Hippocampal sharp-wave ripples are 150-250 Hz oscillations during slow-wave sleep or immobility during which large populations of hippocampal neurons sequentially replay activity patterns that occurred during exploration of the environment. Disruption of ripples during wakefulness disrupts working memory. Recent work has shown that many other extra-hippocampal brain regions are specifically activated during ripples, and this coordination of hippocampal and neocortical networks during ripples may be critical for learning and retrieval. Yet the precise identity of cell types across different neocortical regions and reliability of activation during ripples is not known. The Golshani Laboratory has recently developed a large cranial window preparation that allows us to perform systematic and unbiased calcium imaging of neurons across all brain regions extending from frontal to occipital cortex bilaterally. Here we propose to implant flexible electrode arrays developed by the Tolosa and Frank Labs as a part of the BRAIN initiative into the hippocampus in mouse implanted with the large cranial window. These flexible electrode arrays will be optimal for this purpose because they allow long lasting recordings of local field potential for >200 days; moreover, because they are flexible they can be shaped so they don't obscure the imaging window. We will first learn implantation of electrodes by visiting the Frank Lab at UCSF. We will then obtain flexible electrode arrays from the Tolosa Lab (10 arrays), and implant them into the hippocampus in Thy-1 GCAMP6s animals with the large cranial window. After assuring that we can perform low noise electrophysiological recordings and calcium imaging in head-fixed animals resting on the treadmill, we will train animals to perform a memory retrieval task. We will determine proportion of neurons in different cortical regions activated during ripples during the task and their reliability activation across days. This one year R03 will allow us to collect data showing feasibility of these experiments that we will use as preliminary data for a collaborative BRAIN initiative grant.
to Public Health: Understanding these interactions between the hippocampus and neocortex will be essential for dissecting the mechanisms underlying memory dysfunction in neurodegenerative and neuropsychiatric disease. In this proposal we combine electrophysiological recordings of hippocampal activity with large-scale calcium imaging in the neocortex through a large cranial window preparation. We will learn the identity of neurons co-activated with hippocampal sharp-wave ripple oscillations in cortex and quantify the reliability over days as animals perform memory-based decision making tasks.
