Circuit and cellular analysis of the lateral entorhinal cortex in associative recognition memory
Lead Research Organisation:
University of Bristol
Department Name: Physiology and Pharmacology
Abstract
Associative recognition memory, enables us to recognise distinct objects in the context of the environment or location in which the stimulus was encountered. Thus we quickly recognise that the furniture in our living room has been rearranged, or indeed we can fail to recognise someone when we see them in an unfamiliar location. The formation this type of memory involves rapid 'one-shot' encoding of both the object and location, and the memory association can then be subsequent retrieved, on presentation of a suitable cue. While we form these memories rapidly and with apparent ease, to lose this ability, either during health aging or more dramatically in dementia can be devastating.
Due to the complexity of the processes involved, understanding memory formation and retrieval is a major challenge in neuroscience. It has been shown that memory formation is accompanied by increased neuronal activity within distributed cell populations, which create a physical trace of the memory termed an 'engram'. These engrams exist within connected brain regions, forming memory circuits, and we have identified a memory circuit in which the hippocampus, medial prefrontal cortex and lateral entorhinal cortex are important nodes. In this research proposal we will analyse the circuit and cellular mechanisms by which associative recognition memory information is encoded and retrieved, with a focus on the role of the lateral entorhinal cortex, and its interconnectivity with the hippocampus and medial prefrontal cortex.
Our experiments will examine how LEC engram (memory trace) is set up during learning, by investigating the specific input and output pathways of the engram cells. We will examine whether if we block the function of these engram cells within the defined memory circuit we will disrupt memory processing, and thirdly to investigate the specific cellular processes that determine whether a specific cells becomes incorporated into the memory engram circuit, i.e. what is it about an individual neuron that makes it code a particular type of information, store that information, and enable the information to be retrieved when it is required.
Using mice we will identify the cells in LEC that are activated and reactivated during memory encoding and retrieval respectively, i.e. the engram cells and establish whether the involvement of these cells in memory is determined by incoming information from the hippocampus, and medial prefrontal cortex, or by sending outgoing information back to these regions regions. To answer our research questions we will use newly developed techniques to selectively silence input and output pathways, in behaving animals, use imaging and microscopy to delineate the precise architecture of the neural networks and thirdly investigate whether the engram cells have a unique physiological profile. This combination of techniques, which enables analysis at a synaptic cellular and circuit level enable us to understand the complexity of memory processing. Such research is vital as treatments for memory disorders are a largely unmet clinical need. We therefore need understand the cellular mechanisms with enable memories to be formed and retrieved, however drug treatments for cognitive impairments lack neuroanatomical selectivity. Interventions such as deep brain stimulation (DBS) target distinct neural networks, and thus by understanding how memory network operate on a brain wide level, targeted DBS, may offer an alternative way to ameliorate memory impairments
Due to the complexity of the processes involved, understanding memory formation and retrieval is a major challenge in neuroscience. It has been shown that memory formation is accompanied by increased neuronal activity within distributed cell populations, which create a physical trace of the memory termed an 'engram'. These engrams exist within connected brain regions, forming memory circuits, and we have identified a memory circuit in which the hippocampus, medial prefrontal cortex and lateral entorhinal cortex are important nodes. In this research proposal we will analyse the circuit and cellular mechanisms by which associative recognition memory information is encoded and retrieved, with a focus on the role of the lateral entorhinal cortex, and its interconnectivity with the hippocampus and medial prefrontal cortex.
Our experiments will examine how LEC engram (memory trace) is set up during learning, by investigating the specific input and output pathways of the engram cells. We will examine whether if we block the function of these engram cells within the defined memory circuit we will disrupt memory processing, and thirdly to investigate the specific cellular processes that determine whether a specific cells becomes incorporated into the memory engram circuit, i.e. what is it about an individual neuron that makes it code a particular type of information, store that information, and enable the information to be retrieved when it is required.
Using mice we will identify the cells in LEC that are activated and reactivated during memory encoding and retrieval respectively, i.e. the engram cells and establish whether the involvement of these cells in memory is determined by incoming information from the hippocampus, and medial prefrontal cortex, or by sending outgoing information back to these regions regions. To answer our research questions we will use newly developed techniques to selectively silence input and output pathways, in behaving animals, use imaging and microscopy to delineate the precise architecture of the neural networks and thirdly investigate whether the engram cells have a unique physiological profile. This combination of techniques, which enables analysis at a synaptic cellular and circuit level enable us to understand the complexity of memory processing. Such research is vital as treatments for memory disorders are a largely unmet clinical need. We therefore need understand the cellular mechanisms with enable memories to be formed and retrieved, however drug treatments for cognitive impairments lack neuroanatomical selectivity. Interventions such as deep brain stimulation (DBS) target distinct neural networks, and thus by understanding how memory network operate on a brain wide level, targeted DBS, may offer an alternative way to ameliorate memory impairments
Technical Summary
Due to the complexity of the processes involved, understanding memory formation and retrieval is a major challenge in neuroscience. Our work has shown that the ability to form a memory of an object together with information about the place in which it was encountered, i.e. an associative recognition memory, depends on a hippocampal-cortical network network in which anatomical and functional evidence suggest the lateral entorhinal cortex (LEC) is a key node. Within the LEC we have found discrete populations of neurons (so called 'engrams') which appear to be specialised for both encoding and retrieval of associative recognition memory information yet the circuit and cellular mechanisms which mediate these crucial processes are not known.
Our overarching hypothesis is that specific input and output projections between LEC, medial prefrontal cortex and hippocampus determine the involvement of LEC in encoding and retrieval. We will use our expertise in behavioural analyses of recognition memory in combination with activity-dependent cell labelling to visualize engram cells, state-of-the-art trans-synaptic circuit mapping techniques, optogenetics, ex vitro electrophysiological recordings from identified neurons in LEC to dissect the circuit and cellular basis for the role of LEC in associative recognition memory.
To address our hypothesis we will investigate 1) the precise circuit connectivity of LEC engram cell populations; 2) whether specific input/output-defined LEC neurons are differentially necessary for encoding and retrieval; 3) the cellular and synaptic mechanisms which underlie the recruitment of LEC neurons into the engram population.
Together these objectives will provide an detailed understanding of how the LEC circuitry supports associative recognition memory, and importantly provide an understanding of the principles by which other forms of memory may be encoded and retrieved in brain-wide distributed networks.
Our overarching hypothesis is that specific input and output projections between LEC, medial prefrontal cortex and hippocampus determine the involvement of LEC in encoding and retrieval. We will use our expertise in behavioural analyses of recognition memory in combination with activity-dependent cell labelling to visualize engram cells, state-of-the-art trans-synaptic circuit mapping techniques, optogenetics, ex vitro electrophysiological recordings from identified neurons in LEC to dissect the circuit and cellular basis for the role of LEC in associative recognition memory.
To address our hypothesis we will investigate 1) the precise circuit connectivity of LEC engram cell populations; 2) whether specific input/output-defined LEC neurons are differentially necessary for encoding and retrieval; 3) the cellular and synaptic mechanisms which underlie the recruitment of LEC neurons into the engram population.
Together these objectives will provide an detailed understanding of how the LEC circuitry supports associative recognition memory, and importantly provide an understanding of the principles by which other forms of memory may be encoded and retrieved in brain-wide distributed networks.