EEG power in the theta frequency range (6-9 Hz), particularly during waking and REM sleep, is believed to primarily be due to synchronous firing of hippocampal pyramidal cells. To date, studies supporting this hypothesis have relied on extracellular unit recordings where a relatively small number of cells are monitored and the activity of individual cells can only be followed for short periods of time. Here, we will provide n unprecedented network level view of neural activity in the hippocampus across arousal states by monitoring the activity of hundreds of individually identifiable cells over weeks to months. We will combine telemetric recording of EEG and EMG activity with an exciting new technology that, when used in conjunction with genetically-encoded fluorescent calcium indicators (e.g., GCaMP5 and 6), enables imaging the activity of hundreds of neurons simultaneously from a local brain region in unanesthetized, freely-moving animals. The Inscopix nVista HD imaging system is comprised of a miniature (<2 g) fluorescence microscope that can be borne on the skull of a mouse, software that enables high-speed imaging (20-100 Hz) over a field of view up to ~0.5 mm2, and microendoscopes that allow imaging with micron-scale resolution in subcortical brain structures. Because of the rich history of behavioral studies conducted in the hippocampus and its laminar organization, this region is the ideal neural structure in which to utilize this technology to obtain novel insights into neural activity across arousal states. First,we will determine the activity of localized networks within CA1 across arousal states and during conditions when homeostatic sleep pressure can be expected to differ, such as early in the """"""""lights on"""""""" period vs. early in the dark period and in response to sleep deprivation and subsequent recovery sleep. Concurrent measurement of the activity of hundreds of cells in conjunction with the EEG will enable us to not only follow the activity of individual cells across sleep and wakefulness, but also to evaluate synchrony within the local network with respect to EEG frequencies and specific EEG events. Having defined the parameters of the hippocampal network in wildtype mice, we will then determine the activity of local networks within CA1 in a mouse model of Huntington's disease (HD). We have recently characterized changes in sleep and wakefulness and in the EEG of the R6/2 mouse model of HD and found both tremendously increased power in the theta range and slowing of the theta peak frequency (TPF) as disease progresses. Using theta power and TPF as biomarkers, we will exploit the power of the Inscopix technology to enable long-term recordings of identified neurons to determine how the hippocampal network is reorganized as disease progresses in R6/2 mice. The ability to observe calcium dynamics of hundreds of cells while simultaneously recording EEG in freely-behaving mice may lead to new insights into the role of the hippocampus in behavioral states and the network changes that occur in the hippocampus in HD.

Public Health Relevance

This exploratory proposal will combine telemetric recording of EEG and EMG activity with an exciting new technology that enables imaging of the activity of tens to thousands of neurons simultaneously in local brain regions of freely-moving animals for periods of weeks to months. In this particular application, we will measure the activity of the hippocampal network across arousal states under conditions in which homeostatic sleep pressure varies either spontaneously or in response to sleep deprivation. This approach will enable us to assess the stability of the hippocampal network over time. Using this information as a baseline, we will then assess the integrity of the hippocampal network as cognitive, emotional and motor impairment progresses in the R6/2 mouse model of Huntington's disease. The ability to observe calcium dynamics of hundreds of cells while simultaneously recording electrophysiological activity in freely-behaving animals may lead to new insights regarding the role of the hippocampus in behavioral states and in Huntington's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
He, Janet
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Sri International
Menlo Park
United States
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Williams, Rhîannan H; Vazquez-DeRose, Jacqueline; Thomas, Alexia M et al. (2018) Cortical nNOS/NK1 Receptor Neurons are Regulated by Cholinergic Projections From the Basal Forebrain. Cereb Cortex 28:1959-1979
Black, Sarah Wurts; Yamanaka, Akihiro; Kilduff, Thomas S (2017) Challenges in the development of therapeutics for narcolepsy. Prog Neurobiol 152:89-113
Schwartz, Michael D; Kilduff, Thomas S (2015) The Neurobiology of Sleep and Wakefulness. Psychiatr Clin North Am 38:615-44