Human and animal data indicate that the hippocampus encodes events and the spatial context in which they occur. To understand how this is accomplished, we will use a systems-level approach that compares and contrasts the function of specialized microcircuits within the mouse hippocampus. We will focus on the proximal and distal segments of CA1, which are thought to encode an animal?s spatial location and the location of objects in the environment. To control the activity of these regions during behavior, we will develop new genetic tools that can be used to express the inhibitory opsin ArchT in specified segments of CA1. Targeted laser stimulation will then be used to silence these segments during newly developed place and object learning tasks. We predict that visuospatial learning will require activity in proximal CA1 while object learning will require activity in distal CA1. The information gained from these analyses will improve our models of hippocampal organization and allow us to better understand how this structure stores and retrieves distinct types of memory. In addition, these tools can be used in mouse models of human disease to modify activity or control gene expression in distinct segments of the hippocampus.
The treatment and prevention of memory disorders has been greatly facilitated by basic research on the neurobiology of learning and memory. Mouse models have identified signaling pathways that impair memory in neurofibromatosis, tuberous sclerosis, fragile X and Rett syndrome. These pathways can be targeted with genetics and pharmacology in mice and clinical drug trials in humans are underway. The current project will identify microcircuits in the hippocampus that encode memories about spatial locations and objects. The hippocampus is affected by neurological disorders, strokes, traumatic brain injuries and mental health conditions like anxiety and depression. Understanding the mechanisms by which this structure stores and retrieves information should provide insight into these conditions. !
