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Breathing is the rhythmic motor behavior which maintains homeostasis by driving gas exchange between our blood and the atmosphere. This behavior is essential for life in all terrestrial mammals. This behavior involves two distinct but coupled rhythms: the inspiratory rhythm, the normal breathing rhythm that occurs on the order of seconds, and the sigh rhythm, which produces large amplitude breaths that occur on the order of minutes and maintain pulmonary function. The rhythm for both behaviors and their control originates in a specialized neuronal region of the ventral medulla called the preBötzinger complex (preBötC). While we know the anatomical region that generates these behaviors, the mechanism by which they are generated remains the subject of debate. We used a suite of experiments that utilized transgenic mouse models to falsify a long-standing theory that auto-rhythmic neurons are essential in generating the inspiratory rhythm. Concurrently, we developed a mathematical model which predicts the sigh rhythm emerges due to intracellular calcium oscillation. These findings have led us to investigate the inspiratory rhythm as an emergent network property. This dissertation investigates the underlying network structure of the preBötC by modeling its constituent neurons using a spiking model. The network is driven by neurons that fire stochastically, but none are intrinsically autorhythmic properties. First, we show that synaptic topology influences the ability of a network to form burstlets, a phenomenon that underlies inspiratory rhythmogenesis, the ability of a network to trigger network excitation exogenously, and the robustness of network function. We were able to recapitulate several experimental findings with our model and show that an Erdős–Rényi network with log-normally distributed synaptic weights provides the highest fidelity. Finally, we implement intracellular calcium oscillations within the consitutent neurons of the network to create the first spiking model of the preBötC that can produce burstlets and sighs. This model could help explain respiratory pathologies, such as opioid-induced respiratory depression, and provide insights the other brain rhythmics.

Essential tremor (ET) is a common movement disorder resulting in a postural and kinetic tremor that predominantly affects the upper extremities and varies in amplitude across patients. The etiology of ET is unclear; however, three predominant hypotheses exist. The first hypothesis evaluates rhythmical dysfunction originating from the inferior olivary nucleus that is then propagated throughout the brain and ultimately manifests as tremor. The second hypothesis evaluates γ-aminobutyric acid dysfunction as a causal explanation for ET while the third hypothesis evaluates gross cortical and cerebellar changes that result in ET. The beta-adrenergic blocking medication propranolol and barbiturate primidone are staples for the treatment of this disorder, but often fail to adequately control symptoms. primidone specifically has intolerable side effects for many patients. Ethanol, however, can more effectively treat tremor via a mechanism likely explained by one or more of the aforementioned hypotheses. However, it is not a practical therapeutic option for the treatment of ET primarily as a result of its intoxicating properties among other reasons. Recent attention to the long chain alcohol 1-octanol and its primary metabolite octanoic acid yielded findings of tremorlytic properties, albeit at doses that limit practicality. This study looks to evaluate octanoic acid as an adjunct to primidone and propranolol for the first time and will attempt to demonstrate that as an adjunct, it can be used at lower, more practical doses.

Information is processed in the mammalian cortex through both long-range and local circuits. Our understanding of how neurons in cortical circuits are arranged to process and route these sensory, motor, associative signals during behavior is limited. Here, \textit{in vivo} labelling and recording of projection neurons between primary and secondary mouse somatosensory cortex (S1 and S2) revealed shared and distinct information transfer between areas during a during context-dependent sensory processing task. Development and application of the novel CRACK platform to link the function and transcriptomic identity of hundreds of cells simultaneously revealed specific roles for molecular cell types within S1. The sensory-driven excitatory cell type Baz1a was found to maintain stimulus responsiveness during altered sensory experience and showed increased anatomical connectivity to somatostatin-expressing cells. This suggests Baz1a cells are situated to bias S1 towards bottom-up sensory inputs, answering a mechanistic question as to how the cortex can negotiate between feedforward and feedback input based on need. Together, these findings enhance our understanding of the cellular components and their roles in S1.

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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.

The relationship between neuron morphology and function is a perennial issue in neuroscience. Information about synaptic integration, network connectivity, and the specific roles of neuronal subpopulations can be obtained through morphological analysis of key neurons within any given microcircuit. Breathing is essential behavior for humans and all mammals, yet the neural microcircuit that governs respiration is not completely understood. The respiratory neural microcircuit resides within the ventral respiratory column located in the medulla. Within the respiratory column, the site of respiratory rhythm generation is the bilaterally distributed preBötzinger complex (preBötC). Rhythm-generating neurons in the preBötC are derived from a single genetic line, i.e., precursor cells expressing the transcription factor Developing brain homeobox-1 (Dbx1). An analysis of over 40 dendritic morphological features of rhythmogenic Dbx1 preBötC neurons and putatively premotor Dbx1 neurons in the intermediate reticular formation, revealed these two populations are similar except reticular neurons have a larger dendritic diameter, which may contribute to a greater passive transmembrane conductance. Both populations showed commissural axon projections and reticular formation neurons show premotor-like projections to the XII motor nucleus. These morphological data provide additional evidence supporting bilateral synchronization the preBötC through Dbx1 neurons, and demonstrate that Dbx1 preBötC neuron connectivity includes recurrent interconnections. On the molecular level, the ion channels that mediate rhythm-generating whole-cell ion currents have not been not identified, and were investigated using principally an anatomical approach. The nonspecific cation current, ICAN, underlies robust inspiratory drive potentials in the preBötC and the persistent sodium current, INaP may play a role in the production of robust bursts when respiration is challenged in such cases as anoxia or hypoxia. The leading candidate for ion channels that contribute to ICAN belong to the transient membrane receptor (Trp) ion channel superfamily and the leading ion channel candidate for INaP is Nav1.6. I determined the presence of Trpc3 ion channels and Nav1.6 ion channels on Dbx1 preBötC neurons (as well as their expression in neighboring non-Dbx1 preBötC neurons). Finally, breathing behavior involves periodic sighs, which are slower than normal eupneic breathing but critical for lung function. I examined receptor expression for bomebsin-like peptides neuromedin B (NMB) and gastrin releasing peptide (GRP), which are important for sigh behavior. I show that NMB and GRP receptors are expressed in Dbx1 preBötC neurons and are not expressed by glia in the preBötC, as posited by some because of the low frequency of sigh breaths. These advances in morphological and anatomical knowledge can be used to design targeted in vitro and in vivo experiments to further explore their role in respiratory rhythm and pattern generation.

Despite decades of empirical investigation, there remains active debate about the limitations to dual-task processing. The primary aim of the present research was to determine the roles of attentional and response-set components of task-set in dual-task processing. Through three experiments, we explored the relationships between attentional- and response-set switching in the context of a classic dual-task paradigm. Experiment I (N = 68) validated our novel integration of a dual-task task-switching paradigm. Experiment II (N = 64) replicated and extended Experiment I by integrating a single task subsection of the procedure. Finally, Experiment III (N = 23) integrated electroencephalographic measures of the P3 and lateralized readiness potential (LRP) in attempts to further our understanding of these complex cognitive functions. Results support the robustness of the psychological refractory phenomenon and task-switching resource costs. Evidence supports that both attentional task-set and response-set components possess unique variance in reaction times. Further, the data suggests that attentional task-set selection processing does not allow for parallel processing. Electrophysiological evidence fails to falsify the proposed attentional task-set bottleneck theory. Implications of these results address contemporary disagreements and inconsistencies in the extant literature.

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