Reinforcement-related neurons in the primate basal forebrain respond to the learned significance of task events rather than to the hedonic attributes of reward

The objective of this study was to determine if the responses of basal forebrain neurons are related to the cognitive processes necessary for the performance of behavioural tasks, or to the hedonic attributes of the reinforcers delivered to the monkey as

Suprasellar chordoid neoplasm with expression of thyroid transcription factor 1: evidence that chordoid glioma of the third ventricle and pituicytoma may form part of a spectrum of lineage-related tumors of the basal forebrain.

Chordoid glioma of the third ventricle is a rare neuroepithelial tumor characterized by a unique histomorphology and exclusive association with the suprasellar/third ventricular compartment. Variously interpreted as either astrocytic- or ependymal-like, and speculatively ascribed to the lamina terminalis/subcommissural organ, its histogenesis remains, nevertheless, unsettled. Here, we report on a suprasellar chordoid glioma occurring in a 52-year-old man. Although displaying otherwise typical morphological features, the tumor was notable for expression of thyroid transcription factor 1, a marker of tumors of pituicytic origin in the context of the sellar region. We furthermore found overlapping immunoprofiles of this example of chordoid glioma and pituicytic tumors (pituicytoma and spindle cell oncocytoma), respectively. Specifically, phosphorylated ribosomal protein S6, a marker of mTOR pathway activation, was expressed in both groups. Based on these findings, we suggest that chordoid glioma and pituicytic tumors may form part of a spectrum of lineage-related neoplasms of the basal forebrain.

Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain.

The characteristic features of a brain with Alzheimer disease (AD) include the presence of neuritic plaques composed of amyloid beta-protein (Abeta) and reductions in the levels of cholinergic markers. Neurotoxic responses to Abeta have been reported in vivo and in vitro, suggesting that the cholinergic deficit in AD brain may be secondary to the degeneration of cholinergic neurons caused by Abeta. However, it remains to be determined if Abeta contributes to the cholinergic deficit in AD brain by nontoxic effects. We examined the effects of synthetic Abeta peptides on the cholinergic properties of a mouse cell line, SN56, derived from basal forebrain cholinergic neurons. Abeta 1-42 and Abeta 1-28 reduced the acetylcholine (AcCho) content of the cells in a concentration-dependent fashion, whereas Abeta 1-16 was inactive. Maximal reductions of 43% and 33% were observed after a 48-h treatment with 100 nM of Abeta 1-42 and 50 pM of Abeta 1-28, respectively. Neither Abeta 1-28 nor Abeta 1-42 at a concentration of 100 nM and a treatment period of 2 weeks was toxic to the cells. Treatment of the cells with Abeta 25-28 (48 h; 100 nM) significantly decreased AcCho levels, suggesting that the sequence GSNK (aa 25-28) is responsible for the AcCho-reducing effect of Abeta. The reductions in AcCho levels caused by Abeta 1-42 and Abeta 1-28 were accompanied by proportional decreases in choline acetyltransferase activity. In contrast, acetylcholinesterase activity was unaltered, indicating that Abeta specifically reduces the synthesis of AcCho in SN56 cells. The reductions in AcCho content caused by Abeta 1-42 could be prevented by a cotreatment with all-trans-retinoic acid (10 nM), a compound previously shown to increase choline acetyltransferase mRNA expression in SN56 cells. These results demonstrate a nontoxic, suppressive effect of Abeta on AcCho synthesis, an action that may contribute to the cholinergic deficit in AD brain.

Long-term functional recovery from age-induced spatial memory impairments by nerve growth factor gene transfer to the rat basal forebrain.

Nerve growth factor (NGF) stimulates functional recovery from cognitive impairments associated with aging, either when administered as a purified protein or by means of gene transfer to the basal forebrain. Because gene transfer procedures need to be tested in long-term experimental paradigms to assess their in vivo efficiency, we have used ex vivo experimental gene therapy to provide local delivery of NGF to the aged rat brain over a period of 2.5 months by transplanting immortalized central nervous system-derived neural stem cells genetically engineered to secrete NGF. By grafting them at two independent locations in the basal forebrain, medial septum and nucleus basalis magnocellularis, we show that functional recovery as assessed in the Morris water maze can be achieved by neurotrophic stimulation of any of these cholinergic cell groups. Moreover, the cholinergic neurons in the grafted regions showed a hypertrophic response resulting in a reversal of the age-associated atrophy seen in the learning-impaired aged control rats. Long-term expression of the transgene lead to an increased NGF tissue content (as determined by NGF-ELISA) in the transplanted regions up to at least 10 weeks after grafting. We conclude that the gene transfer procedure used here is efficient to provide the brain with a long-lasting local supply of exogenous NGF, induces long-term functional recovery of cognitive functions, and that independent trophic stimulation of the medial septum or nucleus basalis magnocellularis has similar consequences at the behavioral level.

