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Electrophysiological Evaluation of Brain Regions Vulnerable to Alzheimers Disease

易患阿尔茨海默病的大脑区域的电生理学评估

基本信息

批准号：
10383675
负责人：
Syed Abid Hussaini
金额：
$ 62.53万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10383675
关键词：
20 year old Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Amyloid beta-Protein Animal Testing Animals Arousal Behavior Behavioral Biological Markers Brain Brain Stem Brain region Cognitive Cognitive deficits Computing Methodologies Confusion Data Disorientation Electrophysiology (science)Environment Evaluation Functional disorder Halorhodopsins Head Hippocampus (Brain)Home Human Hyperactivity Immunohistochemistry Impaired cognition Impairment Knock-in Knock-in Mouse Lead Learning Life Location Measures Medial Memory Memory impairment Mus Neurobehavioral Manifestations Neuronal Dysfunction Neurons Neurosciences Pathologic Pathology Performance Physiological Positioning Attribute Property Role Seeds Silicon Sleep Sleep Disorders Sleep Stages Sleep disturbances Slow-Wave Sleep Symptoms Tauopathies Techniques Testing Wild Type Mouse Work behavior measurement cognitive ability cognitive testing computational neuroscience entorhinal cortex locus ceruleus structure machine learning algorithm mouse model neuron loss non rapid eye movement optogenetics predictive test rapid eye movement relating to nervous system sleep behavior sleep regulation spatial memory targeted treatment tau Proteins tau aggregation tool virtual environment virtual reality virtual reality environment way finding

项目摘要

The entorhinal cortex (EC) is long known to be the region affected first in Alzheimer’s disease (AD) with symptoms such as disorientation, confusion and inability to navigate appearing early in life. But more recently, a region in the brainstem- locus coeruleus (LC) was found to have tau accumulation in young healthy adults, making it the first region in the brain with AD pathology. The LC is known to be important for arousal and controls the sleep/wake switch. The neurons of LC project to several regions including EC and hippocampus which are known to be important for spatial memory. Unsurprisingly, one of the earliest symptoms of AD is spatial difficulties and it is possible that early pathology in LC affects sleep leading to spatial memory deficits. With both LC and EC important for memory, we aim to identify which of them is more vulnerable to tau and Aβ pathology. To explore this possibility, we will first inject LC and EC regions of wildtype mouse with pathological tau derived from human AD brains to make them dysfunctional, and evaluate their neuronal function. We will also assess sleep and test memory performance in relevant behavior tasks. To understand how aβ affects tau pathology, we will inject human tau in the APP Knock-In mice which has physiological amounts of APP expressed in them. We will determine if Aβ together with tau worsens the neuronal function of LC and EC neurons and it sleep and memory is impaired further. We will use multi-region silicon probes to simultaneously record activity from LC or medial EC and hippocampal neurons. The MEC and hippocampal neurons are well characterized with properties that can be easily measured using spatial navigation tasks. We will make use of virtual reality head-fixed setup for the animals to navigate in, and allowing us to quickly test animal’s memory in any context and environment. The animals will be tested for object-location memory and context-dependent memory in virtual environment. We will use machine learning algorithms to decode animal’s position in the LC, MEC and HPC neural data and determine if it is affected by tau or Aβ or both. We will also assess sleep parameters and correlate with memory. We hypothesize that tau in LC and EC will make its neurons dysfunctional and directly affect sleep and memory, and this in concert with Aβ will exacerbate neuronal dysfunction leading to increased sleep problems and spatial memory impairment as seen in early AD. With this we aim to identify electrophysiological biomarker of neuronal dysfunction before the onset of behavioral troubles. We will test if increasing the neuronal firing in hypoactive neurons and reducing the firing in hyperactive neurons will restore downstream neuronal dysfunction and reverse sleep problems and cognitive impairment. The proposal brings together diverse fields (neuroscience, pathology and computational neuroscience) applying large-scale recording techniques simultaneously across multiple brain regions to develop analytical and predictive tests to interrogate function in vulnerable brain regions that are dysfunctional in AD.

长期以来，内嗅皮层（EC）被认为是阿尔茨海默病（AD）中首先受到影响的区域