University Email Address: jwatt@medicine.nodak.edu

Office Phone: 701-777-6225

Education/Training:

Images From the Lab:

LEFT IMAGE. Imunofluorescent analysis of Ciliary Neurotrophic Factor (CNTF) in the posterior pituitary of the rat. Red, CNTF-immunoreactive perivascular cells. Green, GFAP immunoreactive pituicytes.

RIGHT IMAGE. Pituicytes express the type 1 receptor for interleukin-1ß (red) in vitro.

Research Interests:

My overall research interest centers around the neuron/glial response(s) to brain injury particularly in regards to the mechanisms of cellular communication involved in regenerative events. Both in terms of neuron to glial signals that induce activation of the appropriate glial response as well as the glia to neuron signals which may underlie or facilitate neural regeneration and repair. These signaling intermediates probably involve both cytokines and neurotrophins in complex communication loops. In order to facilitate our ability to define the communication loops activated during regenerative events, we have developed a model of compensatory sprouting by intact magnocellular neurosecretory axons following partial denervation of the posterior pituitary gland in the rat. The response of the magnocellular neurosecretory system (MNS) to partial denervation is characterized by an initial period of axonal degeneration with concurrent alterations in perivascular microglial cell immunophenotypic characteristics and conversion to neuronophages. This event is followed by a much more prolonged period during which compensatory sprouting of uninjured axons occurs. This model of axonal plasticity avoids the extensive endocrine disruptions associated with stalk transection and does not result in inflammation or invasion of the neurohypophysis by circulating macrophages. An additional advantage is that increased synthetic activity and secretory activity, with concomitant plastic responses within the terminal field, can be induced using non-invasive techniques such as oral salt-loading and chronic hyponatremia. Thus, it provides a useful model system with which to more thoroughly investigate the relationship between expression of cytokines, neurotrophins and their receptors by neurons and/or glial cells in response to injury and axonal sprouting.

We are currently pursuing two aspects of the neuro-immune response to MNS denervation. Our working hypothesis concerning the role of cytokines now focuses on the fundamental role interleukin-1ß plays in the modulation of neurosecretory activity under both physiological and experimental conditions. Findings from this and other laboratories have demonstrated that IL-1ß is present in the oxytocin (OT) and vasopressin (VP) neurons of the rat MNS where it may act to modulate neurosecretion of OT and VP by influencing neuron to glial communication. Hence, we are now focusing our investigations on the physiological conditions under which neuronal IL-1ß and IL-1ß receptor type I gene expression may be altered via application of immunocytochemical, ultrastructural and semi-quantitative autoradiographic in situ hybridization analysis both in vitro and in vivo. In addition, we have recently established an in vitro system comprised of both purified pituicyte monolayers and intact NL's in culture. This in vitro system will allow a series of mechanistic questions to be posed concerning the role of IL-1ß in neuron-glial communication and more specifically, regulation of neurosecretory activity at the level of the NL. Having established the identity of the target tissue/cells and potential signaling mechanisms we are in excellent position to now fully define the functional outcome of IL-1ß-astrocyte interactions. I feel this has direct relevance to a variety of neuron-glial interactions resulting from both trauma-induced as well as normal physiological activities in the CNS.

In addition, we also have very strong evidence linking expression of ciliary neurotrophic factor (CNTF) with the MNS response to denervation. In this regard, CNTF upregulation by astrocytes within the hypothalamic supraoptic nucleus appears to be requisite for the survival of the axotomized magnocellular neurons. While in the NL, both in situ hybridization histochemistry and immunocytochemical evidence indicates that perivascular microglial cells upregulate CNTF in response to the partial denervation and maintain this response throughout the subsequent sprouting of uninjured neurosecretory axons.

Clearly, the MNS provides specific advantages as an experimental system for the examination of neuroimmune interactions. However, neuronal and glial responses to CNS injury, be they toward neurodegenerative disorders such as Alzheimer's Disease, trauma-induced, or a response to invasive pathogens, undoubtably share certain mechanisms. Thus, we believe that pursuit of our experimental objectives will ultimately increase our knowledge of the mechanisms by which cytokines and neurotrophins affect neuroimmune interactions and the neurosecretory systems response to denervating injury. These insights could, in turn, suggest innovative approaches for cytokine therapies in neuroimmune, neuroendocrine and neurodegenerative disorders throughout the nervous system.

Current Research Funding

(7/1/2006–6/30/2007) PI: J.A. Watt, UND COBRE Pilot Grant Program. “Ciliary Neurotrophic Factor Acts as both a Neuronal Survival Factor and Sprouting Factor for Magnocellular Neurosecretory Neurons In Vivo”. Awarded.

(2006–2011) Project DirectorCo-Author, Center of Biological Research Excellence Grant (COBRE), NCRR, NIH # 2 P20 RR017699-06; “Pathophysiological Signaling in Neurodegenerative Disorders”. Priority score 181, $10,092,241 awarded. Funding period, 7/1/2007–6/30/2012.

