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.