Cellular Mechanisms of Sleep Homeostasis : Studies on Brain Energy Metabolism and Aging

Sleep is governed by a homeostatic process in which the duration and quality of previous wake regulate the subsequent sleep. Active wakefulness is characterized with high frequency cortical oscillations and depends on stimulating influence of the arousal systems, such as the cholinergic basal forebrain (BF), while cessation of the activity in the arousal systems is required for slow wave sleep (SWS) to occur. The site-specific accumulation of adenosine (a by-product of ATP breakdown) in the BF during prolonged waking /sleep deprivation (SD) is known to induce sleep, thus coupling energy demand to sleep promotion. The adenosine release in the BF is accompanied with increases in extracellular lactate and nitric oxide (NO) levels. This thesis was aimed at further understanding the cellular processes by which the BF is involved in sleep-wake regulation and how these processes are affected by aging. The BF function was studied simultaneously at three levels of organization: 1) locally at a cellular level by measuring energy metabolites 2) globally at a cortical level (the out-put area of the BF) by measuring EEG oscillations and 3) at a behavioral level by studying changes in vigilance states. Study I showed that wake-promoting BF activation, particularly with glutamate receptor agonist N-methyl-D-aspatate (NMDA), increased extracellular adenosine and lactate levels and led to a homeostatic increase in the subsequent sleep. Blocking NMDA activation during SD reduced the high frequency (HF) EEG theta (7-9 Hz) power and attenuated the subsequent sleep. In aging, activation of the BF during SD or experimentally with NMDA (studies III, IV), did not induce lactate or adenosine release and the increases in the HF EEG theta power during SD and SWS during the subsequent sleep were attenuated as compared to the young. These findings implicate that increased or continuous BF activity is important for active wake maintenance during SD as well as for the generation of homeostatic sleep pressure, and that in aging these mechanisms are impaired. Study II found that induction of the inducible NO synthase (iNOS) during SD is accompanied with activation of the AMP-activated protein kinase (AMPK) in the BF. Because decreased cellular energy charge is the most common cause for AMPK activation, this finding implicates that the BF is selectively sensitive to the metabolic demands of SD as increases were not found in the cortex. In aging (study III), iNOS expression and extracellular levels of NO and adenosine were not significantly increased during SD in the BF. Furthermore, infusion of NO donor into the BF did not lead to sleep promotion as it did in the young. These findings indicated that the NO (and adenosine) mediated sleep induction is impaired in aging and that it could at least partly be due to the reduced sensitivity of the BF to sleep-inducing factors. Taken together, these findings show that reduced sleep promotion by the BF contributes to the attenuated homeostatic sleep response in aging.

Sleep deprivation and brain energy metabolism : in vivo studies in rats and humans

