My laboratory has a long-standing interest in understanding how neurons develop and respond to tissue injury.

We found that activin A from skin has profound effects on sensory neuron differentiation, and more recently, learned that this same factor has a critical role in changing pain behaviors following inflammation. We originally discovered that the differentiation of primary sensory neurons is regulated by a skin-derived factor eventually identified as activin A (Ai et al., 1999; Hall et al., 2001; Hall et al., 2002). In addition to the role in development, we found that after local inflammation, activin A increases in skin and produces an acute increase in pain behaviors resulting from interactions with ion channels and a prolonged effect due to the increase in CGRP containing neurons that mediate swelling and alter pain responses (Cruise et al., 2004; Xu et al., 2005). We have shown that Activin A and NGF have synergistic effects on sensory neuropeptide expression and signal through separate receptors and independent intracellular signals (Xu and Hall, 2007). Further, Activin A injection reduces paw withdrawal thresholds in response to mechanical stimulation as well as heat stimuli, demonstrating that activin increases pain behaviors within minutes, and with our collaborators we have shown that Activin A sensitizes the capsaicin receptor TRPV1, and thermal hyperalgesia after activin is reduced in TRPV1 null animals (Zhu et al.,2007). These exciting discoveries place activin A in a central role in pain regulation after inflammation.

In a second project, we have shown that activin is rapidly increased after focal cerebral ischemia or “stroke” and that activin appears to function as a paracrine agent in neuroprotection after oxidative stress (Mukerji et al., 2007). The role of hypoxia inducible factor in activin induction will be studied using genetic deletion models in transgenic mice. Pilot data suggest that activin A administration spares neurons in vivo and current studies explore its action in mouse stroke models, and exciting new data suggest that we can use the small animal imaging core to capture information about this stroke benefit in our mouse models. We are interested in ways to provide that benefit therapeutically.

1. Zhu W, Xu P, Cuascut FX, Hall AK, and Oxford GS (2007)
   Activin Acutely Sensitizes Dorsal Root Ganglion Neurons and Induces Hyperalgesia via PKC-Mediated Potentiation of Transient Receptor Potential Vanilloid I. Journal of Neuroscience. 27:13770-13780.
   
2. Xu P, Hall AK (2007)
   Activin Acts with Nerve Growth Factor to Regulate Calcitonin Gene Related Peptide mRNA in Sensory Neurons Neuroscience. Neuroscience. Dec 12; 150(3):665-74.
   
3. Mukerji, S, Katsman, E, Wilber E, Haner N, Selman WR and Hall, AK (2007)
   Activin is a neuronal survival factor that is rapidly increased following transient cerebral ischemia and hypoxia in mice. Journal of Cerebral Blood Flow and Metabolism. 27(6):1161-72.
   
4. Xu, P and Hall AK (2006)
   The role of activin in neuropeptide induction and pain sensation (review). Developmental Biology. 299:303-309.
   
5. Hall, AK (2006)
   Rodent Sensory Neuron Culture and Analysis. Current Protocols in Neuroscience,. Unit 3.19.
   
6. Berti-Matera L,N, Gariepy C.E., Burke R.M. and Hall, AK. (2006)
   Reduced expression of endothelin B receptors and mechanical hyperalgesia in experimental chronic diabetes. Experimental Neurology. 201:399-406.
   
7. Hall, AK.and Miller RH (2006)
   Stem cells in the Nervous System. Basic Neurochemistry . 7th Edition ISBN 0-12-088397-X Academic Press/Elsevier
8. Xu P, Van Slambrouck C, Berti-Mattera L, and Hall AK. (2005)
   Activin induces tactile allodynia and increases CGRP after peripheral inflammation. Journal of Neuroscience. 25:9227-9235.
   
9. Cruise, B.A., Xu P and Alison K. Hall (2004)
   Wounds increase activin in skin and a vasoactive neuropeptide in sensory ganglia. Developmental Biology. 271:1-10.
   
10. Hall A.K., Burke, R.M., Anand, M. and K. J. Dinsio (2002)
    Activin and bone morphogenetic proteins are present in perinatal sensory neuron target tissues that induce neuropeptides. Journal of Neurobiology. 52:52-60.