Current Research Projects
CRCNS: State-dependent Neural Mechanisms for Respiratory Pattern Generation
PI: Dr. I. A. Rybak (Drexel U
College of Medicine). |
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| Abstract: Generation of the
respiratory motor pattern is performed in the lower brainstem and involves complex
cross-level interactions of cellular, network, and systems-level mechanisms. Because of
these complex interactions, the system can operate in different functional states and
engage different rhythmogenic mechanisms in each state. We hypothesize that the
rhythmogenic mechanism operating in the respiratory network (i.e., network-based,
pacemaker-driven or hybrid) is defined by the state of the pre-Bötzinger complex, which
in turn operates under control of other medullary and pontine circuits. We also suggest
that the pons controls the state of the pre-Bötzinger complex (and hence the rhythmogenic
mechanism) directly and/or through other medullary circuits, such as the Bötzinger
complex. The overall goal of this
multidisciplinary collaborative project is to investigate and understand these complex interactions
and the state-dependency of respiratory rhythm generation by using experimental studies
combined with computational modeling. The experimental studies will be performed by Dr.
Smith (NINDS, NIH) and Dr. Paton (University of Bristol). The applied experimental
methods will include (1) reduction of the
operating respiratory network by sequential and highly precise transections applied to the
pons and medulla and (2) using specific blockers of intrinsic neuronal properties (e.g.,
persistent sodium and other ionic channels) and network interactions (e.g., inhibitory
synaptic transmission) applied to intact and reduced preparations. The computational model of the ponto-medullary
respiratory network will be further developed by the group of Dr. Rybak (Drexel
University) in close interactive collaboration with Drs. Smith and Paton using data
accumulated in their laboratories. In turn, complementary experimental studies in these
laboratories will be driven by modeling predictions. The resultant comprehensive computational model
will be developed, tested and elaborated to reproduce the experimentally observed
state-dependent changes in the firing patterns of respiratory neurons and in the discharge
patterns of output motor nerves (phrenic, hypoglossal, central vagal and abdominal) under
different experimental conditions. The proposed collaborative study will provide important
insights into the complex neural mechanisms for control of breathing Ultimately, the model
that will be developed in this project may be used for simulation of multiple respiratory
disorders and diseases (e.g., sleep apnea,
brainstem/spinal cord injury, CCHS), and for developing and investigations new methods for
their treatment. |
Spinal Control of Locomotion: Studies and Applications
PI:
Dr. I.
A. Rybak (Drexel U College of Medicine). |
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| Abstract: This Bioengineering Partnership brings together a multidisciplinary team of neuroscientists and engineers with complementary expertise in neural organization of the spinal cord (Dr. David McCrea, University of Manitoba), biomedical engineering and neuromuscular stimulations (Dr. Michel Lemay, Drexel University), physiology and biomechanics of locomotion (Dr. Boris Prilutsky, Georgia Institute of Technology), and computational neuroscience and neural control (Dr. llya Rybak, Drexel University). The goals of this project are (1) to perform a comprehensive multidisciplinary study of neural mechanisms in the mammalian spinal cord responsible for generation of the locomotor pattern and control of locomotion and (2) to find optimal strategies for restoring locomotor function after spinal cord injuries. In this project, two comprehensive databases will be created based on experimental studies of fictive locomotion in the decerebrate cat and on biomechanical studies of freely moving uninjured cats and spinal cats. These databases will be used for the development of (1) a computational model of neural circuitry of the spinal cord responsible for generation and control of the locomotor pattern and (2) a neuro-musculo-skeletal model of cat's locomotion. Special quantitative biomechanical criteria will be developed for evaluation of locomotor capabilities of spinal cats during and after implementation of different treatments for restoring the locomotor function. The computational models and biomechanical criteria developed will provide guidance for the applied treatments and evaluation of their results. Different strategies for the restoration of locomotor capabilities based on the combination of locomotor training on a treadmill with phase-dependent electrical stimulation of the selected sensory afferents will be implemented and investigated. The results of this project will provide significant insights into spinal mechanisms responsible for control of locomotion and will represent an important step toward the development of optimal and effective methods for restoration of locomotor function after various spinal cord injuries. |
Computational Study of the Respiratory Brainstem
PI: Dr. B. G. Lindsey
(University of South Florida). |
