This proposal for a NIH Pathway to Independence Award (K99/ROO) focuses on elucidating neural substrates that may contribute to motor and autonomic symptoms of major depressive disorder (MDD). In addition to cognitive problems, depressed patients also suffer with physical symptoms, including fatigue and altered autonomic function. The etiology of these symptoms is unknown; thus, the proposed experiments will investigate neural circuits that regulate homeostatic and motor functions, which may be altered in MDD. Studies proposed under Specific Aim 1 will utilize a virally-mediated transsynaptic tract-tracing approach to characterize the neurochemical phenotype of neurons that send poly-synaptic projections to skeletal muscle and the adrenal gland. We previously demonstrated that such neurons are enriched in brain areas that mediate physiological responses to stress, and are thus prime candidates to mediate motor and autonomic symptoms of MDD. Studies proposed under Specific Aim 2 will examine potential alterations in the organization of emotional-somatomotor, limbic-autonomic and somatomotor-sympathetic circuits in different genetic and stress rat models of depression. Finally, experiments proposed under Specific Aim 3 will examine organization of caudal serotonergic cell groups in the MDD brain. Extensive evidence implicates abnormalities in serotonergic neurotransmission in the etiology of depression, thus we hypothesize that these cell groups, which send descending projections to the spinal cord and directly modulate somatomotor and autonomic functions, are involved in the etiology of physical symptoms of MDD. Together these studies will characterize neural mechanisms that may underlie autonomic and motor dysfunction in MDD, and will examine potential involvement of brain regions heretofore unrecognized in the pathophysiology of this disease. This work will advance our knowledge of the etiology of MDD, and may ultimately provide novel targets for pharmacological intervention and improved treatment strategies for this debilitating illness. The research and educational components of this K99/ROO application aim to provide necessary training for the applicant to become a successful independent investigator who can integrate molecular, neuroanatomical, physiological, and behavioral findings from animal studies, and effectively translate these results to human studies to improve our understanding of the pathophysiology of psychiatric disease.