Leptin is an adipocyte-derived cytokine originally identified as an anti-obesity hormone but is implicated in other functions including immunity. The work described in this thesis addressed leptin’s role as a neuroimmune mediator during systemic inflammation and the physiological significance of this role. We first demonstrated that leptin stimulates the production of interleukin-1β, a critical pro-inflammatory cytokine, through action on brain-resident macrophages, microglia and endothelial cells known to play key roles in the brain’s innate inflammation. Moreover, leptin displayed atypical inflammatory effects, acting as an enhancer/modulator rather than a bona fide stimulator of brain inflammation. In subsequent studies, we addressed the leptin regulation of inflammation in a physiological context and examined whether malnutrition (which reduces basal leptin levels) attenuates the brain’s innate inflammatory response in a leptin-dependent manner. Food deprivation prior to induction of brain inflammation blunted the up-regulation of cytokines, chemokines and adhesion molecules, and the recruitment of neutrophils to the brain. Repletion of leptin during fasting reversed all the indices of neuroinflammation, demonstrating that leptin modulates the brain’s innate inflammation in relation to the host’s nutritional status. These studies were extended to examine the role of leptin in fever, an energy demanding response to inflammation. Food deprivation significantly attenuated fever, in part through a leptin-dependent mechanism, supporting a role for leptin in linking energy balance and fever. However, leptin regulation of fever was dissociated from the febrigenic inflammatory response, highlighting the complexity of leptin’s role which depends to some degree on the severity of the pathogenic stimulus. Leptin reversed the fever attenuation most likely by activating thermoregulatory functions in the fasted animals. In summary, this thesis demonstrated th / La leptine est une cytokine provenant d'adipocytes identifié à l'origine comme hormone d'anti-obésité. En plus de cette fonction, la leptine est impliquée dans la réponse au stress, la reproduction, le métabolisme et la fonction immunitaire. Cette thèse a étudié le rôle de la leptine sur la réponse inflammatoire du cerveau et sur la fièvre. Les résultats des deux premiers manuscrits ont démontrés que la leptine stimule la production de la cytokine pro-inflammatoire interleukin-1β in vivo et in vitro, en agissant sur les macrophages résidants du cerveau, les microglies et les cellules endothéliales connues pour leurs rôles dans l'inflammation du cerveau. En plus, la leptine a eu des effets inflammatoires atypiques, agissant en tant que renforceur/modulateur plutôt qu'un véritable stimulateur de l'inflammation. La troisième expérience a étudié les effets inflammatoires atypiques de la leptine dans un contexte physiologique et a examiné si la malnutrition (qui réduit les niveaux basiques de leptine) atténue la réponse inflammatoire du cerveau d'une façon dépendante de la leptine. Le jeûne avant l'induction de l'inflammation au cerveau a arreté la production de cytokines, de chémokines et de molécules d'adhérence, ainsi que le recrutement de neutrophiles au cerveau. La réplétion de la leptine pendant le jeûne a renversé tous ces indexes de neuroinflammation, ainsi démontrant que la leptine module l'inflammation du cerveau. Les deux derniers manuscrits ont examiné le rôle de la leptine sur la fièvre. La privation de nourriture a atténué la fièvre de manière significative, en partie par un mécanisme dépendant de la leptine, soutenant un rôle pour celle-ci dans le lien entre le statut énergétique/nutritionnel et la fièvre. Cependant, l' éffet de la leptine sur la fièvre a été attribué à ses effets sur la thermorégulation/métabolisme et a été dissocié de la réponse inflammatoire du cerveau, démontrant un

Background: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in psychotic disorders. Abnormal levels of the HPA axis hormone, cortisol, are associated with various cognitive processes and cognitive deficits are a key feature of psychosis. The cortisol awakening response (CAR) has been shown to be abnormal in first episode psychosis (FEP) patients but has not been explored in individuals at ultra high-risk (UHR) for developing psychosis. Objectives: The objectives of the following set of studies were to examine the relationship between the CAR and cognitive function in FEP patients and in UHR individuals. In addition, based on established sex differences in both HPA axis activity and psychosis, the effect of sex