del Angel, M. | bioRxiv Science

bioRxiv2023

Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.

neuroscience↗

bioRxiv2022

Fear engrams and NPYergic circuit in the dorsal dentate gyrus determine remote fear memory generalization.

Generalization is a critical feature of aversive memories and significantly contributes to post-traumatic stress disorder (PTSD) pathogenesis. While fear memories over time tend to generalize across differences in the contextual background and even to novel contextual settings, this effect can be counteracted by exposure to controlled reminder sessions even at remote time points. Using Pavlovian fear conditioning in mice, we show that generalization to a novel context of remote memory is associated with a loss of cellular engram activation in the dorsal dentate gyrus (dDG) and can be effectively counteracted by a preceding contextual reminder session. In addition to engram cells activation in response to a novel context, the reminder session also leads to a recovery of neuropeptide Y (NPY) function in the dDG and dDG-CA3 neurotransmission. In line with a proposed role of NPY as a resilience factor, we found that chronic viral knockdown of NPY in the dDG and blockage of its activity-dependent expression in NPYergic dDG interneurons with dominant-negative CREBS133A both increase remote memory generalization. With chemogenetic silencing of these interneurons, we could localize their critical involvement to a time window during and immediately following the fear memory acquisition. Together, these findings suggest that NPYergic interneurons of the dDG, shaping the memory engram during fear learning and early consolidation, determine fear generalization.

neuroscience↗