The long-term goal of the current project is to reveal the essential neural circuits underlying the shock-induced reinstatement of extinguished fear. Fear-related anxiety and trauma disorders (e.g., phobias, panic disorder, and post-traumatic stress disorder) are prevalent and pervasive; they represent a tremendous economic and social burden on our society. Regrettably, treatments for these illnesses are plagued by the relapse of extinguished fear: threatening and aversive events can reawaken fear responding after therapeutic interventions for pathological fear. Utilizing Pavlovian fear conditioning and extinction procedures in rats, this project will investigate the behavioral and brain mechanisms contributing to fear relapse after the exposure of rats to a dangerous (shock-associated) context (i.e., reinstatement). In particular, our lab has demonstrated a selective role for the bed nucleus of the stria terminalis (BNST) in mediating contextual fear and the reinstatement of extinguished fear after footshock. Others have revealed that BNST lesions also prevent stress responding (e.g., corticosterone release) when animals are in aversive contexts. However, no one has yet used modern tools to identify the precise circuits through which the BNST contributes to these effects. The BNST sends heavy projections to the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN). The CeA is essential for the expression of conditioned fear, whereas the PVN has an important role in mediating stress responses. We propose that the BNST modulates freezing and stress responses in a shock-associated context by acting on these structures; this pattern of activity may contribute to reinstatement. We will test our hypothesis in two primary aims.
In Aim 1, we will utilize retrograde (cholera toxin subuni B) neuronal tracing techniques combined with immunohistochemistry for markers of neural activity (c-Fos) to identify patterns of activity in CeA- and PVN-projecting cells of the BNST during aversive context exposure (Exp. 1). Additionally, we will use anterograde viral tracing methods (fluorescent recombinants of herpes simplex virus type 1, H129) combined with c-Fos detection to observe the degree of activity in CeA/PVN cells receiving BNST input during reinstatement (Exp. 2).
Aim 2 will ask whether inactivation of BNST:CeA or BNST:PVN circuits make dissociable contributions to context fear, in the form of freezing and stress responding (respectively; Exp. 3), and whether BNST:CeA circuits are the critical pathway by which BNST promotes reinstatement of fear (Exp. 4). Using adeno-associated viral (AAV) vectors for designer receptors exclusively activated by designer drugs (DREADDs), we will selectively silence BNST efferents to the CeA and PVN during exposure to a shock-associated context and during reinstatement of fear. Additionally, we will measure corticosterone release to observe whether inactivation of either of these pathways is capable of modulating stress levels during in a dangerous context. In turn, this project will provide valuable scientific and clinical insight on how fear-regulating systems interact with stress-active nuclei of the brain.
Relapse of fear is common to many forms of therapy for a variety of fear-related anxiety disorders (e.g., phobias, panic disorder, and post-traumatic stress disorder), yet the brain circuits that mediate and modulate the return of fear after aversive events are not well understood. Accordingly, this project seeks to isolate the functional role of fear-regulating brain circuits in the relapse of fear after dangerous (shock-associated) context exposure in rats, especially with regards to interactions of the bed nucleus of the stria terminali (BNST) with the amygdala and hypothalamus. BNST efferents may serve as important clinical targets in the future of pharmacological and therapeutic interventions during times of aversive experiences.
|Goode, Travis D; Maren, Stephen (2017) Role of the bed nucleus of the stria terminalis in aversive learning and memory. Learn Mem 24:480-491|
|Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen (2017) Extinction after fear memory reactivation fails to eliminate renewal in rats. Neurobiol Learn Mem 142:41-47|
|Giustino, Thomas F; Seemann, Jocelyn R; Acca, Gillian M et al. (2017) ?-Adrenoceptor Blockade in the Basolateral Amygdala, But Not the Medial Prefrontal Cortex, Rescues the Immediate Extinction Deficit. Neuropsychopharmacology 42:2537-2544|