Publications by authors named "Colleen A McClung"

66 Publications

High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains.

Sci Rep 2021 Jan 28;11(1):2573. Epub 2021 Jan 28.

Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, ME, USA.

Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders-80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.
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http://dx.doi.org/10.1038/s41598-021-82069-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843998PMC
January 2021

Diurnal rhythms across the human dorsal and ventral striatum.

Proc Natl Acad Sci U S A 2021 Jan;118(2)

Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;

The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology.
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http://dx.doi.org/10.1073/pnas.2016150118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812799PMC
January 2021

Measuring the Effects of Circadian Rhythm-Related Manipulations on Depression-Like Behavior in Rodents: Forced Swim and Tail Suspension Tests.

Methods Mol Biol 2021 ;2130:69-78

Psychiatry and Clinical and Translational Science, Translational Neuroscience Program, Center for Neuroscience University of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

The forced swim and tail suspension tests are commonly used to determine the effects of circadian-related pharmacological, genetic, and environmental manipulations on depression-like behavior in rodents. Both tests involve scoring immobility of rodents in an inescapable condition. Here we describe how to set up and carry out these tests.
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http://dx.doi.org/10.1007/978-1-0716-0381-9_5DOI Listing
March 2021

Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration in Mutant Mice.

J Neurosci 2021 Feb 2;41(5):1046-1058. Epub 2020 Dec 2.

Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219

Substance use disorder (SUD) is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all mutants. Sex differences emerged during the dark (active) phase with mutation increasing self-administration, extinction responding, and reinstatement only in females as well as reinforcement and motivation in males and females. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D1+ neurons in the nucleus accumbens (NAc) core and dorsolateral (DLS) striatum in mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day (TOD)-specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of mutation in females. Circadian disruptions are a common symptom of substance use disorders (SUDs) and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent SU. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to SU vulnerability and drug-induced alterations to these genes may augment drug-seeking. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration in wild-type (WT) and mutant mice at different times of day.
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http://dx.doi.org/10.1523/JNEUROSCI.1830-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880289PMC
February 2021

Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2.

Mol Psychiatry 2020 Nov 24. Epub 2020 Nov 24.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.

Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.
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http://dx.doi.org/10.1038/s41380-020-00958-2DOI Listing
November 2020

12-h clock regulation of genetic information flow by XBP1s.

PLoS Biol 2020 01 14;18(1):e3000580. Epub 2020 Jan 14.

Aging Institute of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

Our group recently characterized a cell-autonomous mammalian 12-h clock independent from the circadian clock, but its function and mechanism of regulation remain poorly understood. Here, we show that in mouse liver, transcriptional regulation significantly contributes to the establishment of 12-h rhythms of mRNA expression in a manner dependent on Spliced Form of X-box Binding Protein 1 (XBP1s). Mechanistically, the motif stringency of XBP1s promoter binding sites dictates XBP1s's ability to drive 12-h rhythms of nascent mRNA transcription at dawn and dusk, which are enriched for basal transcription regulation, mRNA processing and export, ribosome biogenesis, translation initiation, and protein processing/sorting in the Endoplasmic Reticulum (ER)-Golgi in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). We further identified GA-binding proteins (GABPs) as putative novel transcriptional regulators driving 12-h rhythms of gene expression with more diverse phases. These 12-h rhythms of gene expression are cell autonomous and evolutionarily conserved in marine animals possessing a circatidal clock. Our results demonstrate an evolutionarily conserved, intricate network of transcriptional control of the mammalian 12-h clock that mediates diverse biological pathways. We speculate that the 12-h clock is coopted to accommodate elevated gene expression and processing in mammals at the two rush hours, with the particular genes processed at each rush hour regulated by the circadian and/or tissue-specific pathways.
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http://dx.doi.org/10.1371/journal.pbio.3000580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959563PMC
January 2020

Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine.

Psychopharmacology (Berl) 2020 Apr 3;237(4):979-996. Epub 2020 Jan 3.

Department of Genetics, School of Medicine, University of North Carolina, 120 Mason Farm Road, CB7361, Chapel Hill, NC, 27599, USA.

Rationale: Few effective treatments exist for cocaine use disorders due to gaps in knowledge about its complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies. A genetically complex mouse model may better reflect disease-related behaviors.

