Social fear is a learned behavior and can be adaptive, but heightened social fear is frequently a component of anxiety-related disorders such as social anxiety disorder (SAD) or post-traumatic stress disorder (PTSD). Fear responses, both learned and innate, are made up of a continuum of adaptive behaviors and these defensive responses become maladaptive in anxiety disorders. We have developed a novel conditioned social fear paradigm in rats in which a footshock unconditioned stimulus (US) is paired with a social stimulus (a novel same-sex conspecific) as the conditioning stimulus (CS). Then, we re-expose the experimental animal to the CS rat the next day in a different context and assess social and escape behaviors in an escapable social interaction test (ESIT) that we have developed. We have observed that a session of conditioned social fear using our procedure produces increased avoidance behavior in the ESIT as well as increased aggressive behavior. The overall objective of this AREA proposal is to determine the neural circuitry involved in the alterations in social behavior produced by conditioned social fear in male and female rats. We will focus on the medial prefrontal cortex (mPFC) to bed nucleus of the stria terminalis (BNST) neuronal pathway. The BNST has been implicated in fear and anxiety and receives substantial input from the mPFC (Wood et al., 2018). Two primary subregions of the mPFC, the prelimbic cortex (PL) and the infralimbic cortex (IL) both project to the BNST, which is increasingly appreciated as a regulator of fear and anxiety. We propose that learned social fear/anxiety depends on the mPFC ? BNST neurocircuit and that the PL and IL inputs are separately involved in the distinct phases of social fear learning and memory: acquisition and extinction. We will use a cre- dependent intersectional chemogenetic approach to systematically inhibit or activate PL or IL neurons that project to the BNST, and we will test for alterations in social behavior (largely ignored in studies of fear and anxiety) in the ESIT as our dependent measure. We will also measure neuroplasticity-related proteins in this neural pathway using immunohistochemistry. These experiments will be the first to explore the contribution of the mPFC ? BNST circuitry in learned social fear/anxiety. Understanding the neural pathways involved in these phenomena will be valuable in the treatment of anxiety disorders that include a social component, such as SAD and PTSD. We propose to achieve our objectives with 2 Specific Aims.
Aim 1 seeks to determine whether PL ? BNST neurons mediate acquisition of conditioned social fear.
Aim 2 seeks to determine whether IL ? BNST neurons mediate extinction of conditioned social fear.
This proposal explores the involvement of the medial prefrontal cortex to bed nucleus of the stria terminalis neurocircuit in a rat model of conditioned social fear. The results have the potential to increase our understanding of fear- and anxiety-related disorders and to improve pharmacological and behavioral interventions specific to social fear and anxiety.
