05 nM [125I]-OVTA) was competed against concentrations of 0 nM, 10 nM, and 1000 nM excess unlabeled OXT. Autoradiographs demonstrated the high selectivity of the radioligand for infant peripheral OXTR. Specific ligand binding activity for OXTR was observed in the oronasal cavity, the eye, whisker pads, adrenal gland, and anogenital region in the neonatal OXTR WT mouse, but was absent in neonatal OXTR KO. Nonspecific binding was observed in areas with a high lipid content such as the scapular brown adipose tissue and the liver: in these regions, binding was present in both OXTR WT and KO mice, and could not be competed away with OXT in either WT or KO mice. Collectively, these data confirm novel OXT targets in the periphery of the neonate. These peripheral OXTR sites, coupled with the immaturity of the neonate's own OXT system, suggest a role for exogenous OXT in modulating peripheral physiology and development.
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Date Issued: 2017-02-24
Identifier: FSU_pmch_28235051, 10.1371/journal.pone.0172904, PMC5325587, 28235051, 28235051, PONE-D-16-44673
Format: Citation

Title: Neuropeptide Regulation of Social Attachment: The Prairie Vole Model..
Creator: Tabbaa, Manal, Paedae, Brennan, Liu, Yan, Wang, Zuoxin
Abstract/Description: Social attachments are ubiquitous among humans and integral to human health. Although great efforts have been made to elucidate the neural underpinnings regulating social attachments, we still know relatively little about the neuronal and neurochemical regulation of social attachments. As a laboratory animal research model, the socially monogamous prairie vole (Microtus ochrogaster) displays behaviors paralleling human social attachments and thus has provided unique insights into the neural...
Show moreSocial attachments are ubiquitous among humans and integral to human health. Although great efforts have been made to elucidate the neural underpinnings regulating social attachments, we still know relatively little about the neuronal and neurochemical regulation of social attachments. As a laboratory animal research model, the socially monogamous prairie vole (Microtus ochrogaster) displays behaviors paralleling human social attachments and thus has provided unique insights into the neural regulation of social behaviors. Research in prairie voles has particularly highlighted the significance of neuropeptidergic regulation of social behaviors, especially of the roles of oxytocin (OT) and vasopressin (AVP). This article aims to review these findings. We begin by discussing the role of the OT and AVP systems in regulating social behaviors relevant to social attachments, and thereafter restrict our discussion to studies in prairie voles. Specifically, we discuss the role of OT and AVP in adult mate attachments, biparental care, social isolation, and social buffering as informed by studies utilizing the prairie vole model. Not only do these studies offer insight into social attachments in humans, but they also point to dysregulated mechanisms in several mental disorders. We conclude by discussing these implications for human health. © 2017 American Physiological Society. Compr Physiol 7:81-104, 2017.
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Date Issued: 2016-12-06
Identifier: FSU_pmch_28135000, 10.1002/cphy.c150055, PMC5308882, 28135000, 28135000
Format: Citation

Title: Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice.
Creator: Bell, Genevieve A, Fadool, Debra Ann
Abstract/Description: Intranasal insulin delivery is currently being used in clinical trials to test for improvement in human memory and cognition, and in particular, for lessening memory loss attributed to neurodegenerative diseases. Studies have reported the effects of short-term intranasal insulin treatment on various behaviors, but less have examined long-term effects. The olfactory bulb contains the highest density of insulin receptors in conjunction with the highest level of insulin transport within the...
Show moreIntranasal insulin delivery is currently being used in clinical trials to test for improvement in human memory and cognition, and in particular, for lessening memory loss attributed to neurodegenerative diseases. Studies have reported the effects of short-term intranasal insulin treatment on various behaviors, but less have examined long-term effects. The olfactory bulb contains the highest density of insulin receptors in conjunction with the highest level of insulin transport within the brain. Previous research from our laboratory has demonstrated that acute insulin intranasal delivery (IND) enhanced both short- and long-term memory as well as increased two-odor discrimination in a two-choice paradigm. Herein, we investigated the behavioral and physiological effects of chronic insulin IND. Adult, male C57BL6/J mice were intranasally treated with 5μg/μl of insulin twice daily for 30 and 60days. Metabolic assessment indicated no change in body weight, caloric intake, or energy expenditure following chronic insulin IND, but an increase in the frequency of meal bouts selectively in the dark cycle. Unlike acute insulin IND, which has been shown to cause enhanced performance in odor habituation/dishabituation and two-odor discrimination tasks in mice, chronic insulin IND did not enhance olfactometry-based odorant discrimination or olfactory reversal learning. In an object memory recognition task, insulin IND-treated mice did not perform differently than controls, regardless of task duration. Biochemical analyses of the olfactory bulb revealed a modest 1.3 fold increase in IR kinase phosphorylation but no significant increase in Kv1.3 phosphorylation. Substrate phosphorylation of IR kinase downstream effectors (MAPK/ERK and Akt signaling) proved to be highly variable. These data indicate that chronic administration of insulin IND in mice fails to enhance olfactory ability, object memory recognition, or a majority of systems physiology metabolic factors - as reported to elicit a modulatory effect with acute administration. This leads to two alternative interpretations regarding long-term insulin IND in mice: 1) It causes an initial stage of insulin resistance to dampen the behaviors that would normally be modulated under acute insulin IND, but ability to clear a glucose challenge is still retained, or 2) There is a lack of behavioral modulation at high concentration of insulin attributed to the twice daily intervals of hyperinsulinemia caused by insulin IND administration without any insulin resistance, per se.
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Date Issued: 2017-05-15
Identifier: FSU_pmch_28259806, 10.1016/j.physbeh.2017.02.044, PMC5639911, 28259806, 28259806, S0031-9384(16)30820-4
Format: Citation