Objectives: Screening defined, yet genetically complex, intercrosses of the Collaborative Cross (CC) mice revealed two lines, RIX04/17 and RIX41/51, with extreme high and low behavioral responses to cocaine. We characterized these lines as well as their CC parents, CC004/TauUnc and CC041/TauUnc, to evaluate their utility as novel model systems for studying the biological and genetic mechanisms underlying behavioral responses to cocaine.

Methods: Behavioral responses to acute (initial locomotor sensitivity) and repeated (behavioral sensitization, conditioned place preference, intravenous self-administration) exposures to cocaine were assessed. We also examined the monoaminergic system (striatal tissue content and in vivo fast scan cyclic voltammetry), HPA axis reactivity, and circadian rhythms as potential mechanisms for the divergent phenotypic behaviors observed in the two strains, as these systems have a previously known role in mediating addiction-related behaviors.

Results: RIX04/17 and 41/51 show strikingly divergent initial locomotor sensitivity to cocaine with RIX04/17 exhibiting very high and RIX41/51 almost no response. The lines also differ in the emergence of behavioral sensitization with RIX41/51 requiring more exposures to exhibit a sensitized response. Both lines show conditioned place preference for cocaine. We determined that the cocaine sensitivity phenotype in each RIX line was largely driven by the genetic influence of one CC parental strain, CC004/TauUnc and CC041/TauUnc. CC004 demonstrates active operant cocaine self-administration and CC041 is unable to acquire under the same testing conditions, a deficit which is specific to cocaine as both strains show operant response for a natural food reward. Examination of potential mechanisms driving differential responses to cocaine show strain differences in molecular and behavioral circadian rhythms. Additionally, while there is no difference in striatal dopamine tissue content or dynamics, there are selective differences in striatal norepinephrine and serotonergic tissue content.

Conclusions: These CC strains offer a complex polygenic model system to study underlying mechanisms of cocaine response. We propose that CC041/TauUnc and CC004/TauUnc will be useful for studying genetic and biological mechanisms underlying resistance or vulnerability to the stimulatory and reinforcing effects of cocaine.
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http://dx.doi.org/10.1007/s00213-019-05429-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542678PMC
April 2020

Diurnal rhythms in gene expression in the prefrontal cortex in schizophrenia.

Nat Commun 2019 08 9;10(1):3355. Epub 2019 Aug 9.

Translational Neuroscience Program, Department of Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, 15213, PA, USA.

Schizophrenia is associated with disrupted cognitive control and sleep-wake cycles. Here we identify diurnal rhythms in gene expression in the human dorsolateral prefrontal cortex (dlPFC), in schizophrenia and control subjects. We find significant diurnal (24 h) rhythms in control subjects, however, most of these transcripts are not rhythmic in subjects with schizophrenia. Instead, subjects with schizophrenia have a different set of rhythmic transcripts. The top pathways identified in transcripts rhythmic only in subjects with schizophrenia are associated with mitochondrial function. Importantly, these rhythms drive differential expression patterns of these and several other genes that have long been implicated in schizophrenia (including BDNF and GABAergic-related transcripts). Indeed, differential expression of these transcripts is only seen in subjects that died during the night, with no change in subjects that died during the day. These data provide insights into a potential mechanism that underlies changes in gene expression in the dlPFC with schizophrenia.
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http://dx.doi.org/10.1038/s41467-019-11335-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689017PMC
August 2019

Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2.

J Neurosci 2019 06 8;39(24):4657-4667. Epub 2019 Apr 8.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, and

