Interactive function of classical neurotransmitters and neuropeptides

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Neurons do not function in isolation, but rather, as part of an interconnected network. They can do so by releasing neurotransmitters like GABA and glutamate to directly transmit information to the apposing neuron. Additionally, neurons also release neuropeptides in order to regulate neurotransmission. This latter process though critical to neuronal function, is complex and not well-defined. Neuropeptides co-express with neurotransmitters in the same neuron but they are released by different mechanisms and can travel longer distances to reach their target sites. This proposal uses neurons that produce melanin-concentrating hormone (MCH) to determine the interactive functions between neurotransmitters and neuropeptides. MCH is necessary for normal energy homeostasis, reward and social behaviors, and these actions are critical for survival and are conserved across species. Importantly, MCH neurons form an instrumental model for studying the network functions of a neuropeptide because they co-release the neurotransmitter glutamate and are found only in one region of the brain thus are easily isolated for investigation. We recently showed that MCH neurons send long range projections to the lateral septum where they release glutamate and functionally innervate cells in the lateral septum. Here we will determine if 1) MCH itself is also released in the lateral septum; 2) if MCH regulates glutamatergic transmission in the lateral septum; and 3) given the unprecedented role for glutamate in the function of MCH neurons, we will determine if MCH and glutamate have overlapping or independent behavioral roles.Our research program will use a transformative optogenetic technique to enable precise control of neuronal activity, which we can capture via electrophysiological recordings, even within small defined brain regions. Since neuropeptide release may require prolonged high frequency nerve stimulations, we can deliver timed light pulses to specifically activate MCH nerve fibers to evoke MCH release. In order to study the functions of co-expressed MCH and glutamate, we will generate a novel transgenic mouse model, in which we conditionally disrupt glutamatergic transmission by MCH neurons only, then compare it to mice lacking MCH but with an intact glutamate system. In aggregate, these studies will disentangle the roles of MCH and glutamate and provide a detailed, mechanistic understanding of the neuropeptidergic processes that may underlie reward or social behaviors. These findings are significant as they contribute towards a deeper understanding of peptidergic events underlying information processing.We are assembling a team of highly-motivated students who will receive directed hands-on training on cutting-edge techniques. Together we will be at the forefront of this technology and develop translational skills and tools to conduct innovative research.