More than 35 million Americans are subject to hospitalization and bedrest each year. Cardiovascular deconditioning (CVD) due to bedrest or microgravity impairs cardiovascular regulation. CVD in humans and an animal model, hindlimb unloaded (HU) rats, produces autonomic impairments, including enhanced chemoreflex function, that correlate with poor prognosis in disease. The nucleus tractus solitarii (nTS) coordinates basal and reflex cardiorespiratory function via neurotransmitters/neuromodulators acting through a network of synapses which include both neurons and astrocytes (the “tripartite synapse”). We propose that increased excitability within the nTS tripartite synapse contributes to augmented chemoreflex responses in CVD. The goal of this proposal is to determine the cellular, molecular and integrative mechanisms, including the role of the tripartite synapse, by which the nTS influences cardiorespiratory regulation in CVD. We hypothesize that nTS astrocytes tonically restrain excitation of nTS neurons, and CVD attenuates this restraint or reverses it to enhancement. The resulting increased nTS synaptic and/or neuronal activity augments chemoreflex function. Aim 1 determines the extent to which CVD alters 1) reflex and nTS neuronal responses to arterial chemoreflex stimuli; 2) nTS synaptic and neuronal activity; 3) the balance of excitatory and inhibitory modulation of nTS chemoreflex, neuronal and synaptic signaling. Aim 2 determines the magnitude by which cardiovascular deconditioning modulates the integrative role of astrocytes in the nTS tripartite synapse to 1) enhance baseline ventilation, sympathetic and neuronal activity, and responses to chemoreflex activation, and 2) neuronal and synaptic function. Aim 3 determines the extent to which CVD alters the contribution of nTS astrocyte transport mechanisms to 1) baseline and enhanced cardiorespiratory and neuronal responses to chemoreflex stimulation, 2) synaptic and neuronal function, and 3) the influence of neurotransmitters. These studies utilize a comprehensive and integrated approach, including conscious and anesthetized whole animal studies to examine physiological mechanisms, the brainstem slice preparation to determine cellular mechanisms within the nTS tripartite synapse, and molecular approaches. Proposed studies will provide valuable novel information regarding the role of plasticity of the nTS tripartite synapse in normal cardiorespiratory function, and insight into mechanisms of dysfunction in CVD. Importantly, mechanisms of cardiorespiratory dysfunction in CVD also may apply to other disease states that exhibit altered autonomic and respiratory control.