The circadian transcription factor neuronal PAS domain 2 (NPAS2) is linked to psychiatric disorders associated with altered reward sensitivity. The expression of is preferentially enriched in the mammalian forebrain, including the nucleus accumbens (NAc), a major neural substrate of motivated and reward behavior. Previously, we demonstrated that downregulation of NPAS2 in the NAc reduces the conditioned behavioral response to cocaine in mice. We also showed that is preferentially enriched in dopamine receptor 1 containing medium spiny neurons (D1R-MSNs) of the striatum. To extend these studies, we investigated the impact of NPAS2 disruption on accumbal excitatory synaptic transmission and strength, along with the behavioral sensitivity to cocaine reward in a cell-type-specific manner. Viral-mediated knockdown of in the NAc of male and female C57BL/6J mice increased the excitatory drive onto MSNs. Using -tdTomato mice in combination with viral knockdown, we determined these synaptic adaptations were specific to D1R-MSNs relative to non-D1R-MSNs. Interestingly, NAc-specific knockdown of blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSNs. Last, we designed, validated, and used a novel Cre-inducible short-hairpin RNA virus for MSN-subtype-specific knockdown of Cell-type-specific knockdown in D1R-MSNs, but not D2R-MSNs, in the NAc reduced cocaine conditioned place preference. Together, our results demonstrate that NPAS2 regulates excitatory synapses of D1R-MSNs in the NAc and cocaine reward-related behavior. Drug addiction is a widespread public health concern often comorbid with other psychiatric disorders. Disruptions of the circadian clock can predispose or exacerbate substance abuse in vulnerable individuals. We demonstrate a role for the core circadian protein, NPAS2, in mediating glutamatergic neurotransmission at medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a region critical for reward processing. We find that NPAS2 negatively regulates functional excitatory synaptic plasticity in the NAc and is necessary for cocaine-induced plastic changes in MSNs expressing the dopamine 1 receptor (D1R). We further demonstrate disruption of NPAS2 in D1R-MSNs produces augmented cocaine preference. These findings highlight the significance of cell-type-specificity in mechanisms underlying reward regulation by NPAS2 and extend our knowledge of its function.
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http://dx.doi.org/10.1523/JNEUROSCI.2233-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561687PMC
June 2019

Coordination between Prefrontal Cortex Clock Gene Expression and Corticosterone Contributes to Enhanced Conditioned Fear Extinction Recall.

eNeuro 2018 Nov-Dec;5(6). Epub 2018 Dec 21.

Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO 80309.

Post-traumatic stress disorder (PTSD) is associated with impaired conditioned fear extinction learning, a ventromedial prefrontal cortex (vmPFC)-dependent process. PTSD is also associated with dysregulation of vmPFC, circadian, and glucocorticoid hormone function. Rats have rhythmic clock gene expression in the vmPFC that requires appropriate diurnal circulatory patterns of corticosterone (CORT), suggesting the presence of CORT-entrained intrinsic circadian clock function within the PFC. We examined the role of vmPFC clock gene expression and its interaction with CORT profiles in regulation of auditory conditioned fear extinction learning. Extinction learning and recall were examined in male rats trained and tested either in the night (active phase) or in the day (inactive phase). Using a viral vector strategy, and clock gene expression were selectively knocked down within the vmPFC. Circulating CORT profiles were manipulated via adrenalectomy (ADX) ± diurnal and acute CORT replacement. Rats trained and tested during the night exhibited superior conditioned fear extinction recall that was absent in rats that had knock-down of vmPFC clock gene expression. Similarly, the superior nighttime extinction recall was absent in ADX rats, but restored in ADX rats given a combination of a diurnal pattern of CORT and acute elevation of CORT during the postextinction training consolidation period. Thus, conditioned fear extinction learning is regulated in a diurnal fashion that requires normal vmPFC clock gene expression and a combination of circadian and training-associated CORT. Strategic manipulation of these factors may enhance the therapeutic outcome of conditioned fear extinction related treatments in the clinical setting.
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http://dx.doi.org/10.1523/ENEURO.0455-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325539PMC
March 2019

Rhythms of life: circadian disruption and brain disorders across the lifespan.

Nat Rev Neurosci 2019 01;20(1):49-65

University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA, USA.

Many processes in the human body - including brain function - are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep-wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.
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http://dx.doi.org/10.1038/s41583-018-0088-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338075PMC
January 2019

Mood-related central and peripheral clocks.

Eur J Neurosci 2020 01 29;51(1):326-345. Epub 2018 Nov 29.

Department of Psychiatry, Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Mood disorders, including major depression, bipolar disorder, and seasonal affective disorder, are debilitating disorders that affect a significant portion of the global population. Individuals suffering from mood disorders often show significant disturbances in circadian rhythms and sleep. Moreover, environmental disruptions to circadian rhythms can precipitate or exacerbate mood symptoms in vulnerable individuals. Circadian clocks exist throughout the central nervous system and periphery, where they regulate a wide variety of physiological processes implicated in mood regulation. These processes include monoaminergic and glutamatergic transmission, hypothalamic-pituitary-adrenal axis function, metabolism, and immune function. While there seems to be a clear link between circadian rhythm disruption and mood regulation, the mechanisms that underlie this association remain unclear. This review will touch on the interactions between the circadian system and each of these processes and discuss their potential role in the development of mood disorders. While clinical studies are presented, much of the review will focus on studies in animal models, which are attempting to elucidate the molecular and cellular mechanisms in which circadian genes regulate mood.
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http://dx.doi.org/10.1111/ejn.14253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502705PMC
January 2020

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Mol Psychiatry 2019 11 4;24(11):1668-1684. Epub 2018 May 4.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15219, USA.

