ORCID ID

0000-0003-4139-0642

Date Awarded

Summer 2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Applied Science

Advisor

Christopher A Del Negro

Committee Member

Gregory D. Smith

Committee Member

Joshua A Burk

Committee Member

Silvia Pagliardini

Abstract

Breathing is a rhythmic motor behavior essential to sustain homeostasis and life itself in humans and all terrestrial mammals. A specialized neuronal network is responsible for generating and controlling the rhythm and pattern for breathing. The core rhythm-generating microcircuit in particular is located within a site dubbed the preBötzinger complex (preBötC). The preBötC is a heterogeneous region containing neurons with both respiratory and non-respiratory activity that express excitatory and inhibitory transmitters, peptide transmitters and peptide receptors. More recently, preBötC neurons have been characterized by molecular genetics. The markers historically used to define the respiratory CPG within the preBötC intersect with an embryonic transcription factor, developing brain homeobox 1 (Dbx1). Our lab, and our French colleagues, hypothesized that neurons derived from the Dbx1-expressing precursor cells (hereafter referred to as Dbx1 neurons) form the core microcircuit for inspiration breathing rhythm, that is, the Dbx1 core hypothesis. Evidence from many labs supports the role of the Dbx1 core hypothesis at embryonic and neonatal stages of development. However, the role of Dbx1 neurons in adult animals remains incompletely understood. Furthermore, contemporary data suggests the portfolio of functions for brain stem Dbx1 neurons includes premotor and arousal-related functions, which casts doubt on the veracity of the Dbx1 core hypothesis. Here I investigate the role of Dbx1 neurons in adult animals with intact sensorimotor integration systems using intersectional mouse genetics to express light-responsive membrane proteins to excite or depress Dbx1 neurons while simultaneous measuring breathing. Using these light-sensitive proteins to manipulate Dbx1 neuron function, I offer evidence that affirms the Dbx1 core hypothesis by depressing or stopping breathing, enhancing breathing, and altering breathing timing. I conclude that .... Knowing the cellular point of origin for breathing behavior gives us a target to study the cellular and synaptic mechanisms this key physiological behavior and provides general insight into rhythmic networks and physiological brain function.

DOI

http://dx.doi.org/10.21220/s2-gs50-4r43

Rights

© The Author

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