Wednesday, April 2, 2025
4/2/2025
Circuits and neurotransmitters involved in VTA glutamate neuron regulation of the consequences of stress - Project Summary / Abstract Social avoidance and exaggerated threat responding are transdiagnostic constructs related to stress-linked disorders such as anxiety and post-traumatic stress disorder. We have found that these behaviors are recapitulated in mice following exposure to uncontrollable, but not physically identical, controllable stress. Further, we have found that the newly identified group of neurons within the ventral tegmental area (VTA) that release the excitatory neurotransmitter glutamate mediate social avoidance and enhanced fear that result from uncontrollable stress. However, VTA glutamate neurons are diverse in their projection targets and are capable of releasing GABA or dopamine, in addition to glutamate, to distinct targets. We aim to determine which downstream pathways of VTA glutamate neurons are affected by and control the behavioral consequences of uncontrollable stress as well as identify the neurotransmitters within these pathways that control the outcomes produced by uncontrollable stress. In Aim 1 we will determine the responsivity of VTA glutamatergic axons in their two major projection targets, nucleus accumbens shell and lateral habenula, to inescapable or escapable stress treatment, as well as during the outcomes produced by uncontrollable stress. Our preliminary data suggests that inescapable stress potentiates VTA glutamatergic axons in lateral habenula and accumbens shell following fear-inducing stimuli, but in different ways. We will also determine which downstream target of VTA glutamate neurons is responsible for the development and maintenance of the behavioral consequences of inescapable stress via select optogenetic photoinhibition of VTA glutamate axons. Preliminary data support a role of the VTA glutamate pathway to LHb in the development of both social and fear-related consequences of inescapable stress. Given that VTA glutamate neurons are capable of releasing glutamate, dopamine, or GABA, we will identify which neurotransmitters released by VTA glutamate neurons are required for the social and non-social consequences of inescapable stress. Additional studies will monitor how the loss of these neurotransmitters from VTA glutamate neurons affects habenula and accumbens stress-induced activity. Together the studies will identify at the intersection of cell-type, pathway, and neurotransmitter-specificity, how stressor experience alters social, fear, and anxiety-like behavior.
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