| Functional dynamics of BNST neurons during distinct anxiety states Elevated anxiety when exposed to otherwise mild anxiogenic stimuli is the hallmark of many anxiety disorders. This increase in anxiety is believed to be caused by dysfunction in neuronal circuits important for regulating negative valence. However, the precise neural circuits that orchestrate this basic emotional state remains unclear. This is in part due to a lack of experimental feasibility, as it has been difficult to control and monitor the activity of cell-type specific neurons in vivo. The bed nucleus of the stria terminalis (BNST) is highly implicated in both adaptive and pathological anxiety. Despite this, it remains unknown how specific cell populations contribute to different anxiety states. Thus, the objective of this project is to use contemporary tools to study the precise neurocircuitry that engages BNST for the control of anxiety states induced by distinct anxiogenic stimuli. Here, I propose to identify the function and natural dynamics of a unique population of BNST neurons that are characterized by the expression of the genetic marker prepronociceptin (PNOC). We have preliminary evidence showing that we can target these neurons and apply contemporary techniques to assess their precise function. The natural activity dynamics of these genetically identified neurons will be visualized during various anxiety states using deep-brain calcium imaging in freely behaving mice (Aim 1). Furthermore, the role of BNSTPNOC neurons will be evaluated by using both excitatory and inhibitory optogenetic tools during exposure to distinct anxiogenic stimuli (Aim 2). I hypothesize that BNSTPNOC neurons will be hyperactive to different anxiogenic stimuli and may represent a common neural substrate responsible for general and social anxiety disorders. Our current preliminary data suggest that BNSTPNOC neurons are a potential candidate to initiate anxiety states. Identifying the function and natural dynamics of BNSTPNOC neurons may aid in the development of potential targets for pharmacogenetic intervention in patients suffering from anxiety disorders.
The proposed research is relevant to public health because elucidating the neural circuits that contribute to anxious behaviors will increase our understanding of the etiology of many disorders characterized by elevated anxiety, including general and social anxiety disorders. Thus, the proposed research is relevant to NIMH's mission of developing fundamental knowledge that will contribute to the understanding of neural circuits that underlie anxious behaviors.
