Modulation of Network Feedback Shifts the Locus of Rhythm Generation

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Central pattern generator (CPG) networks control important rhythmic behaviors such as chewing, breathing, and locomotion. CPGs must continuously adapt to physiological and environmental challenges, conveyed via sensory pathways, to maintain healthy function. Dysfunction of CPGs or their inputs due to neurological disorders or stroke-induced damage alters CPG function and adaptability, which decreases health and quality of life. One way in which CPG networks adapt is through changes in the spatial distribution of their active components, such as mammalian respiratory CPG activity varying along a brainstem column. However, little is known about the cellular-level mechanisms by which sensory pathways trigger changes in the spatial distribution of CPGs, and how such changes may alter the mechanisms of rhythm generation. Sensory pathways influence CPGs directly or by activating projection neuron inputs to CPGs. Projection neuron activity, which is further regulated by synaptic feedback from their target CPGs, determines CPG output. CPG feedback strength is flexible, and feedback can link different nervous system regions. Thus, the central hypothesis of this proposal is that sensory modulation of CPG feedback can alter rhythm generation locus and mechanism. Small invertebrate neural networks have enabled much insight into network plasticity due to having fewer neurons with well-described connectivity, and complete CPGs that can be maintained in vitro. In this proposal, an in vitro stomatogastric nervous system (STNS) preparation from the crab (Cancer borealis) will provide exceptional access to identified sensory, chewing CPG, feedback, and projection neurons. Sensory activation of distinct chewing rhythms, photoinactivation of identified neurons and neuronal compartments, hybrid computational-biological networks, and independent manipulation of local and distant synaptic actions of a feedback neuron will be used to identify cellular and synaptic mechanisms controlling rhythm generation locus in different modulatory states. It is expected that a novel mechanism for altering CPG spatial distribution will be identified, namely modulation of CPG feedback strength and incorporation of this feedback into rhythm generation. It is further predicted that altering rhythm generation locus in this manner is a novel mechanism for regulating the access of sensory pathways to a motor system. An increased cellular-level understanding of the dynamics of rhythm generation locus is important for future investigation into how damage or dysfunction may change CPG adaptability. Identifying novel principles in a small well-defined system will guide studies of interactions between sensory and CPG feedback pathways that regulate CPG spatial distribution in larger nervous systems during both functional and dysfunctional states. Further, this proposal will provide research and networking opportunities for students, including experience in cutting-edge electrophysiological techniques, quantitative data analysis skills, and oral and written scientific communication skills, helping to fill a large, unmet demand for neuroscience research opportunities at Miami University.