Kaiwen Kam - US grants

[unreadable] DESCRIPTION (provided by applicant): Breathing is a remarkable behavior in vertebrates that mediates gas exchange to support metabolism. Failure to maintain a normal breathing rhythm in humans suffering from disorders such as sleep apnea, Rett syndrome, and perhaps sudden infant death syndrome, leads to serious adverse health consequences, even death. Various neurodegenerative diseases, such as Parkinson's disease, multiple systems atrophy and amyotrophic lateral sclerosis are associated with sleep disordered breathing that may result from the specific loss of neurons in brain areas controlling respiration. Control of breathing lies in the brain stem, where the preBotzinger Complex is both necessary and sufficient to generate respiratory rhythm. preBotzinger Complex bursting produces inspiration, while the interburst interval determines expiratory duration. Remarkably, changes in excitability can produce a fifty-fold range of frequencies by specifically tuning the length of the interburst interval. To determine the mechanisms underlying the dynamic modulation of interburst interval by excitability in the preBotzinger Complex, I propose 3 SPECIFIC AIMS-exploiting validated in vitro models of breathing-that will advance our understanding of the neural control of expiratory duration in respiratory rhythmogenesis. AIM 1: While neither pacemakers nor inhibition are essential for rhythm generation in the preBotzinger Complex, these elements may1 play a role in the effects of excitability on interburst interval. I will determine whether blockers of pacemaker currents or inhibition change the response curves. AIM 2: To determine whether the recruitment of active neurons defines the interburst interval and accounts for the cascade of excitation postulated by the group-pacemaker hypothesis, I will monitor the spontaneous activity of preBotzinger Complex neurons using optical imaging of calcium sensitive dyes. AIM 3: The preBotzinger Complex may employ different mechanisms for rhythm generation depending on excitability. I will investigate whether different mechanisms control expiratory duration at high and low frequencies by comparing temporally evolving intrinsic conductances at multiple time points during the interburst interval. These experiments will elucidate the organization and behavior of a fundamental rhythmic neural circuit, necessary for life. Public health relevance - In humans, continuous breathing from birth is essential to life and requires that the nervous system generate a reliable and robust rhythm. The proposed studies will significantly advance our understanding of the neural mechanisms underlying generation of respiratory rhythm and shed light on human disorders of breathing: [unreadable] [unreadable] [unreadable]

Project Summary/Abstract There is a fundamental gap in understanding how neuronal function or dysfunction in specific inhibitory popula- tions in mammalian central nervous system translates into normal or altered behavior. Natural behavior, often expressed as movement, is generated by excitatory networks whose function is shaped by inhibitory ?-amino- butyric acid (GABA)-ergic and glycinergic neurons. Inhibitory dysfunction underlies a number of disabling neu- rodevelopmental disorders?many, e.g., Rett syndrome, with comorbid motor disturbances. Determining how inhibition shapes basic motor programs represents a strategy for understanding both normal network function and how malfunctioning networks might be repaired/treated clinically. Among basic motor behaviors, only for breathing has a localized rhythmogenic network, the preBötzinger Complex (preBötC), been identified. Within the preBötC are GABAergic and glycinergic neurons, presenting an inimitable opportunity to study the role of inhibition; that this can be done in a slice in vitro presents considerable technical advantages. Current approa- ches for studying inhibition extrapolate from small samples or ignore important heterogeneity within neuronal populations. Overlooked are inhibitory microcircuits?local, embedded networks of GABAergic and glycinergic neurons that target nearby inhibitory and excitatory neurons. Two long-standing obstacles to addressing the role of inhibitory microcircuits are the dynamic complexity that can emerge in neuronal networks and the inabi- lity to dynamically manipulate inhibitory microcircuits. To overcome these obstacles, we combine a conceptu- ally innovative approach, focused on minimal microcircuits, with a technically innovative solution, holographic photostimulation, capable of exciting or inhibiting specific groups of neurons within a population with excep- tional spatiotemporal resolution. Using these approaches in rhythmic medullary slices from transgenic mice, we test our central hypothesis that synaptic and network properties determine how preBötC inhibitory microcircuits control the dynamic repertoire of respiratory-related behaviors in three specific AIMS. In AIM 1, we determine how preBötC inhibitory microcircuits shape respiratory output. In AIM 2, we determine how synaptic and net- work mechanisms underlie the effects of preBötC inhibitory microcircuit activation. In AIM 3, we determine how microcircuit-microcircuit interactions expand the dynamic repertoire of the preBötC. The contribution of the proposed research is expected to be elucidation of specific mechanisms underlying control of breathing by pre- BötC inhibitory microcircuits. This contribution is significant because determining these mechanisms is neces- sary for understanding how inhibitory microcircuits shape breathing in health and disease and are themselves regulated as targets of other circuits to generate complex respiratory-related behaviors. The overall impact of this proposal will be to reveal basic neural circuit mechanisms controlling a vital behavior, demonstrate the potential of dynamic patterned manipulations for dissecting neural circuits, pave the way for understanding more complex behaviors, and possibly uncover general principles of inhibitory microcircuit function.