on this relationship was also explored. Methods: Eighty-two FEP patients, 28 individuals at UHR for psychosis, and 31 community controls were recruited to participate in the two studies. Saliva samples were collected to assess the CAR and a neuropsychological battery was administered to determine performance on six cognitive domains. From these, a global cognition score was also calculated. Results: FEP patients, but not UHR individuals, had a blunted CAR compared to controls and male FEP patients had a more blunted CAR than female FEP patients. A more blunted CAR was associated with a more severe deficit in verbal memory and a lower global cognition score only in female FEP patients. Conclusion: The results suggest that although UHR individuals show deficits in certain cognitive domains, the CAR remains in tact, and there is no association between the two. However, a blunted CAR plays a role in cognitive function for female FEP patients. This may have implications for time and gender specific interventions aimed at stabilizing HPA axis activity. / Contexte: La dérégulation de l'axe hypothalamo-hypophyso-surrénalien (HHS) a été observée dans les troubles psychotiques. Des niveaux anormaux de cortisol, une des hormones de l'axe HHS, sont associés à divers processus cognitifs et les déficits cognitifs sont un élément clé de la psychose. Des études démontrent que la sécrétion de cortisol au réveil (SCR) est anormale dans le premier épisode psychotique (PEP) des patients, mais n'a pas été explorée chez les personnes à très haut risque (THR) de déveloper une épisode de psychose. Objectifs: Les objectifs de ces diverses études étaient d'examiner la relation entre la SCR et la fonction cognitive chez les patients PEP et chez les personnes THR. En dépit des différences de sexe connues sur l'axe HPA et la psychose, l'effet du sexe sur cette relation n'a pas été étudié. Méthodes: Quatre-vingt-deux patients PEP, 28 individus à THR pour la psychose, et 31 contrôles communautaires ont été recrutés pour participer dans les deux études. Des échantillons de salive ont été prélevés pour évaluer la SCR et une batterie de tests neuropsychologiques a été administrée pour déterminer les performances sur six domaines cognitifs. De ceux-ci, un résultat cognitif global a également été calculé. Résultats: Les patients PEP, mais pas les individus THR, avaient une SCR atténuée par rapport aux témoins contrôles et les patients masculins PEP avait une SCR plus atténuée que les patients PEP féminin. Une SCR plus atténuée a été associée à un déficit plus sévère de la mémoire verbale et un résultat inférieur de la cognition globale uniquement chez les patients PEP féminins. Conclusion: Bien que les individus THR présentent des déficits dans certains domaines cognitifs, les résultats montrent que la SCR reste intacte et qu'il n'y a aucun lien entre les deux. Toutefois, une SCR atténuée joue un rôle dans la fonction cognitive chez les patients PEP féminins. Cela peut avoir des implications pour les interventions spécifiques au sexe et au temps visant à stabiliser l'activité de l'axe HHS.

A prominent feature of lordosis, the sexual posturing of female rats, is lumbar dorsiflexion (rump elevation). This movement exposes the perineum and permits the male to intromit. Experiments were done to characterize the muscles used in lumbar dorsiflexion, to locate their motoneurons, and to describe some physiologic inputs to these muscles. First, the dorsal and ventral muscles of the back and tail of the female Norway rat were described. Of these muscles, the lumbar epaxial muscles lateral longissimus and the transversospinalis muscles are both trunk muscles and capable of producing dorsiflexion: they are suited for producing the rump elevation of lordosis. To see if they are used during lordosis, they were selectively ablated in hormone-primed female rats that were subsequently tested in mating encounters with male rats. Lordosis was rated as amount of rump elevation. Compared to control animals, animals with ablations of lumbar transversospinalis muscles or lateral longissimus were considerably impaired in their performance of lordosis. Ablations of medial longissimus, a lumbar epaxial muscle which produces proximal tail movements, did not affect lordosis. Motoneurons to lumbar epaxial muscles were localized following intraxonal retrograde transport of horseradish peroxidase (HRP) injected into muscle. Both lateral longissimus and transversospinalis motoneurons were found medially in the ventral horn throughout the lumbar enlargement, and continued anterior to the enlargement. Following HRP