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.
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http://dx.doi.org/10.1038/s41380-018-0061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215755PMC
November 2019

Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice.

Alcohol Clin Exp Res 2018 05 18;42(5):879-888. Epub 2018 Apr 18.

Research and Development Service, Portland Veterans Affairs Medical Center, Portland, Oregon.

Background: Chronic alcohol intake leads to long-lasting changes in reward- and stress-related neuronal circuitry. The nucleus accumbens (NAc) is an integral component of this circuitry. Here, we investigate the effects of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) on neuronal activity in the NAc and binge-like drinking.

Methods: C57BL/6J mice were stereotaxically injected with AAV2 hSyn-HA hM3Dq, -hM4Di, or -eGFP bilaterally into NAc [core + shell, core or shell]. We measured clozapine-n-oxide (CNO)-induced changes in NAc activity and assessed binge-like ethanol (EtOH) or tastant/fluid intake in a limited access Drinking in the Dark (DID) schedule.

Results: We found that CNO increased NAc firing in hM3Dq positive cells and decreased firing in hM4Di cells, confirming the efficacy of these channels to alter neuronal activity both spatially and temporally. Increasing NAc core + shell activity decreased binge-like drinking without altering intake of other tastants. Increasing activity specifically in the NAc core reduced binge-like drinking, and decreasing activity in the NAc core increased drinking. Manipulation of NAc shell activity did not alter DID. Thus, we find that increasing activity in the entire NAc, or just the NAc core is sufficient to decrease binge drinking.

Conclusions: We conclude that the reduction in EtOH drinking is not due to general malaise, altered perception of taste, or reduced calorie-seeking. Furthermore, we provide the first evidence for bidirectional control of NAc core and binge-like drinking. These findings could have promising implications for treatment.
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http://dx.doi.org/10.1111/acer.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034712PMC
May 2018

Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents.

Biol Psychiatry 2018 06 15;83(12):987-996. Epub 2017 Dec 15.

Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; The Jackson Laboratory, Bar Harbor, Maine. Electronic address:

Sleep homeostasis and circadian function are important maintaining factors for optimal health and well-being. Conversely, sleep and circadian disruptions are implicated in a variety of adverse health outcomes, including substance use disorders. These risks are particularly salient during adolescence. Adolescents require 8 to 10 hours of sleep per night, although few consistently achieve these durations. A mismatch between developmental changes and social/environmental demands contributes to inadequate sleep. Homeostatic sleep drive takes longer to build, circadian rhythms naturally become delayed, and sensitivity to the phase-shifting effects of light increases, all of which lead to an evening preference (i.e., chronotype) during adolescence. In addition, school start times are often earlier in adolescence and the use of electronic devices at night increases, leading to disrupted sleep and circadian misalignment (i.e., social jet lag). Social factors (e.g., peer influence) and school demands further impact sleep and circadian rhythms. To cope with sleepiness, many teens regularly consume highly caffeinated energy drinks and other stimulants, creating further disruptions in sleep. Chronic sleep loss and circadian misalignment enhance developmental tendencies toward increased reward sensitivity and impulsivity, increasing the likelihood of engaging in risky behaviors and exacerbating the vulnerability to substance use and substance use disorders. We review the neurobiology of brain reward systems and the impact of sleep and circadian rhythms changes on addiction vulnerability in adolescence and suggest areas that warrant additional research.
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http://dx.doi.org/10.1016/j.biopsych.2017.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972052PMC
June 2018

Neural Mechanisms of Circadian Regulation of Natural and Drug Reward.

