UNRAVELLING HOW MCH NEURONS MODULATE HIPPOCAMPAL-DEPENDENT MEMORY SUBSTRATES AND SYNAPTIC REFINEMENT

Sleep supports memory consolidation by refining synaptic networks during rapid-eye movement (REM) sleep. Melanin-concentrating hormone (MCH)-producing neurons are highly active during REM sleep and project to the hippocampus, where they reduce synaptic strength and neuronal firing to promote synaptic homeostasis and associative memory consolidation. However, the underlying hippocampal synaptic changes remain unknown. In Alzheimer’s disease (AD), a disorder marked by sleep and memory impairments, MCH neurons show early structural abnormalities and REM sleep is reduced; yet, their contribution to cognitive decline is unclear. Therefore, we aim to characterise MCH-induced synaptic changes in CA1, a major hippocampal output region and one of the earliest areas affected in AD. To address this, we are employing viral tools to analyse spine morphology and the subcellular proteome of CA1 postsynaptic compartments across distinct sleep states and upon MCH neuron manipulations, integrating these approaches with detailed sleep scoring. We are now using PSD95-TurboID to define the proteomic profiles of the postsynaptic compartments across these conditions, and our preliminary data show robust colocalization of CA1 PSD95-TurboID with endogenous PSD95, confirming the efficiency of this method. Finally, in an AD mouse model, we will test whether chronic MCH neuron activation rescues CA1 synaptic proteome alterations, dendritic and sleep defects, and cognitive impairments using immunofluorescence, RNAscope, EEG/EMG recordings, and behavioural assays. We anticipate chronic MCH neuron activation to rescue CA1 synaptic profiles and attenuate sleep and memory deficits in AD.