Title: Dopamine: A Modulator Of Circadian Rhythms In The Central Nervous System.
Creator: Korshunov, Kirill S., Blakemore, Laura J., Trombley, Paul Q.
Abstract/Description: Circadian rhythms are daily rhythms that regulate many biological processes - from gene transcription to behavior - and a disruption of these rhythms can lead to a myriad of health risks. Circadian rhythms are entrained by light, and their 24-h oscillation is maintained by a core molecular feedback loop composed of canonical circadian ("clock") genes and proteins. Different modulators help to maintain the proper rhythmicity of these genes and proteins, and one emerging modulator is dopamine....
Show moreCircadian rhythms are daily rhythms that regulate many biological processes - from gene transcription to behavior - and a disruption of these rhythms can lead to a myriad of health risks. Circadian rhythms are entrained by light, and their 24-h oscillation is maintained by a core molecular feedback loop composed of canonical circadian ("clock") genes and proteins. Different modulators help to maintain the proper rhythmicity of these genes and proteins, and one emerging modulator is dopamine. Dopamine has been shown to have circadian-like activities in the retina, olfactory bulb, striatum, midbrain, and hypothalamus, where it regulates, and is regulated by, clock genes in some of these areas. Thus, it is likely that dopamine is essential to mechanisms that maintain proper rhythmicity of these five brain areas. This review discusses studies that showcase different dopaminergic mechanisms that may be involved with the regulation of these brain areas' circadian rhythms. Mechanisms include how dopamine and dopamine receptor activity directly and indirectly influence clock genes and proteins, how dopamine's interactions with gap junctions influence daily neuronal excitability, and how dopamine's release and effects are gated by low- and high-pass filters. Because the dopamine neurons described in this review also release the inhibitory neurotransmitter GABA which influences clock protein expression in the retina, we discuss articles that explore how GABA may contribute to the actions of dopamine neurons on circadian rhythms. Finally, to understand how the loss of function of dopamine neurons could influence circadian rhythms, we review studies linking the neurodegenerative disease Parkinson's Disease to disruptions of circadian rhythms in these five brain areas. The purpose of this review is to summarize growing evidence that dopamine is involved in regulating circadian rhythms, either directly or indirectly, in the brain areas discussed here. An appreciation of the growing evidence of dopamine's influence on circadian rhythms may lead to new treatments including pharmacological agents directed at alleviating the various symptoms of circadian rhythm disruption.
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Date Issued: 2017-04-03
Identifier: FSU_libsubv1_wos_000398490600001, 10.3389/fncel.2017.00091
Format: Citation

Title: Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats.
Creator: Strong, C E, Schoepfer, K J, Dossat, A M, Saland, S K, Wright, K N, Kabbaj, M
Abstract/Description: Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and...
Show moreClinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction.
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Date Issued: 2017-07-15
Identifier: FSU_pmch_28479397, 10.1016/j.neuropharm.2017.05.003, PMC5520991, 28479397, 28479397, S0028-3908(17)30199-5
Format: Citation

Title: An Examination of the Role of L-Glutamate and Inosine 5'-Monophosphate in Hedonic Taste-Guided Behavior by Mice Lacking the T1R1 + T1R3 Receptor.
Creator: Blonde, Ginger D, Spector, Alan C
Abstract/Description: The heterodimeric T1R1 + T1R3 receptor is considered critical for normal signaling of L-glutamate and 5'-ribonucleotides in the oral cavity. However, some taste-guided responsiveness remains in mice lacking one subunit of the receptor, suggesting that other receptors are sufficient to support some behaviors. Here, mice lacking both receptor subunits (KO) and wild-type (WT, both n = 13) mice were tested in a battery of behavioral tests. Mice were trained and tested in gustometers with a...
Show moreThe heterodimeric T1R1 + T1R3 receptor is considered critical for normal signaling of L-glutamate and 5'-ribonucleotides in the oral cavity. However, some taste-guided responsiveness remains in mice lacking one subunit of the receptor, suggesting that other receptors are sufficient to support some behaviors. Here, mice lacking both receptor subunits (KO) and wild-type (WT, both n = 13) mice were tested in a battery of behavioral tests. Mice were trained and tested in gustometers with a concentration series of Maltrin-580, a maltodextrin, in a brief-access test (10-s trials) as a positive control. Similar tests followed with monosodium glutamate (MSG) with and without the ribonucleotide inosine 5'-monophosphate (IMP), but always in the presence of the epithelial sodium channel blocker amiloride (A). Brief-access tests were repeated following short-term (30-min) and long-term (48-h) exposures to MSG + A + IMP and were also conducted with sodium gluconate replacing MSG. Finally, progressive ratio tests were conducted with Maltrin-580 or MSG + A + IMP, to assess appetitive behavior while minimizing satiation. Overall, MSG generated little concentration-dependent responding in either food-restricted WT or KO mice, even in combination with IMP. However, KO mice licked less to the amino acid stimuli, a measure of consummatory behavior in the brief-access tests. In contrast, both groups initiated a similar number of trials and had a similar breakpoint in the progressive ratio task, both measures of appetitive (approach) behavior. Collectively, these results suggest that while the T1R1 + T1R3 receptor is necessary for consummatory responding to MSG (+IMP), other receptors are sufficient to maintain appetitive responding to this "umami" stimulus complex in food-restricted mice.
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Date Issued: 2017-06-01
Identifier: FSU_pmch_28334294, 10.1093/chemse/bjx015, PMC6075476, 28334294, 28334294, 3073965
Format: Citation

Title: Neuromodulation in Chemosensory Pathways.
Creator: McIntyre, Jeremy C, Thiebaud, Nicolas, McGann, John P, Komiyama, Takaki, Rothermel, Markus
Abstract/Description: Interactions with the environment depend not only on sensory perception of external stimuli but also on processes of neuromodulation regulated by the internal state of an organism. These processes allow regulation of stimulus detection to match the demands of an organism influenced by its general brain state (satiety, wakefulness/sleep state, attentiveness, arousal, learning etc.). The sense of smell is initiated by sensory neurons located in the nasal cavity that recognize environmental...
Show moreInteractions with the environment depend not only on sensory perception of external stimuli but also on processes of neuromodulation regulated by the internal state of an organism. These processes allow regulation of stimulus detection to match the demands of an organism influenced by its general brain state (satiety, wakefulness/sleep state, attentiveness, arousal, learning etc.). The sense of smell is initiated by sensory neurons located in the nasal cavity that recognize environmental odorants and project axons into the olfactory bulb (OB), where they form synapses with several types of neurons. Modulations of early synaptic circuits are particularly important since these can affect all subsequent processing steps. While the precise mechanisms have not been fully elucidated, work from many labs has demonstrated that the activity of neurons in the OB and cortex can be modulated by different factors inducing specific changes to olfactory information processing. The symposium "Neuromodulation in Chemosensory Pathways" at the International Symposium on Olfaction and Taste (ISOT 2016) highlighted some of the most recent advances in state-dependent network modulations of the mouse olfactory system including modulation mediated by specific neurotransmitters and neuroendocrine molecules, involving pharmacological, electrophysiological, learning, and behavioral approaches.
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Date Issued: 2017-06-01
Identifier: FSU_pmch_28379355, 10.1093/chemse/bjx014, PMC5863563, 28379355, 28379355, 3100451
Format: Citation

