Sunday, May 18, 2025
5/18/2025
Locus coeruleus regulation of hippocampal network reset during learning - Project Summary Attention and memory systems closely interact to ensure we encode the things that matter. A growing body of research implicates noradrenergic signaling from the locus coeruleus (LC) to the hippocampus in organizing episodic memories around moments of transition, when arousal is heightened and the focus of attention shifts. These transitions often occur when memory-guided predictions deviate from reality, either due to changes in the external environment, or when mental models fail to capture the key elements of an experience that should guide behavior. Across the brain, norepinephrine (NE) is thought to assist in cognitive flexibility by resetting which neural networks are active before and after a prediction error. It is unknown whether hippocampal output networks can drive NE release. Moreover, how NE contributes to neural coding in hippocampal networks at the time of learning is also poorly understood. Our central thesis is that the hippocampal output region CA1 controls NE release from the LC to facilitate behavioral flexibility through hippocampal network reset. This working model will be tested in three Specific Aims (SAs) that employ electrophysiology, fluorescent imaging of NE binding, and optogenetics in the awake behaving mouse. In SA1, we will examine LC control of hippocampal reset, or remapping, in the context of unexpected changes in external stimuli. In SA2, we will study whether CA1 network reset facilitates spontaneous shifts in behavioral strategy. SA3 will directly test whether hippocampal output networks drive NE release during reset. We hypothesize that, in each case, LC activity promotes remapping dynamics at the time of potential network reset. This proposal will test whether a common, NE-mediated process may segment episodic memory around transition points driven by unexpected changes in external stimuli (SA1), internally-driven changes in which policy drives behavior (SA2), or by a surprise signal directly generated in CA1 (SA3). The goal of this proposal is to establish a causal role of the hippocampal-LC loop in fostering behavioral flexibility by facilitating transitions between the hippocampal representations of remembered, or to-be- remembered, experiences. Psychiatric symptoms across a broad range of disorders have been linked to parallel deficits in memory formation and attentional control. The foundational understanding expected from our planned studies will ground conceptual and computational models of how cognitive problems arise due to maladaptive interactions between the systems that control attention and those that are involved in making long-term memories.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).