Knockdown of Clock in the Ventral Tegmental Area Through RNA Interference Results in a Mixed State of Mania and Depression-Like Behavior

Mukherjee, Shibani; Coque, Laurent; Cao, Jun‐Li; Kumar, Jaswinder; Chakravarty, Sumana; Asaithamby, Aroumougame; Graham, Ami; Gordon, Elizabeth M.; Enwright, John F.; DiLeone, Ralph J.; Birnbaum, Shari G.; Cooper, Donald; McClung, Colleen A.

doi:10.1016/j.biopsych.2010.04.031

Cited by 217 publications

(197 citation statements)

References 35 publications

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“…Moreover, activation of A2AR, which is enriched in the striatum but scant in the hypothalamus, reversed the deficits of ENT1 KO mice. In this regard, other evidence exists for clock genes in reward circuitry contributing to circadian amplitude (Mukherjee et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Ruby

Vadnie

Hinton

et al. 2014

Neuropsychopharmacol

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Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the cooccurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption.

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Section: Discussionmentioning

confidence: 99%

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Ruby

Vadnie

Hinton

et al. 2014

Neuropsychopharmacol

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“…Although the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes rhythms throughout the brain and body, the genes that control circadian rhythms are expressed in nearly every cell (6). In recent years, it has become apparent that these genes serve important functions in specific brain regions, including the control of daily rhythms in neuronal activity and the response to environmental stimuli (7)(8)(9).…”

mentioning

confidence: 99%

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

Chen

Logan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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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“…Depression and anxiety often are comorbid conditions, but in this case these behavioral effects seem to occur in opposition. Interestingly, those incongruent behaviors also are observed in Clock-knockdown mice, which show a mixed state of manic-and depressive-like behavior: less anxiety and hyperactivity but greater depression-like behavior (28). Additionally, HSF1 is reported to act as a circadian transcription factor (29).…”

Section: Discussionmentioning

confidence: 97%

Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1

Uchida

Hara

Kobayashi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1 −/− ) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1 −/− mice. In addition, HSF1 −/− mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1 −/− mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.emotion | spine density | neuronal maturation | polysialylation T here is increasing evidence that aberrant transcriptional regulation is one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders (1, 2). It has been suggested that neuronal activity regulates a complex program of gene expression involved in structural and functional plasticity (3). Recent evidence has indicated that aberrant gene regulation in early brain development can affect brain function and subsequent affective behavior, as well as behavioral responses to stress during adulthood in rodents (4, 5).Heat shock factors (HSFs) bind to the conserved heat shock element (HSE) consensus sequence and facilitate the transcriptional activation or repression of HSE-containing target genes (6). In mammals, the HSF family consists of four members (HSF1-4) that are considered functionally distinct. HSF1 is an essential molecule for facilitating the response to cellular stress (e.g., elevated temperature, oxidative stress, and increased protein misfolding) and also is required for developmental processes, whereas HSF2 and HSF4 are involved in cell differentiation and development (7). Among the mammalian HSFs, HSF1 is the master transactivator of heat shock proteins, which function as molecular chaperones at various...

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Knockdown of Clock in the Ventral Tegmental Area Through RNA Interference Results in a Mixed State of Mania and Depression-Like Behavior

Cited by 217 publications

References 35 publications

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

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

Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1

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