Date of Award

8-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Gennady Cymbalyuk

Second Advisor

Ronald Calabrese

Third Advisor

Remus Osan

Fourth Advisor

Vladimir Bondarenko

Fifth Advisor

Yaroslav Molkov

Sixth Advisor

Astrid Prinz

Abstract

Life-supporting rhythmic motor functions like heart beating in invertebrates and breathing in vertebrates require indefatigable generation of a robust rhythm by specialized oscillatory circuits, Central Pattern Generators (CPGs). Yet, CPGs should be sufficiently flexible to adjust to changes of the environment and behavioral goals. Neuromodulation modifies the CPG’s rhythm by co-regulating multiple ionic currents, including the Na+/K+ pump current, Ipump. In the leech heartbeat CPG, endogenous neuropeptide myomodulin downregulates Ipump and upregulates Ih to speed up the CPG’s rhythm (Tobin & Calabrese, 2005). The interaction of these currents dramatically speeds up rhythm of the leech heartbeat CPG when Ipump is activated by increased internal Na+ concentration, [Na+]i, produced by application of monensin(Kueh et al., 2016a). Comodulation of Ipump and Ih supports the CPG’s functional activity in a wider range of the pattern’s cycle period and avoids dysfunctional regimes (Ellingson et al., 2021).

We anticipate that interaction of Ipump and persistent Na+ current, IP, produces a mechanism supporting functional bursting. Ipump is an outward current activated by [Na+]i and is a major source of Na+ efflux. IP is a low voltage activated inward current and is a major source of Na+ influx. Both currents are active between and during bursts. We apply a combination of electrophysiology, computational modeling, and dynamic clamp to investigate the role of Ipump and IP in the leech heartbeat CPG interneurons (HNs). Applying dynamic clamp, introducing additional Ipump and IP into the dynamics of a living synaptically isolated HN neuron in real time (Erazo-Toscano et al., 2021), we show that their joint upregulation produces transition into a new bursting regime characterized by higher spiking frequency and more depolarized base potential during the burst. Further upregulation of Ipump speeds up the HN rhythm by shortening burst duration and interburst interval.

In summary, dynamic interaction of Na+/K+ pump current with persistent Na+ current offers a mechanism of generation and regulation of robust and flexible pattern of bursting activity.

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