Hippocampus-Accumbens Circuit in Aging: unraveling APP physiology – HACAP

Aging is associated with cognitive decline and constitutes a main risk factor for Alzheimer’s disease (AD). Clinical diagnosis of dementia show co-occurrence of hippocampal mnesic deficits with marked alterations in emotional and motivational states. Altered hippocampal-output networks impacting non-cognitive functions may underpin this comorbidity. The nucleus accumbens (NAc) is a key limbic-motor node that seems well placed to integrate hippocampal information about reward-predicting environments. Recently, a direct functional connection linking the dorsal hippocampus to the NAc has been described. We now propose to investigate if this neuronal network is modified by aging.
The amyloid precursor protein (APP) is highly expressed in the hippocampus. Human genetic evidence indicates that this protein is central to the pathogenesis of AD. Yet, how age modifies APP processing and expression remains poorly characterized. Over the last years, I contributed to elucidate the physiopathological roles of APP and its cleavage products at the hippocampus. In particular, I focused on the APP intracellular domain (AICD), as within it there are sequence motifs of functional relevance. Preliminary data shows APP processing changes with aging, leading to increased AICD/APP ratio in the aged hippocampus. Thus, we will address the causality between these hippocampal molecular modifications and disrupted salient outcomes.
This project relies on the use of age-based models and will be tackled in three aims by using state-of-the-art optogenetic, electrophysiological and molecular techniques. The first two aims will answer the hypothesis that changes of activity of hippocampal neurons, due to aging or to hippocampal APP or AICD altered levels, can significantly modify NAc activity, thus contributing to abnormal salient outcomes. In the third aim we will test whether brain stimulation at gamma-frequency is a suitable strategy to rescue Hippocampus-NAc mal-adaptative behaviours.