Neural Plast 2017 21;2017:5720842. Epub 2017 Nov 21.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Circadian rhythms are endogenously generated near 24-hour variations of physiological and behavioral functions. In humans, disruptions to the circadian system are associated with negative health outcomes, including metabolic, immune, and psychiatric diseases, such as addiction. Animal models suggest bidirectional relationships between the circadian system and drugs of abuse, whereby desynchrony, misalignment, or disruption may promote vulnerability to drug use and the transition to addiction, while exposure to drugs of abuse may entrain, disrupt, or perturb the circadian timing system. Recent evidence suggests natural (i.e., food) and drug rewards may influence overlapping neural circuitry, and the circadian system may modulate the physiological and behavioral responses to these stimuli. Environmental disruptions, such as shifting schedules or shorter/longer days, influence food and drug intake, and certain mutations of circadian genes that control cellular rhythms are associated with altered behavioral reward. We highlight the more recent findings associating circadian rhythms to reward function, linking environmental and genetic evidence to natural and drug reward and related neural circuitry.
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http://dx.doi.org/10.1155/2017/5720842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735684PMC
September 2018

Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus.

Neural Plast 2017 5;2017:1504507. Epub 2017 Nov 5.

Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, USA.

Circadian rhythm disturbances are a common symptom among individuals with mood disorders. The suprachiasmatic nucleus (SCN), in the ventral part of the anterior hypothalamus, orchestrates physiological and behavioral circadian rhythms. The SCN consists of self-sustaining oscillators and receives photic and nonphotic cues, which entrain the SCN to the external environment. In turn, through synaptic and hormonal mechanisms, the SCN can drive and synchronize circadian rhythms in extra-SCN brain regions and peripheral tissues. Thus, genetic or environmental perturbations of SCN rhythms could disrupt brain regions more closely related to mood regulation and cause mood disturbances. Here, we review clinical and preclinical studies that provide evidence both for and against a causal role for the SCN in mood disorders.
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http://dx.doi.org/10.1155/2017/1504507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694588PMC
July 2018

NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors.

Front Mol Neurosci 2017 3;10:360. Epub 2017 Nov 3.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

Abnormal circadian rhythms and circadian genes are strongly associated with several psychiatric disorders. Neuronal PAS Domain Protein 2 (NPAS2) is a core component of the molecular clock that acts as a transcription factor and is highly expressed in reward- and stress-related brain regions such as the striatum. However, the mechanism by which NPAS2 is involved in mood-related behaviors is still unclear. We measured anxiety-like behaviors in mice with a global null mutation in (Npas2 null mutant mice) and found that Npas2 null mutant mice exhibit less anxiety-like behavior than their wild-type (WT) littermates (in elevated plus maze, light/dark box and open field assay). We assessed the effects of acute or chronic stress on striatal expression, and found that both stressors increased levels of . Moreover, knockdown of in the ventral striatum resulted in a similar reduction of anxiety-like behaviors as seen in the Npas2 null mutant mouse. Additionally, we identified genes as transcriptional targets of NPAS2, found that Npas2 null mutant mice exhibit reduced sensitivity to the GABAa positive allosteric modulator, diazepam and that knockdown of reduced expression and response to diazepam in the ventral striatum. These results: (1) implicate in the response to stress and the development of anxiety; and (2) provide functional evidence for the regulation of GABAergic neurotransmission by NPAS2 in the ventral striatum.
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http://dx.doi.org/10.3389/fnmol.2017.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675889PMC
November 2017

Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator.

Neuropsychopharmacology 2018 Jan 31;43(2):435-444. Epub 2017 Aug 31.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Kv3.1 and Kv3.2 voltage-gated potassium channels are expressed on parvalbumin-positive GABAergic interneurons in corticolimbic brain regions and contribute to high-frequency neural firing. The channels are also expressed on GABAergic neurons of the basal ganglia, substantia nigra, and ventral tegmental area (VTA) where they regulate firing patterns critical for movement control, reward, and motivation. Modulation of Kv3.1 and Kv3.2 channels may therefore have potential in the treatment of disorders in which these systems have been implicated, such as bipolar disorder. Following the recent development of a potassium channel modulator, AUT1-an imidazolidinedione compound that specifically increases currents mediated by Kv3.1 and Kv3.2 channels in recombinant systems-we report that the compound is able to reverse 'manic-like' behavior in two mouse models: amphetamine-induced hyperactivity and ClockΔ19 mutants. AUT1 completely prevented amphetamine-induced hyperactivity in a dose-dependent manner, similar to the atypical antipsychotic, clozapine. Similar efficacy was observed in Kv3.2 knockout mice. In contrast, AUT1 was unable to prevent amphetamine-induced hyperactivity in mice lacking Kv3.1 channels. Notably, Kv3.1-null mice displayed baseline hyperlocomotion, reduced anxiety-like behavior, and antidepressant-like behavior. In ClockΔ19 mice, AUT1 reversed hyperactivity. Furthermore, AUT1 application modulated firing frequency and action potential properties of ClockΔ19 VTA dopamine neurons potentially through network effects. Kv3.1 protein levels in the VTA of ClockΔ19 and WT mice were unaltered by acute AUT1 treatment. Taken together, these results suggest that the modulation of Kv3.1 channels may provide a novel approach to the treatment of bipolar mania.
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http://dx.doi.org/10.1038/npp.2017.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729564PMC
January 2018

Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the ClockΔ19 Model of Bipolar Mania.

