Research report Nerve growth factor restores the expression of vasopressin and vasoactive intestinal polypeptide in the suprachiasmatic nucleus of aged rats Pedro A. Pereira, Armando Cardoso, Manuel M. Paula-Barbosa * Department of Anatomy, Porto Medical School, Alameda Herna ˆni Monteiro, 4200-319 Porto, Portugal Accepted 22 April 2005 Available online 24 May 2005 Abstract Aging leads to a decrease in the number of neurons expressing vasopressin (VP) and vasoactive intestinal polypeptide (VIP) in the suprachiasmatic nucleus (SCN) of the rat. Similar results were observed following prolonged alcohol consumption and withdrawal. In the latter circumstances, the administration of nerve growth factor (NGF) restored the synthesis and expression of those neuropeptides despite the absence of TrkA receptors in SCN neurons. Thus, we decided to test whether the administration of NGF would improve the expression of neuropeptides in the SCN of aged rats. For this purpose, NGF was delivered intraventricularly to aged rats over a period of 14 days. The somatic volume and the total number of VP- and VIP-immunostained SCN neurons were estimated by applying stereological methods. No age-related variations were found regarding the volume of the neuronal cell bodies. Yet, a striking reduction in the number of VP- and VIP- immunoreactive neurons was detected in aged animals and found to be completely retrieved by NGF. This finding shows that exogenous NGF administered to aged rats restores the neurochemical phenotype of the SCN. This might occur either through direct signaling of SCN neurons via p75 NTR or through enhancement of the cholinergic input to the SCN. D 2005 Elsevier B.V. All rights reserved. Theme: Development and regeneration Topic: Aging process Keywords: Suprachiasmatic nucleus; Nerve growth factor; Neuropeptide expression; Aging; Stereology 1. Introduction It is well documented that the SCN is responsible for the induction of daily cycles in a variety of physiological, behavioral, and endocrine functions and that this role depends on the intrinsic properties of its neurons, which are entrained and adjusted to the environmental photoperiod [38,39,63]. Light information directly reaches the retinor- ecipient area of SCN via the retinohypothalamic tract [22]. However, the SCN receives neuronal inputs from several other sources [37], including cholinergic fibers arising from the basal forebrain complex and mesopontine tegmentum [4,5,37]. Neurotrophins, namely, nerve growth factor (NGF), have been implicated in the regulation of the circadian pacemaker system [3,31]. For instance, it was shown that physiological levels of NGF are required for the normal functioning of the SCN [3,42]. Furthermore, the SCN contains high levels of NGF low-affinity p75 receptor (p75 NTR ) [5,51], most of which was conveyed from the cholinergic neurons of the nucleus basalis magnocellularis (NBM) [4,5,25]. Recently, it was reported that the reduction of cholinergic inputs from the NBM to the SCN decreases the synthesis and expression of neuropeptides by SCN neurons [36]. Interestingly, these findings have striking similarities with the decreased syn- thesis and expression of vasopressin (VP) and vasoactive intestinal polypeptide (VIP) observed in the SCN following chronic ethanol consumption and withdrawal [35]. Actually, this decrease was subsequently found to be completely restored following administration of NGF despite the 0006-8993/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2005.04.066 * Corresponding author. Fax: +351 22 5505640. E-mail address: mmpb@med.up.pt (M.M. Paula-Barbosa). Brain Research 1048 (2005) 123 – 130 www.elsevier.com/locate/brainres