Astrocytes' roles in the control of mammalian behavior remain poorly understood, but in addition to key roles in tissue maintenance astrocytes are important for neural development and plasticity and can modulate neuronal activity. Indeed, astrocytes and neurons are well poised to interact reciprocally, with astrocytes capable of modulating neural network activity, and with some forms of neural activity prompting dynamical Ca2+ excitation in astrocytes. The significance for mammalian behavior of such reciprocal interactions remains mysterious. There is the very real - but largely unexplored - possibility that astrocytes and their Ca2+ dynamics may be critically involved in the computational processes that underlie cognition and behavior. This vital issue remains largely unexamined due to a general lack of tools for observing astrocytic Ca2+ excitation in behaving animals. We will address this unmet need by creating tools for imaging astrocyte Ca2+ dynamics in freely moving mice. We will combine 4 recently developed optical imaging techniques, which together afford the first chance to track astroctytic Ca2+ dynamics in hundreds of cells over multiple weeks in the live brain. We will focus upon the CA1 area of hippocampus, but the capacity to track large populations of astrocytes over long time periods in behaving mice will be applicable to a wide variety of brain areas, behavioral tasks, and forms of cognition. After developing our approach, we will validate and illustrate its potency by examining the specific question of how do CA1 astrocytic dynamics relate to hippocampal forms of spatial cognition and memory? Hippocampal area CA1 is crucial for many types of spatial cognition, so this question poses a first opportunity to examine how astrocytes may contribute to brain computations underlying cognition and behavior. Our four aims are:
Aim 1 : Establish tools for imaging Ca2+ dynamics in hundreds of individual astrocytes in freely behaving mice.
Aim 2 : Establish and validate time-lapse imaging of CA1 astrocyte Ca2+ dynamics over weeks and across hundreds of individual cells in behaving mice.
Aim 3 : Quantitatively assess the degree to which CA1 astrocytes' Ca2+ dynamics encode spatial information in animals performing a spatial task over 60 days. In mice repeatedly visiting 2 distinct, familiar spatial arenas over 60 days we will test: Hypothesis 1: CA astrocyte activity encodes spatial information; Hypothesis 2: Specific forms of CA1 astrocyte Ca2+ activity are associated with memory recall in a spatial task. Hypothesis 3: The long-term stability of CA1 astrocyte activity correlates with performance on a long-term spatial memory task. Regardless of the data's outcome, the ability to test these ideas will be groundbreaking.
Aim 4 (Resource Sharing): In years 4 and 5 we will hold 3 training sessions per year for astrocyte biologists to come to Stanford to learn our imaging methods firsthand. If successful, our work could have notable impact on multiple fields, including systems/cognitive neuroscience and the study of astroglial biology in both health and disease.

Public Health Relevance

Brain scientists are presently unable to observe astrocytes' dynamical patterns of excitation in freely behaving mammalian subjects, let alone to watch how individual astrocytes' dynamics may evolve over periods of weeks or more. Our work seeks to innovate brain-imaging technologies that will allow researchers to monitor the dynamics of genetically targeted astrocytes over long time periods in the brains of freely behaving mice. We will then use this imaging technique to track over weeks during mouse exploratory behavior the astrocytic patterns of calcium excitation in the hippocampus, a key brain area implicated in many neuropsychiatric disorders including several diseases of memory.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Buhring, Bettina D
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Stanford University
Biomedical Engineering
Schools of Medicine
United States
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Xu, Chun; Krabbe, Sabine; GrĂ¼ndemann, Jan et al. (2016) Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval. Cell 167:961-972.e16