Plasticity of cortical circuits in health, aging, and Alzheimer's disease

项目总结/文摘

Project Summary/Abstract Comprised of six distinct layers, the cerebral cortex is the key brain structure for all of our cognitive abilities, ranging from sensation to decision making to movement. Each layer contains distinct cell types differing in their genes, biophysical properties, and connectivity with other parts of the nervous system. Yet how these diverse cortical layers and cell types are involved in any given behavior remains unresolved. Moreover, we currently lack insight into how aging impacts interactions between cortical layers, which severely limits our understanding of how aging alters cortical circuit function. At the most basic level, the cortex can be divided into deep and superficial layers, each of which receives a complete copy of sensory information from the thalamus. This suggests that the two sets of layers constitute different processing systems, which begs the question: what are the possible purposes of these parallel networks? Because these processing streams differ in input, output, intrinsic membrane, synaptic integration, and spike generation properties, I hypothesize that deep and superficial layers have unique, independent functions. This also raises the intriguing possibility that these pathways are differentially susceptible to aging. I hypothesize that aging leads to layer-specific changes that ultimately lead to unique age-related deficits in cortical circuit function. Investigating the functions and age-related changes in deep and superficial cortical networks requires a cortex-dependent task. In Dr. Bruno’s lab at Columbia University (F99), I developed a whisker-mediated texture discrimination task for head-fixed mice, demonstrated that this behavior requires the cortex, and revealed that both deep and superficial layers are involved in processing texture information (Aim 1.0, progress report). I propose to characterize the sensorimotor strategies required for this behavior (Aim 1.1) and how layer-specific manipulations alter texture representation in the deep and superficial layers (Aim 1.2). Understanding the computations performed by individual layers will not only expand our understanding of the complex cortical circuitry, but will also provide insight into how aging and neurodegeneration – which often involve dysfunction of specific cortical cell types, layers, and their pathways – may be mitigated through the development of targeted therapies. In Dr. Tsai’s lab at Massachusetts Institute of Technology (K00), I will develop a novel therapy that galvanizes the brain’s own mechanisms to noninvasively improve cognitive and behavioral health in aged and Alzheimer’s disease (AD) model mice. To do so, I will first identify how aging and AD alter learning, performance, sensorimotor strategies (Aim 2.1), and sensory processing across cortical circuits (Aim 2.2) on my texture discrimination task. These findings will inform the development of a noninvasive therapy that stimulates cortical circuits to protect sensory and motor functions from aging and AD pathology (Aim 2.3). This proposal will advance our limited understanding of how aging dynamically alters cortical circuits in vivo and may lead to an effective intervention to prevent age and disease-related functional impairments in human patients.