injections into more posterior regions of transversospinalis muscles, motoneurons were also found caudal to the enlargement. Medial longissimus motoneurons were found posterior to the lumbar enlargement, ventrolaterally in the ventral horn. Neuronanatomical localization was confirmed by identifying sites in the spinal cord at which low-level stimulation (mainly (LESSTHEQ) 20 (mu)A) produced visible twitches of transversospinalis, medial longissimus or lateral longissimus. Additionally, cells responding antidromically to stimulation of medial longissimus, lateral longissimus or transversospinalis nerves were identified (extracellular recording) and marked by dye deposition. For each muscle, dye spots fell within the region depicted neuronanatomically. Responses of lateral longissimus or medial longissimus nerves to stimulation of ipsilateral lumbosacral dorsal roots, medial medullary reticular formation, vestibular nuclei, or ventromedial hypothalamus were studied in urethane-anesthetized female rats, some of which were also hormone-primed and had shown lordosis to manual stimulation. Stimulation of appropriate dorsal roots, using with two or more shocks, evoked short-latency (re effective shock), probably monosynaptic, compound potentials in medial longissimus or in lateral longissimus nerves. Supraspinal influence was studied mainly by using a condition-test paradigm. Conditioning stimulation of the vestibular nuclei facilitated occurrence of short-latency responses to single dorsal root shocks in medial longissimus nerves (13/14) and in lateral longissimus nerves (5/10). Reticular formation conditioning stimulation also facilitated segmental responses recorded in medial longissimus nerves. Stimulation within the reticular formation or vestibular nuclei could also evoke responses in medial longissimus and lateral longissimus nerves. Stimulation in the area of the ventromedial nucleus of the hypothalamus had no facilitatory effect in these preparations. No differences associated with hormone treatment were apparent. Vestibular nuclei and reticular formation can influence lumbar back muscles and tail muscles as they do other axial muscles. Possibly, either or both pathways to lumbar back muscles could be active during lordosis.

A commonplace symptom of vestibular endorgan damage is postural dysequilibrium. Vestibular compensation eventually restores balance to intact levels. At issue in describing the compensation process is what role other sensory input plays in balance behavior. Visual and other sensory cues may substitute for the decreased vestibular input or they may contribute to a developing reflexive mechanism that allows for balance at a range of arousal levels. To determine which of the two mechanisms underlies compensated behavior, body sway of squirrel monkeys was measured prior to and following unilateral labyrinthectomy. Visual fixation and alertness were avoided by recording sway during the animals' sleep. In three monkey subjects, body sway was analyzed from epochs of slow-wave sleep. Sway (anteroposterior and lateral), EEG, vertical eye movements, ECG, and respiration were recorded on magnetic tape; simultaneous strip-chart records also illustrated sway episodes. A characteristic sway pattern emerged following labyrinthectomy: slow deviation to the side of the lesion, followed by a rapidly corrective righting movement. This pattern resembled spontaneous eye nystagmus; therefore, the term body nystagmus was coined to refer to this behavior. Frequency of body-nystagmic beats, slow-phase body velocity (SPBV), and power-spectral density of sway were evaluated. Lateral SPBV significantly increased (p < 0.05) after unilateral lesion, then declined to intact levels. Body-nystagmic beat frequency results were inconsistent. For power-spectral density, in the lateral dimension, for both 0.00 to 0.25-Hz and 0.00 to 1.00-Hz bandwidths, energy was significantly greater (p < 0.05) three days postlabyrinthectomy than either the pre-operative condition or the compensated stage (35 days). Differences for the anteroposterior dimension were not significant. When these indices were compared with a standard measure of compensation, spontaneous eye-nystagmic velocity, lateral SPBV described the compensation trend as well or better than the oculomotor measure. These findings suggest that alternate sensory information contributes to the reestablishment of a reflexive balance mechanism. Rather than simply substitute for lost vestibular sensation, the alternate inputs integrate over the compensation period to regulate balance behavior across a range of arousal levels.

