William D. Hendricks - US grants

Project Summary Epilepsy is a chronic condition that can develop after various neurological insults, including traumatic brain injury, stroke, and infection. However, despite years of study, the mechanism for the development of epilepsy from an initial neurological insult has remained elusive. In the hippocampal dentate gyrus, seizures drive pathologic retrograde sprouting of granule cell mossy fiber axons. Although sprouting may contribute to epileptogenesis, the physiologic consequences of mossy fiber sprouting are unknown. Additionally, the dentate gyrus is a locus for adult neurogenesis and adult-born granule cells might directly give rise to sprouted mossy fibers, though this is widely debated and unresolved. In our hands, preliminary data has indicated that adult- born granule cells do give rise to sprouted mossy fibers, which form large boutons in the inner molecular layer of the dentate gyrus. Moreover, whole-cell patch clamp recordings from mature granule cells indicate that these adult-born neurons functionally contribute to recurrent excitatory circuitry. The goal of this project is to better understand mechanisms that contribute to hippocampal hyperexcitability and provide a targetable mechanism for future treatments to prevent epileptogenesis. Our overall hypothesis is that adult-born granule cells provide the bulk of mossy fiber sprouting and that these aberrant synapses create recurrent microcircuits that drive runaway excitation within the hippocampus. This hypothesis will be tested using the pilocarpine model of epilepsy and transgenic labeling of age-defined cohorts of granule cells in mice. Mossy fiber sprouting will be quantified by immunofluorescent staining of granule cells, and whole-cell electrophysiology will be used to detect recurrent circuits and interrogate the sprouted synapse using optogenetic stimulation of granule cell cohorts. The specific aims of this proposal independently examine the contribution of adult-born granule cells to mossy fiber sprouting and the physiological properties of a sprouted synapse. Furthermore, this proposal investigates whether silencing of sprouted mossy fibers can attenuate the hippocampal hyperexcitability that is associated with epilepsy. Taken together, this proposal aims to understand circuit rearrangements functionally affect the epileptic hippocampus, so that future treatments can target the disease of epilepsy, rather than the symptoms.

Project Summary In mammalian neocortex, sensory stimulation evokes highly structured patterns of neural activity. How groups of neurons with specific patterns of neural activity encode information is a question remaining at the forefront of systems neuroscience. Recurrent connections between cells with similar response properties are proposed to amplify stimulus features and serve as building blocks of neural ensembles, but how competing ensembles encoding different stimulus features interact to form a single coherent percept is unknown. In the case of vision, natural visual scenes are often comprised of multiple stimulus features that represent the subject or the background of a visual scene, each of which evoke competing and overlapping ensembles. Therefore, a fundamental computational problem for the brain is the parsing of salient features from the background of a visual scene. Cortical circuits must be able to quickly determine features that correlate to the primary figure and amplify ensembles encoding representation of those features. The overall hypothesis of this proposal is that like-to-like inhibition, mediated by somatostatin-expressing interneurons, suppresses competing ensembles to amplify ensembles encoding unique stimulus features. I hypothesize these mechanisms underly canonical cortical computations, such as surround suppression, as well as visual perceptual phenomena, such as figure-ground segregation. To test this hypothesis, this study uses a combination of in vivo holographic optogenetics, 2-photon calcium imaging, and behavioral assays in an effort to understand the mechanisms underlying the neural basis of perception. The specific aims of this project independently examine the circuit basis of orientation selectivity of surround suppression and tests whether these circuits are a neural correlate of figure-ground perception in mouse primary visual cortex. Taken together, these experiments will test the more fundamental ideas of the nature of neural circuits involved in perception and how percepts are represented in the brain. This proposal will therefore provide a basis for understanding psychiatric and neurological diseases that have yet eluded mechanistic understanding and medical treatment.