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

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 involved in spatial memory which exhibits notable dysfunction early in AD. 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 including the prefrontal cortex (PFC), 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 through regulation of endothelial cells and control of cerebral blood flow. The Gan lab has 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.

The aim of this project is to test whether disrupted cross-region functional connectivity between the hippocampus and the 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 loss. 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.