PROJECT SUMMARY/ABSTRACT
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.