Thursday, November 21, 2024
11/21/2024
Project Summary Memory formation is a fundamental process for the brain to acquire and retain information. Malfunction of memory formation and retrieval causes many cognitive dysfunction-related disorders including dementia, amnesia, post-traumatic stress disorder, and autism spectrum disorder. The general perception that neuronal activity switch between “on” or “off” mediate innate physiological functions and the prevailing “activation and reactivation” model for contextual fear memory may have influenced the common assumption that hippocampal principal neurons have two activity states: the silent and the active. However, we directly observed from in vivo imaging studies, conducted in combination with trace fear conditioning experiments, that hippocampal principal neurons exhibit three distinct activity states: the silent, the primed, and the engaged. The three states differ greatly in their activity levels, sensitivity to sensory stimuli, calcium entry, activity synchronization, and importantly, memory-engaging status. While most hippocampal CA1 principal neurons stay in the silent state, a small portion of highly active neurons (termed primed neurons) fulfill learning and mnemonic duties by transitioning back and forth between the primed and engaged states. Our long-term research goals are to evaluate the three-state model, identify key factors that regulate hippocampal activity homeostasis and state transitions, and determine how the state transition of hippocampal neurons correlates with memory formation, memory retrieval, or the priming of hippocampal neurons. The type 1 and type 8 adenylyl cyclases (AC1/8) are complementary calcium-stimulated adenylyl cyclases highly expressed in synapses. AC1/8 couple neuronal activity-dependent calcium entry with intracellular cAMP signaling, important for late-phase long-term potentiation and memory consolidation. The type 3 adenylyl cyclase (AC3) is predominantly expressed in neuronal primary cilia throughout the brain including the hippocampus. We will test the hypothesis that AC1/8 and AC3 are important modulators of the state transition of hippocampal neurons that regulate the transition by affecting synaptic plasticity and neuronal excitability, respectively. To this end, we will first determine how AC1/8- mediated synaptic plasticity modulates the state transition of hippocampal neurons toward the engaged state with synchronized activity. Second, we will determine the role of AC3 in neuronal primary cilia in regulating basal neuronal activity and affecting the priming of hippocampal neurons. Completion of this work will introduce a novel concept to hippocampal neurons and reveal the roles of cAMP at different locations in regulating the state transition of hippocampal neurons and memory formation. In addition, this AREA proposal will enrich the research environment at the University of New Hampshire (UNH), and benefit the participating undergraduate students, who otherwise would not have the opportunities to be exposed to such research.
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