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Abstract: Sensory hair cells transmit auditory and vestibular information to the brain. While many forms of hearing loss result from hair cell death, increasing evidence shows that noise-induced and age-related hearing loss often stem from synaptic damage. Restoring hearing in these cases will require rebuilding synaptic connections, which depends on understanding how sensory synapses form and function in vivo. Our work combines genetics, CRISPR-based mutagenesis, and live imaging in zebrafish neuromast hair cells to define the molecular and activity-dependent mechanisms that drive synapse formation, function, and regeneration. By visualizing synapses in a live, transparent system, we aim to uncover principles that guide the restoration of hair cells and their synaptic connections after damage.
The goal of research in the Sawtell laboratory is to forge detailed links between the properties of neural circuits and their functions. Our studies of weakly electric fish have shown how a specific form of synaptic plasticity operating within a well-characterized cerebellum-like circuit functions to predict and cancel out sensory inputs generated by the animal’s own behavior. Such a process could allow behaviorally relevant sensory inputs, e.g. those generated by predators or prey, to be processed more effectively. This work provides a mechanistic account of how copies of motor commands are transformed into specific predictions of sensory events as well as insights into the function of the cerebellar granular layer. A tight coordination of experimental and theoretical approaches is a key aspect of the lab’s approach. Experimental work involves intra- and extracellular recordings from identified neuron classes in awake, behaving fish. Theoretical work is performed in collaboration with Larry Abbott’s group at the Center for Theoretical Neuroscience at Columbia University.
Abstract:
To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because the majority of mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a large portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. New data suggests this regulation supports cell body based and local mitochondrial biogenesis at the synapse which we hypothesize work together to support distal mitochondrial populations. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.
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Abstract: Odors – chemical signals from the environment – are primary sensory drivers of behavior in most animal species and provide information essential to survival. In mammals, olfactory sensation is linked to inhalation, which delivers external odorants to olfactory sensory neurons (OSNs). There is strong evidence that both the identity of OSNs activated by an odorant and their timing of activity relative to inhalation are important features of the neural mechanisms underlying olfactory sensation, but how such features are determined by odor identity, odor concentration and odor sampling (i.e., inhalation) remains unclear. In this seminar, I will review work from our laboratory that characterizes the determinants of OSN responses across a large fraction of the sensory neuron population in vivo, as well as the transformation of sensory input patterns by olfactory bulb circuitry. This work has led to the surprising conclusion that the rapid conversion of one odorant to another by nasal enzymes profoundly shapes neural representations of odor identity and underlies much of the diversity in temporal dynamics of sensory responses. I will discuss the implications of these results for reconsidering the role of timing in odor coding and the potential for external versus internally-generated odors to differentially drive sensation and behavior.
To schedule a seminar speaker, please contact James Murray and Jenna Penny