A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep

Hough, D., Bellingham, M. , Haraldsen, J.R., McLaughlin, M. , Robinson, J.E. , Solbakk, A.K. and Evans, N.P. (2017) A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep. Psychoneuroendocrinology, 77, pp. 1-8. (doi:10.1016/j.psyneuen.2016.11.029) (PMID:27987429) (PMCID:PMC5333793)

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Abstract

Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P < 0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Robinson, Dr Jane and Bellingham, Dr Michelle and Evans, Professor Neil and McLaughlin, Dr Mark and Hough, Dr Denise
Authors: Hough, D., Bellingham, M., Haraldsen, J.R., McLaughlin, M., Robinson, J.E., Solbakk, A.K., and Evans, N.P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Psychoneuroendocrinology
Publisher:Elsevier
ISSN:0306-4530
ISSN (Online):1873-3360
Published Online:30 November 2016
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Psychoneuroendocrinology 77:1-8
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
536311Effects of GnRH blockade on neurocognitive and physiological endpoints.Neil EvansBiotechnology and Biological Sciences Research Council (BBSRC)BB/K002821/1RI BIODIVERSITY ANIMAL HEALTH & COMPMED