Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Rapid eye movement (REM) sleep is characterized by intense cortical activation, giving rise to its wake-like electroencephalogram (EEG). Disturbances in REM sleep are symptomatic of mood disorders including major depressive disorder (MDD), which is associated with dysfunction of the prefrontal cortex (PFC). However, to what extent altered cortical activity in mood disorders may directly cause changes in REM sleep remains largely unknown. Particularly, because REM sleep is thought to be primarily controlled by subcortical nuclei, the mechanisms by which the PFC may regulate REM sleep are unknown. A prominent biomarker for depression is an increase in phasic REM sleep, reflected in an increased density (frequency) of rapid eye movements during REM sleep. However, despite its clinical relevance, the mechanisms and brain structures underlying the regulation of phasic REM sleep are still largely unknown. Our preliminary results show that pyramidal neurons in the medial PFC (mPFC) promote REM sleep in mice through their projections to the lateral hypothalamus (LH). In addition, we found that activation of mPFC pyramidal neurons enhances the density of rapid eye movements during REM sleep. The central objective of this proposal is to identify the neural mechanisms by which the mPFC regulates the induction and maintenance of REM sleep and rapid eye movement density. This will be accomplished in two aims. First, we will combine in vivo calcium imaging, optogenetics, optrode recordings, and viral tracing to identify the activity, connectivity, and functional role in brain state regulation of the LH neurons innervated by the mPFC. Second, we will investigate the mechanisms by which the mPFC regulates rapid eye movements during REM sleep. We will combine pupillometry with optogenetic manipulation, in vivo calcium, and optrode recordings to examine whether the axonal projections from the mPFC to the pons induce rapid eye movements and test whether mPFC neurons and their postsynaptic pontine neurons are recruited during rapid eye movements. Unraveling the mechanisms by which the mPFC controls REM sleep and the rapid eye movement density is a critical precursor to resolving the causal relationship between changes in prefrontal circuits associated with depression and REM sleep disturbances. Our results have the potential to develop more refined biomarkers to infer from disturbances in the regulation of REM sleep and rapid eye movements information about the integrity of prefrontal circuits in health and disease.
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