Project Summary Memory formation is a fundamental biological process that enables the brain to acquire and retain experiences and knowledge. Impaired learning and memory formation affect our cognitive capacity and cause various cognitive dysfunction-related disorders, including dementia, schizophrenia, and post-traumatic stress disorder (PTSD). It is known that a subset of memory-eligible “primed” neurons with elevated excitability is preferentially allocated to engage in associative memory formation. We recently found that hippocampal principal neurons exhibit three distinct activity states: the silent, the primed, and the engaged states, pertaining to associative learning and memory formation. Most hippocampal principal neurons stay in the relatively silent state; however, a subset of “primed neurons” switch from the primed state with irregular activity to the engaged state with activity synchronization to engage in associative learning or memory retrieval. To date, little is known how a “silent - primed” neural activity hierarchy is established in the hippocampus. The N-methyl-D-aspartate (NMDA) receptors are among the most important drug targets and ionotropic receptors that mediate the excitatory neurotransmission in the central nervous system. Blockade or hypofunction of NMDA receptors are associated with dissociation and schizophrenia. Due to voltage-dependent magnesium blockade and calcium permeability, NMDA receptors are best known to mediate multiple forms of synaptic plasticity. However, NMDA receptors also mediate the voltage-dependent non-linear ionic conductance in the post-synapses, contributing to synaptic transmission different from AMPA receptors. Our neural network simulation demonstrated that the non-linear NMDA receptor-mediated conductance controls the development of neural activity hierarchy, in which a subset of neurons become more active than others. Leveraging in vivo calcium imaging data collected from mice performing trace fear conditioning tasks, we have developed a unique method to quantify real-time neural activity hierarchy in the hippocampus. The objective of this research is to identify key factors that gate neural activity hierarchy in the hippocampus. Our central hypothesis is that NMDA receptors control the development of neural activity hierarchy initially through the non-linear ionic conductance, which is subsequently consolidated by the late-phase long-term potentiation. This work will examine the roles of NMDA receptors in hippocampal neuronal priming and assess the relevance of NMDA receptor blockade to disruption of neural activity hierarchy, which may partially account for dissociation and psychosis. This Academic Research Enhancement Award (AREA)- sponsored research will enhance our understanding of associative learning and schizophrenia and enrich the environment of neuroscience research at the University of New Hampshire (UNH), as well as provide valuable opportunities to at least five undergraduates to participate in meritorious lab research and numerical analysis.

Narrative We propose that hippocampal principal neurons exhibit three distinct activity-states pertaining to associative learning and hippocampal memory formation (the silent, the primed, and the engaged states). We will examine if NMDA receptors control the development of neural activity hierarchy in the hippocampus. This research will advance our fundamental understanding of associative learning and shed light on the pathophysiology of schizophrenia, while simultaneously providing valuable research opportunities to undergraduates.