Orexinergic neurons are potent mediators of circadian fluctuation in cognitive function. In the proposed project, we aim to explore the potential of orexinergic neuromodulation and the associated wakefulness promoting system to mobilise neural resources by stimulating prefrontal cortex (PFC)-to-hippocampus signalling and to build up resources through increasing neural plasticity in the hippocampus. We will impose circadian disturbances together with pharmacological and viral interventions to dissect the circuit mechanisms that underlie the circadian neuromodulation of memory formation, pattern recognition and cognitive flexibility. Engram labelling, slice physiology and molecular analysis will be utilised to determine the cellular mechanisms of resource formation within hippocampal microcircuits. Our project will closely connect with other CRC projects that target cellular and circuit mechanism of resource management and ultimately aims to investigate the potential of orexinergic modulation for the mobilisation of cognitive reserve beyond circadian modulation. Thus, the interactive approach within the CRC will provide fundamental insights into neuronal circuits and cellular mechanism that may be utilised to battle cognitive decline, e.g. during ageing.

Conceptual framework of the project:

Cognitive performance is controlled by orexinergic neuromodulation of prefrontal cortex (PFC)-to-hippocampus (HIP) pathways via their relay stations supramammillary nucleus (SUM) and nucleus reuniens (NRe), and of arousal systems (locus coerules, LC). Disturbances of circadian rhythm, genetic disruption of clock components and blockage of orexin receptors represent strains that impair cognitive performance by disturbing information flow in the proposed pathway as well as local microcircuit function in the hippocampus. We will explore whether stimulation of the orexinergic system and the interdependent pathways can be utilised to mobilise neural resources.

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