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Neuronal dynamics in health and Alzheimer’s disease
Neuronal dynamics in health and Alzheimer’s disease
Neuroscience has been both investigating fundamental questions about the nature of cognitive processes and giving medical sciences an understanding of biological mechanism that can be used to prevent or cure diseases. While these two branches of research are commonly separated, in the present study we will try to answer questions about memory formation while studying Alzheimer’s disease (AD) development. It is by now well known that the hippocampal formation plays a fundamental role in the acquisition, consolidation and retrieval of episodic memory. These processes are currently hypothesized to be supported or at least reflected in the appearance and synchronization of oscillatory activity patterns within and across regions. However, it is still unclear how these functions emerge from the underlying processes. Studying these phenomena through correlation alone is limited and does not allow to find causal effects. For this reason, scientists have resorted to various perturbations to better understand the causal links in the system. These perturbations of the normal brain activity range from the complete ablation of brain regions to more subtle manipulations like opto- or chemogenetics. Neuropathology can be seen as a more naturalistic perturbation of the brain function and research on the mechanisms underlying cognitive deficits can also contribute to our understanding of the internal computation of the brain. In particular, we will focus on AD, a chronic neurodegenerative disease and the most common cause of dementia, recognized by the World Health Organization as a global public health priority. Notoriously, AD symptoms include disorientation and memory loss. One of the first brain regions suffering from neuronal damage in AD, after the entorhinal cortex, is the hippocampus. Given this clear connection between symptoms and the affected brain region, investigating the development of AD in this area has medical relevance, since understanding the systemic origin of the functional deficits of AD would open the door for the development of new medical approaches, and improve early diagnoses. Using a model of amyloid pathology, APP NL-G-F knock-in mice, in the present study we aim to answer to the following questions: • Do APP NL-G-F mice present changes in the firing patterns of neurons in the hippocampal formation and in the cortical region above it? • Are there different patterns of oscillatory activity in the hippocampus of APP NL-G-F mice compared to wild type animals? • Is there a distinguishable progression of electrophysiological changes for mice of different ages? Our findings show minimal changes on the system level during the active state, the most prominent of which is a significant decrease in the average frequency of theta. On the neuronal level, principal cells tend to have a later theta phase. Since the changes at the system level don’t explain the behavioural deficit, further studies focusing on the active state could focus on the single cell contributions. During the resting state we found multiple differences, the most interesting of which is the diminished occurrence rate of gamma bursts in CA1lm and DGml, reflecting a reduced input from the entorhinal cortices, i.e. the first areas affected by AD. Sharp wave-ripples had a significantly decreased frequency of the ripple itself. Moreover, the strength of respiratory modulation of sharp wave-ripples was diminished, while their occurrence rate did not significantly differ. This points at the possibility that the behavioural changes observed in APP NL-G-F knock-in mice are due to changes mainly happening during the resting state and not during activity.
Alzheimer, Alzheimer's Disease, Hippocampus, APP
Itzcovich, Elena
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Itzcovich, Elena (2021): Neuronal dynamics in health and Alzheimer’s disease. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)
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Abstract

Neuroscience has been both investigating fundamental questions about the nature of cognitive processes and giving medical sciences an understanding of biological mechanism that can be used to prevent or cure diseases. While these two branches of research are commonly separated, in the present study we will try to answer questions about memory formation while studying Alzheimer’s disease (AD) development. It is by now well known that the hippocampal formation plays a fundamental role in the acquisition, consolidation and retrieval of episodic memory. These processes are currently hypothesized to be supported or at least reflected in the appearance and synchronization of oscillatory activity patterns within and across regions. However, it is still unclear how these functions emerge from the underlying processes. Studying these phenomena through correlation alone is limited and does not allow to find causal effects. For this reason, scientists have resorted to various perturbations to better understand the causal links in the system. These perturbations of the normal brain activity range from the complete ablation of brain regions to more subtle manipulations like opto- or chemogenetics. Neuropathology can be seen as a more naturalistic perturbation of the brain function and research on the mechanisms underlying cognitive deficits can also contribute to our understanding of the internal computation of the brain. In particular, we will focus on AD, a chronic neurodegenerative disease and the most common cause of dementia, recognized by the World Health Organization as a global public health priority. Notoriously, AD symptoms include disorientation and memory loss. One of the first brain regions suffering from neuronal damage in AD, after the entorhinal cortex, is the hippocampus. Given this clear connection between symptoms and the affected brain region, investigating the development of AD in this area has medical relevance, since understanding the systemic origin of the functional deficits of AD would open the door for the development of new medical approaches, and improve early diagnoses. Using a model of amyloid pathology, APP NL-G-F knock-in mice, in the present study we aim to answer to the following questions: • Do APP NL-G-F mice present changes in the firing patterns of neurons in the hippocampal formation and in the cortical region above it? • Are there different patterns of oscillatory activity in the hippocampus of APP NL-G-F mice compared to wild type animals? • Is there a distinguishable progression of electrophysiological changes for mice of different ages? Our findings show minimal changes on the system level during the active state, the most prominent of which is a significant decrease in the average frequency of theta. On the neuronal level, principal cells tend to have a later theta phase. Since the changes at the system level don’t explain the behavioural deficit, further studies focusing on the active state could focus on the single cell contributions. During the resting state we found multiple differences, the most interesting of which is the diminished occurrence rate of gamma bursts in CA1lm and DGml, reflecting a reduced input from the entorhinal cortices, i.e. the first areas affected by AD. Sharp wave-ripples had a significantly decreased frequency of the ripple itself. Moreover, the strength of respiratory modulation of sharp wave-ripples was diminished, while their occurrence rate did not significantly differ. This points at the possibility that the behavioural changes observed in APP NL-G-F knock-in mice are due to changes mainly happening during the resting state and not during activity.