Institut de Psychiatrie et Neurosciences Paris, IPNP
Cholinergic modulation of cortical inhibitory circuits and its dysfunction in psychiatric disorders
The neocortex is essential for all cognitive functions, facilitated by the complex interplay of neuronal networks formed through synaptic interactions among various neuron types. In this context, inhibitory interneurons play a critical role in coordinating cortical activity. These inhibitory circuits are regulated by a variety of neuromodulators, with acetylcholine standing out for its significant control over cortical dynamics. Cholinergic signalling is central to the modulation of neuronal circuits and underpins key cognitive functions such as attention, learning, memory, perception, and motivation.
Thus, it is not surprising that human genetic variants of acetylcholine receptors are strongly associated with psychiatric disorders like schizophrenia, as well as neurodegenerative diseases such as Alzheimer’s disease. Research has shown that both cortical inhibitory circuits and cholinergic signalling are disrupted in these conditions. However, the actual interplay between these systems remains unclear.
Our team employs a multiscale and integrative approach, combining genetics, two-photon calcium imaging in awake behaving mice, cognitive behavioural analysis, electrophysiology, and optogenetics to investigate: i) how cholinergic transmission influences specific cortical subnetworks in the context of psychiatric disorders, ii) the cellular, molecular, and synaptic mechanisms that govern the modulation of inhibitory circuits by cholinergic inputs in both health and disease and iii) the impact of human polymorphisms in acetylcholine receptor genes, which predispose individuals to psychiatric disorders, on inhibitory interneuron function.