Demetrio Sierra-Mercado - US grants

DESCRIPTION (provided by applicant): When emotions such as fear and anxiety are unregulated, several behaviors develop that are detrimental to mental and physical health. Such debilitating features are characteristic of anxiety disorders like post-traumatic stress disorder (PTSD). Biological markers of emotional regulation can be understood in an animal model involving Pavlovian fear conditioning and extinction. Fear extinction occurs when a tone that had been presented with an aversive stimulus is repeatedly presented in the absence of the stimulus. In humans, failure to extinguish fear responses is thought to contribute to PTSD and other anxiety disorders. Extinction, as a learning process, requires three phases: acquisition, consolidation, and retrieval. Recent evidence from rodent studies implicates the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in extinction. It is unclear, however, when and how these structures interact during extinction. In Aim 1, we will determine in which phases of extinction training mPFC and BLA is necessary. This will be achieved by: 1) reversible inactivation of mPFC during different phases of extinction training;2) reversible inactivation of BLA during different phases of extinction training. Once the critical phase of BLA-mPFC interaction is determined, Aim 2 will assess the contribution of BLA to tone-evoked and spontaneous neuronal activity in IL during extinction. This will be achieved by reversible inactivation of BLA while simultaneously recording neuronal activity in mPFC during extinction. Understanding the interaction of structures necessary for fear extinction could elucidate the mechanisms of emotional regulation. Deficiencies in these mechanisms may be the underlying factors in PTSD and other anxiety disorders. PUBLIC HEALTH RELEVANCE: In humans, the inability to extinguish fear responses is believed to be an underlying factor of anxiety disorders and post-traumatic stress disorder (PTSD). This research aims to understand how and when neural structures necessary for extinction interact. Deficiencies in the physiological mechanisms between the amygdala and prefrontal cortex could be rescued, thus reducing extinction failure. This could lead to novel treatments for extinction-based therapies for PTSD.

Project Summary / Abstract Traumatic brain injury (TBI) affects about 4 million civilians and soldiers each year, many of whom are diagnosed with mental health conditions like post-traumatic stress disorder (PTSD). There are common mechanisms that contribute to the neurobiology of TBI and PTSD, and both conditions can impair learning, neuroplasticity, and emotional regulation. Epidemiological studies of veterans show a strong correlation between sustaining TBI and developing PTSD. However, animal studies show conflicting results. To determine whether a relationship exists between TBI and PTSD, a biological link must be established using reliable brain injury models and behavioral tests. Clinically, there are two broad classes of TBI in which research models exist: focal (e.g. contusion), produced by controlled cortical impact (CCI), and diffuse (e.g. concussion), produced by weight drop onto the closed head. With CCI, injury level and extent of tissue deformation resemble physiological parameters related to contusion. In concussion, impact to the head plus angular acceleration produces neurological and cognitive dysfunction. Furthermore, repeat concussions as seen in sports and combat, result in axonal damage that disrupts communication and activity between brain regions, potentially impairing emotional regulation. A form of emotional regulation that may be modified by TBI is fear extinction, a type of learning that reduces fear expression. Extinction is the basis of exposure therapy for fear and anxiety disorders. In addition to impaired extinction, PTSD patients display excess avoidance, which reduces the attainment of goals and rewards. Notably, there are homologous brain regions in rodents and humans needed for extinction and avoidance. We will use CCI or repeat closed head injury (rCHI; model of repeat concussion) to test the hypotheses that TBI impairs fear extinction (causing high fear), and impairs the extinction of avoidance (causing excess avoidance). After TBI, we propose that dysfunction in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) will underlie impaired extinction, whereas dysfunction in the amygdala, mPFC, and ventral striatum will underlie excess avoidance. This work will increase the base of scientific and public health evidence about the effects of TBI to extinction and avoidance. Principal techniques in this project include neuronal tract tracing and immunohistochemical approaches that identify activity in brain areas. These protocols rely heavily on the instrumentation and expertise available in the COBRE Neuroimaging and Electrophysiology Facility. The microscopy equipment and image analysis support at the Molecular Sciences Research Center will provide essential tools for achieving the objectives of this project.