Gating memory in health and disease

Memories are not typically overwritten by new learning. Instead, we continue to acquire memories throughout our lifetime, which we can recall in a highly selective manner. However, we don't understand the specialized biological mechanisms within the brain that control selective memory recall. This has important implications for our understanding of neuropsychiatric disease where memories may remain inaccessible or become inappropriately activated to form spurious connections between memories or hallucinatory experiences. What prevents us from establishing the biological mechanisms that control selective memory recall within the brain? Perhaps the greatest challenge to contemporary neuroscience is that it is simply not possible to record cell- and circuit-level activity in the living human brain, except in rare circumstances. Instead, non-invasive methods are coarse, providing an aggregate readout of the diverse responses of thousands of neurons over space and time. To gain access to neural activity at the cell- and circuit-level we instead rely on invasive procedures in animals. But it remains highly challenging to relate findings in animals to an understanding of human cognition and neuropsychiatric disease. To address this challenge, I have recently pioneered a novel cross-species approach that involves measuring neural activity in both humans and mice in the same behaviour. By translating measures of neural activity into a common statistical framework, this approach provides a means to describe the neural basis of human cognition and behaviour in terms of cell- and circuit-level mechanisms. The aim of this fellowship is to use this cross-species approach to establish the specialized biological mechanisms that gate and control selective memory recall. In mice, I will use state-of-the-art electrophysiology, calcium-imaging and optogenetic tools to establish the neural mechanisms that gate and control memory recall. I will then acquire non-invasive markers for these mechanisms in healthy humans using Magnetic Resonance Imaging (MRI). Finally, I will translate these findings into clinical populations diagnosed with schizophrenia, where memory gating is likely disturbed. These studies will establish how memories are selectively recalled and explain why disturbances in memory gating may underpin core symptoms in neuropsychiatric disease. My research will take place at the University of Oxford, across a uniquely interdisciplinary environment which integrates state-of-the-art research in rodents with innovative technologies for investigating the human brain in both healthy and clinical populations.