Publications by authors named "Darius Becker-Krail"

10 Publications

  • Page 1 of 1

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

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

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

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

Implications of circadian rhythm and stress in addiction vulnerability.

F1000Res 2016 13;5:59. Epub 2016 Jan 13.

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

In the face of chronic stress, some individuals can maintain normal function while others go on to develop mental illness. Addiction, affecting one in every twelve people in America, is a substance use disorder long associated with stressful life events and disruptions in the sleep/wake cycle. The circadian and stress response systems have evolved to afford adaptability to environmental changes and allow for maintenance of functional stability, or homeostasis. This mini-review will discuss how circadian rhythms and stress individually affect drug response, affect each other, and how their interactions may regulate reward-related behavior. In particular, we will focus on the interactions between the circadian clock and the regulation of glucocorticoids by the hypothalamic-pituitary-adrenal (HPA) axis. Determining how these two systems act on dopaminergic reward circuitry may not only reveal the basis for vulnerability to addiction, but may also illuminate potential therapeutic targets for future investigation.
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http://dx.doi.org/10.12688/f1000research.7608.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743143PMC
February 2016

Persistent phototransformation products of vardenafil (Levitra®) and sildenafil (Viagra®).

Chemosphere 2015 Sep 10;134:557-62. Epub 2015 Jan 10.

Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC, United States. Electronic address:

As pharmaceutically active compounds (PhACs) are increasingly detected in the aquatic environment, the importance of investigating their transformation products-products of naturally occurring hydrolysis, biodegradation, and solar-mediated photochemical reactions - for persistence and ecotoxicity remains an important part of assessing the pharmaceutical's environmental impact and fate. In this study, the solar phototransformation of vardenafil (active ingredient in Levitra®) and sildenafil (Viagra®), two structurally similar compounds used to treat erectile dysfunction, was studied, with special attention to potentially persistent phototransformation (PT) products. PT products for vardenafil are identified here for the first time. Dilute solutions were prepared in buffered (pH=7.4) aqueous solutions, both with and without Suwanee River humic acid (SRHA) and fulvic acid (SRFA), and exposed to simulated sunlight. The PT products were identified via Liquid Chromatography-Electrospray Ionization-Mass Spectrometry (LC-ESI-MS) and confirmed by MS/MS. Both SRHA and SRFA were observed to lead to more extensive degradation of VRD while having minimal effect on SLD. At least two PT products, SLD-392 and VRD-392, were observed to be notably persistent, indicating their potential impact in the aquatic environment and highlighting the need for investigations of transformation products in natural water samples.
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http://dx.doi.org/10.1016/j.chemosphere.2014.12.011DOI Listing
September 2015