Title: Paternal deprivation affects social behaviors and neurochemical systems in the offspring of socially monogamous prairie voles.
Creator: Tabbaa, Manal, Lei, Kelly, Liu, Yan, Wang, Zuoxin
Abstract/Description: Early life experiences, particularly the experience with parents, are crucial to phenotypic outcomes in both humans and animals. Although the effects of maternal deprivation on offspring well-being have been studied, paternal deprivation (PD) has received little attention despite documented associations between father absence and children health problems in humans. In the present study, we utilized the socially monogamous prairie vole (Microtus ochrogaster), which displays male-female pair...
Show moreEarly life experiences, particularly the experience with parents, are crucial to phenotypic outcomes in both humans and animals. Although the effects of maternal deprivation on offspring well-being have been studied, paternal deprivation (PD) has received little attention despite documented associations between father absence and children health problems in humans. In the present study, we utilized the socially monogamous prairie vole (Microtus ochrogaster), which displays male-female pair bonding and bi-parental care, to examine the effects of PD on adult behaviors and neurochemical expression in the hippocampus. Male and female subjects were randomly assigned into one of two experimental groups that grew up with both the mother and father (MF) or with the mother-only (MO, to generate PD experience). Our data show that MO subjects received less parental licking/grooming and carrying and were left alone in the nest more frequently than MF subjects. At adulthood (∼75days of age), MO subjects displayed increased social affiliation (SOA) toward a conspecific compared to MF subjects, but the two groups did not differ in social recognition (SOR) and anxiety-like behavior. Interestingly, MO subjects showed consistent increases in both gene and protein expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) as well as the levels of total histone 3 and histone 3 acetylation in the hippocampus compared to MF subjects. Further, PD experience increased glucocorticoid receptor beta (GRβ) protein expression in the hippocampus of females as well as increased corticotrophin receptor 2 (CRHR2) protein expression in the hippocampus of males, but decreased CRHR2 mRNA in both sexes. Together, our data suggest that PD has a long-lasting, behavior-specific effect on SOA and alters hippocampal neurochemical systems in the vole brain. The functional role of such altered neurochemical systems in social behaviors and the potential involvement of epigenetic events should be further studied.
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Date Issued: 2017-02-20
Identifier: FSU_pmch_27998780, 10.1016/j.neuroscience.2016.12.011, PMC5266501, 27998780, 27998780, S0306-4522(16)30701-1
Format: Citation

Title: Trichostatin A (tsa) Facilitates Formation Of Partner Preference In Male Prairie Voles (microtus Ochrogaster).
Creator: Duclot, F., Wang, H., Youssef, C., Liu, Y., Wang, Z., Kabbaj, M.
Abstract/Description: In the socially monogamous prairie voles (Microtus ochrogaster), the development of a social bonding is indicated by the formation of partner preference, which involves a variety of environmental and neurochemical factors and brain structures. In a most recent study in female prairie voles, we found that treatment with the histone deacetylase inhibitor trichostatin A (TSA) facilitates the formation of partner preference through up-regulation of oxytocin receptor (OTR) and vasopressin V1a...
Show moreIn the socially monogamous prairie voles (Microtus ochrogaster), the development of a social bonding is indicated by the formation of partner preference, which involves a variety of environmental and neurochemical factors and brain structures. In a most recent study in female prairie voles, we found that treatment with the histone deacetylase inhibitor trichostatin A (TSA) facilitates the formation of partner preference through up-regulation of oxytocin receptor (OTR) and vasopressin V1a receptor (V1aR) genes expression in the nucleus accumbens (NAcc). In the present study, we tested the hypothesis that TSA treatment also facilitates partner preference formation and alters OTR and V1aR genes expression in the NAcc in male prairie voles. We thus observed that central injection of TSA dose-dependently promoted the formation of partner preference in the absence of mating in male prairie voles. Interestingly, TSA treatment up-regulated OTR, but not V1aR, gene expression in the NAcc similarly as they were affected by mating - an essential process for naturally occurring partner preference. These data, together with others, not only indicate the involvement of epigenetic events but also the potential role of NAcc oxytocin in the regulation of partner preference in both male and female prairie voles. (C) 2016 Elsevier Inc. All rights reserved.
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Date Issued: 2016-05
Identifier: FSU_libsubv1_wos_000377846900009, 10.1016/j.yhbeh.2016.04.001
Format: Citation

Title: Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats.
Creator: Dossat, Amanda M, Jourdi, Hussam, Wright, Katherine N, Strong, Caroline E, Sarkar, Ambalika, Kabbaj, Mohamed
Abstract/Description: In humans, some males experience reductions in testosterone levels, as a natural consequence of aging or in the clinical condition termed hypogonadism, which are associated with impaired cognitive performance and mood disorder(s). Some of these behavioral deficits can be reversed by testosterone treatment. Our previous work in rats reported that sex differences in the expression of the transcription factor Zif268, a downstream target of testosterone, within the medial prefrontal cortex (mPFC)...
Show moreIn humans, some males experience reductions in testosterone levels, as a natural consequence of aging or in the clinical condition termed hypogonadism, which are associated with impaired cognitive performance and mood disorder(s). Some of these behavioral deficits can be reversed by testosterone treatment. Our previous work in rats reported that sex differences in the expression of the transcription factor Zif268, a downstream target of testosterone, within the medial prefrontal cortex (mPFC) mediates sex differences in social interaction. In the present study, we aimed to examine the effects of gonadectomy (GNX) in male rats on mPFC Zif268 expression, mood and cognitive behaviors. We also examined whether reinstitution of Zif268 in GNX rats will correct some of the behavioral deficits observed following GNX. Our results show that GNX induced a downregulation of Zif268 protein in the mPFC, which was concomitant with impaired memory in the y-maze and spontaneous object recognition test, reduced social interaction time, and depression-like behaviors in the forced swim test. Reinstitution of mPFC Zif268, using a novel adeno-associated-viral (AAV) construct, abrogated GNX-induced working memory and long-term memory impairments, and reductions in social interaction time, but not GNX-induced depression-like behaviors. These findings suggest that mPFC Zif268 exerts beneficial effects on memory and social interaction, and could be a potential target for novel treatments for behavioral impairments observed in hypogonadal and aged men with declining levels of gonadal hormones.
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Date Issued: 2017-01-06
Identifier: FSU_pmch_27816701, 10.1016/j.neuroscience.2016.10.062, PMC5154846, 27816701, 27816701, S0306-4522(16)30603-0
Format: Citation

