Vulnerability to helpless behavior is regulated by the circadian clock component CRYPTOCHROME in the mouse nucleus accumbens

Abstract

<jats:p>The nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in the postmortem brains of depressed patients. We hypothesized that normal mood regulation requires proper circadian timing in the NAc, and that mood disorders are associated with dysfunctions of the NAc cellular circadian clock. In mice exhibiting stress-induced depression-like behavior (helplessness), we found altered circadian clock function and high nighttime expression of the core circadian clock component CRYPTOCHROME (CRY) in the NAc. In the NAc of helpless mice, we found that higher expression of CRY is associated with decreased activation of dopamine 1 receptor-expressing medium spiny neurons (D1R-MSNs). Furthermore, D1R-MSN–specific CRY-knockdown in the NAc reduced susceptibility to stress-induced helplessness and increased NAc neuronal activation at night. Finally, we show that CRY inhibits D1R-induced G protein activation, likely by interacting with the Gs protein. Altered circadian rhythms and CRY expression were also observed in human fibroblasts from major depressive disorder patients. Our data reveal a causal role for CRY in regulating the midbrain dopamine reward system, and provide a mechanistic link between the NAc circadian clock and vulnerability to depression.</jats:p>

Circadian transcription factor NPAS2 and the NAD+‐dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward

“…Previous studies from our lab have found in mice that core clock genes Npas2 , Clock and Period all show diurnal variation in the NAc (Falcon et al, 2013), as well as rhythmicity measured by Per2 :luciferase luminescence assays (Logan et al, 2015). This is further supported by studies from the Welsh group demonstrating NAc Per2 :luciferase rhythms (Landgraf, Long, & Welsh, 2016; Porcu et al, 2020), as well as diurnal variation in CRYPTOCHROME protein levels in the NAc (Porcu et al, 2020). Interestingly, this is also seen in time of death analyses of gene expression in human post‐mortem tissue, where the canonical clock genes (e.g., Bmal1 , Npas2 , Period , Cryptochrome , Rev‐erbα ) are all highly rhythmic in the NAc of healthy donors (Ketchesin et al, 2021; Li et al, 2013).…”

Altered Affective Behaviors in Casein Kinase 1 Epsilon Mutant Mice

“…The knockdown Bmal1 expression restricted to the SCN could increase depressive-and anxiety-like behaviors in mice (Landgraf et al, 2016). CRY in nucleus accumbens was found to regulate depressive-like behaviors in mice (Porcu et al, 2020).…”

The Ventral Tegmental Area and Nucleus Accumbens as Circadian Oscillators: Implications for Drug Abuse and Substance Use Disorders

“…Studies in both rodents and human post-mortem tissue have shown significant rhythmicity in NAc circadian molecular clock function. Using the PER2:LUC mouse model, sustained bioluminescent rhythms have been detected in the NAc ex vivo ( Logan et al, 2015 ; Landgraf et al, 2016a ; Porcu et al, 2020 ). This corroborates gene expression analyses in mice showing significant diurnal variation in molecular clock mRNA levels in the NAc ( Falcon et al, 2013 ; Natsubori et al, 2014 ; Logan et al, 2015 ; Brami-Cherrier et al, 2020 ; Porcu et al, 2020 ; Becker-Krail et al, 2022b ), as well as protein expression analyses in the striatum ( Schnell et al, 2015 ).…”

“…Using the PER2:LUC mouse model, sustained bioluminescent rhythms have been detected in the NAc ex vivo ( Logan et al, 2015 ; Landgraf et al, 2016a ; Porcu et al, 2020 ). This corroborates gene expression analyses in mice showing significant diurnal variation in molecular clock mRNA levels in the NAc ( Falcon et al, 2013 ; Natsubori et al, 2014 ; Logan et al, 2015 ; Brami-Cherrier et al, 2020 ; Porcu et al, 2020 ; Becker-Krail et al, 2022b ), as well as protein expression analyses in the striatum ( Schnell et al, 2015 ). This is also seen in human post-mortem NAc tissue RNA-sequencing analyses where transcript levels are organized by time-of-death and tested for rhythmicity.…”