Glycinergic inhibition in the ventral brainstem

Project Summary The autonomic nervous system (ANS) regulates multiple aspects of energy homeostasis including food intake, energy expenditure, lipid metabolism, and glucose homeostasis via modulation of peripheral organs' functions. Imbalance of the ANS, primarily increased activity of the sympathetic nervous system, is recognized as a

contributing factor to the pathogenesis of a variety of diseases, including obesity and type 2 diabetes mellitus (T2DM). Increased activity of pre-sympathetic neurons in the ventral brainstem leads to higher sympathetic nerve activity (SNA). Since neuronal excitability is largely determined by inhibitory and excitatory synaptic inputs,

reduced inhibition results in increased activity of pre-sympathetic neurons. The overall goal of this proposal is to reveal inhibitory neural circuits involved in the sympathetic regulation of metabolically important organs that may allow the development of strategies to control energy homeostasis via central inhibitory pathways. It has been

generally assumed that inhibitory neurons release only one classical neurotransmitter (e.g., GABA or glycine); however, our preliminary data identified a novel inhibitory mechanism regulating pre-sympathetic neurons in the ventral brainstem. Our preliminary data demonstrate that glycine and GABA are co-released in the ventral

brainstem, and blockade of glycine receptors produces a prolonged increase of sympathetic nerve activity, which was associated with elevated systemic glucose levels. Moreover, glycinergic inhibition of ventral brainstem neurons was decreased in high-fat diet fed mice These data led to the central hypothesis that the inhibition of

pre-sympathetic neurons in the ventral brainstem is determined by co-release of glycine and GABA, and glycinergic inhibition is reduced in obesity. The proposed studies will map inhibitory circuits controlling sympathetic output to the liver and adrenal gland. The electrophysiological studies, in combination with

optogenetics, will define the mechanisms of inhibition of liver- and adrenal gland-related neurons, whereas the in vivo studies will determine the significance of glycinergic inhibition in the regulation of SNA and energy homeostasis in control and high-fat diet fed mice. Completing the proposed studies will advance our knowledge

of inhibitory circuits involved in the regulation of the sympathetic nervous system and may provide new strategies for proper maintenance of energy homeostasis via central mechanisms.