Sleep deprivation leads to increased subsequent sleep length and depth and to deficits in cognitive performance in humans. In animals extreme sleep deprivation is eventually fatal. The cellular and molecular mechanisms causing the symptoms of sleep deprivation are unclear. This thesis was inspired by the hypothesis that during wakefulness brain energy stores would be depleted, and they would be replenished during sleep. The aim of this thesis was to elucidate the energy metabolic processes taking place in the brain during sleep deprivation. Endogenous brain energy metabolite levels were assessed in vivo in rats and in humans in four separate studies (Studies I-IV). In the first part (Study I) the effects of local energy depletion on brain energy metabolism and sleep were studied in rats with the use of in vivo microdialysis combined with high performance liquid chromatography. Energy depletion induced by 2,4-dinitrophenol infusion into the basal forebrain was comparable to the effects of sleep deprivation: both increased extracellular concentrations of adenosine, lactate, and pyruvate, and elevated subsequent sleep. This result supports the hypothesis of a connection between brain energy metabolism and sleep. The second part involved healthy human subjects (Studies II-IV). Study II aimed to assess the feasibility of applying proton magnetic resonance spectroscopy (1H MRS) to study brain lactate levels during cognitive stimulation. Cognitive stimulation induced an increase in lactate levels in the left inferior frontal gyrus, showing that metabolic imaging of neuronal activity related to cognition is possible with 1H MRS. Study III examined the effects of sleep deprivation and aging on the brain lactate response to cognitive stimulation. No physiologic, cognitive stimulation-induced lactate response appeared in the sleep-deprived and in the aging subjects, which can be interpreted as a sign of malfunctioning of brain energy metabolism. This malfunctioning may contribute to the functional impairment of the frontal cortex both during aging and sleep deprivation. Finally (Study IV), 1H MRS major metabolite levels in the occipital cortex were assessed during sleep deprivation and during photic stimulation. N-acetyl-aspartate (NAA/H2O) decreased during sleep deprivation, supporting the hypothesis of sleep deprivation-induced disturbance in brain energy metabolism. Choline containing compounds (Cho/H2O) decreased during sleep deprivation and recovered to alert levels during photic stimulation, pointing towards changes in membrane metabolism, and giving support to earlier observations of altered brain response to stimulation during sleep deprivation. Based on these findings, it can be concluded that sleep deprivation alters brain energy metabolism. However, the effects of sleep deprivation on brain energy metabolism may vary from one brain area to another. Although an effect of sleep deprivation might not in all cases be detectable in the non-stimulated baseline state, a challenge imposed by cognitive or photic stimulation can reveal significant changes. It can be hypothesized that brain energy metabolism during sleep deprivation is more vulnerable than in the alert state. Changes in brain energy metabolism may participate in the homeostatic regulation of sleep and contribute to the deficits in cognitive performance during sleep deprivation.

Molecular Pathways of Disturbed Sleep and Depression: Studies on Adenosine and Gene Expression Patterns

Background: Adenosine is a potent sleep-promoting substance, and one of its targets is the basal forebrain. Fairly little is known about its mechanism of action in the basal forebrain and about the receptor subtype mediating its regulating effects on sleep homeostasis. Homeostatic deficiency might be one of the causes of the profoundly disturbed sleep pattern in major depressive disorder, which could explain the reduced amounts of delta-activity-rich stages 3 and 4. Since major depression has a relatively high heritability, and on the other hand adenosine regulates sleep homeostasis and might also be involved in mood modulation, adenosine-related genes should be considered for their possible contribution to a predisposition for depression and disturbed sleep in humans. Depression is a complex disorder likely involving the abnormal functioning of several genes. Novel target genes which could serve as the possible common substrates for depression and comorbid disturbed sleep should be identified. In this way specific brain areas related to sleep regulation should be studied by using animal model of depression which represents more homogenous phenotype as compared to humans. It is also important to study these brain areas during the development of depressive-like features to understand how early changes could facilitate pathophysiological changes in depression. Aims and methods: We aimed to find out whether, in the basal forebrain, adenosine induces recovery non-rapid eye movement (NREM) sleep after prolonged waking through the A1 or/and A2A receptor subtype. A1 and A2A receptor antagonists were perfused into the rat basal forebrain during 3 h of sleep deprivation, and the amount of NREM sleep and delta power during recovery NREM sleep were analyzed. We then explored whether polymorphisms in genes related to the metabolism, transport and signaling of adenosine could predispose to depression accompanied by signs of disturbed sleep. DNA from 1423 individuals representative of the Finnish population and including controls and cases with depression, depression accompanied by early morning awakenings and depression accompanied by fatigue, was used in the study to investigate the possible association between polymorphisms from adenosine-related genes and cases. Finally to find common molecular substrates of depression and disturbed sleep, gene expression changes were investigated in specific brain areas in the rat clomipramine model of depression. We focused on the basal forebrain of 3-week old clomipramine-treated rats which develop depressive-like symptoms later in adulthood and on the hypothalamus of adult female clomipramine-treated rats. Results: Blocking of the A1 receptor during sleep deprivation resulted in a reduction of the recovery NREM sleep amount and delta power, whereas A2A receptor antagonism had no effect. Polymorphisms in adenosine-related genes SLC29A3 (equilibrative nucleoside transporter type 3) in women and SLC28A1 (concentrative nucleoside transporter type 1) in men associated with depression alone as well as when accompanied by early morning awakenings and fatigue. In Study III the basal forebrain of postnatal rats treated with clomipramine displayed disturbances in gamma-aminobutyric acid (GABA) receptor type A signaling, in synaptic transmission and possible epigenetic changes. CREB1 was identified as a common transcription denominator which also mediates epigenetic regulation. In the hypothalamus the major changes included the expression of genes in GABA-A receptor pathway, K+ channel-related, glutamatergic and mitochondrial genes, as well as an overexpression of genes related to RNA and mRNA processing. Conclusions: Adenosine plays an important role in sleep homeostasis by promoting recovery NREM sleep via the A1 receptor subtype in the basal forebrain. Also adenosine levels might contribute to the risk of depression with disturbed sleep, since the genes encoding nucleoside transporters showed the strongest associations with depression alone and when accompanied by signs of disturbed sleep in both women and men. Sleep and mood abnormalities in major depressive disorder could be a consequence of multiple changes at the transcriptional level, GABA-A receptor signaling and synaptic transmission in sleep-related basal forebrain and the hypothalamus.