Title: Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model.
Creator: McCarthy, Deirdre M, Bell, Genevieve A, Cannon, Elisa N, Mueller, Kaly A, Huizenga, Megan N, Sadri-Vakili, Ghazaleh, Fadool, Debra A, Bhide, Pradeep G
Abstract/Description: Prenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF)...
Show morePrenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF) is a key regulator of cognitive functions, and because prenatal cocaine exposure increases the expression of BDNF and the phosphorylated form of its receptor, tyrosine kinase B (TrkB), we examined whether BDNF-TrkB signaling is involved in mediating the reversal learning deficit in prenatally cocaine-exposed mice. Systemic administration of a selective TrkB receptor antagonist restored normal reversal learning in prenatally cocaine-exposed mice, suggesting that increased BDNF-TrkB signaling may be an underlying mechanism of reversal learning deficits. Our findings provide novel mechanistic insights into the reversal learning phenomenon and may have significant translational implications because impaired cognitive flexibility is a key symptom in psychiatric conditions of developmental onset.
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Date Issued: 2016-01-01
Identifier: FSU_pmch_27951531, 10.1159/000452739, PMC5360472, 27951531, 27951531, 000452739
Format: Citation

Title: Ca2+ Effects on ATP Production and Consumption Have Regulatory Roles on Oscillatory Islet Activity.
Creator: McKenna, Joseph P, Ha, Joon, Merrins, Matthew J, Satin, Leslie S, Sherman, Arthur, Bertram, Richard
Abstract/Description: Pancreatic islets respond to elevated blood glucose by secreting pulses of insulin that parallel oscillations in β-cell metabolism, intracellular Ca(2+) concentration, and bursting electrical activity. The mechanisms that maintain an oscillatory response are not fully understood, yet several models have been proposed. Only some can account for experiments supporting that metabolism is intrinsically oscillatory in β-cells. The dual oscillator model (DOM) implicates glycolysis as the source of...
Show morePancreatic islets respond to elevated blood glucose by secreting pulses of insulin that parallel oscillations in β-cell metabolism, intracellular Ca(2+) concentration, and bursting electrical activity. The mechanisms that maintain an oscillatory response are not fully understood, yet several models have been proposed. Only some can account for experiments supporting that metabolism is intrinsically oscillatory in β-cells. The dual oscillator model (DOM) implicates glycolysis as the source of oscillatory metabolism. In the companion article, we use recently developed biosensors to confirm that glycolysis is oscillatory and further elucidate the coordination of metabolic and electrical signals in the insulin secretory pathway. In this report, we modify the DOM by incorporating an established link between metabolism and intracellular Ca(2+) to reconcile model predictions with experimental observations from the companion article. With modification, we maintain the distinguishing feature of the DOM, oscillatory glycolysis, but introduce the ability of Ca(2+) influx to reshape glycolytic oscillations by promoting glycolytic efflux. We use the modified model to explain measurements from the companion article and from previously published experiments with islets.
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Date Issued: 2016-02-02
Identifier: FSU_pmch_26840737, 10.1016/j.bpj.2015.11.3526, PMC4744176, 26840737, 26840737, S0006-3495(15)04814-6
Format: Citation

Title: Role of proteasome-dependent protein degradation in long-term operant memory in Aplysia.
Creator: Lyons, Lisa C, Gardner, Jacob S, Gandour, Catherine E, Krishnan, Harini C
Abstract/Description: We investigated the in vivo role of protein degradation during intermediate (ITM) and long-term memory (LTM) in Aplysia using an operant learning paradigm. The proteasome inhibitor MG-132 inhibited the induction and molecular consolidation of LTM with no effect on ITM. Remarkably, maintenance of steady-state protein levels through inhibition of protein synthesis using either anisomycin or rapamycin in conjunction with proteasome inhibition permitted the formation of robust 24 h LTM. Our...
Show moreWe investigated the in vivo role of protein degradation during intermediate (ITM) and long-term memory (LTM) in Aplysia using an operant learning paradigm. The proteasome inhibitor MG-132 inhibited the induction and molecular consolidation of LTM with no effect on ITM. Remarkably, maintenance of steady-state protein levels through inhibition of protein synthesis using either anisomycin or rapamycin in conjunction with proteasome inhibition permitted the formation of robust 24 h LTM. Our studies suggest a primary role for proteasomal activity in facilitation of gene transcription for LTM and raise the possibility that synaptic mechanisms are sufficient to sustain 24 h memory.
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Date Issued: 2016-12-15
Identifier: FSU_pmch_27980077, 10.1101/lm.043794.116, PMC5159658, 27980077, 27980077, 24/1/59
Format: Citation

Title: Upregulation Of An Inward Rectifying K+ Channel Can Rescue Slow Ca2+ Oscillations In K (atp) Channel Deficient Pancreatic Islets.
Creator: Yildirim, Vehpi, Vadrevu, Suryakiran, Thompson, Benjamin, Satin, Leslie S., Bertram, Richard
Abstract/Description: Plasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting beta-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the beta-cell plasma...
Show morePlasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting beta-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the beta-cell plasma membrane and terminates islet oscillations. Surprisingly, when K(ATP) channels are genetically knocked out, oscillations in islet activity persist, and relatively normal blood glucose levels are maintained. Compensation must therefore occur to overcome the loss of K(ATP) channels in K(ATP) knockout mice. In a companion study, we demonstrated a substantial increase in Kir2.1 protein occurs in beta-cells lacking K(ATP) because of SUR1 deletion. In this report, we demonstrate that beta-cells of SUR1 null islets have an upregulated inward rectifying K+ current that helps to compensate for the loss of K (ATP) channels. This current is likely due to the increased expression of Kir2.1 channels. We used mathematical modeling to determine whether an ionic current having the biophysical characteristics of Kir2.1 is capable of rescuing oscillations that are similar in period to those of wild-type islets. By experimentally testing a key model prediction we suggest that Kir2.1 current upregulation is a likely mechanism for rescuing the oscillations seen in islets from mice deficient in K(ATP) channels.
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Date Issued: 2017-07
Identifier: FSU_libsubv1_wos_000406619800052, 10.1371/journal.pcbi.1005686
Format: Citation

Title: Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle..
Creator: Wright, Katherine N, Strong, Caroline E, Addonizio, Marjorie N, Brownstein, Naomi C, Kabbaj, Mohamed
Abstract/Description: Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine's antidepressant-like effects, the abuse potential for ketamine in females is unknown. The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether...
Show moreRepeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine's antidepressant-like effects, the abuse potential for ketamine in females is unknown. The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females' response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine. Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior. Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation. These findings indicate that females's responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine's reinforcing effects under this treatment paradigm.
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Date Issued: 2017-02-01
Identifier: FSU_pmch_27837330, 10.1007/s00213-016-4470-z, PMC5384643, 27837330, 27837330, 10.1007/s00213-016-4470-z
Format: Citation

