Kei M. Igarashi - US grants

Abstract The entorhinal cortex (EC) and the hippocampus are the brain areas which are critically involved in the formation and retrieval of declarative memory, and damage to this circuit results in memory impairment. In order to cure dementias, including Alzheimer?s disease, which currently affects 5 million people in the United States, it is critical to forward an understanding of the cellular and circuit mechanisms involved in the encoding and retrieval of memory in this entorhinal-hippocampal circuit. The EC is anatomically segregated into two halves, the lateral entorhinal cortex (LEC), and the medial entorhinal cortex (MEC). Although previous studies have significantly advanced our understanding of the functional role of the MEC in spatial memory and navigation, our understanding of the functions of the LEC remain largely unclear. Here we propose studies to investigate the function of the LEC in the associative memory to address this critical gap in knowledge. Our approach involves multi-faceted analytical methods including in vivo electrophysiology, associative learning tasks, optogenetic circuit analysis methods, optical imaging and transgenic mouse lines that express Cre mice under the promoter of cell-type-specific markers. There are three Specific Aims to the studies: (Aim 1) identify functional roles of LEC layer II cell types in associative learning; (Aim 2) identify the role of LEC dopamine input in associative learning; and (Aim 3) determine the causal role of LEC 20-40Hz oscillations in associative learning. If successful, our studies will identify the circuit mechanisms for associative memory formation in the LEC and will help establish new frameworks for understanding how the entorhinal-hippocampal circuit enables the formation of declarative memory via the integration of multiple dimensions of sensory information.

Abstract Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the US, a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic mental functions, but severely batters families and caregivers. Its costs are currently estimated at $236 billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need for combating AD is pressing. Histological and imaging studies in AD patients and animal models have shown that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. However, it is still largely unclear what type of activity is lost in the entorhinal cortex in early AD. Using in vivo neurophysiological recording methods, we recently demonstrated that gamma oscillations, a network activity reflecting summed neuronal membrane potentials, are impaired in the entorhinal cortex of an AD mouse model. Our results and recent literature suggest a possibility that entorhinal gamma oscillations can be used for both a biomarker and a therapeutic target of AD. Here we propose studies to investigate the role of gamma oscillations of entorhinal cortex in memory impairments using AD mouse models. Our approach involves in vivo recording of local field potentials (theta and gamma oscillations) and spike activity, optogenetic and chemogenetic methods, closed- loop stimulation, cell-type specific histological analyses of neuronal loss and a novel APP knock-in mouse model. There are three Specific Aims: (Aim 1) identify the extent and time course of entorhinal cortex (EC) gamma impairments; (Aim 2) determine whether the reactivation of network activity using gamma stimulation of EC attenuates or eliminates memory impairments in APP-KI mice, and (3) determine cell types that underlie the EC gamma impairment. If successful, our studies will identify in vivo network mechanisms of memory impairment in AD, and will help identify neuronal activities as therapeutic targets to prevent or slow the progression of disease. Furthermore, our study will help us develop more effective and safer procedures for deep-brain stimulation as a powerful tool to preserve or improve memory function that may eventually be used to slow the rate of memory decline in AD patients.

Abstract Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the U.S., a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic mental functions, but severely batters families and caregivers. Its annual costs are currently estimated at $236 billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need to combat AD grows increasingly pressing. Histological and imaging studies in AD patients and animal models have shown that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. Inside the entorhinal cortex, neurons in layer II are known to undergo earliest neurodegeneration. However, it is still largely unclear what cell type in layer II of the entorhinal cortex exhibits such neurodegeneration. Our preliminary results and recent literature suggest a possibility that layer II neurons show cell-type-specific vulnerability to neurodegeneration. Here we propose studies to characterize the cell-type-specific neurodegeneration of layer II neurons in the entorhinal cortex, and to investigate the circuit mechanisms by which cell-type-specific cell death causes memory impairment in AD. Our approach involves cell-type-specific histological analyses, cell-type- specific in vivo recording of spike activity, cell-type-specific optogenetic and chemogenetic methods, and a novel APP knock-in mouse model. There are three Specific Aims: (Aim 1) To identify histological and molecular properties of degenerating entorhinal cortex neuronal types in APP-KI mice; (Aim 2) To identify in vivo electrophysiological spike activities of entorhinal cortex cell types; and (Aim 3) To determine the effect of entorhinal neurodegeneration on hippocampal place cell activity and on memory loss of APP knock-in mice. If successful, our studies will identify cellular and circuit mechanisms of cell-type-specific neurodegeneration in the entorhinal cortex in AD. Such knowledge of entorhinal cell-type-specific vulnerability is expected to be a breakthrough for future identification of therapeutic targets to prevent or slow AD progression.