Saturday, November 23, 2024
11/23/2024
Abstract Early signs of age-related cognitive decline are associated with deficits in novelty processing. Older individuals often mistake new events for familiar ones. This bias for familiarity is thought to cause memory interference, which occurs when established memories from everyday life interfere with newly acquired information. The brain dysfunctions promoting the reactivation of familiar memories and causing interference in aging remain unknown. Studies show that older adults with reduced familiarity bias exhibit enhanced cognitive abilities, emphasizing the need to investigate the neural circuits involved in familiarity and memory interference in aging. In older adults, reduced LEC activity is linked to difficulty distinguishing new from familiar objects, indicating insufficient activation by novelty-signaling inputs. The exact circuit changes that give rise to this dysfunction have not been identified. Our latest research suggests that dopamine neurons (DANs) that project to the LEC in mice deteriorate with age. Previously, we demonstrated that inhibiting DANs in young mice — thereby simulating the aging effect — leads to a bias towards familiarity. Based on these findings, we propose that aging-related decline in DAN functions predisposes the LEC to prioritize familiarity, enhancing memory interference. In this project, we seek to investigate how dysfunction in LEC-projecting DANs affects memory interference in old mice, using the latent inhibition paradigm. We will examine the role of LEC DA release in promoting familiarity processing in Aim 1 and assess DANs' effect on reactivating neuronal representations of familiar memories in the LEC in Aim 2. Experiments in Aim 1 will use fiber photometry and optogenetic manipulations to measure DA transients in the LEC during the transition from novelty to familiarity and establish a role of DA in memory interference. Aim 2 will determine if reactivation of neuronal representations of familiar stimuli in the LEC during a recall phase is necessary to produce memory interference. We will use activity-dependent tagging strategies to label neuronal presentations in the LEC and examine their modulation by DANs. The project will determine the LEC microcircuits involved in proactive memory interference and will build the foundation for further inquiry into why older adults are biased towards familiarity, hindering novelty detection and learning in rapidly changing environments.
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