The role of adult-born dentate granule cells in hippocampal information processing and memory function.
Lead Research Organisation:
University of Oxford
Department Name: Experimental Psychology
Abstract
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.
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.
Technical Summary
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.
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.
Planned Impact
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 target for 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.
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 target for 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.
Publications
Gava GP
(2021)
Integrating new memories into the hippocampal network activity space.
in Nature neuroscience
Lima J
(2019)
Enhanced discriminative aversive learning and amygdala responsivity in 5-HT transporter mutant mice.
in Translational psychiatry
McHugh SB
(2022)
Adult-born dentate granule cells promote hippocampal population sparsity.
in Nature neuroscience
| Description | The most significant achievements from the award were as follows: 1. We have generated a large database of single-neuron recordings from the hippocampus of behaving mice. This database includes simultaneous recordings from dentate gyrus, CA3 and CA1 subfields as mice perform hippocampal dependent tasks. Overall, we have recorded from over 2750 hippocampal neurons. Moreover, we have recorded during both the stimulation and silencing of adult-born dentate granule cells. This is a truly unique dataset. 2. We have discovered that adult-born dentate granule cells exert a strong inhibitory influence over other principal cells in the hippocampal network, including mature dentate granule cells, CA3 and CA1 pyramidal cells. Silencing adult-born dentate granule cells increased firing in these principal cells. Moreover, silencing adult-born dentate granule cells changed the location of place fields in some, but not all, principal cells in CA3 and CA1. These findings answers our first objective (1. 'To determine whether/how new, adult-born granule cells influence rate and spatial 'remapping' in CA3 and CA1 hippocampal subfields'). 3. We have discovered that silencing adult-born dentate granule cells impairs behavioural discrimination in a novel 'morphed' environment task. In this task, we placed four objects in the north, south, east and west positions of a box and on each trial we replaced one object (with a new object) until all four objects were replaced. In trials where we silenced adult-born dentate granule cells, mice explored the environment quite differently than on trials where we did not silence the adult-born dentate granule cells, and they demonstrated significantly reduced preference for the new object location. This suggests that adult-born dentate granule cells may be important for signalling that the environment has changed. This finding met our second objective (2. 'To determine when new, adult-born granule cells are important for differentiating between hippocampal representations of similar environments'). 4. We have discovered that new learning causes marked changes in the functional connectivity (co-firing) patterns of neurons throughout the hippocampus, and that silencing adult-born dentate granule cells generates excessive co-firing, thereby reducing the sparsity of activity in CA1 principal cells. 5. Finally, we found that silencing adult-born dentate granule cells impairs the ability of mice to distinguish behaviourally between cues that are predictive of aversive outcomes versus cues that are not predictive of aversive outcomes. We did not find clear evidence that adult-born granule cells selectively influence rate remapping for ambiguous aversive cues (Objective 4) but rather that silencing adult-born granule cells increased firing rates of CA3 and CA1 neurons in all circumstances (including during sleep). However, using a machine learning approach, we found that silencing adult-born dentate granule cells during fear memory retrieval impaired cue discrimination performance when using the information contained in the firing rates of CA1 principal cells. Collectively these data address the questions posed in our third and fourth objectives (3. 'To determine when new, adult-born granule cells are important for disambiguating (or pattern separating) between overlapping, ambiguous fear memories'. 4. 'To determine whether new, adult-born granule cells selectively influence rate remapping for ambiguous aversive cues'). We have one publication arising from these data (https://doi.org/10.1038/s41593-021-00804-w), and we have two further manuscripts in preparation, with one of these to be submitted imminently, and the other to be submitted later this year. |
| Exploitation Route | 1. Publication of high quality research papers: One has been published and another two manuscript are in preparation, which will report our key findings in detail. There is also the possibility of further subsequent publications depending on on-going data analysis from our extensive data set. In addition, McHugh will continue to present findings at both national and international meetings. We will thus contribute to the knowledge base available for other researchers in academia and industry. 2. Links with local groups: With data analysis nearing completion we are now in a position to communicate and discuss our findings with local groups (e.g. Oxford Drug Discovery Institute, Oxford Dementia & Aging Research). Although we have made significant advances, we would not, however, want to overstate the importance of our research to current drug discovery programs. More research is required in this area. 3. Pharmaceutical industry: Bannerman continued to contribute to the Eli Lilly Centre for Cognitive Neuroscience throughout the lifetime of the award (although data from the current project were not at a stage for presentation to Lilly). Unfortunately, Lilly have now pulled out of preclinical research in the U.K. 4. Researcher training: McHugh received extensive training in multiple single-unit recordings combined with optogenetics and is now actively training other researchers in these skills locally within Oxford. 5. Animal research framework: We have generated a unique data set, combining electrophysiological recordings from three hippocampal subfields, with optogenetic manipulation of cell activity, and sophisticated behaviour. This provides an important framework for future studies by ourselves and other researchers. 6. Public engagement: McHugh and Bannerman continue to contribute to public engagement. |
| Sectors | Pharmaceuticals and Medical Biotechnology |