Table 2.

Effect of clock gene manipulation on molecular and behavioral phenotypes.

Manipulation	Affected region/system	Cell-type	Species	Molecular/cellular phenotype	Behavioral phenotype	Reference
Chrono-KO	SCN	AVP	Mouse	Larger corticosterone response, abnormal glucocorticoid levels	N/A	Goriki et al. (2014)
Clock-Δ19	SCN	N/A	Mouse	Altered circadian rhythm	Increased motivation for rewarding stimuli, decreased depression-like behavior in the forced swim test and learned helplessness tests	Easton et al. (2003) and Roybal et al. (2007)
Per1-Per2 knock-out	N/A	N/A	Mouse	N/A	Depression-like behavior in the forced swim test	Spencer et al. (2013)
Cry1 or Cry2 single-KO and Cry1/2 double-KO	N/A	N/A	Mouse	N/A	Increased anxiety states but not depression-like behaviors	De Bundel et al. (2013)
Cry1/2 double-KO	N/A	N/A	Mouse	N/A	Increased anhedonia	Savalli et al. (2015a,b)
Cry2-KO	N/A	N/A	Mouse	N/A	Reduced despair-like behavior and increased anhedonia	Sokolowska et al. (2021)
Bmal1-KD	SCN	N/A	Mouse	Reduced rhythmicity	Increased behavioral despair, anxiety-like behavior, and helplessness compared to control	Landgraf et al. (2016a,b)
SOX2-KO	SCN	GABA	Mouse	Altered clock gene and neuropeptide expression	Less explorative behavior in the elevated plus maze, increased immobility time in the forced swimming test and tail suspension test, and decreased sucrose preference compared to control mice	Cheng et al. (2019)
CLOCK short-hairpin RNA	VTA	N/A	Mouse	DA release into the NAc and downregulation of GABAergic genes	N/A	Mukherjee et al. (2010)
Cck-KD	VTA	N/A	Mouse	N/A	Manic-like behavioral phenotype	Arey et al. (2014)
Clock-Δ19	VTA	N/A	Mouse	Increased TH mRNA, reduced cholecystokinin mRNA, increased dopamine neuron function as evidenced by increased glutamatergic tone as well as increased mean firing rate and bursting of DA neurons	Increased anxiety-related behavior	McClung et al. (2005) and Coque et al. (2011)
REV-ERBα deletion	VTA	N/A	Mouse	Repressed TH gene transcription by competing with nuclear receptor-related 1 protein	Hyperdopaminergic state and mania-like behavior	Chung et al. (2014)
Clock-Δ19	NAc	N/A	Mouse	Deficits in low-gamma and single-neuron phase coupling, dendritic morphology and reduced GluR1 expression	Increase exploratory drive	Dzirasa et al. (2010)
Clock-Δ19	NAc	N/A	Mouse	Reduced functional synaptic response in MSN, decrease protein levels and the rhythm of GRIA1 in MSN	Exploratory drive and reward sensitivity	Parekh et al. (2017)
NR1D1-KD	NAc	N/A	Mouse	Changes in circadian rhythm, including upregulation of Per1 and Per2 genes, and histone deacetylase genes	Enhanced social interaction and reduced anxiety	Zhao and Gammie (2018)
CR1/CRY2-KD	NAc	D1R-MSN	Mouse	Increased MSN neuronal activation at night.	Reduced susceptibility to helplessness	Porcu et al. (2020)
Per1/Per2-KD	NAc	N/A	Mouse	N/A	Regulation of anxiety related behavior	Spencer et al. (2013)
Npas2-KD	NAc	N/A	Mouse	Alters expression of GABA-A receptor subunits, prevents diazepam-induced potentiation of IPSC amplitude in MSNs	Reduced anxiety-like behavior	Ozburn et al. (2017)
Npas2-KD	NAc	D1R-MSN	Mouse	Blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSN	Reduced cocaine conditioned place preference	Parekh et al. (2019)
Per2 deletion	NAc	Glia cells	Mouse	Increased GABA transporter 2 and dopamine receptor D3 mRNA and reduced glutamate levels	Reduced despair and anxiety	Martini et al. (2021)
Bmal1 deletion	NAc	Astrocytes	Mouse	Complex changes in AMPA receptor function and increased expression of AMPA and NMDA receptor subunits	Enhanced reward related behaviors including motivation for food and exploratory behavior	Becker-Krail et al. (2022a,b)
Per2-KD	LHb	N/A	Mouse	N/A	Induced depression-related behavior	Li et al. (2021)
Per1-KO	LHb	N/A	Mouse	N/A	Suppressed the beneficial effects of light on mood	Olejniczak et al. (2021)
SST -KO	BLA	SST	Mouse	N/A	Lack of circadian fluctuation of anxiety-like behavior	Albrecht et al. (2013)