The primary goal of this training proposal is to dissect the functional neurocircuitry of pericoerulear (peri-LC) GABA neurons in anxiety-like behaviors. By providing inhibitory input to noradrenergic neurons in the locus coeruleus (LC), this GABAergic population may act to limit the activity of LC neurons, thereby reducing the behavioral affects associated with LC activation, i.e. anxiety-like and stress behaviors.
The first aim of this training proposal seeks to determine how peri-LC GABA neurons tune LC activity and impact anxiety-like behaviors through cell-type specific optogenetic and chemogenetic manipulation and observation in transgenic mouse lines.
Aim 1 A uses fiber photometry to observe the endogenous activity of this circuit, while Aim 1B uses optogenetic activation and chemogenetic inhibition to determine the effects of peri-LC GABA neurons on behavior.
Aim 1 C combines optogenetic observation of the LC with activation of the peri-LC network to determine if the effects of peri-LC activation affect behavioral responses to stress in an LC-dependent manner.
Aim 2 of this proposal seeks to determine the anatomy, molecular identity, and network characteristics of this GABAergic population through use of single-cell RNA sequencing, in situ hybridization, and circuit-tracing. This will be the first study to use a series of high-resolution approaches to dissect the genetic characteristics, behavioral implications, and diversity of this pericoerulear population. This research training proposal will provide a basic understanding of how inputs onto a local inhibitory network can affect the activity of LC, thereby affecting arousal across the brain and affecting stress response and anxiety-like behaviors.
Anxiety disorders affect 19.1% of adults in a given year, and 31.1% of adults in their lifetime. Anxiety is in part driven by the locus coeruleus, a brainstem nucleus that is a primary source of norepinephrine across the brain. The goal of this proposal is to dissect and elucidate how local circuit mechanisms integrate input from diverse brain areas, exert control over the locus coeruleus, and ultimately affect anxiety behaviors, thereby identifying new circuits and potential therapeutic targets for anxiety disorders.