The role of the GABAergic system in the production of ultrasonic vocalization in rats /

Ultrasonic vocalization plays an important role in intraspecies communication for rats. It has been well demonstrated that rats will emit 22kHz vocalization in stressfiil or threatening situations. Although the neural mechanism underlying vocahzation is not well understood, it is known that chohnergic input to the basal forebrain induces such alarm calls. A number of experiments have found that intracerebral injection of carbachol, a predominantly muscarinic agonist, into die anterior hypothalamic/preoptic area (AH/POA) rehably induces vocalization similar to naturally emitted ultrasonic calls. It has also been shown that carbachol has extensive inhibitory effects on neuronal firing in the same area. This result impUes that the inhibitory effects of carbachol in the AH/POA could trigger vocahzation, and that the GABAergic system could be involved. The purpose of this study is to investigate the effects ofGABA agonists and antagonists on flie production of carbachol induced 22kHz vocalization. The following hypotheses were examined: 1) apphcation ofGABA (a naturally occurring inhibitory neurotransmitter) will have a synergistic effect with carbachol, increasing vocalization; and 2) tiie apphcation ofGABA antagonists (picrotoxin or bicuculline) will reduce caibachol-induced vocalization. A total of sixty rats were implanted with stainless steel guide cannulae in the AH/POA area. After recovery, animals were locally pretreated with 1) GABA (l-40ng), 2) picrotoxin (1 .5^g) or bicuculhne (0.03ng), or 3) sahne; before injection with carbachol (1 .5^g). The resulting vocalization was measured and quantitated. The results indicate that pretreatment with GABA or GABA antagonists had no significant effect on vocalization. Local pretreatment with GABA did not potentiate the vocal response as measured by its duration, latraicy, and total number of calls. Similarly, pretreatment with picrotoxin or bicuculline had no effects on the same measures of vocalization. The results suggest tfiat chohnoceptive neurons involved in the production of alarm calls are not under direct GABAergic control.

Cholinergic enhancement of perceptual learning : behavioral, physiological, and neuro-pharmacological study in the rat primary visual cortex

