The long-term goal of this proposal is to establish successful independent laboratory focused on dissecting medial prefrontal cortex (mPFC) circuits underlying behaviors that become maladaptive in psychiatric disorders. mPFC plays a critical role in cognition, memory, and emotional behaviors which become maladaptive in diseases such as ADHD, dementia, and anxiety and trauma-related disorders. mPFC projects widely to cortical association areas, limbic centers, and midbrain and brainstem nuclei which are uniquely implicated in mPFC-dependent behaviors. How does mPFC coordinate its diverse projections to give rise to specific behaviors? Here I propose to use learned fear and fear extinction as entry points to elucidate classes of mPFC neurons that underlie behavior. Memories of fearful associations promote survival and can last a lifetime, but become extinguished when a stimulus no longer poser threat. Anxiety and trauma-related disorders have a lifetime prevalence of 28% and are characterized by maladaptive threat assessment that leads to inappropriate fear responses. The mPFC subregion PL is required for expression of learned fear at recent and remote time points, but, largely due to the lack of appropriate tools, the processes by which the remote trace forms in PL remains mysterious. Furthermore, it is unclear how behavioral extinction affects the memory trace in PL, and the classes of PL projections neurons underlying fearful behaviors remain unknown. The objective of this proposal is to determine 1) how the remote memory trace forms in PL, 2) which classes of PL projection neurons underlie remote memory retrieval, and 3) how extinction impacts the PL remote memory trace. The central hypothesis is that specific classes of mPFC neurons can be accessed based on their activity during behavior, and subsequently characterized based on their projection patterns and behavioral function. This hypothesis will be tested using cutting-edge neuroscience technologies in combination with TRAP2, a new mouse genetic tool for permanently accessing neurons that are transiently activated during a particular experience. Completion of the proposed studies will elucidate the behavioral function and projection patterns of PL neurons that contribute to remote memory retrieval, and determine how their function is influenced by extinction. These contributions are significant because they will reveal the functional circuit organization underlying mPFC-dependent fear behaviors that are relevant to psychiatric disorders. A team of world-renowned neuroscientists will oversee this research. Drs. Liqun Luo, Gregory Quirk, Vikaas Sohal, Marc Tessier-Lavigne, and Mark Schnitzer and will provide new training to link the organization of neural circuits to behavior and offer career advice. Together with a comprehensive training plan that includes additional coursework and numerous career development activities, completion of this proposal will provide the necessary skills for Dr. DeNardo to secure an independent faculty position at a top research institution.
The medial prefrontal cortex (mPFC) participates in many behaviors that become maladaptive in psychiatric disorders, including fear memory retrieval and extinction. mPFC projects broadly throughout the brain, but an intriguing possibility is that unique subclasses of projection neurons underlie distinct behaviors. To goal of this project is to elucidate the connectivity patterns and behavioral function of mPFC neurons that are activated during disease-relevant behaviors, which will build a foundational understanding of circuits to target for interventional therapies.
