Gordon S. Mitchell

Plasticity in Respiratory Motor Control; Applications to Spinal Cord Injury, Sleep Apnea and ALS

E-mail: mitchell@svm.vetmed.wisc.edu

Research Strengths: Development: Plasticity and Repair, Membrane Excitability and Synaptic Transmission, Neurobiology of Disease

The primary focus of the Mitchell laboratory concerns mechanisms of neuroplasticity, particularly as it pertains to the respiratory motor control system. We investigate mechanisms of plasticity elicited by alterations in respiratory gases (adults and during development), exercise and neural injury. An underlying theme that has emerged from our work is that serotonin is a key molecule, initiating and orchestrating important forms of plasticity in respiratory motor nuclei, particularly in adult animals. An important role of serotonin is to regulate synthesis of the neurotrophin, brain derived neurotrophic factor (BDNF). A fundamental understanding of respiratory plasticity has led to novel insights with potential relevance to the pathogenic mechanisms of critical respiratory disorders such as obstructive sleep apnea and sudden infant death syndrome. On the other hand, our basic research has also suggested new strategies in the treatment of respiratory insufficiency following spinal cord injury.

Members of our group perform experiments using a wide range of techniques that allow inferences at multiple levels of biological organization (cell/molecular, neurophysiological, neuroanatomical and whole animal techniques). Areas currently receiving major funding include:

Brainstem and spinal plasticity induced by intermittent hypoxia:

• Cellular and synaptic mechanisms of serotonin-dependent respiratory long-term facilitation following intermittent hypoxia. We have developed a comprehensive model of the cellular/synaptic mechanisms of phrenic (and hypoglossal) long-term facilitation following brief exposures to intermittent hypoxia. Respiratory long-term facilitation requires serotonin-receptor activation within the respiratory motor nucleus and new BDNF synthesis. BDNF is both necessary and sufficient for phrenic long-term facilitation in anesthetized rats. We are exploring the cellular/synaptic mechanisms of long-term facilitation in vivo.
• Metaplasticity in long-term facilitation induced by chronic intermittent hypoxia, sensory denervation and spinal cord injury. Each of these experimental treatments augments respiratory long-term facilitation following intermittent hypoxia, apparently by different mechanisms.
• Age, gender and genetic influences on respiratory plasticity. Age and gender alter serotonergic function and serotonin-dependent respiratory plasticity. The details of genetic influences on serotonin-dependent plasticity are under investigation.
• RNAi investigations of neuroplasticity. We were among the first to demonstrate that siRNA can be used effectively to control gene expression and protein synthesis in the mammalian nervous system in vivo.
• Cell culture experiments have been initiated using a model for motoneurons (NSC 34 cells) to investigate cellular mechanisms elicited by episodic (not continuous) serotonin receptor activation.
• A new initiative concerns the potential role of ATP purinergic receptors in mechanisms of plasticity (respiratory LTF) and metaplasticity (enhanced LTF) induced by intermittent hypoxia.

Respiratory plasticity and functional recovery following spinal injury:

• Mechanisms enhancing silent synaptic pathways to spinal respiratory motoneurons following spinal injury (intermittent hypoxia, spinal denervation, trophic factor supplementation and exercise). We demonstrated that ineffective synaptic pathways that cross the spinal midline to innervate phrenic motoneurons can be converted to effective synaptic pathways by chronic intermittent hypoxia, spinal sensory denervation, chronic spinal hemisection and trophic factor supplementation. The detailed mechanisms of these effects will be a topic of extensive investigation in the next few years.
  
• Differential regulation of spinal neurotrophins and serotonin receptor expression following intermittent hypoxia or exercise in spinally injury rats of different strains. We are investigating both mRNA and protein changes.
  
• Induced functional recovery of respiratory and somatic motor control following spinal hemisection and contusion injury. We are developing a cervical contusion injury as an adjunct to studies of spinal hemisection. Whereas hemisection provides powerful experimental advantages in terms of providing a well-defined and interpretable lesion, contusion injuries are more representative of spontaneous injuries seen in a clinical setting.

Developmental plasticity in ventilatory control

• Mechanisms that impair adult ventilatory responses to hypoxia following perinatal hypoxia and hyperoxia. We developed experimental models to test the hypothesis that neonatal exposure to altered oxygen environments alters adult hypoxic chemoreflexes. Most notably, developmental hyperoxia impairs carotid body development. The mechanism of this impairment is under active investigation.
• Induced functional recovery of hypoxic chemoreflexes following perinatal hyperoxia. Chronic intermittent and chronic sustained hypoxia reverse functional impairment caused by developmental hyperoxia. The persistence of functional recovery is not yet known.

Lab Website:

http://www.vetmed.wisc.edu/cbs/mitchell/lab/index.html

Selected Publications:

• Baker-Herman, T.L, D.D. Fuller, R.W. Bavis, A.G. Zabka, F.J. Golder, N.J. Doperalski, R.A. Johnson, J.J. Watters, and G.S. Mitchell. 2004. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat. Neurosci. 7: 48-55. [PDF]
• Fuller, D.D., S.M. Johnson, E.B. Olson Jr., and G.S. Mitchell. 2003. Synaptic pathways to phrenic motoneurons are enhanced by chronic intermittent hypoxia after cervical spinal cord injury. J. Neurosci. 23: 2993-3000. [PDF]
• Feldman J.L., G.S. Mitchell, and E.E. Nattie. 2003. Breathing: Rhythmicity, plasticity, chemosensitivity. Annu. Rev. Neurosci. 26: 239-266.
• Mitchell, G.S. and S.M. Johnson. 2003. Neuroplasticity in respiratory motor control. J. Appl. Physiol. 94: 358-374.
• Baker-Herman T.L., and G.S. Mitchell. 2002. Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J. Neurosci. 22: 6239-6246. [PDF]