Causal assessment of bilateral CA3-CA1 communication in hippocampal content representation

"You see at this moment, everything looks clear to me. But what happened just before? That's what worries me. It's like waking from a dream; I just don't remember."
The quote above is from Henry Molaison (H.M.), a patient who had part of his brain surgically removed to cure his epilepsy. H.M., and others like him, taught us that a region of the brain called the hippocampus, and surrounding regions, are crucial for the formation of memories of events and places. In order to understand how the hippocampus and surrounding regions process memories, researchers have turned to animals, particularly rodents. Nerve cells in both the human and rodent hippocampus behave as 'place cells'; that is nerve cells that are preferentially active when the subject is at a particular location. These cells, acting together as a population, might provide the brain with a representation of the surrounding environment used to guide behaviour in space. Hippocampal place cells can also change their activity in response to particular items, odours or sounds experienced at a particular location. These changes may allow the brain to associate discrete locations with a particular piece of information, such as a reward or punishment.

The aim of our project is to understand how place cells can acquire information about where a reward is. We will record from the hippocampus in both hemispheres while mice learn to locate reward in different enclosures. Furthermore, we will interfere with learning by temporarily silencing communication between two parts of the hippocampus circuit during learning. This will allow us to determine exactly where within the hippocampus learning-related changes happen.

In the final part of the project, we will look at the role of sleep in stabilizing memories. Certain neuronal activity patterns observed during active waking behaviour are reactivated during sleep, possibly for the purpose of stabilizing related memories. We will test this hypothesis by interfering with the communication between hippocampal neurons during sleep and testing the effect of this interference on memory stabilization.
Our work should further our understanding of how the hippocampus binds information together to form memories, and how these memories are stabilized during sleep. This will in turn aid efforts to enhance learning and memory in both healthy individuals and those with memory related disorders. In particular, sleep malfunctions have been linked to memory impairments and sleep related interventions seem to help. Understanding exactly how sleep promotes memory stabilization will allow us to refine and optimize sleep-related interventions. Moreover, this work should reveal strategies used by brain circuits to optimize learning, which could inform efforts to mimic what the brain does to achieve efficient machine learning.

The hippocampus processes information about the spatial environment an animal is in ('context') and the items, odours and sounds ('content') present within this environment. This project aims to assess the neuronal circuit mechanisms underlying context-content binding in the hippocampus.
We have recently demonstrated a central contribution for the left CA3 neurons in a hippocampus-dependent associative learning task in mice. In the first phase of our project we will therefore record extracellular field potentials and multiple single-unit activities bilaterally from the mouse CA3 and CA1 subfields during learning. Mice will learn to associate either a location or an item with reward in two separate contexts. This will reveal whether learning modulation of place cell firing (e.g., changes in firing rate, place cell numbers or population synchrony) is distinct across the CA3 and CA1 subfields, whether it occurs preferentially in the left compared to right CA3, and whether any cross-hippocampi asymmetry observed is task dependent.

In phase 2 of the project we will address the causal relationship between the CA3 and CA1 during learning using optogenetic projection silencing informed by findings from phase 1. Such an analysis will allow us to understand the routing of information across hippocampal subfields and hence the types of computations task relevant 'content' information has to go through before reaching the CA1 subfield, the major output of the hippocampus.
Phase 3 will look at the reactivation of hippocampal cell assemblies during sleep-associated sharp wave-ripple (SWR) network events following learning. We will furthermore assess the necessity of SWRs arising in left and/or right CA3 in memory consolidation using an optogenetic feedback loop silencing system.

The proposed project deals with the network-level mechanisms underlying learning and memory processes during complex behaviour. It is thus well positioned to have a broad impact, particularly on the educational front. This will involve both communicating the broad aspects of memory research in general and more project specific information. On the broad front, we will communicate some of the basics of neuronal network function during learning to schools and during science festivals and departmental open days. On the project specific front, we will emphasize the impact of learning and sleep on neural activity associated with the persistence of memory and education to teachers and students. In particular, we will communicate our findings regarding the causal contribution of certain activity states to memory stability and emphasize how this may impact on sleep related interventions in an educational setting. We also envisage that our analysis of cell assembly dynamics during learning will reveal novel insights into learning computations that can be used in the machine learning field to optimize learning algorithms. We intend to work closely with researchers in the machine learning field in both Oxford and Cambridge University. In all of these interactions, we will ensure communication is bidirectional, making use of feedback gained from the educational and machine learning fields to inform our own research activities.