Drugs of abuse are thought to have the common action of increasing dopaminergie transmission in the mesolimbic dopamine (DA) pathway, specifically in the nucleus accumbens (NAc). However, sedative-hypnotics, including the barbiturates, are anomalous in that they appear to stimulate DA release from the NAc at doses that are generally lower than their reinforcing doses. The fact that barbiturates have a long history of abuse in humans and are potent reinforcers in laboratory animals, but are behaviourally reinforcing only at doses that decrease DA release from the NAc, raises questions about the neuropharmacological mechanism of reinforcement in these drugs. Indeed, of the numerous studies that have examined the reinforcing properties of barbiturates, none have examined the pharmacological basis of their reinforcing effects. / The conditioned place preference (CPP) paradigm is a widely used behavioural test that assesses the reinforcing capacity of stimuli by the ability of conditioned stimuli to evoke an approach response. Using this paradigm, systemic administration of pentobarbital (15 mg/kg) induced a significant place preference. Furthermore, pretreatment with GABAA, DA, and opioid receptor antagonists blocked the pentobarbital-induced place preference. Sodium barbital, a longer-acting barbiturate also induced a significant CPP when systemically administered (8 and 24 mg/kg). Moreover, the reinforcing effect of this place preference is centrally mediated, assessed by the significant CPP obtained with intracerebroventricular (ICV) injections of barbital (240 and 480 mug). / A number of different brain sites are involved in the reinforcing effects of drugs of abuse. Microinjections of barbital into the periaqueductal gray (25 mug) or posterior ventral tegmental area (VTA; 15 mug), but not into other areas, such as the amygdala and anterior VTA, produced a place preference. Furthermore, opioid (naloxone methiodide) and GABAA receptor (SR 95531) antagonists administered into these areas blocked the ICV barbital place preference. Given these findings, barbiturate reinforcement appears to be mediated by the same neural substrates and neurochemical systems as other drugs of abuse, such as opiates and ethanol. The implications of these results and the use of barbital in the place preference paradigm to investigate the neuropharmacological mechanisms of barbiturate reinforcement are discussed.

Depression is among the most common psychiatric disorders and is associated with significant disability, including pain, physical dysfunction, and a number of serious medical conditions. The pathophysiological mechanisms underlying this relationship are unclear, but are thought to involve dysfunction of the stress system. This thesis explores sensory and stress function in young adults with subclinical low mood – i.e. below the threshold for a clinical depressive disorder – and normal mood controls. Pain and somatic problems were frequent in men and women with depressive symptoms, despite the fact that their pain thresholds were normal. This suggests that their aches and pains were not the result of generalized hypersensitivity. The inflammatory response induced by capsaicin was significantly reduced in low mood, indicating impaired function, or even loss, of small-diameter afferent fibres in the superficial layers of the skin. Function of the autonomic system was also abnormal in subclinical depression. Heart rate variability at rest was lower, reflecting a shift in sympathovagal balance characterized by decreased vagal and/or increased sympathetic tone. The response to a mild stressor was similarly abnormal, but increased autonomic reactivity to stress was more strongly associated with anxiety than depression scores. The peripheral sympathetic vasoconstriction reflex was intact in low mood subjects, with an increased vasoconstrictive response in low mood women, but not men, suggesting sympathetic hyperreactivity. The data imply that, like clinical depression, subclinical low mood is not a benign condition, but is associated with impaired health, pain and somatic complaints, and sensory dysfunction in apparently healthy young adults. The autonomic dysfunction is similar to that observed in clinical populations, and it provides a plausible explanation for the sensory and somatic problems. / La dépression est un des troubles psychiatriques les plus communs et est associée avec des incapacités significatives, telles la douleur, un dysfonctionnement physique, et un nombre de conditions médicales sérieuses. Les mécanismes pathophysiologiques sous-jacents cette association ne sont pas bien compris, mais semblent impliquer le système du stress. Cette thèse explore le fonctionnement des systèmes sensoriel et du stress chez de jeunes adultes avec une humeur dépressive sous-clinique – c'est-à-dire sous le seuil de la dépression majeure – et des participants contrôles ayant une humeur normale. La douleur et les problèmes somatiques sont fréquents chez les hommes et les femmes ayant des symptômes dépressifs, malgré le fait que leur seuil de la douleur soit normal. Ceci suggère que leurs maux et douleurs ne sont pas le résultat d'une hypersensibilité généralisée. La réponse inflammatoire induite par la capsaïcine était réduite de façon significative chez les participants à l'humeur basse, suggérant un fonctionnement détérioré, ou même, une perte de fibres afférentes à petit diamètre dans les couches superficielles de la peau. Le fonctionnement du système nerveux autonome était aussi anormal dans la dépression sous-clinique. La variabilité du rythme cardiaque au repos était plus basse, reflétant un changement dans la balance sympathovagale, caractérisé par une activité vagale réduite et/ou une activité sympathique augmentée. La réponse à un stress mineur était similairement anormale, mais l'augmentation de la réactivité autonome au stress était plus fortement associée aux symptômes anxieux que dépressifs. Le réflexe vasoconstricteur sympathique était intact chez les participants à l'humeur basse, mais une augmentation de la réponse vasoconstrictrice chez les femmes à l'humeur basse, mais pas les hommes, suggère une hyperréactivité sympathique. Les données impliquent que, comme lors d'une dépression majeure, une humeur basse sous-clinique n'est pas une condition bénigne, mais est associée avec une santé détériorée, des plaintes somatiques, de la douleur, et un dysfonctionnement sensoriel chez des adultes en apparence en bonne santé. Le dysfonctionnement du système autonome est similaire à ce qui a été observé dans les populations cliniques, et il fournit une explication plausible aux problèmes sensoriels et somatiques.

