Memories of our experiences guide our behavior and help us to shape our mind and personality – define who we are. Given this fundamental importance for healthy and diseased individuals, my group addresses the question: What defines the strength and longevity of our memories and what makes them vulnerable in the context of neurodegenerative diseases?

We are focussing on Alzheimer’s disease (AD), the most common form of dementia. AD is characterized by progressive memory loss attributable to neuropathological changes in brain regions like the hippocampus, the entorhinal and the prefrontal cortex. These brain regions are highly connected, structurally and functionally. They are known to fulfil crucial cognitive tasks, like spatial coding, learning, recognition and recall of declarative memories. This is giving rise to the hypothesis that these hubs are primarily vulnerable under AD-like conditions, causing a majority of AD-related cognitive deficits. To address this hypothesis, we are exploring the structural and functional connectivity of the prefrontal cortex, the hippocampus and entorhinal cortex and investigating their role in spatial working memory deficits observed in mouse models with AD-like pathology.

Another brain region that is even earlier and more severely affected during AD progression is the small brainstem nucleus locus coeruleus. This region is a neuromodulatory system that exhibits an anatomically unique role, sending extensive catecholaminergic (noradrenergic and dopaminergic) projections throughout the brain, including the hippocampus. It is involved in facilitating higher cognitive processes like decision making, novelty detection, memory formation and retrieval by influencing cellular excitability and the plasticity of neuronal connections. However, very little is known about the functional consequences of early neuropathological changes in the locus coeruleus during AD. Therefore, we are deciphering the role of locus coeruleus for hippocampus-dependent mnemonic processes and investigate its impairments in the context of AD-associated memory decline.

To address these questions we are applying cutting-edge microscopy techniques, combined with neuronal manipulation tools (opto- and chemogenetics) and behavioral readouts in transgenic mouse models. This allows the longitudinal monitoring and interrogation of neuronal activity in relation to mnemonic processes. Moreover, this approach will help us to reveal the functional importance of neuronal circuits and decipher their deficits in the context of AD.