Project B1: Microvascular, neural network and synaptic remodeling in aged mice

Ageing is a natural process involving activation of Neurovascular Unit (NVU), accumulation of Extracellular Matrix (ECM) molecules, low-grade neuroinflammation, BBB damage, dysregulation of hemodynamics and paravascular clearance. These processes lead to synaptic and network dysfunction. We hypothesize that the balance between microvascular injury and repair cumulatively fail with ageing. In young mice, rapid repair of blood vessels and clearance takes place whereas in aged mice with low-grade inflammation, a BBB damage turns into long-lasting/chronic inflammation and the vascular damage promotes neuroinflammatory activation of microglia, astroglia and other cells and leads to synaptic and network changes through remodeling of perineuronal and perisynaptic ECM. The chronic inflammation results in elevation of cytokines, dysregulation in the expression of Matrix Metalloproteinases (MMPs)/ Tissue Inhibitors of Metalloproteinases (TIMPs) and complement factors, affecting synaptic transmission and functional and structural synaptic plasticity.

PhD project B1.1 – Ph.D. candidate Akilashree Senthilnathan

Here, we aim to study the vascular ageing-associated changes in microvascular resistance/recovery against physical stress and associated decline in synaptic functions and abnormalities in neural network hyperactivity. Futhermore, we aim to restore synaptic and cognitive function via targeted pharmacological treatments at the neurovascular unit in mice as shown in Figure 1. The project involves two-photon imaging of vasomotion, clearance, dendritic spines and neuronal activity and is complemented by multiplexed immunohistochemistry to identify early fingerprints of vascular, microglial, synaptic, and neuronal activity alterations following damage of blood vessels

Team B1: Alexander Dityatev (supervisor), Stepan Aleshin (postdoc), Akilashree Senthilnathan (Ph.D. candidate), Carla Cangalaya (postdoc)