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| Abstract: Understanding the control of breathing is an important goal in integrative biology and medicine. Sleep disorders in newborns and adults that disrupt breathing have been implicated in the development of pulmonary and systemic hypertension and other disorders and risks. The goal of this collaborative project is to develop a unified model of the brainstem respiratory network and to identify potential sites where abnormalities can disrupt breathing and its control. Detailed biophysical and large-scale simulations will guide associated in vivo and in vitro neurophysiological and pharmacological experiments to test model-based hypotheses on sub-cellular, cellular, network and systems level mechanisms that transform the respiratory network during the transitions between eupnea and hyperventilation apnea, from eupnea to gasping, and during sleep and waking. Experimental feedback will be used to iteratively tune the model. The project has five aims: 1. Develop a comprehensive computational model of the ventrolateral medullary "core" respiratory network and use it as a tool for interactive modeling/experimental studies on the neural control of breathing. 2. Evaluate interactions among the medullary central pattern generator (CPG), the pontine respiratory group, the nuclei of the solitary tract, and the raphe nuclei. 3. Elucidate mechanisms underlying network reconfiguration and the respiratory motor patterns associated with transient changes in chemical drive and gasping. 4. Identify inputs to the pontine-medullary respiratory network that can produce the respiratory motor patterns observed during the sleep-wake cycle and that can cause sleep apnea. These inputs or their absence are ultimately responsible for sleep disorders. 5. Test biophysical, cellular, and network mechanisms for a) rate and synchrony "coding" and network stability. This project will bring together researchers from universities in five states. Members of the group have a common interest in the control of breathing, complementary areas of expertise, large and growing experimental databases, and long-standing collegial relationships. The project will be a catalyst for the development and sharing of advanced multi-array recording technologies and computational methods, modeling and simulation tools, and large data sets. |
PI: Dr. D. R. McCrimmon
(Northwestern University). |
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| Abstract: Identifying the neuronal circuitry responsible for respiratory rhythm generation has been a search that can be traced back to the late 18th and early 19th centuries when Lorry and then Legallois isolated the essential circuitry to the rostral medulla (q.v., Feldman & McCrimmon, 1999). Recent conceptual breakthroughs in our understanding of respiratory rhythm generation have emanated from the use of in vitro preparations. Particularly relevant to the present proposal is the hypothesis advanced by Smith et al (1991) that neurons within a small region of the ventrolateral medulla, termed the preBötzinger complex, contain the kernel, or basic circuitry for respiratory rhythm generation. This idea has been a focus of considerable recent research both in vitro and in vivo. Although the role of this region in rhythm generation (especially in vivo) is still under contention (q.v., St. John, 1996), this and many other laboratories have contributed evidence that provides increasing support for the unique nature of the preBötzinger complex and its potential importance to rhythm generation. Important recent additions to this picture include the demonstration that substance P (neurokinin-1; NK1) receptors appear to be preferentially colocalized on respiratory neurons in the preBötzinger complex (Gray et al, 1999), and the fact that selective ablation of these NK1 receptive neurons disrupts respiratory rhythm in unanesthetized rats (Gray et al, 2001). As a result, several laboratories have begun to focus on the role of these neurons by identifying their neurotransmitter and morphological phenotypes (Makeham et al, 2001; Wang et al, 2001; Liu and Wong-Riley, 2001). Despite this progress, an understanding of how respiratory rhythm is generated awaits a comprehensive description of the pertinent properties and network interactions of the relevant neurons. In a region the size of the preBötzinger complex (in the rat it is approximately 0.6 mm long and about 1.5 mm in diameter, including dendrites), it is within our means to provide a detailed and comprehensive analysis in which the classes of constituent respiratory neurons are defined in vivo, based on a combination of functional criteria including their discharge patterns, neurotransmitter content, and synaptic interactions. Such an undertaking is justified by the central role of the preBötzinger complex in research on respiratory rhythm generation and by the need for a clear understanding of its role within the larger framework of the ventral respiratory group of the ventrolateral medulla. The focus for this application will be to define the preBötzinger circuitry that produces changes in respiratory rhythm during activation of selected afferent pathways including those with large myelinated pathways in the vagus and superior laryngeal nerves. Activation of these pathways elicits stereotypic changes in respiratory rhythm. Accordingly, with respect to the preBötzinger complex, we are proposing to answer the following questions: 1) What unique neuronal phenotypes are defined by a combination of discharge patterns, response patterns during afferent perturbations of respiratory rhythm, neurotransmitter content, and synaptic interactions with other preBötzinger neurons? 2) Which of these neuron subtypes are key elements in the control of inspiratory termination, expiratory termination and the control of inspiratory and expiratory durations? |
Selected projects:
Requirements: PhD degree, experience in modeling of single neurons
(Hodgkin-Huxley style) and biological neural networks, and strong C++ programming skills.
Experience in the analysis of nonlinear systems is an advantage. |
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Rybak
Last updated 01/01/08