(2006) Project Contributor; Major Research Instrumentation Grant, NSF #0722956; “Acquisition of a multi-photon confocal microscope imaging system with live cell scan capabilities for interdisciplinary research and education”. Pending.

Invited Seminars and Lectures

(2004) Invited Seminar, “Ciliary Neurotrophic Factor is Upregulated During Axonal Sprouting in the Rat Magnocellular Neurosecretory System”. North Dakota Academy of Sciences April, (2004), Televised-Web Simulcast.

(2004) Invited Speaker, University of Manitoba School of Medicine, "Axonal Sprouting in the Magnocellular Neurosecretory System: A Role for Ciliary Neurotrophic Factor as Both Survival and Sprouting Factor."

(2005) Invited Lectures. Roatan Institute for Marine Sciences, Roatan, Honduras. 2 lectures delivered: Comparative Dive Physiology; (1) Anatomical and Physiological Characteristics of Deep Diving Mammals". (2) "The Human Factor: High Pressure Nervous Syndrome and Nitrogen Narcosis."

(2006) Invited Presenter, 4th Annual Symposium, Center for Biological Research Excellence, University of North Dakota. “The Application of Ciliary Neurotrophic Factor as a Neuronal Survival Factor and Target-Derived Sprouting Factor in the Injured Rat Magnocellular Neurosecretory System”.

Selected Publications:

1. Compensatory Sprouting of Uninjured Magnocellular Neurosecretory Axons in the Rat Neural Lobe following Unilateral Hypothalamic Lesion. John A. Watt and Charles M. Paden. Exp. Neurol., 111:9-24, (1991)
2. Ultrastructural Analysis of ß-Amyloid Induced Programmed Cell Death in Cultured Hippocampal Neurons. John A. Watt, Christian J. Pike, Andrea J. Walencewicz and Carl W. Cotman. Brain Res., 661:147-156, (1994).
3. Possible Role of Apoptosis in Alzheimer's Disease. Carl W. Cotman, Edward E. Whittemore, John A. Watt, Aileen J. Anderson and Deryk T. Loo. Ann. N.Y. Acad. Sci., Dec 15 747:36-49 (1994).
4. A Detailed Analysis of Hydrogen Peroxide-Induced Cell Death in Primary Neuronal Culture. Edward R. Whittemore, Deryk T. Loo, John A. Watt and Carl W. Cotman. Neuroscience, Aug., 67(4):921-932 (1995).
5. Cultured Rat Microglia Express C1q and Receptor for C1q: Implications for Amyloid Effects on Microglia. Andrew R. Korotzer, John A.Watt, David Cribs, Andrea J. Tenner, Debra Burdick, Charles Glabe and Carl Cotman. Exp. Neurol., 134:214-221 (1995).
6. Distribution of Growth-Associated Class I a-Tubulin and Class II ß-Tubulin mRNAs in Adult Rat Brain. Charles M. Paden, Xingrong Zhou, John A. Watt, Rebecca Burton, Judith Pickett and Monica M. Oblinger. J. Comp. Neurol., 362:368-384 (1995).
7. Coordinated Upregulation of a1- and ßII- Tubulin mRNA's During Collateral Sprouting of Central Peptidergic Neurons. C.M. Paden, X.Zhou, J.A. Watt, R. Burton, J. Picket and M.M. Oblinger. J. Neurosci. Res., 42:402-412 (1995).
8. Neuronal Activity is Increased During Collateral Sprouting by Central Peptidergic Neurons, and Chronic Inhibition of Activity Suppresses Sprouting. John A. Watt, Christopher W. Moffet, Xinrong Zhou, Shannon Walden, Sonja Short, James P. Herman and Charles M. Paden. J. Neurosci.,19(5):1586-1598 (1999).
9. Interleukin-1ß Immunoreactivity in Identified Neurons of the Rat Magnocellular Neurosecretory System: Evidence for Activity-Dependent Release. John A. Watt and Nicole K. Hobbs. J. Neuroscience Res., 60:478-489 (2000).
10. Upregulation of the p75 Low Affinity Neurotrophin Receptor by Phagocytically Active Perivascular Cells in the Rat Neural Lobe. John A. Watt, Xinrong Zhou and Charles M. Paden. Cell and Tissue Res., 303:81-91 (2001)
11. Ciliary Neurotrophic Factor is Expressed in the Magnocellular Neurosecretory System of the Rat In Vivo: Evidence for Injury- and Activity-Induced Upregulation. John A. Watt, Sven Bone, Mandy Pressler, Harwood J. Cranston and Charles M. Paden. Experimental Neurology, 197: 206–214 (2006).
12. The neuronal growth-associated protein (GAP)-43 is expressed by corticotrophs in the rat anterior pituitary after Adrenalectomy. Paden, C.M., Watt, J.A., Selong, T.H., Paterson, C.L., Cranston, H.J. Endocrinology, 147(2):952–958 (2006).