Impaired cognitive performance in rats after complete epithalamus lesions, but not after pinealectomy alone.
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.
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ABSTRACT: The habenular complex linking forebrain and midbrain structures is subdivided into the medial (mHb) and the lateral nuclei (lHb). The mHb is characterized by the expression of specific nicotinic acetylcholine receptor isoforms and the release of acetylcholine to the interpeduncular nucleus (IPN), the sole output region of the mHb. The specific function of this circuit, however, is poorly understood. Here we generated transgenic mice in which mHb cells were selectively ablated postnatally. These lesions led to large reductions in acetylcholine levels within the IPN. The mutant mice exhibited abnormalities in a wide range of behavioral domains. They tended to be hyperactive during the early night period and were maladapted when repeatedly exposed to new environments. Mutant mice also showed a high rate of premature responses in the 5-choice serial reaction time task (5-CSRTT), indicating impulsive and compulsive behavior. Additionally, mice also exhibited delay and effort aversion in a decision-making test, deficits in spatial memory, a subtle increase in anxiety levels, and attenuated sensorimotor gating. IntelliCage studies under social housing conditions confirmed hyperactivity, environmental maladaptation, and impulsive/compulsive behavior, delay discounting, deficits in long-term spatial memory, and reduced flexibility in complex learning paradigms. In 5-CSRTT and adaptation tasks, systemic administration of nicotine slowed down nose-poke reaction and enhanced adaptation in control but not mutant mice. These findings demonstrate that the mHb-IPN pathway plays a crucial role in inhibitory control and cognition-dependent executive functions.Frontiers in Behavioral Neuroscience 01/2013; 7:17. · 4.76 Impact Factor
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ABSTRACT: The habenular complex is composed of important relay nuclei linking the limbic forebrain to the midbrain and brain stem nuclei. Based on clinical observations, experiments with animals and theoretical considerations, it has been speculated that this brain area might be involved in psychiatric diseases (i.e. schizophrenia and depression). However, evidence in favour of this hypothesis is still lacking because the human habenular complex has rarely been studied with regard to mental illness. We examined habenular volumes in post-mortem brains of 17 schizophrenia patients, 14 patients with depression (six patients with major depression and eight patients with bipolar depression) and 13 matched controls. We further determined the neuronal density, cell number and cell area of the medial habenular nuclei of the same cohorts using a counting box and a computer-assisted instrument. Significantly reduced habenular volumes of the medial and lateral habenula were estimated in depressive patients in comparison to normal controls and schizophrenia patients. We also found a reduction in neuronal cell number and cell area in depressive patients for the right side compared to controls and schizophrenia patients. No such changes were seen in schizophrenia. Our anatomical data argue against prominent structural alterations of the habenular nuclei in schizophrenia but demonstrate robust alterations in depressive patients. We are currently applying immunohistochemical markers to better characterize neuronal subpopulations of this brain region in schizophrenia and depression.Psychological Medicine 09/2009; 40(4):557-67. · 5.59 Impact Factor
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ABSTRACT: Melatonin is the main hormone of the pineal gland that informs the body about the environmental light and darkness regimen and is considered to regulate many important physiological and behavioural activities. In the present study, we examined the effects of pinealectomy, constant-release melatonin implants and timed melatonin injections on spatial memory in male Wistar rats by using Morris water maze. Pinealectomy, melatonin injection and melatonin implantation were performed on groups, including controls for all groups. After a week of the pinealectomy and melatonin implantation surgeries, we applied the injections and made the training trials throughout 4 days. At the fifth day, experiments were performed and recorded. Spatial memory performance of the rats was impaired by the pinealectomy and melatonin injections, since they elongated the latency and shortened the time passed in the correct quadrant. Melatonin implantation did not affect the spatial memory performance of the rats. The latency and the time passed in correct quadrant were not statistically different from their controls. The results suggest that while the removal of the pineal gland and exogenous administration of melatonin via injections are causing impairment, constant-release melatonin administration via implantation does not affect the spatial memory in Wistar albino rats.Biological Rhythm Research 12/2011; 42(6):457-472. · 0.47 Impact Factor