Biol Psychiatry 2018 12 27;84(11):817-826. Epub 2017 Jun 27.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Electronic address:

Background: Disruptions in circadian rhythms are associated with an increased risk for bipolar disorder. Moreover, studies show that the circadian protein CLOCK (circadian locomotor output cycles kaput) is involved in regulating monoaminergic systems and mood-related behavior. However, the molecular and synaptic mechanisms underlying this relationship remain poorly understood.

Methods: Using ex vivo whole-cell patch-clamp electrophysiology in ClockΔ19 mutant and wild-type mice we characterized alterations in excitatory synaptic transmission, strength, and intrinsic excitability of nucleus accumbens (NAc) neurons. We performed protein crosslinking and Western blot analysis to examine surface and intracellular levels and rhythm of the glutamate receptor subunit, GluA1, in the NAc. Viral-mediated overexpression of Gria1 in the NAc and behavioral assays were also used.

Results: Compared with wild-type mice, ClockΔ19 mice display reduced alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory synaptic responses at NAc medium spiny neurons. These alterations are likely postsynaptic, as presynaptic release of glutamate onto medium spiny neurons is unaltered in mutant mice. Additionally, NAc surface protein levels and the rhythm of GRIA1 are decreased in ClockΔ19 mice diurnally, consistent with reduced functional synaptic response. Furthermore, we observed a significantly hyperpolarized resting membrane potential of ClockΔ19 medium spiny neurons, suggesting lowered intrinsic excitability. Last, overexpression of functional Gria1 in the NAc of mutant mice was able to normalize increased exploratory drive and reward sensitivity behavior when mice are in a manic-like state.

Conclusions: Together, our findings demonstrate that NAc excitatory signaling via Gria1 expression is integral to the effects of Clock gene disruption on manic-like behaviors.
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http://dx.doi.org/10.1016/j.biopsych.2017.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745309PMC
December 2018

Dynamically Timed Stimulation of Corticolimbic Circuitry Activates a Stress-Compensatory Pathway.

Biol Psychiatry 2017 Dec 15;82(12):904-913. Epub 2017 Jun 15.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina; Department of Biomedical Engineering, Duke University Medical Center, Durham, North Carolina; Department of Neurobiology, Duke University Medical Center, Durham, North Carolina; Center for Neuroengineering, Duke University Medical Center, Durham, North Carolina; Duke Institute for Brain Sciences, Duke University Medical Center, Durham, North Carolina. Electronic address:

Background: The prefrontal cortex plays a critical role in regulating emotional behaviors, and dysfunction of prefrontal cortex-dependent networks has been broadly implicated in mediating stress-induced behavioral disorders including major depressive disorder.

Methods: Here we acquired multicircuit in vivo activity from eight cortical and limbic brain regions as mice were subjected to the tail suspension test (TST) and an open field test. We used a linear decoder to determine whether cellular responses across each of the cortical and limbic areas signal movement during the TST and open field test. We then performed repeat behavioral testing to identify which brain areas show cellular adaptations that signal the increase in immobility induced by repeat TST exposure.

Results: The increase in immobility observed during repeat TST exposure is linked to a selective functional upregulation of cellular activity in infralimbic cortex and medial dorsal thalamus, and to an increase in the spatiotemporal dynamic interaction between these structures. Inducing this spatiotemporal dynamic using closed-loop optogenetic stimulation is sufficient to increase movement in the TST in stress-naive mice, while stimulating above the carrier frequency of this circuit suppressed movement. This demonstrates that the adaptations in infralimbic cortex-medial dorsal thalamus circuitry observed after stress reflect a compensatory mechanism whereby the brain drives neural systems to counterbalance stress effects.