Title: Margatoxin-bound quantum dots as a novel inhibitor of the voltage-gated ion channel Kv1.3.
Creator: Schwartz, Austin B, Kapur, Anshika, Wang, Wentao, Huang, Zhenbo, Fardone, Erminia, Palui, Goutam, Mattoussi, Hedi, Fadool, Debra Ann
Abstract/Description: Venom-derived ion channel inhibitors have strong channel selectivity, potency, and stability; however, tracking delivery to their target can be challenging. Herein, we utilized luminescent quantum dots (QDs) conjugated to margatoxin (MgTx) as a traceable vehicle to target a voltage-dependent potassium channel, Kv1.3, which has a select distribution and well-characterized role in immunity, glucose metabolism, and sensory ability. We screened both unconjugated (MgTx) and conjugated MgTx (QD...
Show moreVenom-derived ion channel inhibitors have strong channel selectivity, potency, and stability; however, tracking delivery to their target can be challenging. Herein, we utilized luminescent quantum dots (QDs) conjugated to margatoxin (MgTx) as a traceable vehicle to target a voltage-dependent potassium channel, Kv1.3, which has a select distribution and well-characterized role in immunity, glucose metabolism, and sensory ability. We screened both unconjugated (MgTx) and conjugated MgTx (QD-MgTx) for their ability to inhibit Shaker channels Kv1.1 to Kv1.7 using patch-clamp electrophysiology in HEK293 cells. Our data indicate that MgTx inhibits 79% of the outward current in Kv1.3-transfected cells and that the QD-MgTx conjugate is able to achieve a similar level of block, albeit a slightly reduced efficacy (66%) and at a slower time course (50% block by 10.9 ± 1.1 min, MgTx; vs. 15.3 ± 1.2 min, QD-MgTx). Like the unbound peptide, the QD-MgTx conjugate inhibits both Kv1.3 and Kv1.2 at a 1 nM concentration, whereas it does not inhibit other screened Shaker channels. We tested the ability of QD-MgTx to inhibit native Kv1.3 expressed in the mouse olfactory bulb (OB). In brain slices of the OB, the conjugate acted similarly to MgTx to inhibit Kv1.3, causing an increased action potential firing frequency attributed to decreased intraburst duration rather than interspike interval. Our data demonstrate a retention of known biophysical properties associated with block of the vestibule of Kv1.3 by QD-MgTx conjugate compared to that of MgTx, inferring QDs could provide a useful tool to deliver ion channel inhibitors to targeted tissues in vivo.
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Date Issued: 2017-02-01
Identifier: FSU_pmch_27861889, 10.1111/jnc.13891, PMC5250575, 27861889, 27861889
Format: Citation

Title: Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis.
Creator: Kettner, Nicole M, Voicu, Horatio, Finegold, Milton J, Coarfa, Cristian, Sreekumar, Arun, Putluri, Nagireddy, Katchy, Chinenye A, Lee, Choogon, Moore, David D, Fu, Loning
Abstract/Description: Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a mechanism very similar to that observed in obese humans. The process initiates with non-alcoholic fatty liver disease (NAFLD) that progresses to steatohepatitis and fibrosis before HCC detection. This pathophysiological pathway is driven by jet-lag-induced genome-wide gene deregulation and global liver metabolic dysfunction, with nuclear receptor-controlled cholesterol/bile acid and xenobiotic...
Show moreChronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a mechanism very similar to that observed in obese humans. The process initiates with non-alcoholic fatty liver disease (NAFLD) that progresses to steatohepatitis and fibrosis before HCC detection. This pathophysiological pathway is driven by jet-lag-induced genome-wide gene deregulation and global liver metabolic dysfunction, with nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism among the top deregulated pathways. Ablation of farnesoid X receptor dramatically increases enterohepatic bile acid levels and jet-lag-induced HCC, while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.
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Date Issued: 2016-12-12
Identifier: FSU_pmch_27889186, 10.1016/j.ccell.2016.10.007, PMC5695235, 27889186, 27889186, S1535-6108(16)30494-9
Format: Citation

Title: Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia.
Creator: Lyons, Lisa C, Gardner, Jacob S, Lentsch, Cassidy T, Gandour, Catherine E, Krishnan, Harini C, Noakes, Eric J
Abstract/Description: In addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term...
Show moreIn addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term operant memory formation using the learning that food is inedible (LFI) paradigm. A single LFI training session, in which the animal associates a specific netted seaweed with the failure to swallow, generates short (30min), intermediate (4-6h) and long-term (24h) memory. Using the calpain inhibitors calpeptin and MDL-28170, we found that ITM requires calpain activity for induction and consolidation similar to the previously reported requirements for persistent protein kinase C activity in intermediate-term LFI memory. The induction of LTM also required calpain activity. In contrast to ITM, calpain activity was not necessary for the molecular consolidation of LTM. Surprisingly, six hours after LFI training we found that calpain activity was necessary for LTM, although this is a time at which neither persistent PKC activity nor protein synthesis is required for the maintenance of long-term LFI memory. These results demonstrate that calpains function in multiple roles in vivo during associative memory formation.
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Date Issued: 2017-01-01
Identifier: FSU_pmch_27913293, 10.1016/j.nlm.2016.11.018, PMC6179366, 27913293, 27913293, S1074-7427(16)30358-6
Format: Citation

Title: Genetic Dissection of Dual Roles for the Transcription Factor six7 in Photoreceptor Development and Patterning in Zebrafish.
Creator: Sotolongo-Lopez, Mailin, Alvarez-Delfin, Karen, Saade, Carole J, Vera, Daniel L, Fadool, James M
Abstract/Description: The visual system of a particular species is highly adapted to convey detailed ecological and behavioral information essential for survival. The consequences of structural mutations of opsins upon spectral sensitivity and environmental adaptation have been studied in great detail, but lacking is knowledge of the potential influence of alterations in gene regulatory networks upon the diversity of cone subtypes and the variation in the ratio of rods and cones observed in numerous diurnal and...
Show moreThe visual system of a particular species is highly adapted to convey detailed ecological and behavioral information essential for survival. The consequences of structural mutations of opsins upon spectral sensitivity and environmental adaptation have been studied in great detail, but lacking is knowledge of the potential influence of alterations in gene regulatory networks upon the diversity of cone subtypes and the variation in the ratio of rods and cones observed in numerous diurnal and nocturnal species. Exploiting photoreceptor patterning in cone-dominated zebrafish, we uncovered two independent mechanisms by which the sine oculis homeobox homolog 7 (six7) regulates photoreceptor development. In a genetic screen, we isolated the lots-of-rods-junior (ljrp23ahub) mutation that resulted in an increased number and uniform distribution of rods in otherwise normal appearing larvae. Sequence analysis, genome editing using TALENs and knockdown strategies confirm ljrp23ahub as a hypomorphic allele of six7, a teleost orthologue of six3, with known roles in forebrain patterning and expression of opsins. Based on the lack of predicted protein-coding changes and a deletion of a conserved element upstream of the transcription start site, a cis-regulatory mutation is proposed as the basis of the reduced expression of six7 in ljrp23ahub. Comparison of the phenotypes of the hypomorphic and knock-out alleles provides evidence of two independent roles in photoreceptor development. EdU and PH3 labeling show that the increase in rod number is associated with extended mitosis of photoreceptor progenitors, and TUNEL suggests that the lack of green-sensitive cones is the result of cell death of the cone precursor. These data add six7 to the small but growing list of essential genes for specification and patterning of photoreceptors in non-mammalian vertebrates, and highlight alterations in transcriptional regulation as a potential source of photoreceptor variation across species.
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Date Issued: 2016-04-08
Identifier: FSU_pmch_27058886, 10.1371/journal.pgen.1005968, PMC4825938, 27058886, 27058886, PGENETICS-D-15-02805
Format: Citation

