How does the brain store and retrieve distinct memories of episodes that closely resemble each other? This task is critically important for our everyday lives, as it allows us to distinguish between similar places, routes, events, or people. A brain region called the hippocampus has been suggested to serve this purpose: when similar information enters the hippocampus, its input gate, the “dentate gyrus”, is thought to produce non-overlapping memory representations in a process termed “pattern separation”.
Intriguingly, during adult life, the dentate gyrus is also one of the few mammalian brain regions that is constantly supplied with new neurons, providing new circuit elements that can incorporate into the neuronal network. How the activity of new adult-born neurons and mature granule cells combines to drive the production and storage of distinct memories represents a new frontier in understanding brain function.
However, to determine how these neurons transform similar synaptic input patterns into decorrelated spike output patterns representing distinct memories, we need to monitor and manipulate their activity during behaviour. To address these challenges, we combine molecular, physiological and optical approaches in the mouse hippocampus during navigation in a virtual reality environment. We use intracellular recordings to assess how hippocampal neurons convert synaptic inputs into spike output, single- and 2-photon Ca2+ imaging to monitor population activity in the hippocampal circuit, and optogenetic tools to causally test the involvement of specific cell types. These experiments allow us to address the following key questions:
Which behaviours trigger activity in identified newborn and mature dentate gyrus neurons?
How do synaptic inputs drive spiking in newborn and mature neurons during behaviour?
How does neuronal activity in different hippocampal areas discriminate between small changes in the environment, and how does this discrimination relate to behaviour?
How are small changes in an environment encoded by synaptic inputs to newborn and mature neurons?
Can we differentially manipulate the activity of new and mature cells to selectively interfere with animal behaviour during pattern separation and completion tasks?
Understanding the role of new and mature neurons in hippocampal function will give us critical insights into the cellular mechanisms of memory formation. It will also provide fundamental knowledge that is required to unravel the mechanisms underlying debilitating diseases that affect the hippocampus, such as Alzheimer’s dementia.
