Physiological relevance of synaptic compensatory plasticity in freely behaving animals

Project Description for Find-A-PhD Advert (max 400 words).

Alzheimer's disease (AD) is characterised by the loss of synapses, which strongly correlates with the onset of cognitive decline. Although much is known about the mechanisms underlying synaptic loss in AD, the neuroprotective mechanisms implemented by the brain to compensate for this loss remain unexplored. In order to model this aspect of AD, we have recently developed an optogenetic tool to artificially eliminate synapses both in-vitro and in-vivo to investigate synaptic loss, compensation and repair over time using two-photon (2P) microscopy.

Previous work in the lab has demonstrated that the elimination of dendritic spines - used as a proxy of excitatory synapses- leads to the compensatory enlargement of surviving synapses in the short-term (24 hours) and more remarkably, to the regeneration of spines in the long-term (>1 week), both in-vitro in organotypic slice culture and in-vivo in anaesthetised animals. To assess the physiological relevance of these findings, the aim of this PhD project is to determine the role of synaptic compensation in freely behaving animals.

To this end, we will combine two complementary state-of-the-art microscopy approaches: miniscope technology - small and lightweight (~2gr) microscopes that can will be reversibly clamped on the animal head without interfering with behaviour - and benchtop in-vivo two-photon microscopy. The cellular-resolution of the miniscope will be critical for identifying behaviourally relevant neurons during a freely moving behavioural task, whereas the sub-cellular resolution of two-photon microscopy will be essential for visualizing dendritic spine plasticity in the very same neurons.

In addition to imaging, we will use an optogenetic approach to artificially eliminate dendritic spines to promote the emergence of synaptic compensation and regeneration over time. More importantly, we will investigate the impact of these compensatory events in the function of behaviourally relevant neurons, and ultimately in the animal behaviour.

Together, the knowledge gained in this project will not only reveal the physiological relevance of these inherently protective synaptic compensatory events, but will also set the stage for exploring their molecular mechanisms; a first step toward the development of alternative therapeutics targeting synaptic compensation to counteract synaptic loss and cognitive decline in AD.

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