The septohippocampal circuit plays a crucial role in multiple cognitive Research Domain Criteria (RDoC) domains, including memory, attention, anxiety, and sensorimotor processing. This circuit is comprised primarily of the medial septal nucleus (MSN), hippocampus and medial prefrontal cortex (mPFC). Pharmacological and genetic models targeting glutamate N-methyl-D-aspartate (NMDA) receptor hypofunction within this circuit result in memory deficits, difficulty with attention, and social interaction impairments. Therefore, we are studying the relationship between MSN-mPFC- hippocampal oscillatory activity in NMDA receptor hypofunction models to better create treatments for disrupted theta and gamma oscillations which are altered in a variety of psychiatric disorders. Recent evidence suggests that deep brain stimulation (DBS) may be one such promising treatment modality for circuit disorders. This NIMH K08 Career Development Award will provide the necessary foundation for Darrin J. Lee, MD, PhD to pursue the development of novel DBS techniques for septohippocampal circuit disorders. The project and training plan are rooted in the electrophysiological and molecular underpinnings of NMDA receptor hypofunction, while concomitantly enabling the candidate to collaborate with and learn from his mentors and consultants. This program will enable him to supplement his current skillsets in areas where he has identified gaps in his knowledge base, including relevant research methodology, study design, machine learning, and structural connectivity. The proposed research will focus on 1) characterizing neural oscillations within the septohippocampal circuit in two complementary models of NMDA receptor hypofunction (pharmacological: chronic MK-801 administration and genetic: parvalbumin interneuron-selective NR1 knockout); 2) evaluating the cognitive effects of DBS in these rodent models, and 3) evaluating the relationship between electrophysiological biomarkers and behavior using machine learning. The interpretation of data from this research will improve understanding of specific electrophysiological aspects of impaired brain function in septohippocampal circuit disorders and serve as a catalyst for a research program centered on neuromodulation for these disorders. Moreover, data collected, skills procured, and collaborations developed will enable Dr. Lee to seek R01 funding and obtain career independence. Taken together, the data collected, and training developed will ultimately facilitate development of an investigator with unique skills in service of ameliorating suffering caused by septohippocampal circuit disorders.
Current treatments for psychiatric disorders with deficits in cognitive and emotional Research Domain Criteria (RDoC) domains have limited efficacy, necessitating more effective treatment strategies. Disorders with NMDA receptor hypofunction lead to septohippocampal circuit dysfunction and circuit-specific cognitive dysfunction. Deep brain stimulation (DBS) alters focal and diffuse networks and has recently been posited as a treatment for psychiatric disorders. This project aims to evaluate the the role of electrophysiological networks involved in NMDA receptor hypofunction and utilize DBS to improve cognitive behavior.
