Jose Rodriguez-Romaguera, Ph.D. - US grants

DESCRIPTION (provided by applicant):Deep brain stimulation (DBS) of the ventral capsule/ventral striatum in humans reduces symptoms of intractable obsessive-compulsive disorder (OCD); however the mechanisms of action are unknown. In most OCD patients, obsessive behaviors include repetitive avoidance behaviors to perceived threats, suggesting a deficit in circuits that regulate fear extinction. Models of fear extinction can shed light on the mechanisms of DBS. Using a model of fear extinction, we recently reported that DBS of a specific zone in the ventral striatum facilitated fear extinction and induced plasticity in cortico-amygdalar circuits. Using anatomical tract-tracing techniques, we found that descending cortical fibers from the medial portion of the orbitofrontal cortex (mOFC) may play a key role in the DBS mediated enhancement of extinction. Furthermore, our previous findings showed that DBS at this specific striatal site induced plasticity (pERK) in the lateral portion of the orbitofrontal cortex (lOFC). This grant will study the role of both mOFC and lOFC in fear extinction and in mediating the deep brain stimulation (DBS) effects of extinction memory. In Aim 1, we will investigate the role of OFC subregions in fear extinction using pharmacological inactivation tools. In Aim 2, we will use optogenetic techniques to selectively activate mOFC fibers in the ventral striatum with DBS frequencies and assess fear extinction and plasticity in cortico-amygdalar circuits.

PROJECT SUMMARY | 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.