The long term objectives of this project are: 1) to determine the mechanisms that link neuronal activity to axonal sprouting in the adult CNS; 2) to discover the cause of maturational decrements in axonal sprouting; and 3) to examine potential means of compensating for these decrements. These objectives will be addressed using a model neuroendocrine system that displays unusually vigorous axonal plasticity, the hypothalamic magnocellular neurosecretory system, or MNS. Uninjured neurons in the MNS of young adult (35 day-old) rats undergo robust collateral axonal sprouting in response to a lesion that destroys the contralateral side of this bilateral system. This sprouting response is activity-dependent. MNS neurons are hyperactive during axonal sprouting, secreting more of the neuropeptides oxytocin and vasopressin, while simultaneously sprouting new axon collaterals that reestablish the neurosecretory axon population within the neurohypophysis. Sprouting does not occur if activity of MNS neurons is inhibited by establishment of a chronic hyposmolar state, and MNS neurons in more mature (125 day-old) rats do not become hyperactive in response to the lesion and do not sprout.
The specific aims of the proposal are: 1) to determine if it is the initiation and/or the maintenance of the growth process that is activity-dependent, and to examine the role of glutamatergic and noradrenergic afferents in stimulating sprouting; 2) to determine if activity-dependent axonal sprouting is mediated by the growth factors IGF-I, CNTF, and BDNF and the cytokine IL-1beta, synthesized by and acting upon the neurons and glia of the MNS; and 3) to identify mechanisms responsible for the maturational decline in collateral sprouting and to determine if chronic hyperosmotic stimulation of MNS neurons can reverse this decline.
These aims will be accomplished by altering MNS activity by receptor blockade or through chronic osmostimulation and correlating changes in the expression, cellular localization, and activity of the above factors and their receptors with the extent of axonal sprouting in animals of different ages. Fulfillment of these aims will provide new insights regarding the cellular mechanisms involved in reestablishment of axon populations in the injured brain and the alterations that occur in these mechanisms during brain maturation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032507-06
Application #
6393652
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Kleitman, Naomi
Project Start
1994-08-01
Project End
2004-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$229,914
Indirect Cost
Name
Montana State University Bozeman
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
City
Bozeman
State
MT
Country
United States
Zip Code
59717
Watt, John A; Lo, David; Cranston, Harwood J et al. (2009) CNTF receptor alpha is expressed by magnocellular neurons and expression is upregulated in the rat supraoptic nucleus during axonal sprouting. Exp Neurol 215:135-41
Paden, Charles M; Watt, John A; Selong, Tiffany H et al. (2006) The neuronal growth-associated protein (GAP)-43 is expressed by corticotrophs in the rat anterior pituitary after adrenalectomy. Endocrinology 147:952-8
Watt, John A; Bone, Sven; Pressler, Mandy et al. (2006) Ciliary neurotrophic factor is expressed in the magnocellular neurosecretory system of the rat in vivo: evidence for injury- and activity-induced upregulation. Exp Neurol 197:206-14
Mueller, Nancy K; Di, Shi; Paden, Charles M et al. (2005) Activity-dependent modulation of neurotransmitter innervation to vasopressin neurons of the supraoptic nucleus. Endocrinology 146:348-54
Babcock, A M; Standing, D; Bullshields, K et al. (2005) In vivo inhibition of hippocampal Ca2+/calmodulin-dependent protein kinase II by RNA interference. Mol Ther 11:899-905
Babcock, Alex M; Everingham, Andi; Paden, Charles M et al. (2002) Baclofen is neuroprotective and prevents loss of calcium/calmodulin-dependent protein kinase II immunoreactivity in the ischemic gerbil hippocampus. J Neurosci Res 67:804-11
Watt, J A; Paden, C M (2001) Upregulation of the p75 low-affinity neurotrophin receptor by phagocytically active perivascular active cells in the rat neural lobe. Cell Tissue Res 303:81-91
Watt, J A; Hobbs, N K (2000) Interleukin-1beta immunoreactivity in identified neurons of the rat magnocellular neurosecretory system: evidence for activity-dependent release. J Neurosci Res 60:478-89
Zhou, X; Herman, J P; Paden, C M (1999) Evidence that IGF-I acts as an autocrine/paracrine growth factor in the magnocellular neurosecretory system: neuronal synthesis and induction of axonal sprouting. Exp Neurol 159:419-32
Babcock, A M; Liu, H; Paden, C M et al. (1999) In vivo glutamate neurotoxicity is associated with reductions in calcium/calmodulin-dependent protein kinase II immunoreactivity. J Neurosci Res 56:36-43

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