An investigation of medial prefrontal cortex -hippocampal circuit function in a mouse model of familial Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by progressive atrophy in multiple brain regions, accompanied by a decline in memory and cognitive function. Early stages of AD show a disruption of synaptic connectivity, which is followed by a gradual loss of neurons. The deficits in synaptic connectivity that accompany AD manifest as specific impairments in inhibitory neurotransmission that can be observed both at the level of the single synapse and through a more widespread disruption of synchronous neuronal network activity.

Neuronal oscillations are waves of electrical activity, generated by the synchronous firing of large numbers of neurons, that are categorised by frequency band. Each oscillation band is associated with different behavioural states: e.g. gamma oscillations (30 - 80 Hz) are associated with working memory, while slow oscillations (<1 Hz) occur during sleep and are essential to memory consolidation. These oscillations are generated through the activity of inhibitory interneurons, and are known to be impaired in AD, both in human patients and animal models of dementia. While comprising only a minority of cortical neurons, inhibitory interneurons exert a powerful control over network rhythms. Inhibitory interneurons exist in numerous varieties, each with unique morphological and physiological specialisations that allow them to control specific aspects of neural circuit function.

The aim of this project is to study the circuit mechanisms through which slow oscillations are disrupted in AD with a view to identifying particular interneuron subtypes as therapeutic targets for improving function. This will be achieved using a electrophysiological methods in mouse models of dementia, e.g. those overexpressing amyloid-beta. The specific aims are:

1. Using in vitro models of slow oscillations, determine which neuron types display altered behaviour during network activity, through patch clamp recordings and post hoc morphological recovery in neocortex and thalamus.
2. Once candidate cell types have been identified in vitro, test whether the function of these neurons is disrupted in vivo. This will be carried out using a combination of in vivo large neuronal ensemble recordings with optogenetic or pharmacogenetic manipulations of neuronal activity using interneuron-specific transgenic Cre driver lines.
3. Slow oscillations are generated through reciprocal connections between the thalamus and the cortex. Neurodegeneration in the thalamus has been implicated in the pathophysiology of AD, so the final aim is to determine whether increasing the excitability of the thalamus can improve the synchrony and propagation of slow oscillations in vivo, using two photon calcium imaging.

This project combines advanced electrophysiological and imaging techniques with cutting-edge genetic manipulations of neuronal activity, presenting an exciting training opportunity for the student to become competent in these methods.