Comparison of afferent inputs to the retrosplenial cortex in healthy and pathological conditions using a mouse model of amyloidopathy
Lead Research Organisation:
University of Exeter
Department Name: Clinical and Biomedical Sciences
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder, currently affecting 50 million people per year. AD is characterised by impaired memory and cognitive function, accompanied by progressive atrophy in multiple brain regions. Most research into AD-related memory loss has focused on the hippocampus, the region of the brain most associated with learning and memory. However, multiple other brain regions are involved in memory, and the focus of this project is on one of those regions, the retrosplenial cortex (RSC).
The RSC is a midline cortical region that forms reciprocal connections with many regions including the hippocampal formation, entorhinal cortex and anterior thalamic nuclei (ATN). Lesion studies show that the RSC plays an important role in spatial memory, with recent research showing that it is essential for providing contextual information. Reduced activity in the RSC is one of the first pathological changes that can be detected in humans with AD, and occurs before changes can be observed in the hippocampus. Similarly, mouse models that overexpress amyloid beta display reduced activity in RSC before anatomical markers of AD-like pathology become clear. Interestingly, the earliest cognitive deficits that can be detected in mouse models of AD are usually impaired spatial and contextual learning.
The overall aim of this project is to study the RSC during the prodromal (early) phase of pathology in a mouse model of Alzheimer's disease, with the goal of linking deficits in cognitive function with impairments at the cellular and synaptic level. The specific aims are:
1. Determine whether inputs from hippocampus and ATN to RSC are altered in prodromal AD (3 to 5 months old mice).
2. Confirm that spatial learning is impaired in prodromal AD and determine how this relates to function of ATN and hippocampal afferents in RSC.
Aim 1 will be approached using a combination of optogenetic circuit mapping using patch-clamp recordings in ex vivo slices, and in vivo calcium imaging. Aim 2 will be addressed via optogenetic manipulation of long-range inputs to RSC during memory tasks. Traditional mouse models of Alzheimer's disease use animals that overexpress mutant tau or amyloid precursor protein (APP, which is the precursor to amyloid beta), but these models have received some criticism due to the artificially high levels of mutant protein. In this project, we will use a newly described knock-in mice (AppNL-F/NL-F mice) that have had the mouse APP gene humanised and then altered to carry APP mutations seen in familial AD, circumventing the problems of overexpression models.
This project will use advanced optogenetic methods in a cutting-edge mouse model of AD, to study behaviour- and circuit-level changes in an understudied region of the brain. As such, this presents the student with an exceptional training opportunity in an exciting field.
The RSC is a midline cortical region that forms reciprocal connections with many regions including the hippocampal formation, entorhinal cortex and anterior thalamic nuclei (ATN). Lesion studies show that the RSC plays an important role in spatial memory, with recent research showing that it is essential for providing contextual information. Reduced activity in the RSC is one of the first pathological changes that can be detected in humans with AD, and occurs before changes can be observed in the hippocampus. Similarly, mouse models that overexpress amyloid beta display reduced activity in RSC before anatomical markers of AD-like pathology become clear. Interestingly, the earliest cognitive deficits that can be detected in mouse models of AD are usually impaired spatial and contextual learning.
The overall aim of this project is to study the RSC during the prodromal (early) phase of pathology in a mouse model of Alzheimer's disease, with the goal of linking deficits in cognitive function with impairments at the cellular and synaptic level. The specific aims are:
1. Determine whether inputs from hippocampus and ATN to RSC are altered in prodromal AD (3 to 5 months old mice).
2. Confirm that spatial learning is impaired in prodromal AD and determine how this relates to function of ATN and hippocampal afferents in RSC.
Aim 1 will be approached using a combination of optogenetic circuit mapping using patch-clamp recordings in ex vivo slices, and in vivo calcium imaging. Aim 2 will be addressed via optogenetic manipulation of long-range inputs to RSC during memory tasks. Traditional mouse models of Alzheimer's disease use animals that overexpress mutant tau or amyloid precursor protein (APP, which is the precursor to amyloid beta), but these models have received some criticism due to the artificially high levels of mutant protein. In this project, we will use a newly described knock-in mice (AppNL-F/NL-F mice) that have had the mouse APP gene humanised and then altered to carry APP mutations seen in familial AD, circumventing the problems of overexpression models.
This project will use advanced optogenetic methods in a cutting-edge mouse model of AD, to study behaviour- and circuit-level changes in an understudied region of the brain. As such, this presents the student with an exceptional training opportunity in an exciting field.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013794/1 | 01/10/2016 | 30/09/2025 | |||
| 2074085 | Studentship | MR/N013794/1 | 01/10/2018 | 30/06/2022 | Gabriella Margetts-Smith |