Les cortices sensoriels sont des régions cérébrales essentielles pour la perception. En particulier, le cortex visuel traite l’information visuelle en provenance de la rétine qui transite par le thalamus. Les neurones sont les unités fonctionnelles qui transforment l'information sensorielle en signaux électriques, la transfèrent vers le cortex et l'intègrent. Les neurones du cortex visuel sont spécialisés et analysent différents aspects des stimuli visuels. La force des connections entre les neurones peut être modulée par la persistance de l'activité pré-synaptique et induit une augmentation ou une diminution du signal post-synaptique à long terme. Ces modifications de la connectivité synaptique peuvent induire la réorganisation de la carte corticale, c’est à dire la représentation de ce stimulus et la puissance de son traitement cortical. Cette réorganisation est connue sous le nom de plasticité corticale. Elle est particulièrement active durant la période de développement, mais elle s’observe aussi chez l’adulte, par exemple durant l’apprentissage. Le neurotransmetteur acétylcholine (ACh) est impliqué dans de nombreuses fonctions cognitives telles que l’apprentissage ou l’attention et il est important pour la plasticité corticale. En particulier, les récepteurs nicotiniques et muscariniques du sous-type M1 et M2 sont les récepteurs cholinergiques impliqués dans l’induction de la plasticité corticale. L’objectif principal de la présente thèse est de déterminer les mécanismes de plasticité corticale induits par la stimulation du système cholinergique au niveau du télencéphale basal et de définir les effets sur l’amélioration de la perception sensorielle. Afin d’induire la plasticité corticale, j’ai jumelé des stimulations visuelles à des injections intracorticales d’agoniste cholinergique (carbachol) ou à une stimulation du télencéphale basal (neurones cholinergiques qui innervent le cortex visuel primaire). J'ai analysé les potentiels évoqués visuels (PEVs) dans le cortex visuel primaire des rats pendant 4 à 8 heures après le couplage. Afin de préciser l’action de l’ACh sur l’activité des PEVs dans V1, j’ai injecté individuellement l’antagoniste des récepteurs muscariniques, nicotiniques, α7 ou NMDA avant l’infusion de carbachol. La stimulation du système cholinergique jumelée avec une stimulation visuelle augmente l’amplitude des PEVs durant plus de 8h. Le blocage des récepteurs muscarinique, nicotinique et NMDA abolit complètement cette amélioration, tandis que l’inhibition des récepteurs α7 a induit une augmentation instantanée des PEVs. Ces résultats suggèrent que l'ACh facilite à long terme la réponse aux stimuli visuels et que cette facilitation implique les récepteurs nicotiniques, muscariniques et une interaction avec les récepteur NMDA dans le cortex visuel. Ces mécanismes sont semblables à la potentiation à long-terme, évènement physiologique lié à l’apprentissage. L’étape suivante était d’évaluer si l’effet de l’amplification cholinergique de l’entrée de l’information visuelle résultait non seulement en une modification de l’activité corticale mais aussi de la perception visuelle. J’ai donc mesuré l’amélioration de l’acuité visuelle de rats adultes éveillés exposés durant 10 minutes par jour pendant deux semaines à un stimulus visuel de type «réseau sinusoïdal» couplé à une stimulation électrique du télencéphale basal. L’acuité visuelle a été mesurée avant et après le couplage des stimulations visuelle et cholinergique à l’aide d’une tâche de discrimination visuelle. L’acuité visuelle du rat pour le stimulus d’entrainement a été augmentée après la période d’entrainement. L’augmentation de l’acuité visuelle n’a pas été observée lorsque la stimulation visuelle seule ou celle du télencéphale basal seul, ni lorsque les fibres cholinergiques ont été lésées avant la stimulation visuelle. Une augmentation à long terme de la réactivité corticale du cortex visuel primaire des neurones pyramidaux et des interneurones GABAergiques a été montrée par l’immunoréactivité au c-Fos. Ainsi, lorsque couplé à un entrainement visuel, le système cholinergique améliore les performances visuelles pour l’orientation et ce probablement par l’optimisation du processus d’attention et de plasticité corticale dans l’aire V1. Afin d’étudier les mécanismes pharmacologiques impliqués dans l’amélioration de la perception visuelle, j’ai comparé les PEVs avant et après le couplage de la stimulation visuelle/cholinergique en présence d’agonistes/antagonistes sélectifs. Les injections intracorticales des différents agents pharmacologiques pendant le couplage ont montré que les récepteurs nicotiniques et M1 muscariniques amplifient la réponse corticale tandis que les récepteurs M2 muscariniques inhibent les neurones GABAergiques induisant un effet excitateur. L’infusion d’antagoniste du GABA corrobore l’hypothèse que le système inhibiteur est essentiel pour induire la plasticité corticale. Ces résultats démontrent que l’entrainement visuel jumelé avec la stimulation cholinergique améliore la plasticité corticale et qu’elle est contrôlée par les récepteurs nicotinique et muscariniques M1 et M2. Mes résultats suggèrent que le système cholinergique est un système neuromodulateur qui peut améliorer la perception sensorielle lors d’un apprentissage perceptuel. Les mécanismes d’amélioration perceptuelle induits par l’acétylcholine sont liés aux processus d’attention, de potentialisation à long-terme et de modulation de la balance d’influx excitateur/inhibiteur. En particulier, le couplage de l’activité cholinergique avec une stimulation visuelle augmente le ratio de signal / bruit et ainsi la détection de cibles. L’augmentation de la concentration cholinergique corticale potentialise l’afférence thalamocorticale, ce qui facilite le traitement d’un nouveau stimulus et diminue la signalisation cortico-corticale minimisant ainsi la modulation latérale. Ceci est contrôlé par différents sous-types de récepteurs cholinergiques situés sur les neurones GABAergiques ou glutamatergiques des différentes couches corticales. La présente thèse montre qu’une stimulation électrique dans le télencéphale basal a un effet similaire à l’infusion d’agoniste cholinergique et qu’un couplage de stimulations visuelle et cholinergique induit la plasticité corticale. Ce jumelage répété de stimulations visuelle/cholinergique augmente la capacité de discrimination visuelle et améliore la perception. Cette amélioration est corrélée à une amplification de l’activité neuronale démontrée par immunocytochimie du c-Fos. L’immunocytochimie montre aussi une différence entre l’activité des neurones glutamatergiques et GABAergiques dans les différentes couches corticales. L’injection pharmacologique pendant la stimulation visuelle/cholinergique suggère que les récepteurs nicotiniques, muscariniques M1 peuvent amplifier la réponse excitatrice tandis que les récepteurs M2 contrôlent l’activation GABAergique. Ainsi, le système cholinergique activé au cours du processus visuel induit des mécanismes de plasticité corticale et peut ainsi améliorer la capacité perceptive. De meilleures connaissances sur ces actions ouvrent la possibilité d’accélérer la restauration des fonctions visuelles lors d’un déficit ou d’amplifier la fonction cognitive.

