Role of the nucleus reuniens within a neural circuit for recognition memory

Lead Research Organisation: University of Bristol
Department Name: Physiology and Pharmacology


Visual recognition memory lets us know whether something that we see, or encounter in our lives, is new or familiar. The formation of such memory is very rapid and is usually taken for granted but it is essential for all our normal daily activities and so a loss of recognition memory can be devastating. A loss of such memory is characteristic of neurodegenerative conditions such as dementia, but is also a feature of Mild Cognitive Impairment and schizophrenia. To successfully learn and store the information needed for successful recognition memory several brain regions are known to interact in a memory circuit. These regions include the hippocampus and also the frontal cortex. Here we propose that a third region, the nucleus reuniens, which when damaged results in poor memory function, is a critical node in this hippocampal-cortical memory circuit. However it is not known when or how these regions interact, and how information within these regions is coordinated.

The programme of research that we propose will answer questions about the role of the nucleus reuniens in recognition memory and how information between these three brain regions is integrated and stored. Specifically we will answer the question of whether the nucleus reuniens orchestrates and coordinates activity in the hippocampus and frontal cortex necessary for specific memory tasks. We will approach the questions from a behavioural angle, but also investigate the cellular processes that ensure memory information can be stored over the long-term.

Understanding memory formation is one of the foremost challenges in neuroscience today, and this proposal will increase our knowledge about how the brain combines memory information obtained in normal every-day life, which ultimately provides us with our own personal history.

Technical Summary

The experiments in this research proposal will test the hypothesis that the nucleus reuniens (NRe) is a key component of a neural circuit, that includes the hippocampus (HPC) and medial prefrontal cortex (mPFC) critical for recognition memory. Studies in our laboratory have shown that both associative and recency recognition memory depend upon a neural network involving the mPFC and HPC. However these regions are anatomically connected via direct projections from the HPC to the mPFC, but also indirectly via the nucleus reuniens (NRe). Damage to the NRe can result in mnemonic deficits, although the question of how and when the NRe is involved in memory formation are not known. The aim of this project is to investigate the role of the NRe, and NRe-hippocampal and NRe-prefrotnal connections in recognition memory. The project will also assess whether the role of these specific connections differs depending on the type of recognition information to be remembered. To answer these questions a multi-level approach involving both behavioural and cellular analyses will be used. We will combine behavioural paradigms that isolate specific types of recognition memory information with state of the art optogenetic and molecular biology tools to inactivate specific anatomical pathways. In parallel we will conduct a series of in vitro electrophysiological studies to examine the physiology of the synaptic connections between the NRe, HPC and mPFC with the following objectives:

1. To provide a systematic investigation of the role of the NRe in recognition memory function.
2. To examine the role of the selective NRe-cortical, NRe-hippocampal interactions in encoding and retrieval of recognition memory.
3. To delineate (a) the functional synaptic connectivity between the NRe, HPC and mPFC and (b) the role of NRe in modulating synaptic function in the HPC and mPFC.

Planned Impact

Who will benefit and how will they benefit
The research will be of benefit to:
i. Members of the academic community in the UK and internationally. The research programme involves the application of a multidisciplinary approach to the study of brain systems in specific types of memory processes. The proposal utilises a variety of cutting edge techniques including genetically modified viruses, specific behavioural protocols and in vitro techniques to assess synaptic function. Thus the programme will have impact on the neuroscience, psychology and physiological research communities.
ii. Patient populations Thalamic damage including damage to the nucleus reuniens of the midline thalamic nuclei, can occur as a result of stroke. The paramedian and tuberthalamic arteries supply the midline thalamic nuclei and infarcts of these arteries can result in learning and memory impairments.
iii. Commercial companies Impairments in cognition are recognised to have significant impact on both the patient and on society. Thus there is a recognised need to develop treatments that facilitate learning and memory.
iv. Charities and organisations The research will be of particular benefit to those within health care systems who are seeking to support patients with memory disorders and their families.
v. Research staff Those employed on the grant will benefit from training in multidisciplinary approaches to understanding memory processes, and synaptic physiology as well as training in transferable skills. The laboratory and transferrable skills are considerably attractive to potential employers in the medial and commercial sphere.
vi. Members of the general public with an interest in memory function, or those wishing to improve memory function.
How will they benefit?
The insights gained from this research will help ultimately in understanding memory loss that occurs with ageing dementia and brain damage following stroke. The research will therefore be of benefit to neuroscience researchers and those in related disciplines. Further, the research could provide therapeutic targets of benefit to commercial companies seeking to develop treatments that facilitate learning and memory. Progress in understanding memory requires a global perspective on brain function, i.e. it is not sufficient to study one brain region alone. A more global analysis will provide a more accurate picture of the neurobiology of memory, but also highlight the range of brain structures that when damaged contribute to memory loss in disease.
The impact of the research on patient groups and their families will be in terms of potential new therapies and also in being able to provide a better understanding of what is happening in these distressing conditions. Further by providing insights into memory function, the research will enable charities which support patients with memory dysfunction, to realise their mission of providing education and help to patients.
The findings from this project will prove applicable to understanding human memory. Such knowledge is of wide interest to the general public and thus be relevant to display and disseminate through science museums, to audiences of school-age children and interested adults.
Staff employed on the project will be trained to use the specific scientific techniques necessary for the successful completion of the project. Staff will also gain a number of transferable skills such as time/project management; communication skills training (oral & written presentations) to scientific and general audiences through public engagement opportunities; team working and networking.
Description We established that permanent inactivation of the nucleus reuniens (NRe) produces a selective deficit in long-term associative recognition memory, i.e. the type of memory that enables someone to recognise an object with respect to the location in which it was previously encountered. Temporary inactivation of the NRe revealed that this structure is critical during memory encoding and retrieval. Encoding of associative memory was found to be dependent on cholinergic neurotransmission, but not on NMDA receptor transmission. Protien synthesis within the NRe was also found to be required.

The NRes is strongly interconnected with the hippocampus and medial prefrontal pathway, we next tested the hypothesis that projections from the NRe to the HPC mediate associative recognition memory formation. To inactivate NRe projections to the HPC, rats were injected with a virus expressing an inhibitory DREADD (AAV5-hsyn- hM4Di) into the NRe and bilateral cannulae were implanted into the HPC. Object-in-place and temporal order memory was tested. Inactivation of NRe inputs to the HPC during encoding impaired both OIP and temporal order memory (Fig 3). In contrast inactivation of the NRe->iHPC selectively impaired OIP memory retrieval. Current experiments are investigating the effects of inactivation of NRe->dHPC on temporal order memory. Thus the projection from the NRe to the HPC regulates associative recognition memory formation in distinct anatomical regions of the HPC dependent on the stage of memory processing and the type of association formed.
Exploitation Route We have identified parallel neural pathways between the nucleus reuniens of the thalamus and the hippocampus that mediate the encoding and retrieval of associative recognition memory information. . These results reveal opportunities for the novel modulation of object memory.
Sectors Other