Abstract
While disruption of the circadian clock triggers a spectrum of affective abnormalities, how the clock regulates mammalian emotionality remains unclear. Here, we characterized the time-of-day-dependent regulation of mouse anxiety-like behaviors. We show that anxiety-like behaviors are expressed in a circadian manner in mice and demonstrate that the clock machineries in the dorsal telencephalon (dTel) are required for the time-of-day-dependent regulation of anxiety-like behaviors. We identify suprachiasmatic nucleus circadian oscillatory protein (SCOP/PHLPP1β) as an essential intracellular signaling molecule mediating this temporal regulation downstream of the clock. Using viral-mediated, basolateral amygdala (BLA)-specific knockout of Scop, we demonstrate that deletion of SCOP in the BLA exerts anxiolytic effects on the elevated plus maze at early subjective night, thereby blunting the circadian variation in the anxiety-like behavior. We conclude that the circadian expression of SCOP in the BLA plays a key role in generating circadian rhythmicity in the anxiety-like behavior. Our results demonstrate SCOP as a regulator of anxiety-like behaviors and reveal its key roles in the anxiogenic functions of the BLA.
Highlights
Recent evidence points to a mechanism by which dysfunctions in the circadian clockwork lead to abnormal emotionality through aberrant dopaminergic activity in the ventral tegmental area (VTA), a major dopaminergic nucleus[12,13]
Our results demonstrate that the anxiogenic function of SCOP in the basolateral amygdala (BLA) drives circadian rhythms in elevated plus maze (EPM)-anxiety-like behavior in mice
We show that the clock machinery and SCOP in the dorsal telencephalon (dTel) are required for the circadian expression of anxiety-like behaviors in both the EPM and open field (OF) tests (Figs 2 and 4)
Summary
Recent evidence points to a mechanism by which dysfunctions in the circadian clockwork lead to abnormal emotionality through aberrant dopaminergic activity in the ventral tegmental area (VTA), a major dopaminergic nucleus[12,13]. Despite the established roles of dopamine and other monoamine systems in anxiety regulation, their causality in mood/anxiety disorders and sufficiency in the regulation of emotionality per se have been questioned[14,15,16,17] While these studies provide important insights into affective abnormalities arising from clock dysfunction, much remains unknown as to how the circadian clock maintains emotionality-related behaviors at physiological levels. In humans, both positive and negative affect are reported to display diurnal variation[18], whereas excessive diurnal variations in mood states are a hallmark of major depressive and bipolar disorders[19], implicating the physiological importance of precise time-of-day-dependent regulation of emotionality. We describe SCOP-mediated time-of-day-dependent regulation of anxiety-like behaviors
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