Symposium
Session Room: Alsh
Session Room: Alsh
Monday, June 29, 12:15 PM – 01:30 PM
Symposium 26:
Corticolimbic modulation of fear and extinction: clinical implications for treating trauma and anxiety disorders
Corticolimbic modulation of fear and extinction: clinical implications for treating trauma and anxiety disorders
Extinction refers to the process through which conditioned fear responses are reduced over time through repeated exposure to fear-inducing stimuli without negative consequences. Understanding the mechanisms underlying memory extinction is crucial for identifying molecules and genes that could serve as therapeutic targets for fear-related disorders such as post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). This symposium will showcase the latest research aimed at elucidating novel extinction-related neural mechanisms. Gregory Quirk will discuss how anxiety disorders are characterized by persistent avoidance of perceived threats. This maladaptive behavior reinforces fear responses and prevents the natural extinction of fear memories, thereby prolonging stress and contributing to the chronic nature of these disorders. Using a combination of pharmacological interventions, neural recordings, and optogenetic tools, we demonstrate that the prelimbic (PL) region of the medial prefrontal cortex (aka dorsal mPFC) is crucial to suppressing avoidance behavior during extinction learning. The PL integrates contextual and emotional information from hippocampus and orbitofrontal cortex, and modulates behavioral responses by projecting to ventral striatum, a region involved in action selection and motivation. These findings identify a key neural pathway that could be targeted to reduce pathological avoidance in anxiety-related conditions. Next, Satoshi Kida will compare molecular and cellular signatures of contextual fear extinction and reconsolidation. Analysis of global transcription of hippocampus shows that while reconsolidation induces activation of transcription through the activation of transcription factor CREB in the hippocampus, extinction learning shut down this transcription activation through trimethylation of Histone 3 at K9 (H3K9-3me). Furthermore, low frequency stimulation that induces long-term depression on memory engram neurons induces extinction-like behaviors, increases levels of H3K9-3me (marker of extinction) and blocks increases in levels of phosphorylated CREB at S133 (marker of reconsolidation). These observations suggest transcription inactivation in hippocampus plays a critical role in initiating memory extinction and extinction learning. Lastly, Andrew Holmes will present new finding related to multiple brain systems which have evolved to detect, learn about, respond, and extinguish responding to threats. These systems collectively enable animals to rapidly adapt their behavior in response to threatening stimuli. However, the degree to which these neural circuits operate redundantly, complementarily, or competitively remains poorly understood. Understanding these interactions is critical, as the expression of defensive behaviors must be finely tuned—responses that are too weak or easily extinguished may lead to harm, while overly strong reactions can be maladaptive and contribute to anxiety disorders. Among these systems, the amygdala plays a central role in threat processing, but while the canonical model of fear memory formation and extinction implicates the lateral and basolateral nuclei of the amygdala at its center, this presentation will show evidence that this fear and extinction circuit is just one part of a broader network that regulates complex threat responses across the brain. Together these three presentations will highlight how discovering the molecular pathways that facilitate this process has the potential to significantly enhance the effectiveness of exposure therapy—a widely used treatment for PTSD.
12:40 PM – 01:05 PM
25 min
25 min