cAMP signaling and three activity states of hippocampal neurons

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.

Grant Number: 2R15MH125305-02
NIH Institute/Center: NIH
Principal Investigator: Xuanmao Chen