All-Optical Dissection of Hippocampal Circuits Using Voltage Imaging

Nerve cells, or neurons, are complex processing devices that transmits information using fast electrical signals. There are many different types of neurons which are interconnected into circuits that process information and provide outputs that eventually lead to behavior. To understand the combined activity of multiple neurons and how it guides behavior, we have to be able to record and manipulate the fine details of the activity of many neurons, at single cell resolution and at the millisecond timescale, during behavior. In this project we use a new technology that I developed to record and manipulate the electrical properties of multiple neurons, simultaneously, in behaving animals. We aim to generate new discoveries on the mechanisms by which neural circuits in a brain region called hippocampus, process information and help to store of spatial memories. The hippocampus is an important brain region in the storage and retrieval of memories for events, and its role in the memory of locations has been extensively studied for almost five decades. The hippocampus is also an important model in the study of how the strength of the connections between neurons can changes. This phenomenon, called neuronal plasticity, is believed to be a key mechanism for learning and memory. The experiments in this project are aimed to connect between these studies that are typically performed in isolated neurons outside of the brain, with research describing how memory of locations is represented in the activity of hippocampal neurons in behaving rodents in order to understand how the fine details of neuronal activity change during the learning process.
Our specific objectives In this project are to: 1) Elucidate how the neuronal circuits in the hippocampus changes their activity in the formation of memories of new places, 2) Develop tools that will allow to tag selected neurons that represent the memory of specific places in order to study their structure, and 3) Use this tool to tag cells that provide information to the hippocampus to understand how this input is involved in memory formation by hippocampal circuits. This research is a first step towards broader understanding of how the brain stores and retrieves memories of events. Importantly, memory storage is a central brain function which is impaired in devastating brain pathologies such as Alzheimer’s disease. Therefore, understanding the basic mechanisms behind memory storage might have important clinical implications.

So far, we developed a unique microscope which is necessary for our experiments and designed a new virtual reality system for mice. We then trained mice to learn virtual locations and imaged the electrical activity of two distinct types of neurons during navigation in familiar locations and during transition into a new virtual space. These experiments provide rich information about the fine details of the electrical activity of these neurons during spatial learning. We revealed interesting changes in the neuronal activity during learning which are reflected both in the inputs that the neurons receive and in the output they transmit to other neurons. We also successfully managed to tag selected neurons and we are now working to combine our tagging technique in the virtual learning experiments.

Our method is providing data at unprecedented resolution in space and time which allows us to reveal detailed changes in neuronal activity during spatial learning. Making sense of these data is a long and complicated process, but already at the early stages of the data analysis we revealed interesting and unexpected changes in the neuronal circuit function during learning. We believe that our work will have important implication for our understanding on the formation of new memories.

Periodic Reporting for period 2 - AllOptHIPP (All-Optical Dissection of Hippocampal Circuits Using Voltage Imaging)

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