Prof. dr. Huibert Mansvelder awarded with ERC grant

With his application entitled “Optical dissection of circuits underlying fast cholinergic signalling during cognitive behaviour” he was award with the highest scores. Enclosed is the executive summary of his grant. Mansvelder – being one of the program leaders of the Research Program Photonics and Life Cell Imaging of the Neuroscience Campus Amsterdam – was thrilled when the announcement came. Quote: “Together with the acceptance of our Science paper last week, this is probably the most important acknowledgement of our scientific work thus far. With this grant we can enforce more breakthrough science achievements in the near future. Needless to say this work is only possible through team effort and by using the most advanced techniques available today. With the optogenetics dissection methods recently implemented in our lab, we hope to further clarify the seminal role the cholinergic signalling in the brain plays during cognitive behavior.”

Summary from the ERC grant to Huibert Mansvelder:

Optical dissection of circuits underlying fast cholinergic signalling during cognitive behaviour

Our ability to think, to memorize and focus our thoughts depends on acetylcholine signaling in the brain. The loss of cholinergic signalling in for instance Alzheimer’s disease strongly compromises these cognitive abilities. The traditional view on the role of cholinergic input to the neocortex is that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. This view has been challenged by recent studies demonstrating that rapid phasic changes in ACh levels at the scale of seconds are correlated with focus of attention, suggesting that these signals may mediate defined cognitive operations. Despite a wealth of anatomical data on the organization of the cholinergic system, very little understanding exists on its functional organization. How the relatively sparse input of cholinergic transmission in the prefrontal cortex elicits such a profound and specific control over attention is unknown. The main objective of this proposal is to develop a causal understanding of how cellular mechanisms of fast acetylcholine signalling are orchestrated during cognitive behaviour.

Cognitive behaviour depends on coordinated activity of pyramidal neurons and interneurons in the cortex. Acetylcholine critically shapes this activity. In a series of studies, I have identified several synaptic and cellular mechanisms by which the cholinergic system can alter neuronal circuitry function, both in cortical and subcortical areas. I have used a combination of behavioral, physiological and genetic methods in which I manipulated cholinergic receptor functionality in prefrontal cortex in a subunit specific manner and found that ACh receptors in the prefrontal cortex control attention performance. Recent advances in optogenetic and electrochemical methods now allow to rapidly manipulate and measure acetylcholine levels in freely moving, behaving animals. I plan to push the frontier of the study of cholinergic signalling in behaviour by combiningoptical control over cholinergic neurons with fast ACh measurements during attention behaviour. I aim to uncover which cholinergic neurons are involved in fast cholinergic signaling during cognition and uncover the underlying neuronal mechanisms that alter prefrontal cortical network function. This will yield understanding of the causal relations underlying cholinergic control of prefrontal circuits during attention behaviour. In addition, dissecting functional cholinergic circuits will also permit insight in the mechanistic basis of cognitive decline during loss of cholinergic signaling in ageing and disease.