Title

Characterizing co-modulation of multiple components of an oscillatory neural circuit

Date of Award

Summer 2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biology - (Ph.D.)

Department

Federated Department of Biological Sciences

First Advisor

Farzan Nadim

Second Advisor

Dirk Bucher

Third Advisor

Jorge P. Golowasch

Fourth Advisor

Gal Haspel

Fifth Advisor

Eve Marder

Abstract

All nervous systems adapt to changes in the environment and the internal state of the animal. At any time, every stage of neuronal processing is actively shaped by a number of neuromodulatory substances to provide the neural circuit with this essential flexibility. The increasing number of neuromodulators identified in the nervous system across species clearly indicates that, at any given time, every neuronal circuit is subject to co-modulation by multiple substances. Although different neuromodulators usually activate distinct receptors, there is considerate convergence and interaction at subcellular, cellular and circuit levels. As such, neuronal circuit function, the resulting physiological output and ultimately the behavior depend on how multiple modulators act in concert, a topic that is poorly understood.

The combined actions of neuromodulators at the circuit output level depends on complex patterns of divergence and convergence at the level of synapses and ionic currents. To understand co-modulation at the network level, it is important to clarify the rules of co-modulation of these individual circuit components. This dissertation used the pyloric circuit in the stomatogastric ganglion (STG) of the crab Cancer borealis to address how flexibility is introduced to neural circuits by neuromodulation and co-modulation, with a focus on assaying the combined actions of multiple neuropeptides on various circuit components.

The first part of the dissertation explored and compared the quantitative rules of co-modulation on two circuit components: chemical synapses and voltage-gated ionic currents. A simple quantitative rule was examined simultaneously at these two components. This rule predicted the combined actions of two modulators as a linear summation of their dose-dependent individual actions, up to saturation. While this linear summation rule was valid for co-modulation of chemical synapses, co-modulation of the voltage-gated ionic current was distinctly sublinear.

The second part of the dissertation examined neuromodulation and co-modulation of the gap junction-mediated electrical coupling. Multiple neuromodulators were found to affect the electrical coupling conductance. Among them, multiple peptides modulated the electrical coupling conductance in opposite directions. Furthermore, when peptides with opposite actions were co-applied, their actions canceled each other out.

The third part of the dissertation assayed the dependence of the electrical coupling on the frequency of the voltage activity, and how neuromodulation influenced this frequency dependence. Driving the coupled neurons at different frequencies showed that the electrical coupling conductance exhibited resonance, a maximum strength at a nonzero frequency, that was distinct from the membrane potential resonance of the coupled neurons. In addition, the resonance of the electrical coupling was subject to neuromodulation and different peptides affected the resonance frequency in different directions.

This dissertation provided a useful entry point towards understanding how co-modulation shapes circuit dynamics by assaying the influences of modulators individually and in combination on multiple circuit components, in the context of neural oscillation.

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