Conclusions: Our findings provide evidence that targeting endogenous spatiotemporal dynamics is a potential therapeutic approach for treating stress-induced behavioral disorders, and that dynamics are a critical axis of manipulation for causal optogenetic studies.
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http://dx.doi.org/10.1016/j.biopsych.2017.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013844PMC
December 2017

Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis.

Proc Natl Acad Sci U S A 2017 05 12;114(22):E4462-E4471. Epub 2017 May 12.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.
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http://dx.doi.org/10.1073/pnas.1700111114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465887PMC
May 2017

Constance E. Lieber, Theodore R. Stanley, and the Enduring Impact of Philanthropy on Psychiatry Research.

Biol Psychiatry 2016 07;80(2):84-86

Department of Psychiatry, University Neuropsychiatric Institute, University of Utah Health Sciences Center, Salt Lake City, Utah.

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http://dx.doi.org/10.1016/j.biopsych.2016.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150945PMC
July 2016

Functional Implications of the CLOCK 3111T/C Single-Nucleotide Polymorphism.

Front Psychiatry 2016 21;7:67. Epub 2016 Apr 21.

Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine , Pittsburgh, PA , USA.

Circadian rhythm disruptions are prominently associated with bipolar disorder (BD). Circadian rhythms are regulated by the molecular clock, a family of proteins that function together in a transcriptional-translational feedback loop. The CLOCK protein is a key transcription factor of this feedback loop, and previous studies have found that manipulations of the Clock gene are sufficient to produce manic-like behavior in mice (1). The CLOCK 3111T/C single-nucleotide polymorphism (SNP; rs1801260) is a genetic variation of the human CLOCK gene that is significantly associated with increased frequency of manic episodes in BD patients (2). The 3111T/C SNP is located in the 3'-untranslated region of the CLOCK gene. In this study, we sought to examine the functional implications of the human CLOCK 3111T/C SNP by transfecting a mammalian cell line (mouse embryonic fibroblasts isolated from Clock(-/-) knockout mice) with pcDNA plasmids containing the human CLOCK gene with either the T or C SNP at position 3111. We then measured circadian gene expression over a 24-h time period. We found that the CLOCK3111C SNP resulted in higher mRNA levels than the CLOCK 3111T SNP. Furthermore, we found that Per2, a transcriptional target of CLOCK, was also more highly expressed with CLOCK 3111C expression, indicating that the 3'-UTR SNP affects the expression, function, and stability of CLOCK mRNA.
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http://dx.doi.org/10.3389/fpsyt.2016.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838618PMC
May 2016

Circadian Mechanisms Underlying Reward-Related Neurophysiology and Synaptic Plasticity.

Front Psychiatry 2015 12;6:187. Epub 2016 Jan 12.

Department of Psychiatry, University of Pittsburgh School of Medicine , Pittsburgh, PA , USA.

Evidence from clinical and preclinical research provides an undeniable link between disruptions in the circadian clock and the development of psychiatric diseases, including mood and substance abuse disorders. The molecular clock, which controls daily patterns of physiological and behavioral activity in living organisms, when desynchronized, may exacerbate or precipitate symptoms of psychiatric illness. One of the outstanding questions remaining in this field is that of cause and effect in the relationship between circadian rhythm disruption and psychiatric disease. Focus has recently turned to uncovering the role of circadian proteins beyond the maintenance of homeostatic systems and outside of the suprachiasmatic nucleus (SCN), the master pacemaker region of the brain. In this regard, several groups, including our own, have sought to understand how circadian proteins regulate mechanisms of synaptic plasticity and neurotransmitter signaling in mesocorticolimbic brain regions, which are known to be critically involved in reward processing and mood. This regulation can come in the form of direct transcriptional control of genes central to mood and reward, including those associated with dopaminergic activity in the midbrain. It can also be seen at the circuit level through indirect connections of mesocorticolimbic regions with the SCN. Circadian misalignment paradigms as well as genetic models of circadian disruption have helped to elucidate some of the complex interactions between these systems and neural activity influencing behavior. In this review, we explore findings that link circadian protein function with synaptic adaptations underlying plasticity as it may contribute to the development of mood disorders and addiction. In light of recent advances in technology and sophisticated methods for molecular and circuit-level interrogation, we propose future directions aimed at teasing apart mechanisms through which the circadian system modulates mood and reward-related behavior.
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http://dx.doi.org/10.3389/fpsyt.2015.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709415PMC
January 2016

Effects of aging on circadian patterns of gene expression in the human prefrontal cortex.

