Longitudinal tracking and functional dissection of the cortical head direction network in a mouse model of Alzheimers disease

Alzheimer's disease affects millions of people worldwide. As the global population ages, it will put an increasing burden on patients, families and health care systems. Much of what we know about brain function in Alzheimer’s has come from human studies. However, tools for measuring brain activity in humans do not have high enough resolution to accurately tell us what types of brain cells are affected and how their activity changes over time. However, in mice, the development of new groundbreaking methods over the past 15 years has given us the opportunity to monitor brain activity in specific cell types, non-invasively, over time. Widespread brain systems adjust activity levels according to how alert or drowsy we are. One such system, the cholinergic system, is known to be dysfunctional in Alzheimer’s. This system conveys information about body movement and alertness to cortical circuits. How does the balance between alertness and disengagement impact memory? Our research has shown that memory consolidation, in wakefulness, occurs during 1-2 second pauses in brain activity (Chambers et al, 2022), which is strongly tied to pauses in body and face movements (Chambers et al, in preparation). In the retrosplenial cortex (RSC), an early target of Alzheimer’s pathology, these pauses allow for memory-related activity to ‘stand out’ more effectively against a background that is normally dominated by movement- and sensory-related signals. Based on our research, we hypothesize that Alzheimer’s disease disrupts the brain’s ability to change the flow of information through cortical circuits based on our current body state. This is particularly important in the RSC, whose neurons are both strongly driven by movement and strongly engaged during stillness and memory consolidation, compared to other parts of the cortex (Chambers et al, in preparation). Further, the RSC is critical for representing our heading direction in space (Hennestad et al, 2021). Taken together, our evidence supports that disruptions to the balance of activity and silence in the RSC would be devastating for both memory and navigation. Finally, a major aspect of the project has focused on cellular activity in the RSC during sleep. Not only do RSC neurons show sleep-stage specific activity (Berge et al, in preparation), but recent reports have implicated these cells in the regulation of sleep architecture. We have found that disruptions to circuit activity in the RSC would have major implications for memory processing during both sleep and wakefulness, making it a prominent potential target for therapies to ameliorate Alzheimer’s-related symptoms.

Two major outcomes of this project are increased interdisciplinary research and increased international collaboration. Although memory research in rodent models typically focuses on a small number of brain regions and utilizes a limited number of techniques, our study has shown the potential of modern optical tools for the non-invasive and chronic study of specific cell types and circuits across large areas of the brain. These areas include those that have classically been implicated in memory, and those that are typically associated with other brain functions but have been nonetheless implicated in our research as important for memory-related processes. Our international research stay at Harvard Medical School has led to the preparation of two collaborative research articles, which will be submitted for publication later in 2023. This has formed the basis for a longer term collaboration involving trainee exchange, grant writing and complementary studies in mice and humans. The main societal impact of the project is to expand the range of possibilities for the treatment of dementia beyond just pharmaceuticals, to behavioral interventions targeting body movement and sleep-- both aspects of brain function that can be non-invasively monitored and manipulated. A greater understanding of the broader involvement of brain-wide systems (such as the cholinergic system, which is one of our research targets) in disorders of memory will lead to more impactful future research and increased understanding of both preventive and acute treatment of dementia.

Given the aging global population, dementia is projected to place an ever-increasing burden on health systems, governments, and families. Of the forms of dementia, Alzheimer's disease is most prevalent. From decades of research, we have learned about the genetic, molecular and subcellular pathology of Alzheimer's, yet we know little about how it affects the high-level microcircuit processing that underlies cognition and behavior. Given that Alzheimer's specifically targets these higher-level processes, such as memory and spatial navigation, it is paramount that we apply cutting-edge tools in systems neuroscience to this question. This project aims to monitor the activity of neuronal subtypes in a part of the cortex that is specifically damaged in Alzheimer's disease. With this information, we will, for the first time, be able to identify the most vulnerable elements in a cortical region that deals with memory and spatial navigation. The monitoring will be performed longitudinally, using two-photon microscopy in vivo, while animals perform relevant behaviors. Stimultaneous behavioral and functional testing will allow us to associate specific dysfunctions in neuronal subtypes with cognitive deficits. In addition, a second major objective of the study is to apply a newly developed stimulation protocol to inhibitory interneurons. Chronic application of this protocol as disease progresses in the mouse model will allow us to test to what extent it is effective at halting or reversing cognitive decline. These experiments will allow, to date, the most comprehensive picture of cortical microcircuit function during memory formation. They will also provide an unprecedented platform for testing an innovative potential therapy for Alzheimer's disease in an awake, behaving mouse model.