The long term goal of our research team is to understand how brain stem motor circuits that control life sustaining autonomous breathing patterns develop, mature and maintain rhythmic neural activity. It is also relevant to determine how these circuits respond to abnormal environments and stress. This project proposes to use a new experimental model system to explore the location(s), synaptic physiology, and plasticity of breathing-related central pattern generators (CPGs) in the isolated Zebra Finch brain stem during early development. The avian embryonic model is uniquely tractable for experimental manipulation and provides unparalleled access to central neuronal networks throughout prenatal development. We will use anatomical techniques, nerve cell activities, and pharmacology to test our hypotheses in the context of understanding normal breathing behaviors and breathing-related neuropathologies in which the modification or loss of brain stem structures that control normal rhythm and motor patterns can lead to increased morbidity and mortality in neonates and adults. Importantly, funds from this proposal will introduce students to Biomedically-based research at Idaho State University (ISU) using hands-on lab experiences and focused individual training in a variety of professional and scientific practices. We seek to address three key aspects associated with the field of developmental neurobiology and the control of breathing: 1. Identification of spatially separate respiratory-related brain stem CPGs.
Aim 1 will test the role of the avian nucleus paraambiguus (PAm) and the retroambiguus (RAm) in the neurogenesis of automatic breathing rhythms. Historically, in vitro studies have focused on the inspiratory phase. Yet, the breathing cycle involves both inspiration and expiration. Since birds employ active inspiration and active expiration, even at rest, we hypothesize that avian embryos at the internal hatching stage (i.e., when continuous air-breathing begins) generate breathing rhythms with two independent yet coupled CPGs, similar to the situation in exercising humans when high levels of ventilatory drive is necessary. 2. Mechanisms of burst generation and pattern formation in the avian brain stem.
Aim 2 will test the hypothesis that respiratory-related CPG behavior in birds is critically dependent on inhibitory synaptic input, similar to many network-based locomotor CPG circuits. Specifically, we hypothesize spontaneous rhythms will be critically dependent on chloride-mediated neurotransmission as a mechanism to control duty cycles for breathing pattern. As an alternate hypothesis, we will test the role of endogenous pacemaker mechanisms in the maintenance and shape of respiratory-related CPG output.3. Mechanisms of homeostatic/developmental plasticity in the breathing-related brain stem.
Aim 3 will test how persistent embryonic manipulations of rhythmic electrical activity with and without manipulations of specific neurotransmitters may alter the developmental expression of CPG behavior as well as the phenotype of neurotransmitter systems that support breathing.

Public Health Relevance

The human health relevance of the research described here is twofold: First, the information will be used to encourage interest and provide practical hands-on and minds-on scientific experiences to undergraduate and graduate students at Idaho State University who are interested in research careers in the Biomedical Sciences. Our second objective is to define mechanisms responsible for breathing-related health and disease during prenatal development, when chemical communication in the nervous system must reliably generate and maintain a motor program to produce inspiratory and expiratory activity. We reason that significant knowledge will be obtained, which will ultimately aid in the development of effective clinical treatments (and effective clinicians) to better address pathological respiratry control early in life.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-MDCN-R (86))
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Gnadt, James W
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Idaho State University
Schools of Arts and Sciences
United States
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Pickett, Kaci L; Stein, Paxton S; Vincen-Brown, Michael A et al. (2018) Maturation of Breathing-Related Inhibitory Neurotransmission in the Medulla Oblongata of the Embryonic and Perinatal Zebra Finch (Taeniopygia guttata). Dev Neurobiol 78:1081-1096
Vincen-Brown, Michael A; Whitesitt, Kaitlyn C; Quick, Forrest G et al. (2016) Studying respiratory rhythm generation in a developing bird: Hatching a new experimental model using the classic in vitro brainstem-spinal cord preparation. Respir Physiol Neurobiol 224:62-70
Vincen-Brown, Michael A; Revill, Ann L; Pilarski, Jason Q (2016) Activity-dependent plasticity in the isolated embryonic avian brainstem following manipulations of rhythmic spontaneous neural activity. Respir Physiol Neurobiol 229:24-33