Proc Natl Acad Sci U S A 2016 Jan 22;113(1):206-11. Epub 2015 Dec 22.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;

With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. Expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ∼ 10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain. Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.
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http://dx.doi.org/10.1073/pnas.1508249112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711850PMC
January 2016

Chronic Stress Induces Brain Region-Specific Alterations of Molecular Rhythms that Correlate with Depression-like Behavior in Mice.

Biol Psychiatry 2015 Aug 4;78(4):249-58. Epub 2015 Feb 4.

Department of Psychiatry and Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.. Electronic address:

Background: Emerging evidence implicates circadian abnormalities as a component of the pathophysiology of major depressive disorder (MDD). The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates rhythms throughout the brain and body. On a cellular level, rhythms are generated by transcriptional, translational, and posttranslational feedback loops of core circadian genes and proteins. In patients with MDD, recent evidence suggests reduced amplitude of molecular rhythms in extra-SCN brain regions. We investigated whether unpredictable chronic mild stress (UCMS), an animal model that induces a depression-like physiological and behavioral phenotype, induces circadian disruptions similar to those seen with MDD.

Methods: Activity and temperature rhythms were recorded in C57BL/6J mice before, during, and after exposure to UCMS, and brain tissue explants were collected from Period2 luciferase mice following UCMS to assess cellular rhythmicity.

Results: UCMS significantly decreased circadian amplitude of activity and body temperature in mice, similar to findings in MDD patients, and these changes directly correlated with depression-related behavior. While amplitude of molecular rhythms in the SCN was decreased following UCMS, surprisingly, rhythms in the nucleus accumbens (NAc) were amplified with no changes seen in the prefrontal cortex or amygdala. These molecular rhythm changes in the SCN and the NAc also directly correlated with mood-related behavior.

Conclusions: These studies found that circadian rhythm abnormalities directly correlate with depression-related behavior following UCMS and suggest a desynchronization of rhythms in the brain with an independent enhancement of rhythms in the NAc.
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http://dx.doi.org/10.1016/j.biopsych.2015.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509914PMC
August 2015

In vivo optogenetic stimulation of the rodent central nervous system.

J Vis Exp 2015 Jan 15(95):51483. Epub 2015 Jan 15.

Department of Psychiatry, University of Pittsburgh Medical Center.

The ability to probe defined neural circuits in awake, freely-moving animals with cell-type specificity, spatial precision, and high temporal resolution has been a long sought tool for neuroscientists in the systems-level search for the neural circuitry governing complex behavioral states. Optogenetics is a cutting-edge tool that is revolutionizing the field of neuroscience and represents one of the first systematic approaches to enable causal testing regarding the relation between neural signaling events and behavior. By combining optical and genetic approaches, neural signaling can be bi-directionally controlled through expression of light-sensitive ion channels (opsins) in mammalian cells. The current protocol describes delivery of specific wavelengths of light to opsin-expressing cells in deep brain structures of awake, freely-moving rodents for neural circuit modulation. Theoretical principles of light transmission as an experimental consideration are discussed in the context of performing in vivo optogenetic stimulation. The protocol details the design and construction of both simple and complex laser configurations and describes tethering strategies to permit simultaneous stimulation of multiple animals for high-throughput behavioral testing.
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http://dx.doi.org/10.3791/51483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354526PMC
January 2015

Circadian clock genes: effects on dopamine, reward and addiction.

Alcohol 2015 Jun 8;49(4):341-9. Epub 2015 Jan 8.

University of Pittsburgh School of Medicine, Department of Psychiatry, 450 Technology Drive, Suite 223, Pittsburgh, PA 15219, USA. Electronic address:

Addiction is a widespread public health issue with social and economic ramifications. Substance abuse disorders are often accompanied by disruptions in circadian rhythms including sleep/wake cycles, which can exacerbate symptoms of addiction and dependence. Additionally, genetic disturbance of circadian molecular mechanisms can predispose some individuals to substance abuse disorders. In this review, we will discuss how circadian genes can regulate midbrain dopaminergic activity and subsequently, drug intake and reward. We will also suggest future directions for research on circadian genes and drugs of abuse.
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http://dx.doi.org/10.1016/j.alcohol.2014.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457686PMC
June 2015

Glucocorticoid receptor function and resilience: a tale of mice and men.

Biol Psychiatry 2015 Feb;77(4):310-1

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2014.11.009DOI Listing
February 2015