Stress-related disturbances in sleep, in particular in rapid eye movement (REM) sleep, have been linked to the processing of stress-related emotion in ways that have implications for the development of psychopathology. In turn, sleep disturbances are associated with virtually all psychiatric disorders. Several lines of research indicate that the amygdala, a brain region critical for fear memory, can regulate the effects of stress and stressful memories on REM sleep and that it is neuroanatomically situated to influence various brainstem regions involved in the regulation and generation of REM sleep. However, even though the potential neural substrate by which the amygdala can regulate the generation of REM sleep has been identified, its actual influence on these brainstem regions and the mechanisms by which the amygdala regulates REM sleep are poorly understood. We propose to begin determining the neural circuits and mechanisms by which the amygdala regulates REM sleep. We will focus on one brainstem region, the locus coeruleus (LC), and its regulation by the central nucleus of the amygdala (CNA), the origin of the amygdala's descending projections to the brain stem. We chose the LC for these studies because is strongly implicated in the regulation of REM sleep as well as the stress response and because both it and the amygdala have been implicated in the role that REM sleep may play in processing emotional experiences.
In Aim 1 of this project, we will use cutting-edge optogenetic methods to specifically target and manipulate CNA projections to the LC and to determine the effects of activating and inhibiting these projections on LC activity and their potential effect on sleep and arousal. We will also use sophisticated techniques to determine the role that GABA may play in mediating the effects of CNA on LC activity.
In Aim 2, we will use optogenetic methods to target and manipulate CNA inputs into LC in conjunction with our well-established conditioned fear paradigm to determine whether CNA regulation of LC is a significant regulator of stress-induced reductions in REM. Our guiding hypothesis for this work is that inhibitory regulation of LC by CNA plays a functional role in regulating both normal REM sleep and stress- induced alterations in REM sleep. Our proposed studies will provide insight into how amygdala regulates LC and REM sleep and will improve our understanding of the neurobiological substrate underlying sleep pathology associated with emotional stress. This understanding will be critical for developing informed therapies for treating emotional disorders associated with disturbed sleep.
Stress-related disturbances in rapid eye movement (REM) sleep have been linked to the processing of stress- related emotion in ways that have implications for the development of psychopathology. We will assess critical components of the neurobiological substrate by which stress comes to alter REM sleep at both mechanistic and functional levels. Our proposed studies will improve our understanding of the neurobiological substrate underlying sleep pathology associated with emotional stress and provide information crucial for developing informed therapies for treating emotional disorders associated with disturbed sleep.
