Neurons in the brain integrate information from thousands of synaptic inputs into a single axonal output. Yet, we understand little of how synaptic integration influences cognitive processes, including learning and memory.
Recently, I found that deletion from forebrain neurons of HCN1 channels, which are important for synaptic integration, enhances spatial memory, suggesting that HCN1 channels may constrain memory processes. This raises a fundamental question: Is the primary function of HCN channels to constrain memory, or does expression of HCN1 channels confer some behavioural advantage at the expense of memory?
The experiments that I now propose to address this question use behavioural pradigms based on spontaneous novelty recognition in an open arena and on rewarded identification of a goal location in a radial maze. Initial experiments will use mice with forebrain-restricted deletion of HCN1 channels. Later experiments will focus on the paradigm that reveals the most profound phenotype and will investigate more localized manipulations of forebrain areas, using viruses to knock-down or turn off expression of HCN1 channels in restricted populations of neurons.
By enabling dissociation of the influence of HCN1 channels on different components of information processing underlying memory storage and recall, the proposed project will develop new principles for understanding the roles of HCN1 channels and synaptic integration in episodic memory. This may suggest new experimental strategies to investigate common psychiatric and neurological disorders that are increasingly recognized to involve disruptions to the integration of information, for example schizophrenia, autism and epilepsy.
The proposed project will contribute to European re-integration by enabling me on my return to Europe to carry out high-quality research exploring the molecular basis of memory and by assisting me in developing an internationally competitive research programme.
Call for proposal
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