Discrete retinal input to the parabrachial complex of a new-world primate, the common marmoset (Callithrix jacchus)

Traditional retinal projections target three functionally complementary systems it) the brain of mammals: the primary visual system, the visuomotor integration systems and the circadian timing system. In recent years, studies in several animals have been conducted to investigate the retinal projections to these three systems, despite some evidence of additional targets. The aim of this study was to disclose a previously unknown connection between the retina and the parabrachial complex of the common marmoset, by means of the intraocular injection of cholera toxin Subunit b. A few labeled retinal fibers/terminals that are detected in the medial parabrachial portion of the marmoset brain show clear varicosities, Suggesting terminal fields. Although the possible role of these projections remains unknown, they may provide a modulation of the cholinergic parabrachial neurons which project to the thalamic dorsal lateral geniculate nucleus. (c) 2008 Elsevier Ireland Ltd. All rights reserved.

The anatomical connections of the macaque monkey orbitofrontal cortex. A review

The orbitofrontal cortex (OfC) is a heterogeneous prefrontal sector selectively connected with a wide constellation of other prefrontal, limbic, sensory and premotor areas. Among the limbic cortical connections, the ones with the bippocampus and parabippocampal cortex are particularly salient. Sensory cortices connected with the OfC include areas involved in olfactory, gustatory, somatosensory, auditory and visual processing. Subcortical structures with prominent OfC connections include the amygdala, numerous thalamic nuclei, the striatum, hypothalamus, periaqueductal gray matter, and biochemically specific cell groups in the basal forebrain and brainstem. Architectonic and connectional evidence supports parcellation of the OfC. The rostrally placed isocortical sector is mainly connected with isocortical areas, including sensory areas of the auditory, somatic and visual modalities, whereas the caudal non-isocortical sector is principally connected with non-isocortical areas, and, in the sensory domain, with olfactory and gustatory areas. The connections of the isocortical and non- isocortical orbital sectors with the amygdala, thalamus, striatum, hypotbalamus and periaqueductal gray matter are also specific. The medial sector of the OfC is selectively connected with the bippocampus, posterior parabippocampal cortex, posterior cingulate and retrosplenial areas, and area prostriata, while the lateral orbitofrontal sector is the most heavily connected with sensory areas of the gustatory, somatic and visual modalities, with premotor regions, and with the amygdala.