Title: Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory..
Creator: Lieberwirth, Claudia, Pan, Yongliang, Liu, Yan, Zhang, Zhibin, Wang, Zuoxin
Abstract/Description: Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning...
Show moreAdult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk).
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Date Issued: 2016-08-01
Identifier: FSU_pmch_27174001, 10.1016/j.brainres.2016.05.015, PMC5064285, 27174001, 27174001, S0006-8993(16)30370-5
Format: Citation

Title: Mitochondrial Ultrastructure and Glucose Signaling Pathways Attributed to the Kv1.3 Ion Channel.
Creator: Kovach, Christopher P, Al Koborssy, Dolly, Huang, Zhenbo, Chelette, Brandon M, Fadool, James M, Fadool, Debra A
Abstract/Description: Gene-targeted deletion of the potassium channel Kv1.3 (Kv1.3(-∕-)) results in "Super-smeller" mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3(-∕-) mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity,...
Show moreGene-targeted deletion of the potassium channel Kv1.3 (Kv1.3(-∕-)) results in "Super-smeller" mice with a sensory phenotype that includes an increased olfactory ability linked to changes in olfactory circuitry, increased abundance of olfactory cilia, and increased expression of odorant receptors and the G-protein, Golf. Kv1.3(-∕-) mice also have a metabolic phenotype including lower body weight and decreased adiposity, increased total energy expenditure (TEE), increased locomotor activity, and resistance to both diet- and genetic-induced obesity. We explored two cellular aspects to elucidate the mechanism by which loss of Kv1.3 channel in the olfactory bulb (OB) may enhance glucose utilization and metabolic rate. First, using in situ hybridization we find that Kv1.3 and the insulin-dependent glucose transporter type 4 (GLUT4) are co-localized to the mitral cell layer of the OB. Disruption of Kv1.3 conduction via construction of a pore mutation (W386F Kv1.3) was sufficient to independently translocate GLUT4 to the plasma membrane in HEK 293 cells. Because olfactory sensory perception and the maintenance of action potential (AP) firing frequency by mitral cells of the OB is highly energy demanding and Kv1.3 is also expressed in mitochondria, we next explored the structure of this organelle in mitral cells. We challenged wildtype (WT) and Kv1.3(-∕-) male mice with a moderately high-fat diet (MHF, 31.8 % kcal fat) for 4 months and then examined OB ultrastructure using transmission electron microscopy. In WT mice, mitochondria were significantly enlarged following diet-induced obesity (DIO) and there were fewer mitochondria, likely due to mitophagy. Interestingly, mitochondria were significantly smaller in Kv1.3(-∕-) mice compared with that of WT mice. Similar to their metabolic resistance to DIO, the Kv1.3(-∕-) mice had unchanged mitochondria in terms of cross sectional area and abundance following a challenge with modified diet. We are very interested to understand how targeted disruption of the Kv1.3 channel in the OB can modify TEE. Our study demonstrates that Kv1.3 regulates mitochondrial structure and alters glucose utilization; two important metabolic changes that could drive whole system changes in metabolism initiated at the OB.
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Date Issued: 2016-05-19
Identifier: FSU_pmch_27242550, 10.3389/fphys.2016.00178, PMC4871887, 27242550, 27242550
Format: Citation

Title: Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats.
Creator: Sarkar, Ambalika, Kabbaj, Mohamed
Abstract/Description: The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1,...
Show moreThe mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine density was also examined in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle. Male rats showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 weeks of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus female rats could not be reversed by ketamine. Spine density was higher in female rats during proestrus than in diestrus. Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 and medial prefrontal cortex spine density in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.
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Date Issued: 2016-09-15
Identifier: FSU_pmch_26957131, 10.1016/j.biopsych.2015.12.025, PMC4940294, 26957131, 26957131, S0006-3223(16)00010-X
Format: Citation

Title: Prostaglandin levels, vaginal innervation, and cyst innervation as peripheral contributors to endometriosis-associated vaginal hyperalgesia in rodents.
Creator: McAllister, Stacy L, Giourgas, Barbra K, Faircloth, Elizabeth K, Leishman, Emma, Bradshaw, Heather B, Gross, Eric R
Abstract/Description: Endometriosis is a painful condition characterized by growth of endometrial cysts outside the uterus. Here, we tested the hypothesis that peripheral innervation and prostaglandin levels contribute to endometriosis-associated pain. Female Sprague-Dawley rats (n = 16) were surgically instrumented by transplanting uterine tissue onto mesenteric arteries within the peritoneal cavity to create a model of endometriosis which forms extra-uterine endometrial cysts and vaginal hyperalgesia. Our...
Show moreEndometriosis is a painful condition characterized by growth of endometrial cysts outside the uterus. Here, we tested the hypothesis that peripheral innervation and prostaglandin levels contribute to endometriosis-associated pain. Female Sprague-Dawley rats (n = 16) were surgically instrumented by transplanting uterine tissue onto mesenteric arteries within the peritoneal cavity to create a model of endometriosis which forms extra-uterine endometrial cysts and vaginal hyperalgesia. Our results describe a significant positive correlation between endometriosis-induced vaginal hyperalgesia and cyst innervation density (sensory, r = 0.70, p = 0.003; sympathetic, r = 0.55, p = 0.03), vaginal canal sympathetic innervation density (r = 0.80, p = 0.003), and peritoneal fluid levels of the prostaglandins PGE2 (r = 0.65, p = 0.01) and PGF2α (r = 0.63, p = 0.02). These results support the involvement of cyst innervation and prostaglandins in endometriosis-associated pain. We also describe how sympathetic innervation density of the vaginal canal is an important predictor of vaginal hyperalgesia.
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Date Issued: 2016-12-05
Identifier: FSU_pmch_27524411, 10.1016/j.mce.2016.08.017, PMC5048574, 27524411, 27524411, S0303-7207(16)30311-2
Format: Citation

