Could disrupted functional connectivity between the hippocampus and the prefrontal cortex be an early marker of vascular cognitive impairment in dementia?

Supervisor(s): Dr Jian Gan, Dr Axel Montagne, Prof Simon Hanslmayr [University of Glasgow]

Background

The healthy blood-brain barrier (BBB) maintains selective permeability and controls cerebral blood flow to ensure efficient energy supply, prompt waste removal, and balance chemical composition in the interstitial fluid. By doing so, BBB maintains a homeostatic micro-environment in the brain which is essential for neuronal signalling and normal cognitive functions. BBB dysfunction is among the earliest changes in Alzheimer’s disease and vascular dementia. Recent human evidence shows an age-dependent BBB breakdown in the hippocampus, a region critically important in spatial memory and selectively affected early in AD¹. Furthermore, white matter deficit due to BBB breakdown is a key diagnostic indicator of vascular dementia. Encoding a spatial memory is hippocampus-dependent but its retrieval and consolidation require functional long-range connectivities across brain regions where intact white matter is necessary to ensure neural activities are coordinated in a temporally precise manner. A question arises as to what aspect of such long-range neural circuitry is affected by BBB breakdown, and how such alterations ultimately result in cognitive impairment. Pericytes innervate capillaries in the brain and are critical for maintaining BBB integrity. We have generated an inducible pericyte-deficient mouse line Atp13a5-CreER::iDTR mice, in which age and region-specific pericyte loss can be induced, causing BBB dysfunction and microvascular reductions in a spatiotemporally controlled manner.  Therefore, the Atp13a5-CreER::iDTR mouse line is a valuable model to test the effects of region-specific BBB leakage and microcirculation deficiency on neural circuits that are critical in spatial memory which is affected early in dementia.

Aims

The aim is to test whether disrupted cross-region functional connectivity between the hippocampus and the prefrontal cortex (PFC) can be a detectable early marker in response to gradual BBB leakage and microcirculation deficiency to predict later cognitive deficits. We will train young adult Atp13a5-CreER::iDTR mice (3- 6 months) and their littermate controls to perform a simple spatial task in a virtual reality environment and perform simultaneous high-density silicon probe recordings from the hippocampus and the PFC, before and after pericyte loss induction. Contrast MRI will be used to detect the severity of BBB leakage in vivo. This study will come with three work packages (WPs). WP1: Test whether theta oscillations in the hippocampus and theta-entrainment of neuronal firings in the PFC are altered in Atp13a5-CreER::iDTR mice upon pericyte loss. WP1 will enable us to test whether the ‘temporal encoding’ of spatial memory is altered with BBB breakdown. WP2: Test whether place cell properties in the hippocampus are altered in Atp13a5-CreER::iDTR mice upon pericyte loss.  WP2 will enable us to examine the cellular substrate of ‘spatial encoding’ in response to BBB breakdown. WP3: Test whether hippocampus-PFC synchrony and sharp-wave ripple (SWR) oscillation properties are altered in Atp13a5-CreER::iDTR mice upon pericyte loss². WP3 will allow us to examine cross-region information transfer and memory consolidation mechanisms. We will test oscillatory coherence and examine the ‘memory content’, as to how many hippocampal CA1 pyramidal cells are recruited during SWRs, and cross-brain region ‘memory transfer’, as to how many PFC cells are entrained in hippocampal SWRs.

Training Outcomes

The student will obtain extensive quantitative skills. This will include 1) programming skills involving Matlab and Python in controlling the virtual reality system and data acquisition and analysis; 2) signal processing ability to analyse electrophysiological data; 3) computational modelling to evaluate behavioural performance. The student will also gain in-depth knowledge of brain vasculature and neural circuits for memory and spatial navigation. Finally, the student will have the unique opportunity to combine computational skills required in neurophysiology with molecular techniques involving mouse genetics and cutting-edge neuroimaging strategies. Together, the skill set will empower the student to shape the future of early diagnosis of dementia with strong quantitative skills and neurological knowledge that can be implemented readily in a preclinical or clinical career.

References

1. Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296-302, doi:10.1016/j.neuron.2014.12.032 (2015).

2. Gan, J., Weng, S. M., Pernia-Andrade, A. J., Csicsvari, J. & Jonas, P. Phase-Locked Inhibition, but Not Excitation, Underlies Hippocampal Ripple Oscillations in Awake Mice In Vivo. Neuron 93, 308-314, doi:10.1016/j.neuron.2016.12.018 (2017).