Both alpha(1)- and beta(1)-adrenoceptors in the bed nucleus of the stria terminalis are involved in the expression of conditioned contextual fear

BACKGROUND AND PURPOSE The bed nucleus of the stria terminalis (BNST) is a limbic structure that is involved in the expression of conditioned contextual fear. Among the numerous neural inputs to the BNST, noradrenergic synaptic terminals are prominent and some evidence suggests an activation of this noradrenergic neurotransmission in the BNST during aversive situations. Here, we have investigated the involvement of the BNST noradrenergic system in the modulation of behavioural and autonomic responses induced by conditioned contextual fear in rats. EXPERIMENTAL APPROACH Male Wistar rats with cannulae bilaterally implanted into the BNST were submitted to a 10 min conditioning session (6 footshocks, 1.5 ma/ 3 s). Twenty-four hours later freezing and autonomic responses (mean arterial pressure, heart rate and cutaneous temperature) to the conditioning box were measured for 10 min. The adrenoceptor antagonists were administered 10 min before the re-exposure to the aversive context. KEY RESULTS L-propranolol, a non-selective beta-adrenoceptor antagonist, and phentolamine, a non-selective a-adrenoceptor antagonist, reduced both freezing and autonomic responses induced by aversive context. Similar results were observed with CGP20712, a selective beta 1-adrenoceptor antagonist, and WB4101, a selective a1-antagonist, but not with ICI118,551, a selective beta 2-adrenoceptor antagonist or RX821002, a selective a2-antagonist. CONCLUSIONS AND IMPLICATIONS These findings support the idea that noradrenergic neurotransmission in the BNST via a1- and beta 1-adrenoceptors is involved in the expression of conditioned contextual fear.

Decision-making in amnesia: do advantageous decisions require conscious knowledge of previous behavioural choices?

Previous work has reported that in the Iowa gambling task (IGT) advantageous decisions may be taken before the advantageous strategy is known [Bechara, A., Damasio, H., Tranel, D., ; Damasio, A. R. (1997). Deciding advantageously before knowing the advantageous strategy. Science, 275, 1293-1295]. In order to test whether explicit memory is essential for the acquisition of a behavioural preference for advantageous choices, we measured behavioural performance and skin conductance responses (SCRs) in five patients with dense amnesia following damage to the basal forebrain and orbitofrontal cortex, six amnesic patients with damage to the medial temporal lobe or the diencephalon, and eight control subjects performing the IGT. Across 100 trials healthy participants acquired a preference for advantageous choices and generated large SCRs to high levels of punishment. In addition, their anticipatory SCRs to disadvantageous choices were larger than to advantageous choices. However, this dissociation occurred much later than the behavioural preference for advantageous alternatives. In contrast, though exhibiting discriminatory autonomic SCRs to different levels of punishment, 9 of 11 amnesic patients performed at chance and did not show differential anticipatory SCRs to advantageous and disadvantageous choices. Further, the magnitude of anticipatory SCRs did not correlate with behavioural performance. These results suggest that the acquisition of a behavioural preference--be it for advantageous or disadvantageous choices--depends on the memory of previous reinforcements encountered in the task, a capacity requiring intact explicit memory.

Implicit task sequence learning in patients with Parkinson's disease, frontal lesions and amnesia: The critical role of fronto–striatal loops

The purpose of this study was to investigate the role of the fronto–striatal system for implicit task sequence learning. We tested performance of patients with compromised functioning of the fronto–striatal loops, that is, patients with Parkinson's disease and patients with lesions in the ventromedial or dorsolateral prefrontal cortex. We also tested amnesic patients with lesions either to the basal forebrain/orbitofrontal cortex or to thalamic/medio-temporal regions. We used a task sequence learning paradigm involving the presentation of a sequence of categorical binary-choice decision tasks. After several blocks of training, the sequence, hidden in the order of tasks, was replaced by a pseudo-random sequence. Learning (i.e., sensitivity to the ordering) was assessed by measuring whether this change disrupted performance. Although all the patients were able to perform the decision tasks quite easily, those with lesions to the fronto–striatal loops (i.e., patients with Parkinson's disease, with lesions in the ventromedial or dorsolateral prefrontal cortex and those amnesic patients with lesions to the basal forebrain/orbitofrontal cortex) did not show any evidence of implicit task sequence learning. In contrast, those amnesic patients with lesions to thalamic/medio-temporal regions showed intact sequence learning. Together, these results indicate that the integrity of the fronto–striatal system is a prerequisite for implicit task sequence learning.

Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.