Title: Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness.
Creator: Crabtree, Gregg W, Sun, Ziyi, Kvajo, Mirna, Broek, Jantine A C, Fénelon, Karine, McKellar, Heather, Xiao, Lan, Xu, Bin, Bahn, Sabine, O'Donnell, James M, Gogos, Joseph A
Abstract/Description: Using a genetic mouse model that faithfully recapitulates a genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter...
Show moreUsing a genetic mouse model that faithfully recapitulates a genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit K1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of K1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to K1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity. Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes, , upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity-parameters that critically govern neural circuit information processing-suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.
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Date Issued: 2017-04-12
Identifier: FSU_pmch_28283561, 10.1523/JNEUROSCI.4345-15.2017, PMC5391686, 28283561, 28283561, JNEUROSCI.4345-15.2017
Format: Citation

Title: Heterogeneous organization and connectivity of the chicken auditory thalamus (Gallus gallus).
Creator: Wang, Yuan, Zorio, Diego A R, Karten, Harvey J
Abstract/Description: The auditory ascending system contains parallel pathways in vertebrate brains. In chickens (Gallus gallus), three pathways arise from nucleus laminaris (NL), nucleus angularis (NA), and regio intermedius (RI) in the brainstem, innervating three subdivisions of the nucleus mesencephalicus lateralis pars dorsalis (MLd) in the midbrain. The current study reveals the segregation of these pathways in their subsequent projections to the nucleus ovoidalis (Ov) in the thalamus. Based on...
Show moreThe auditory ascending system contains parallel pathways in vertebrate brains. In chickens (Gallus gallus), three pathways arise from nucleus laminaris (NL), nucleus angularis (NA), and regio intermedius (RI) in the brainstem, innervating three subdivisions of the nucleus mesencephalicus lateralis pars dorsalis (MLd) in the midbrain. The current study reveals the segregation of these pathways in their subsequent projections to the nucleus ovoidalis (Ov) in the thalamus. Based on cytoarchitecture and myelin distribution, we identified seven Ov subregions, including five neuronal clusters within the Ov proper, the nucleus semilunaris parovoidalis (SPO), and the circum-ovoidalis (cOv). Immunocytochemistry further revealed that a ventromedial cluster of the Ov proper (Ovvm) contains unique cell types expressing α8 subunit nicotinic acetylcholine receptor, while SPO and cOv are characterized with expression of calcitonin-gene-related peptide and cholecystokinin. Tract tracing studies demonstrated that Ovvm is a major target of the NL-recipient zone of MLd, while the RI-recipient zone of MLd predominantly projects to a ventrolateral cluster of the Ov proper. Afferent inputs to the remaining regions of the Ov proper mostly arise from the NA-recipient zone of MLd. SPO and cOv receive a projection from the surrounding areas of MLd, named the nucleus intercollicularis. Importantly, the Ov proper, SPO and cOv all project to the Field L2 in the forebrain, the avian auditory cortex. Taken together, these results demonstrate that the avian auditory thalamus is a structurally and functionally heterogeneous structure, implicating an important role in generating novel representations for specific acoustic features.
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Date Issued: 2017-10-01
Identifier: FSU_pmch_28614906, 10.1002/cne.24262, PMC5558206, 28614906, 28614906
Format: Citation

Title: Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes.
Creator: Saland, Samantha K, Duclot, Florian, Kabbaj, Mohamed
Abstract/Description: In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest-particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of...
Show moreIn major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest-particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N-methyl-D-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies.
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Date Issued: 2017-04-01
Identifier: FSU_pmch_28584860, 10.1016/j.cobeha.2016.11.002, PMC5456295, 28584860, 28584860
Format: Citation

Title: Liraglutide suppression of caloric intake competes with the intake-promoting effects of a palatable cafeteria diet, but does not impact food or macronutrient selection.
Creator: Hyde, Kellie M, Blonde, Ginger D, le Roux, Carel W, Spector, Alan C
Abstract/Description: Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) receptor agonist, is used as a treatment for Type 2 diabetes mellitus and obesity because it improves glycemia and decreases food intake. Here, we tested whether chronic activation of the GLP-1 receptor system with liraglutide would induce decreases in intake accompanied by changes in proportional food or macronutrient intake similar to those seen following RYGB in rats when a variety of palatable food options are available. A "cafeteria diet"...
Show moreLiraglutide, a Glucagon-Like Peptide-1 (GLP-1) receptor agonist, is used as a treatment for Type 2 diabetes mellitus and obesity because it improves glycemia and decreases food intake. Here, we tested whether chronic activation of the GLP-1 receptor system with liraglutide would induce decreases in intake accompanied by changes in proportional food or macronutrient intake similar to those seen following RYGB in rats when a variety of palatable food options are available. A "cafeteria diet" was used that included: laboratory rodent chow, refried beans (low-fat/low-sugar), low-fat yogurt (low-fat/high-sugar), peanut butter (high-fat/low-sugar) and sugar-fat whip (high-fat/high-sugar). Liraglutide (1mg/kg daily, sc, n=6) induced significant reductions in body weight and total caloric intake compared to saline-injected control rats (n=6). Although access to a cafeteria diet induced increases in caloric intake in both groups relative to chow alone, liraglutide still effectively decreased intake compared with saline-injected rats suggesting that chronic GLP-1 activation competes with the energy density and palatability of available food options in modulating ingestive behavior. Even with the substantial effects on overall intake, liraglutide did not change food choice or relative macronutrient intake when compared to pre-treatment baseline. When drug treatment was discontinued, the liraglutide group increased caloric intake and rapidly gained body weight to match that of the saline group. These results demonstrate that, while liraglutide effectively decreases caloric intake and body weight in rats, it does not cause adjustments in relative macronutrient consumption. Our data also show that drug-induced decreases in intake and body weight are not maintained following termination of treatment.
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Date Issued: 2017-08-01
Identifier: FSU_pmch_28366815, 10.1016/j.physbeh.2017.03.045, PMC5545097, 28366815, 28366815, S0031-9384(16)31043-5
Format: Citation

Title: Mtor Signaling Regulates Central And Peripheral Circadian Clock Function.
Creator: Ramanathan, Chidambaram, Kathale, Nimish D., Liu, Dong, Lee, Choogon, Freeman, David A., Hogenesch, John B., Cao, Ruifeng, Liu, Andrew C.
Abstract/Description: The circadian clock coordinates physiology and metabolism. mTOR (mammalianmechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of...
Show moreThe circadian clock coordinates physiology and metabolism. mTOR (mammalianmechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2(-/-)fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.
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Date Issued: 2018-05-01
Identifier: FSU_libsubv1_wos_000434016500019, 10.1371/journal.pgen.1007369
Format: Citation

