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What role do different interneurons in medial prefrontal cortex play in associative recognition memory?

Reference	BB/X000915/1
Principal Investigator / Supervisor	Professor Zafar Bashir
Co-Investigators / Co-Supervisors	Dr Paul Banks, Prof. Clea Warburton
Institution	University of Bristol
Department	Physiology and Pharmacology
Funding type	Research
Value (£)	681,884
Status	Current
Type	Research Grant
Start date	01/01/2023
End date	31/12/2025
Duration	36 months

Abstract

We have shown in rodents that a brain circuit centered around the medial prefrontal cortex (mPFC) which receives inputs from hippocampus (HPC), nucleus reuniens (NRe) and medial dorsal thalamus (MD) is critical for associative recognition memory. Inputs from HPC and NRe are necessary for encoding and MD is necessary for retrieval of such memories. The mPFC contains different interneuron types but how these contribute to associative memory is unknown. It is also not known whether these interneuron subtypes are differentially driven by inputs from HPC, NRe or MD to bring about encoding and retrieval. Our hypothesis is that different interneuron subtypes receive inputs from either HPC, NRe or MD to bring about the mPFC dynamics necessary for the separate encoding and retrieval phases of associative recognition memory. This hypothesis will be tested through examining 3 objectives: 1. We will test the roles of mPFC parvalbumin, somatostatin and neuron-derived neurotrophic factor interneurons in different phases (encoding and retrieval) of associative recognition memory. This will be achieved using appropriate Cre mouse lines and viral methods to target selective interneurons for silencing by inhibitory opsins during each phase of associative memory. 2. We will next examine whether the inputs from HPC, NRe and MD differentially target the different interneuron types by using mGRASPi to label specific synapses for confocal imaging analyses. 3. We will finally investigate the synaptic and transmitter mechanisms by which inputs from HPC, NRe and MD control the different interneurons in mPFC. This will use optogenetic transduction of the HPC, NRe and MD input regions and in vitro electrophysiological recordings in mPFC from identified subclasses of interneurons. Overall, this program of research will provide a detailed mechanistic insight into how interneurons in mPFC control the encoding and retrieval of associative recognition memory.

Summary

Associative recognition memory is the process that enables us to form normal, every-day memories. This allows us to remember where we parked the car, where we left our keys, or our phone. This type of memory is essential for us to be able to live our normal lives and underlies some of the first noticeable deficits that occur when cognitive decline or Alzheimer's disease begins to set in. Defining the brain processes which give rise to associative memory is important for understanding how the brain operates under normal conditions but is also important in beginning to understand the mechanisms that start to break down in old age or in Alzheimer's disease. Rodents such as rats and mice also use associative recognition memory in their normal lives, and we have shown that a number of different brain regions including the prefrontal cortex, hippocampus, and regions of the thalamus work together during associative recognition memory. These different regions work together with the prefrontal cortex to control the initial learning and then the remembering of the original memory. However, there are still many things that we don't know about how these brain regions operate. One of the questions we will answer is: how do inhibitory cells in the prefrontal cortex control the function of this brain region during associative memory? We propose that the hippocampus and the nuclei of the thalamus control different types of inhibitory cells in the prefrontal cortex and that the separate activation of the different inhibitory cells by these different brain regions separately brings about the initial encoding and then the retrieval of the memory. We will test these ideas in mice by selectively targeting and silencing the major types of interneurons in prefrontal cortex during different phases of memory. We will use advanced anatomical markers and light microscopy methods to detect whether the hippocampus and the thalamic connections to prefrontal cortex terminate on the different inhibitory cell types. Finally, we will examine how these different connections control activity of the different inhibitory cells and therefore control the function of the prefrontal cortex. The project is timely because we have only recently identified the different regions that work together to bring about the different phases of associative recognition memory and it is now possible to identify and selectively target different inhibitory cells while a mouse is performing a learning task. Furthermore, the anatomical methods have recently been developed that now allow us to identify which brain regions connect with which inhibitory cells and finally we can record from these cells to measure how their activity is controlled by the different brain regions that control associative memory. Overall, this work will provide a detailed mechanistic insight into how brain regions work collectively to bring about associative recognition memory.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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