In this proposal, I will investigate the influence of sex hormones and aging on galanin (GAL) gene expression and release in two brain pathways implicated in learning and memory processes: the acetylcholine/galanin containing neurons of the basal forebrain and the vasopressin/galanin containing neurons of the bed nucleus of the stria terminalis (BNST) and medial amygdala (AMe). GAL is a 29 amino acid peptide recently observed to induce amnesia in rats. GAL is colocalized with acetylcholine (ACh) and has been postulated to induce amnesia by acting presynaptically to modulate the release of Co-secreted ACh and post-synaptically to antagonize the actions of ACh. I have recently reported that GAL is coexpressed by the majority of vasopressin (VP) neurons in the BNST and AMe. Like ACh, VP appears to enhance memory functions and we have suggested that GAL regulation of VP pathways could provide an additional mechanism by which GAL influences learning and memory processes. Estrogen and nerve growth factor appear to regulate GAL gene expression in some model systems, however, the regulation of GAL by these factors has not been systematically studied in ACh/GAL or VP/GAL containing neurons. Recent evidence suggests that estrogen and nerve growth factor may stimulate cholinergic function and reduce cognitive impairments associated with age or lesion. If these treatments also enhance GAL inhibitory input to ACh and VP pathways, their therapeutic efficacy may be enhanced by the concomitant administration of GAL receptor antagonists. My first objective is to characterize gonadal hormone regulation of GAL in extrahypothalamic VP/GAL neurons and ACh/GAL neurons in the basal forebrain. I will determine which hormones regulate GAL gene expression and release in these pathways and assess the regulation of VP and ACh release by endogenous GAL. In addition, I will determine whether sex differences exist in the incidence of coexpression of GAL with ACh as we have recently observed for GAL with VP. My second objective is to determine whether nerve growth factor regulates GAL in ACh/GAL and VP/GAL pathways. Finally, I propose to determine whether aging is associated with alterations in GAL gene expression and GAL binding within ACh/GAL and VP/GAL pathways. Since hypertrophy of GAL pathways has recently been postulated to contribute to the development of cognitive deficits associated with normal aging and Alzheimer's disease, I believe that a clearer understanding of the regulation of GAL in memory pathways may prove beneficial for the development of novel therapeutic interventions aimed at reversing memory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS033606-01
Application #
2272498
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1994-09-30
Project End
1998-09-29
Budget Start
1994-09-30
Budget End
1995-09-29
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Washington
Department
Psychiatry
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Miller, M A; Kolb, P E; Leverenz, J B et al. (1999) Preservation of noradrenergic neurons in the locus ceruleus that coexpress galanin mRNA in Alzheimer's disease. J Neurochem 73:2028-36
Miller, M A; Ferris, C F; Kolb, P E (1999) Absence of vasopressin expression by galanin neurons in the golden hamster: implications for species differences in extrahypothalamic vasopressin pathways. Brain Res Mol Brain Res 67:28-35
Ferris, C F; Delville, Y; Bonigut, S et al. (1999) Galanin antagonizes vasopressin-stimulated flank marking in male golden hamsters. Brain Res 832:1-6
Miller, M A; Kolb, P E; Planas, B et al. (1998) Few cholinergic neurons in the rat basal forebrain coexpress galanin messenger RNA. J Comp Neurol 391:248-58
Planas, B; Kolb, P E; Raskind, M A et al. (1998) Galanin receptors in the hippocampus and entorhinal cortex of aged Fischer 344 male rats. Neurobiol Aging 19:427-35
Miller, M A; Kolb, P E; Raskind, M A (1997) GALR1 galanin receptor mRNA is co-expressed by galanin neurons but not cholinergic neurons in the rat basal forebrain. Brain Res Mol Brain Res 52:121-9
Tseng, J Y; Kolb, P E; Raskind, M A et al. (1997) Estrogen regulates galanin but not tyrosine hydroxylase gene expression in the rat locus ceruleus. Brain Res Mol Brain Res 50:100-6
Planas, B; Kolb, P E; Raskind, M A et al. (1996) Galanin gene expression declines with adulthood in the cholinergic fields of the horizontal diagonal band of male rats. Brain Res 728:57-64