Title: Diverse Intrinsic Properties Shape Functional Phenotype Of Low-frequency Neurons In The Auditory Brainstem.
Creator: Hong, Hui, Wang, Xiaoyu, Lu, Ting, Zorio, Diego A. R., Wang, Yuan, Sanchez, Jason Tait
Abstract/Description: In the auditory system, tonotopy is the spatial arrangement of where sounds of different frequencies are processed. Defined by the organization of neurons and their inputs, tonotopy emphasizes distinctions in neuronal structure and function across topographic gradients and is a common feature shared among vertebrates. In this study we characterized action potential firing patterns and ion channel properties from neurons located in the extremely low-frequency region of the chicken nucleus...
Show moreIn the auditory system, tonotopy is the spatial arrangement of where sounds of different frequencies are processed. Defined by the organization of neurons and their inputs, tonotopy emphasizes distinctions in neuronal structure and function across topographic gradients and is a common feature shared among vertebrates. In this study we characterized action potential firing patterns and ion channel properties from neurons located in the extremely low-frequency region of the chicken nucleus magnocellularis (NM), an auditory brainstem structure. We found that NM neurons responsible for encoding the lowest sound frequencies (termed NMc neurons) have enhanced excitability and fired bursts of action potentials to sinusoidal inputs <= 10 Hz; a distinct firing pattern compared to higher-frequency neurons. This response property was due to lower amounts of voltage dependent potassium (K-v) conductances, unique combination of K-v subunits and specialized sodium (Na-v) channel properties. Particularly, NMc neurons had significantly lower K(v)1 and K(v)3 currents, but higher K(v)2current. NMc neurons also showed larger and faster transient Nav current (I-NaT) with different voltage dependence of inactivation from higher-frequency neurons. In contrast, significantly smaller resurgent sodium current (I-NaR) was present in NMc with kinetics and voltage dependence that differed from higher-frequency neurons. Immunohistochemistry showed expression of Na(v)1.6 channel subtypes across the tonotopic axis. However, various immunoreactive patterns were observed between regions, likely underlying some tonotopic differences in I-N(aT) and I-NaR. Finally, using pharmacology and computational modeling, we concluded that K(v)3, K(v)2 channels and I-NaR work synergistically to regulate burst firing in NMc.
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Date Issued: 2018-06-26
Identifier: FSU_libsubv1_wos_000436338700001, 10.3389/fncel.2018.00175
Format: Citation

Title: Proteomic analyses of nucleus laminaris identified candidate targets of the fragile X mental retardation protein.
Creator: Sakano, Hitomi, Zorio, Diego A R, Wang, Xiaoyu, Ting, Ying S, Noble, William S, MacCoss, Michael J, Rubel, Edwin W, Wang, Yuan
Abstract/Description: The avian nucleus laminaris (NL) is a brainstem nucleus necessary for binaural processing, analogous in structure and function to the mammalian medial superior olive. In chickens (Gallus gallus), NL is a well-studied model system for activity-dependent neural plasticity. Its neurons have bipolar extension of dendrites, which receive segregated inputs from two ears and display rapid and compartment-specific reorganization in response to unilateral changes in auditory input. More recently,...
Show moreThe avian nucleus laminaris (NL) is a brainstem nucleus necessary for binaural processing, analogous in structure and function to the mammalian medial superior olive. In chickens (Gallus gallus), NL is a well-studied model system for activity-dependent neural plasticity. Its neurons have bipolar extension of dendrites, which receive segregated inputs from two ears and display rapid and compartment-specific reorganization in response to unilateral changes in auditory input. More recently, fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates local protein translation, has been shown to be enriched in NL dendrites, suggesting its potential role in the structural dynamics of these dendrites. To explore the molecular role of FMRP in this nucleus, we performed proteomic analysis of NL, using micro laser capture and liquid chromatography tandem mass spectrometry. We identified 657 proteins, greatly represented in pathways involved in mitochondria, translation and metabolism, consistent with high levels of activity of NL neurons. Of these, 94 are potential FMRP targets, by comparative analysis with previously proposed FMRP targets in mammals. These proteins are enriched in pathways involved in cellular growth, cellular trafficking and transmembrane transport. Immunocytochemistry verified the dendritic localization of several proteins in NL. Furthermore, we confirmed the direct interaction of FMRP with one candidate, RhoC, by in vitro RNA binding assays. In summary, we provide a database of highly expressed proteins in NL and in particular a list of potential FMRP targets, with the goal of facilitating molecular characterization of FMRP signaling in future studies.
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Date Issued: 2017-10-15
Identifier: FSU_pmch_28685837, 10.1002/cne.24281, PMC5564178, 28685837, 28685837
Format: Citation

Title: Upregulation of an inward rectifying K+ channel can rescue slow Ca2+ oscillations in K(ATP) channel deficient pancreatic islets.
Creator: Yildirim, Vehpi, Vadrevu, Suryakiran, Thompson, Benjamin, Satin, Leslie S, Bertram, Richard
Abstract/Description: Plasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting β-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the β-cell plasma...
Show morePlasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting β-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the β-cell plasma membrane and terminates islet oscillations. Surprisingly, when K(ATP) channels are genetically knocked out, oscillations in islet activity persist, and relatively normal blood glucose levels are maintained. Compensation must therefore occur to overcome the loss of K(ATP) channels in K(ATP) knockout mice. In a companion study, we demonstrated a substantial increase in Kir2.1 protein occurs in β-cells lacking K(ATP) because of SUR1 deletion. In this report, we demonstrate that β-cells of SUR1 null islets have an upregulated inward rectifying K+ current that helps to compensate for the loss of K(ATP) channels. This current is likely due to the increased expression of Kir2.1 channels. We used mathematical modeling to determine whether an ionic current having the biophysical characteristics of Kir2.1 is capable of rescuing oscillations that are similar in period to those of wild-type islets. By experimentally testing a key model prediction we suggest that Kir2.1 current upregulation is a likely mechanism for rescuing the oscillations seen in islets from mice deficient in K(ATP) channels.
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Date Issued: 2017-07-27
Identifier: FSU_pmch_28749940, 10.1371/journal.pcbi.1005686, PMC5549769, 28749940, 28749940, PCOMPBIOL-D-17-00183
Format: Citation

Department of Biological Science (19)	+ -
Department of Psychology (16)	+ -
Department of Biomedical Sciences (14)	+ -
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Department of Behavioral Sciences and Social Medicine (1)	+ -

Animals (42)	+ -
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Female (15)	+ -
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Rats (9)	+ -

Humans (8)	+ -
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Disease Models, Animal (5)	+ -
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Pair Bond (4)	+ -
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Analysis of Variance (3)	+ -
Arvicolinae/physiology (3)	+ -
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Hippocampus/physiology (3)	+ -
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Insulin/metabolism (3)	+ -
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