The prefrontal cortex (PFC) is a brain region thought to mediate cognitive functions such as working memory. Chronic stress has been shown to reduce working memory. In this thesis study, the effect of chronic stress on PFC functions was assessed in adult rats. / First, contrary to previous evidences, chronic stress induces working memory performance alterations differentially in two populations of rats. One group displayed a decrease of performance only at 30 second delay, while the other had a decrease and increase at 0 and 30 seconds respectively. / Then, the effect of chronic stress on synaptic plasticity induction in the hippocampus-PFC network was investigated. High-frequency tetanic stimulation (HFS) of the dorsal hippocampus that induced long-term potentiation (LTP) in the prelimbic and infralimbic cortex in normal conditions was unable to induce LTP after chronic stress in the infralimbic cortex, whereas long-term depression (LTD) instead of LTP was induced in the prelimbic cortex. / Given that synaptic plasticity has been shown to depend on NMDA receptors in the PFC, NMDA subunit expressions before and after chronic stress was examined. There was a decrease of NR1 subunits expression in the prelimbic, but not infralimbic cortex. In contrast, the NR2A/NR2B ratio was increased in the infralimbic, but not prelimbic cortex. These results suggest that chronic stress disrupts PFC functions through dynamic modulation of distinct neural networks within the PFC. / Le cortex préfrontal (PFC) est une région du cerveau qui contrôle les fonctions cognitives comme la mémoire de travail. Dans cette thèse, l'effet du stress chronique sur des fonctions du PFC a été analysé chez des rats adultes. / Premièrement, les performances de la mémoire de travail ont été mesurées avant et après exposition au stress chronique. Nous avons constaté que le stress chronique induit des changements de performances de la mémoire de travail différemment selon deux populations de rats. Une des populations a démontré une diminution de performance seulement à 30 secondes de délai. Au contraire, l'autre a démontré une diminution de performance à 0 seconde et une amélioration de performance à 30 secondes. / En plus, nous avons évalué l'effet du stress chronique sur l'induction de la plasticité synaptique dans le réseau reliant l'hippocampe au PFC. Dans les conditions initiales, une stimulation tétanique à haute fréquence (HFS) dans l'hippocampe dorsal provoquait une potentialisation à long terme (LTP) dans le cortex prélimbique et infralimbique Or après exposition au stress chronique, une stimulation tétanique à haute fréquence n'a pas entraîné de potentialisation à long terme dans le cortex infralimbique. De plus, une exposition au stress chronique a provoqué l'apparition dans le cortex prélimbique d'une dépression à long terme (LTD) plutôt qu'une potentialisation à long terme. / Étant donné que la plasticité synaptique dépend des récepteurs de NMDA dans le PFC, nous avons examiné l'expression de sous-unité de NMDA avant et après exposition au stress chronique. En accord avec les changements synaptiques distincts de plasticité entre le cortex prélimbique et infralimbique après exposition au stress chronique, nous avons observé que l'expression de la sous-unité NR1 a diminué dans le prélimbique, mais non dans l'infralimbique. En revanche, le ratio de NR2A/NR2B a augmenté dans le cortex infralimbique, mais non dans le prélimbique. Ces résultats suggèrent que le stress chronique perturbe les fonctions du PFC par la modulation dynamique des réseaux distincts neurologiques dans le PFC.

