Functional role of dual neurotransmission in aggression

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ABSTRACT Dual neurotransmission has the potential to transform the way we consider neuronal signaling and the transmission of information within circuits and networks. The importance of dual transmission is evident by the large and increasing number of identified dual transmitting neurons in every system. However we still have only limited insight into the regulation and functional effects of co-transmission. During our previous funding period, we established: 1) the majority of octopamine (OA, the invertebrate analogue of norepinephrine), neurons co-express glutamate, 2) OA and glutamate have overlapping, as well as distinct, roles in reproductive and aggressive behaviors, and 3) manipulation of a glutamate-OA neuronal subset leads to high intensity aggression. Although aggression is a critical component of social behavior observed across species, when expressed at elevated levels aggression in humans can threaten lives and incur economic burdens on society. Given the importance of maintaining a critical balance of aggression and understanding the implications of dual transmission signaling in general, in this proposal we are identifying the molecular and physiological mechanisms that constrain aggression as well as dynamically regulate the release of co-transmitters. Leveraging our deep understanding of aggression- promoting neurons, genetic tools, and functional imaging, we will test our hypothesis in three specific aims. First, using fluorescent biosensors to visualize neurotransmitter release and Ca2+ imaging to quantify neuron activity, we will test the hypothesis that glutamatergic and adrenergic receptors expressed by glutamate-OA neurons are required for the regulation of co-transmission. Second, using epitope-tagged vesicular transporters and antibodies we will test the hypothesis that sexually dimorphic glutamate-OA neurons exhibit dynamic age-related changes in VGLUT levels. Finally, we will determine if VMAT-VGLUT terminal phenotypes are dependent on external cues from postsynaptic neurons. The significance of our study is that it addresses a fundamental neuroscience question, namely the molecular and potentially sexually dimorphic regulation of the dual transmission phenomenon, as well as potentially leading to the targeting of the glutamatergic system within glutamate-monoamine neurons as a therapeutic strategy for unchecked aggression.