Title: Real-time interrogation of neural circuit dynamics underpinning cognition and its collapse in dementia
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added from 2020. How neuronal interactions support cognition is a long-sought-after yet challenging question in neuroscience. A key prerequisite in understanding neuronal interactions supporting cognition is to dissect out its underlying neural circuit dynamics, a key level of computation between single cells and systems. The overall aim of this programme is to investigate real-time neurocircuit mechanisms underlying network oscillations, cognition, and decision-making in vivo at the level of single-cell and population dynamics in a living brain. With such knowledge, we seek to elaborate on what, where, when and how such dynamism goes wrong in disease conditions, e.g. dementia, in the hope of identifying potential targets or time windows for their prevention and treatment. We approach these questions by a combination of state-of-the-art methodologies in neuroscience, for instance in vivo patch-clamp recording, large-scale silicon probe recording, well-controlled quantitative behaviours in virtual reality and optogenetics. Objective 1. Elucidate intrinsic properties of specific neuronal types, basal synaptic transmission, and synaptic plasticity at major synapses in the hippocampus and prefrontal cortices (PFC) in wildtype and mouse models of dementias by establishing in vivo single-cell physiology assay platform. We will first perform whole-cell patch-clamp recording or Ca2+ imaging experiment under anaesthesia. Then, we will perform these experiments in fully awake conditions. Objective 2. Determine how neuronal circuits underlying hippocampal oscillations and cross-region oscillatory synchrony are impaired at levels of synaptic transmission and neural assembly in wildtype and mouse models of dementia in vivo. Under anaesthesia, we will perform e.g. multi-channel silicon probe recording and whole-cell patch-clamp recording. Then, we will perform these experiments in fully awake conditions when animals performing simple tasks. Objective 3. Test key elements of ‘neurogliaovascular unit’ in safeguarding homeostasis condition, particularly the neuro-glial interactions in wildtype mice and how a breakdown of these elements controls the trajectory of cognitive deterioration/neurodegeneration in mouse models of dementia in vivo. We will perform experiments under anaesthesia. We will make e.g. whole-cell patch-clamp recordings, silicon probe recording, and Ca2+ imaging. Objective 4 (long-term). Elucidate neural circuits mechanism underlying spatial coding in the hippocampus and simple decision-making process in the PFC at the levels of synaptic transmission and assembly dynamics in wildtype mice in vivo during behaviour, and then determine how these mechanisms are impaired in mouse models of dementia. We will make experiments when the animals are fully awake and performing cognitive tasks. We will record neural assembly dynamics using silicon probe recording or Ca2+ imaging. After achieving these, we will make whole-cell patch-clamp recordings from single neurons, which is technically more challenging but scientifically well sought after.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL