Behavioural Brain Research 161 (2005) 276–285 Research report Impaired cognitive performance in rats after complete epithalamus lesions, but not after pinealectomy alone Lucas Lecourtier a,b , Michel Saboureau c , Christopher D. Kelly d , Paul P´ evet c , Peter H. Kelly a,∗ a NS Research, WSJ-386.262, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland b CNRS UMR 5106, Laboratoire de Neurosciences Cognitives, Universit´ e de Bordeaux 1, Avenue des Facult´ es, 33405 Cedex Talence, France c CNRS UMR 7518, Laboratoire de Neurobiologie des Rythmes, Universit´ e Louis Pasteur, 12 rue de l’Universit´ e, 67000 Strasbourg, France d University of Basel, School of Medicine, CH-4051 Basel, Switzerland Received 23 September 2004; received in revised form 11 February 2005; accepted 17 February 2005 Available online 21 March 2005 Abstract In the midbrain, the epithalamus comprises the habenular nuclei and the pineal gland. Based on evidence including imaging studies in schizophrenia patients, several investigators have postulated that dysfunction of this structure is causally involved in symptoms of schizophrenia. Recently, we showed that bilateral habenula lesions in the rat induced some schizophrenia-like behavioural changes, namely memory and attention impairments, but unaltered social interaction in a brief encounter and prepulse inhibition (PPI) of the startle reflex. Here, the possible involvement of the pineal gland in the same behaviours was assessed, by examining them in two series of experiments. In the first, these behaviours were examined in pinealectomized rats compared to sham-operated controls. In the second, they were examined in rats with combined lesion of habenula plus pinealectomy compared to sham-operated controls, to examine whether pinealectomy induced further deficits when combined with habenula damage. Lesions of habenula were confirmed histologically and neurochemically by reduction of choline acetyltransferase in the interpeduncular nucleus. Pinealectomy was confirmed post mortem by careful visual inspection. Pinealectomy induced no deficits in any test, while combined lesions led to the same pattern of deficits as previously observed after habenula lesion, i.e. marked memory impairment in the Morris water maze without affecting the amount of social interaction or PPI of the startle reflex. Thus, loss of pineal function causes no deficits in these behaviours and does not alter the qualitative pattern of deficits resulting from habenula damage. © 2005 Elsevier B.V. All rights reserved. Keywords: Pineal gland; Habenular nuclei; Morris maze; Spatial memory; Social interaction; Prepulse inhibition; Schizophrenia 1. Introduction The epithalamus is a structure that belongs to the dien- cephalon and forms its dorsal posterior subdivision. It is com- posed of the pineal gland, the habenula and associated fiber bundles. The habenula has been shown to be involved in many Abbreviations: ANOVA, analysis of variance; ChAT, choline acetyl- transferase; EDTA, ethylene diamine tetraacetate; i.p., intraperitoneal; IPN, interpeduncular nucleus; PA, pulse alone; PPI, prepulse inhibition; PPP, prepulse–pulse; s.c., subcutaneously ∗ Corresponding author. Tel.: +41 61 324 4367; fax: +41 61 324 3811. E-mail address: peter.kelly@novartis.com (P.H. Kelly). behaviors [55] such as olfactory guided behaviour [55], ma- ternal behaviour [13,19], mating [55], control of behaviour by aversive stimuli [11], anxiety [42], brain stimulation reward [56], sleep [26,61], behavioural flexibility [59], endocrine se- cretion [55], memory [32] and attention [33], while the pineal gland is a major component of the photoneuroendocrine sys- tem, responsible for the release of the indoleamine melatonin, whose functions include regulation of circadian rhythms [31]. A number of recent studies have suggested that there is dysfunction of the epithalamus in patients with schizophre- nia. For example, computer tomography (CT) studies have suggested that large calcifications of the habenula and of the pineal are more frequent in patients with schizophrenia 0166-4328/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2005.02.014