Sleep disorders are a pervasive feature of a wide variety of neuropsychiatric conditions, and social stress is known to cause or exacerbate both sleep and neuropsychiatric disorders; however, it is not known how sleep is involved in regulating the limbic structures and circuits that control resilience to social stress. The long-term goal of this work is to determine the role of sleep in regulating maladaptive behavior. The overall objective of this application is to understand the mechanistic role of sleep in the limbic circuits that regulate resilience to social stress. These studies use a mouse model wherein sustained social avoidance occurs following social-defeat stress. Preliminary data from this model are the first to demonstrate that development of social avoidance can be predicted by differences in sleep regulation that exist before exposure to social stress. Furthermore, these data demonstrate that increased sleep occurring after social-defeat stress is associated with resilience to social avoidance. The central hypothesis of these studies is that increased sleep following social-defeat stress is a resilience response that protects against defeat-induced changes in the mPFC known to result in maladaptive behavior. In order to test this hypothesis the application pursues the following specific aims: 1) Determine if cortical differences in sleep amount, mPFC electrophysiology and sleep homeostasis underlie resilience to social defeat stress; 2) Determine if sleep plays a causal role in the development of defeat-induced social-avoidance; and 3) Determine if sex-differences in the homeostatic regulation of sleep underlie sex-differences in resilience. In the first aim, a detailed analysis will be performed on electroencephalographic recordings from the cortex and local field potential recordings from the mPFC recorded in mice identified as either resilient or susceptible to the effects of social-defeat stress. This will include an analysis of these signals in both the frequency and time domain along with the measurement of homeostatic responses to sleep deprivation. In the second aim, sleep will be prevented or promoted (using sleep deprivation or chemogenetics, respectively) at multiple time-points pre, post and during defeat. This will determine if sleep is sufficient and/or necessary for preventing the behavioral con- sequences of social-defeat stress.
This aim will also characterize the effect of sleep manipulations on molecular changes in the limbic system, namely ?FosB, associated with resilience and susceptibility.
The third aim will focus on developing a female model with which to study the role of sleep in resilience and will begin to conduct investigations with this model. The approach proposed in this application is innovative because it aims to char- acterize sleep in both resilient and susceptible populations of mice. The contributions of the proposed research will be significant because it is expected to yield a mechanistic model of the neural networks through which sleep regulates maladaptive behaviors; understanding the role of sleep in these neural pathways will have a major impact on the understanding, diagnosis and treatment of multiple neuropsychiatric disorders.
The proposed research is relevant to public health because the results are expected to yield a mechanistic model of the neuronal circuits through which sleep regulates resilience to social avoidance. Successful completion of these studies will allow investigations into the effect of sleep on stress-induced behavioral regulation that is not currently possible. An increased understanding of how sleep regulates the neural pathways responsible for social avoidance is likely to reveal novel targets, new therapies and new diagnostic criteria for neuropsychiatric disorders.
