Date Thesis Awarded

5-2024

Access Type

Honors Thesis -- Access Restricted On-Campus Only

Degree Name

Bachelors of Science (BS)

Department

Neuroscience

Advisor

Christopher A. Del Negro

Committee Members

Gregory Conradi Smith

Christy Porter

Paul Kieffaber

Abstract

This computational study delves into the neural mechanisms governing opioid-induced respiratory depression (OIRD) within the preBötzinger complex (preBötC). The preBötC, in the lower brainstem, functions as the rhythm generator for breathing in humans and all mammals. Neurons of the preBötC comprise the respiratory central pattern generator, producing the rudimentary rhythm and pattern for inspiratory breathing movements. Despite the evolutionary conservation and robustness of this neural oscillator, its Achilles heel is sensitivity to opioid drugs. Here, we present a project assessing the preBötC function relevant to OIRD.

Previously, we presented a firing rate activity model of the preBötC that exhibits episodic bursting mediated by the combination of recurrent excitation, synaptic depression, and cellular adaptation (Borrus et al., 2024). To investigate the pre-synaptic and post-synaptic effects of opioids on the preBötC, we extended this model to include two populations that either lack or express the mu-opioid receptor (MOR- and MOR+, respectively), demonstrating synchronization under varying intrinsic excitability of MOR+ neurons. Parameter studies explore how pre-synaptic suppression of excitation, post-synaptic decreases in excitability, and MOR+/- population sizes may contribute to OIRD.

Notably, modulating MOR+ excitability slows down the entire system, impacting both MOR- and MOR+ populations. Our findings indicate that inspiratory frequencies decrease with depression of intrinsic excitability, possibly due to the activation of G-protein-gated inwardly rectifying potassium (GIRK) channels. Post-synaptic inhibition analysis reveals that a MOR+ population size exceeding 50% is necessary for opioids to depress rhythmicity. Surprisingly, weaker MOR+ to MOR- connections render the system more sensitive to opioids, possibly because weaker connections render smaller-amplitude activities and higher firing thresholds during inspiratory bursts.

Future investigations should consider incorporating calcium channel dynamics and additional respiratory rhythms, such as sigh rhythms, to enhance the model's comprehensiveness. Furthermore, exploring the modulation from MOR- to MOR+ populations and refining synaptic weight interactions could improve the model's accuracy. Despite its limitations in representing these aspects, our model is able to show that the MOR+ population slows the entire preBötC system down and contribute to our understanding on the effects of population size and MOR+ synaptic strength on OIRD.

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