The Suprachiasmatic Nucleus Regulates Anxiety-Like Behavior in Mice.

Chelsea A Vadnie,Darius D Becker-Krail,Jennifer N Burns,Lauren M Depoy,Ryan W Logan,Mariah A Hildebrand,Lauren A Eberhardt,Kaitlyn A Petersen,Hui Zhang,Allison J Cerwensky,Colleen A Mcclung

doi:10.3389/fnins.2021.765850

Chelsea A Vadnie, Darius D Becker-Krail + Show 9 more

Open Access

https://doi.org/10.3389/fnins.2021.765850

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Abstract

Individuals suffering from mood and anxiety disorders often show significant disturbances in sleep and circadian rhythms. Animal studies indicate that circadian rhythm disruption can cause increased depressive- and anxiety-like behavior, but the underlying mechanisms are unclear. One potential mechanism to explain how circadian rhythms are contributing to mood and anxiety disorders is through dysregulation of the suprachiasmatic nucleus (SCN) of the hypothalamus, known as the “central pacemaker.” To investigate the role of the SCN in regulating depressive- and anxiety-like behavior in mice, we chronically manipulated the neural activity of the SCN using two optogenetic stimulation paradigms. As expected, chronic stimulation of the SCN late in the active phase (circadian time 21, CT21) resulted in a shortened period and dampened amplitude of homecage activity rhythms. We also repeatedly stimulated the SCN at unpredictable times during the active phase of mice when SCN firing rates are normally low. This resulted in dampened, fragmented, and unstable homecage activity rhythms. In both chronic SCN optogenetic stimulation paradigms, dampened homecage activity rhythms (decreased amplitude) were directly correlated with increased measures of anxiety-like behavior. In contrast, we only observed a correlation between behavioral despair and homecage activity amplitude in mice stimulated at CT21. Surprisingly, the change in period of homecage activity rhythms was not directly associated with anxiety- or depressive-like behavior. Finally, to determine if anxiety-like behavior is affected during a single SCN stimulation session, we acutely stimulated the SCN in the active phase (zeitgeber time 14-16, ZT14-16) during behavioral testing. Unexpectedly this also resulted in increased anxiety-like behavior. Taken together, these results indicate that SCN-mediated dampening of rhythms is directly correlated with increased anxiety-like behavior. This work is an important step in understanding how specific SCN neural activity disruptions affect depressive- and anxiety-related behavior.

Highlights

Circadian rhythms are physiological processes that oscillate with an approximate 24-h period
We did not carry out further behavioral testing on the mice in this experiment since there are differences in the genetic backgrounds of Vgat-Cre and Vgat-Cre;ChR2 mice which we found affected anxiety-like behaviors
To determine whether optogenetic stimulation of the suprachiasmatic nucleus (SCN) increases SCN neuronal activity, we quantified the number of c-Fos-positive cells in the SCN of Vgat-Cre;ChR2 mice 1 h after stimulation or sham stimulation at circadian time 21 (CT21) ended

Summary

Introduction

Circadian rhythms are physiological processes that oscillate with an approximate 24-h period These rhythms are frequently disrupted in psychiatric disorders, where they are typically dampened or shifted (Souetre et al, 1989; Emens et al, 2009; Hasler et al, 2010; Robillard et al, 2013). Treatments that directly affect circadian rhythms, including social rhythm therapy and bright light therapy, have therapeutic effects for some patients (Frank et al, 2005; Penders et al, 2016). These data suggest that circadian rhythm disruption plays a key role in depression and/or anxiety. The underlying mechanisms linking rhythm disruption to mood and anxiety disorders remain unclear

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