Deciphering the role of locus coeruleus for hippocampus-dependent learning and its impairment in a mouse model of Alzheimer's disease

Abstract

The locus coeruleus (LC) is a key neuromodulatory nucleus and the brain's main source of norepinephrine. It is involved in a wide range of functions, notably, memory processing. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by memory loss. It is the most common cause of dementia and presents a major burden for patients worldwide. The biological mechanisms underlying AD are still not fully understood and currently no cure exists. Importantly, the LC is among the earliest brain regions to exhibit pathological changes associated with AD in the form of tau accumulation and neuron loss. It is therefore crucial to investigate how LC function contributes to memory formation and how these processes are altered in AD. Our project examines the structural integrity of LC-hippocampus connectivity and the contribution of LC activity to memory recall in a transgenic mouse model of AD (APP/PS1). Using histology and confocal imaging, we assessed multiple indicators of neuronal integrity, such as LC neuron number and the presence of Aβ-pathology in the LC and hippocampus. Our findings show that, although the LC appears structurally preserved in this model, its axonal projections in the hippocampal CA1 region show a reduced density compared to WT mice. We then investigated how enhanced LC activity influences memory recall. We optimized stereotactic viral delivery methods to achieve specific targeting of LC neurons and evaluated the efficiency of two common approaches for neuronal manipulation, chemogenetics and optogenetics. Lastly, we conducted behavioral tests to probe recognition and associative memory in APP/PS1 mice. We found that chemogenetic activation of LC neurons improved short-term object recognition memory in wildtype mice. In a fear conditioning paradigm, APP/PS1 mice showed a higher level of contextual fear memory recall following LC stimulation compared to non-stimulated controls. These experiments also revealed a pronounced effect of chemogenetic LC activation on general mobility of the mice. This factor may confound interpretations of behavioral data and warrants further investigation. Additionally, our results point to a sex-specific difference in the fear conditioning test upon LC neuronal stimulation in this AD mouse model. Overall, our experiments characterize the morphology of LC-hippocampal connectivity in APP/PS1 mice and evaluate the impact of chemogenetic LC activation on memory performance. We identify a reduction in the density of LC axons in the CA1 region of APP/PS1 mice. We further show that chemogenetic LC activation affects the performance in memory tests as well as the mobility state of mice. Based on these findings, we propose a more refined experimental framework to examine the contribution of LC activity to memory mechanisms under AD-like conditions. Our project is thus part of an effort to develop methods that could target and alleviate cognitive deficits at an early stage of AD.