Network function in tauopathic neurodegeneration
Lead Research Organisation:
University College London
Department Name: Experimental Psychology
Abstract
We are living longer and there is an increased occurrence of neurodegenerative diseases such as Alzheimer's Disease. Alzheimer's Disease and many other dementias are often called tauopathies, because they are associated with dysfunction of an important protein in the brain called tau. It is therefore important that we have a better understanding of how dysfunctional tau affects brain function. It is also important to establish straightforward assays that offer the possibility of detecting and tracking the impact of dysfunctional tau on brain function.
Nerve cells communicate with each other via electrical impulses, and Alzheimer's Disease is known to have an impact on electrical activity in the brain, which is usually measured by electroencephalogram (EEG). However, there is very little knowledge of how electrical activity is affected in the brains of animal models of tauopathy, and so we do not know how the changes in EEG relate to tauopathy-induced changes in brain circuitry. We therefore propose to study the communication of electrical nerve signals within and between brain areas in animal models of tauopathy.
Clinical measurements of EEG usually characterise the amplitude of brain oscillations at different frequencies. EEG also provides potentially more sensitive measures including the coupling of electrical activity between different brain areas. Alzheimer's Disease is known to be associated with an increase in slower brain oscillations and a decrease in faster brain oscillations. These changes are accompanied by a decoupling of oscillations between brain areas. A prominent theory proposes that these physiological changes, and related cognitive changes, can be explained by disconnection of brain areas during Alzheimer's Disease. But how tauopathy changes the functional connections between brain areas is not known.
We hypothesise that tauopathy has more impact on the coordination of long-distance nerve signals between brain areas, and less impact on the local signals within brain areas, because tauopathy has more impact on sparser long-distance connections than denser local connections. To test our hypothesis, we will measure brain oscillations and functional and structural markers of signal coordination between neurons. We will make these measurements in a well-characterised pathway through the brain (the visual pathway), in two key animal models of tauopathy.
The proposed experiments will open new directions for research, because we will study the activity of nerve cells in key areas of this visual pathway. Visual deficits are common symptoms of dementia and recent studies in humans show that the visual pathways are as susceptible to tau-accumulation as other parts of the brain. Our experiments will therefore push research by determining how tauopathy has an impact on nerve cell signals in the visual pathway, and potentially push clinical practice by allowing better targeting of EEG and cognitive measurements.
Nerve cells communicate with each other via electrical impulses, and Alzheimer's Disease is known to have an impact on electrical activity in the brain, which is usually measured by electroencephalogram (EEG). However, there is very little knowledge of how electrical activity is affected in the brains of animal models of tauopathy, and so we do not know how the changes in EEG relate to tauopathy-induced changes in brain circuitry. We therefore propose to study the communication of electrical nerve signals within and between brain areas in animal models of tauopathy.
Clinical measurements of EEG usually characterise the amplitude of brain oscillations at different frequencies. EEG also provides potentially more sensitive measures including the coupling of electrical activity between different brain areas. Alzheimer's Disease is known to be associated with an increase in slower brain oscillations and a decrease in faster brain oscillations. These changes are accompanied by a decoupling of oscillations between brain areas. A prominent theory proposes that these physiological changes, and related cognitive changes, can be explained by disconnection of brain areas during Alzheimer's Disease. But how tauopathy changes the functional connections between brain areas is not known.
We hypothesise that tauopathy has more impact on the coordination of long-distance nerve signals between brain areas, and less impact on the local signals within brain areas, because tauopathy has more impact on sparser long-distance connections than denser local connections. To test our hypothesis, we will measure brain oscillations and functional and structural markers of signal coordination between neurons. We will make these measurements in a well-characterised pathway through the brain (the visual pathway), in two key animal models of tauopathy.
The proposed experiments will open new directions for research, because we will study the activity of nerve cells in key areas of this visual pathway. Visual deficits are common symptoms of dementia and recent studies in humans show that the visual pathways are as susceptible to tau-accumulation as other parts of the brain. Our experiments will therefore push research by determining how tauopathy has an impact on nerve cell signals in the visual pathway, and potentially push clinical practice by allowing better targeting of EEG and cognitive measurements.
Technical Summary
The aim of this proposal is to understand how tauopathy affects the communication and coordination of signals in the brain, and causes deficits in brain function. Our central hypothesis is that tauopathy has a greater impact on long-distance interactions (connectivity) between brain regions.
We will test this hypothesis by making measurements from the cortical visual system of two preclinical mouse models of tauopathy: an important new model in which the entire mouse tau gene has been humanised before introducing relevant mutations, and a well-characterised model (rTg4510).
We will test four predictions of the central hypothesis in four experiments. The first prediction is that tauopathy has an earlier and stronger impact on global brain oscillations. We will analyse the amplitude and coordination of oscillations in the local field potential (LFP) from multiple brain regions, during longitudinal measurements over the early course of disease.
The second prediction is that tauopathy has more impact on long-distance functional connectivity than local connectivity. We will simultaneously record LFP and spiking activity across multiple brain regions using large-scale devices ('Neuropixels'). We will measure the coordination of spiking and LFP activity within and between areas.
The third prediction is that tauopathy disrupts long-distance structural connectivity. We will use retrograde tracing to quantify projections within and between areas, and immunohistological methods to establish which projections are more likely to develop tau-inclusions.
The fourth prediction is that tauopathy will have a cascading impact, such that there will be more disruption to functional signals in the higher visual cortical areas that feed into cognitive function. We will measure the visual responses of neurons along the visual hierarchy and characterise how tauopathy affects the response amplitude, reliability, latency and tuning of neurons in each area.
We will test this hypothesis by making measurements from the cortical visual system of two preclinical mouse models of tauopathy: an important new model in which the entire mouse tau gene has been humanised before introducing relevant mutations, and a well-characterised model (rTg4510).
We will test four predictions of the central hypothesis in four experiments. The first prediction is that tauopathy has an earlier and stronger impact on global brain oscillations. We will analyse the amplitude and coordination of oscillations in the local field potential (LFP) from multiple brain regions, during longitudinal measurements over the early course of disease.
The second prediction is that tauopathy has more impact on long-distance functional connectivity than local connectivity. We will simultaneously record LFP and spiking activity across multiple brain regions using large-scale devices ('Neuropixels'). We will measure the coordination of spiking and LFP activity within and between areas.
The third prediction is that tauopathy disrupts long-distance structural connectivity. We will use retrograde tracing to quantify projections within and between areas, and immunohistological methods to establish which projections are more likely to develop tau-inclusions.
The fourth prediction is that tauopathy will have a cascading impact, such that there will be more disruption to functional signals in the higher visual cortical areas that feed into cognitive function. We will measure the visual responses of neurons along the visual hierarchy and characterise how tauopathy affects the response amplitude, reliability, latency and tuning of neurons in each area.
