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The role of adult-born dentate granule cells in hippocampal information processing and memory function.

Reference	BB/N002547/1
Principal Investigator / Supervisor	Professor David Bannerman
Co-Investigators / Co-Supervisors	Professor David Dupret, Dr Stephen McHugh
Institution	University of Oxford
Department	Experimental Psychology
Funding type	Research
Value (£)	734,587
Status	Completed
Type	Research Grant
Start date	01/01/2016
End date	30/06/2019
Duration	42 months

Abstract

The dentate gyrus continues to produce new granule cells throughout the lifetime of the animal (adult neurogenesis). Levels of adult neurogenesis decrease with age and this has been linked to age-associated memory impairments. Therefore, understanding the contribution of these new, adult-born neurons to hippocampus-dependent memory is potentially of great importance. A key step towards this goal, is to establish how these new neurons influence the downstream network activity of populations of neurons in the CA3 and CA1 hippocampal subfields. To achieve this goal we will use optogenetics to temporarily and reversibly silence this population of new, adult-born granule cells. We will virally transfect newborn dentate gyrus granule cells in Nestin-Cre expressing mice, such that they express the microbial opsin ArchT. These cells can then be selectively silenced by stimulation with yellow light. We will record simultaneously from many neurons in different hippocampal subfields and investigate how silencing new, adult-born granule cells affects remapping in downstream populations of hippocampal neurons. It has been suggested that remapping provides a mechanism by which the hippocampus can differentiate between similar environments, or between similar or overlapping memories. By silencing at different stages of these experiments we will determine when new neurons are important. Are they required to form distinct hippocampal neuronal representations, or for accurate recall when there is a choice between similar representations? In parallel, we will study the role of new neurons in processing ambiguous cues which become associated with two distinct but overlapping memories. We will establish whether new neurons are important at the point of learning, or during the memory recall test session (i.e. encoding vs. retrieval). Together, these studies will enhance our understanding of how and when new, adult-born granule cells contribute to hippocampus-dependent memory.

Summary

The dentate gyrus in the hippocampal formation continues to produce new neurons (granule cells) throughout the lifetime of the animal (adult neurogenesis). Importantly, levels of adult neurogenesis decrease with aging. In fact, there is a strong correlation between levels of neurogenesis and memory performance in animals (as levels of adult neurogenesis decrease, memory performance also decreases), leading to the suggestion that a decrease in the number of new neurons may make a significant contribution to age-associated memory impairment. This population of adult-born neurons represents a potential therapeutic target because exercise, environmental enrichment, and certain drugs can all increase adult neurogenesis. However, to understand the importance of these adult-born neurons for age-related memory loss, we first need to understand their contribution to memory in young adults. Despite intensive study over 15 years or so, we still don't understand their contribution to hippocampus-dependent memory. A key step is to understand how these new, adult-born neurons influence the activity of populations of neurons in the CA3 and CA1 hippocampal subfields (cells which are respectively either one or two synapses downstream from the dentate gyrus granule cells). Surprisingly, to our knowledge, nobody has assessed the effects of destroying or silencing these new granule cells on the population activity of CA3 and CA1 neurons. In this series of experiments we will determine how new, adult-born granule cells shape the neuronal network activity of downstream hippocampal subfields, and how they contribute to hippocampus-dependent memory. Hippocampal neurons characteristically fire action potentials when the animal is at a particular spatial location in an environment (the place field). The combined activity of many of these place cells provides a place map of the environment. However, these place maps are flexible and various experimental manipulations (e.g. changing environmental stimuli, introduction of salient non-spatial cues, changes in behavioural task demands) can lead to changes in the firing characteristics of neurons, a process known as remapping. It has been suggested that remapping provides a mechanism by which the hippocampus can differentiate between similar environments, or between similar or overlapping memories. We will implant arrays of microelectrodes into the hippocampus to record simultaneously the electrical activity of many neurons in different hippocampal subfields. We will alter the environment in different ways to cause remapping. We will investigate how new, adult-born granule cells affect remapping in downstream populations of hippocampal neurons. To temporarily and reversibly silence this population of new, adult-born granule cells we will use optogenetics. We will use a virus which contains DNA that encodes for a microbial protein that is sensitive to a particular wavelength of light. The virus will be injected into the dentate gyrus of genetically modified mice which are specially chosen so that only new, adult-born granule cells that are transfected with the virus will express the light-sensitive microbial protein on their neuronal membranes. When light is shone onto these neurons, the microbial protein is activated. This reduces the excitability of neuronal membranes in cells expressing the protein, and thus we can selectively silence the newborn neurons. We will use this optogenetic approach to determine the importance of new, adult born granule cells for selecting between overlapping memories. By selectively silencing the newborn neurons, either at the point of learning, or during the memory recall test session, we will ascertain when newborn cells are important (i.e. encoding vs. retrieval). This will greatly enhance our understanding of how new, adult-born granule cells contribute to hippocampus-dependent memory.

Impact Summary

Who will benefit? In addition to the academic community (see Academic Beneficiaries), the other main potential beneficiaries of our work will be the pharmaceutical industry, clinicians, and ultimately patient populations from within the general public. How will they benefit? Memory impairment is a major aspect of aging, which has considerable impact on the quality of life of individuals. As people live longer, Age-Associated Memory Impairment (AAMI) will become even more of an issue. The hippocampus is a brain region that is intimately associated with memory, and it exhibits important structural, physiological and neurochemical changes with aging. Hippocampus-dependent memories (e.g. episodic memories) appear to be particularly vulnerable to decline with aging, consistent with the neurobiological changes that occur in the hippocampus as individuals get older. Indeed, age-related cognitive decline has been strongly linked to impairments in hippocampus-dependent forms of spatial and/or episodic memory. In addition, hippocampal dysfunction is a key feature of various other psychiatric and neurological disorders including Alzheimer's Disease, anxiety, depression, schizophrenia and ischaemic brain injury. Thus, understanding how the hippocampus subserves memory function is likely to be of great importance to both pre-clinical and clinical researchers, the pharmaceutical industry, clinicians and ultimately to the patient population. Notably, the dentate gyrus in the hippocampal formation is one of just two brain areas that continue to produce new neurons (granule cells) throughout the lifetime of the animal. Levels of adult neurogenesis decrease with aging and there is a strong correlation between levels of neurogenesis and memory performance, leading to the suggestion that a decrease in the numbers of new neurons may make a significant contribution to AAMI. Importantly, this population of new, adult born granule cells represent a genuinely viable and tractable targetfor therapy, as both environmental (enrichment, exercise) and pharmacological treatments can increase neurogenesis levels. However, before we can understand the contribution of new, adult-born neurons to age-related memory loss and identify possible therapeutic approaches, we first need to understand their contribution in normal, young adults. We need to understand how the new neurons influence downstream hippocampal network properties (in CA3 and CA1 subfields), and exactly how they contribute to hippocampus-dependent memory. By the end of this grant we will be in a position to move forward and then establish how the contribution of new neurons to these electrophysiological and behavioural processes is affected by aging. Our work will therefore ultimately add to an improved level of understanding of both the normal and aging brain. Our research therefore has the potential to identify targets for the pharmaceutical industry for the treatment of dementia (not only in specific patients groups with conditions like Alzheimer's Disease, but also in the aging population more generally). Indeed, treatments that might restore hippocampal function could also be relevant for a variety of psychiatric disorders (e.g. schizophrenia, anxiety and depression). The development of novel treatment strategies and therapies will produce both economic and societal benefits, with the ultimate endpoint of improving human health.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour
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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