Temporal organization is critical to many perceptual, cognitive, and behavioral functions. These temporal abilities are adversely impacted in several mental health disorders such as schizophrenia and attention-deficit hyperactivity disorder (ADHD). However, the neurobiological underpinnings of the temporal organization of memory and behavior remain poorly understood. Here, we will focus on specific circuits of the medial prefrontal cortex (mPFC). mPFC is positioned to influence sequence memory through extensive top-down inputs to regions heavily interconnected with the hippocampus (HC), notably the nucleus reuniens of the thalamus (RE) and perirhinal cortex (PER). We hypothesize that these different mPFC projection pathways, and their associated mPFC neuron populations differentially contribute to short- and long-term aspects of the retrieval of memory for sequences of events. We will use a sophisticated behavioral strategy testing sequence memory in rats with probes that differentially depend on working memory and temporal context memory using repeats (e.g., ABAD) and skips (e.g., ABDD) across three aims:
AIM1 tests the causal roles of mPFC projections using virally-delivered inhibitory designer receptors exclusively activated by designer drugs (DREADDs; AAV- hM4Di).
AIM2 examines the neural correlates (single-units, ensembles, and local field potentials) of mPFC and HC during memory for sequences of events. Additionally, we will use antidromic optogenetic stimulation (AAV- hChR2) to separate mPFC neurons based on their long-range projection targets innervating RE and PER.
AIM3 extends Ms. Jayachandran's training as a post-doctoral researcher by further investigating the vulnerability of these mPFC pathways in genetic rodent models related to mental health disorders such as schizophrenia and Alzheimer's disease. These experiments will establish foundational knowledge about two specific mPFC pathways critical to memory and behavior, which will aid the development of future therapeutic strategies. Completion of the F99 phase will set a strong technical and professional foundation for the postdoctoral (K00) phase of this award. Specifically, Ms. Jayachandran will gather the skills and techniques such as high-density electrophysiological recordings, optogenetics, and professional development (e.g., attending conferences) in order to transition to the postdoctoral phase and allow progress toward the long-term goal of becoming an independent investigator.
The focus of this research is on the neural mechanisms of the temporal organization of memory and behavior. This research is relevant to public health because it will increase knowledge about the role of medial prefrontal cortex in the temporal organization of memory, which is dysfunctional in numerous mental health disorders including, but not limited to, schizophrenia and attention-deficit hyperactivity disorder (ADHD). The proposal is relevant to NIH's mission in that it is an innovative research project to expand the knowledge base, will establish new research avenues for several mental health disorders, and will provide training in technical and professional skillsets to a graduate student from an underrepresented background to progress toward the goal of an independent research career.