Capsaicin was applied to the sciatic and saphenous nerves of rats under anaesthesia. The time-course of the response to intraplantar formalin and formalin-induced c-FOS expression and alterations in substance P (SP) immunoreactivity (IR) were assessed in capsaicin-treated rats. The foot withdrawal latency to 48°C water was also recorded from 1--75 days after surgery. Formalin-induced pain was reduced by both capsaicin and its vehicle at the earliest test, 3 days after surgery. Formalin pain in the vehicle-treated group recovered by 14 days, and scores in the capsaicin-treated group remained depressed until 28 days. By 75 days, capsaicin-treated rats were hyperalgesic in the first phase. Thermal hyposensitivity was apparent from the first day after surgery until day 75. Capsaicin reduced c-FOS IR and both treatments reduced SP IR at day 14. Thermal hypoalgesia occurs prior to changes at the terminals of unmyelinated afferents and may involve depletion of peptides in the periphery due to disrupted axonal transport. The effects on formalin-induced pain may be due to axonal transport disruption, and by desensitization of the afferents.

Short-term memory (STM) consists of two major components. The first is an active articulatory loop, responsible for the internal articulation of verbal items that permits the recycling and continuous refreshing of information. The second involves a passive phonological store into which auditory speech information enters directly. / The first part of this thesis consists of a general evaluation of the cognitive impairments in three brain-damaged patients, who show a similar reduction in their auditory span, related to the components of STM. The word length effect, the phonological similarity effect and the primacy and recency effects are examined under normal conditions and under articulatory suppression. / The second part of this work is based on a mathematical model from which derived three variables: "a" and "b" representing the internal rehearsal mechanism, and "T" which is the temporal capacity limiting the operation of auditory short-term memory. A double dissociation was found between the articulatory mechanism and the temporal capacity, and a further one between two different processes within the articulatory mechanism. "a" reflecting the activation and recovery of an entire chunk, and "b" the articulation of syllables.

A large body of evidence indicates that dopamine (DA) neurotransmission regulates approach toward rewards and reward-related cues. The best-cited hypothesis proposes that DA accomplishes this by mediating the pleasurable effects of a variety of natural and drug rewards. This "anhedonia hypothesis" has received support from some pre-clinical models of reward and a few drug challenge studies in humans. However, direct assessment of DA's role in mood and other subjective states in healthy humans has been largely limited to the use of psychostimulant drugs, which elevate brain levels of multiple neurotransmitters in addition to DA. This thesis is comprised of one study which examined the effect of more selectively elevated DA neurotransmission, as produced by administration of the immediate DA precursor, L-DOPA, in healthy human volunteers. L-DOPA failed to alter mood and other subjective states. These results add to the evidence that DA neurotransmission does not directly influence mood in healthy humans. / La contribution précise de récompense et de motivation de la neurotransmission de la dopamine (DA) n'est pas entièrement comprise. La meilleure hypothèse citée propose que la DA forme un trait d'union des effets agréables d'une variété de récompenses naturelles et narcotiques. Cette hypothèse « anhédoniste » a reçu l'appui de quelques modèles précliniques de récompense et de quelques études chez l'humain mettant la drogue en question. Cependant, l'évaluation directe du rôle de la DA sur la disposition et autres états subjectifs chez l'humain en santé a été principalement limitée à l'utilisation de drogues psychostimulantes, ce qui élève le niveau de neurotransmetteurs multiples en plus de la DA dans le cerveau. La présente thèse comprend une étude qui examine l'effet d'une neurotransmission sélectivement plus élevée de la DA, produite par l'administration du précurseur immédiat de la DA, L-DOPA, chez des volontaires en santé. L-DOPA n'a modifié ni disposition ni autres états subjectifs. Ces résultats s'ajoutent à l'évidence la neurotransmission de DA n'influence pas directement la disposition chez l'humain en santé.