De nombreuses pathologies psychiatriques, telles que la schizophrénie, les troubles bipolaires ou la dépression majeure, bien que très différentes, ont en commun une dysfonction du système de récompense et de motivation en lien avec une altération de la transmission dopaminergique. Par ailleurs, ces pathologies s’accompagnent de modifications du métabolisme lipidique et en particulier d’une diminution des taux en acide docosahexaenoic (DHA), le principal acide gras polyinsaturé (AGPI) n-3 dans le système nerveux central. Cependant, bien que certaines études cliniques décrivent des effets bénéfiques de supplémentations en AGPI n-3 sur certains symptômes psychiatriques, ces résultats restent controversés, et l’implication de la modification du statut lipidique dans l’étiologie de ces pathologies reste très peu étudiée. Le but de ce travail a été d’établir s’il existe un lien causal entre une déficience en AGPI n-3 et certains endophénotypes neurobiologiques et comportementaux caractéristiques de pathologies psychiatriques. En particulier, nous avons fait l’hypothèse que la déficience en AGPI n-3 pourrait conduire à un dysfonctionnement de la transmission dopaminergique mésolimbique. Dans cette étude, des tâches de conditionnement opérant chez la souris nous ont permis de mettre en évidence un déficit motivationnel à l’âge adulte induit par une déficience développementale en AGPI n-3 qui est partiellement prévenu par une supplémentation en AGPI n-3 à la naissance, mais pas au sevrage. Ce déficit motivationnel s’accompagne d’une altération de la transmission dopaminergique comme le suggère la réduction de la sensibilité au psychostimulant, l’amphétamine. Plus précisément, nous avons pu montrer que la déficience en AGPI n-3 conduit à une dysfonction des propriétés électrophysiologiques des neurones épineux moyens (medium spinyneurons ou MSN) dans le noyau accumbens (NAc), population neuronale centrale pour la modulation de la motivation. En effet la carence en AGPI n-3 induit une réduction de l’excitabilité des MSNs de la voie directe (dMSNs) qui expriment le récepteur dopaminergique de type D1, associée à une augmentation de la transmission inhibitrice reçue par ces neurones. Ces modifications sont restaurées par l’application de l’agoniste des récepteurs dopaminergiques D2 (RD2), le quinpirole. Ces données nous ont amené à faire l’hypothèse que la diminution d’excitabilité des dMSNs sous déficience en AGPI n-3 résulte de l’augmentation de la transmission GABA issue des MSNs de la voie indirecte (iMSNs) exprimant le RD2. En accord avec ces résultats, par utilisation d’un transgène Cre-dépendant permettant l’expression de l’acide gras désaturase FAT1, nous démontrons que la normalisation des taux d’AGPI dans les iMSN sélectivement, est suffisante pour restaurer les propriétés électrophysiologiques des dMSNs. Par ailleurs, l’expression de la FAT1 dans les neurones exprimant le D2R – mais pas ceux exprimant le D1R - est suffisante pour normaliser le déficit motivationnel en situation de carence. Nos résultats montrent donc un lien causal entre des modifications de taux d’AGPI dans une sous-population neuronale spécifique et une altération comportementale. Par ailleurs, notre étude suggère que la diminution des taux d’AGPI décrite dans plusieurs pathologies psychiatriques pourrait directement participer à l’expression de certains symptômes tels que l’avolition ou l’apathie. / Various, though distinct psychiatric disorders, such as Schizophrenia, bipolar disorder or major depression are associated with a dysfunction of the reward system linked to an alteration of dopamine transmission. Furthermore, these pathologies are also accompanied by changes in lipid metabolism and in particular a decrease in the brain content of docosahexaenoic acid (DHA), the main n-3 polyunsaturated fatty acid (PUFA) in the nervous system. However, despite that n-3 PUFA supplementation seems to improve or prevent some psychiatric symptoms, these results are still controversial and the implication of brain lipid composition in the etiology of psychiatric endophenotypes has been overlooked. The aim of this study was to investigate a potential causal link between n-3 PUFA deficiency and common neurobiological and behavioral endophenotypes of psychiatric disorders. In particular, the hypothesis was that n-3 PUFA deficiency could lead to dysfunctions of mesolimbic dopamine transmission and associated behaviors. Using operant conditioning tasks in mice, we showed that developmental n-3 PUFA deficiency leads to a motivational deficit at adulthood, that is partially reversed by n-3 PUFA supplementation starting at birth, but not at weaning. This motivational deficit was associated with an alteration of dopaminergic transmission as revealed by the reduced sensitivity to the psychostimulant amphetamine. More precisely, we showed that n-3 PUFA deficiency leads to alterations in electrophysiological properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), main actors in motivational processes. Indeed, MSNs from the direct pathway (dMSNs), that express dopaminergic D1 receptors, displayed a decrease in neuronal excitability in parallel with an increase of inhibitory input onto these neurons. These alterations were reversed by the dopaminergic D2 receptor (D2R) agonist quinpirole. These data led us to hypothesize that the decreased dMSN excitability induced by n-3 PUFA deficiency could result from an increase of the inhibitory input of MSNs from the indirect pathway (iMSNs that expresses D2R), called lateral inhibition. Accordingly, using a transgenic approach that allows the expression of the fatty acid desaturase FAT1 in a credependent manner, we showed that rescuing appropriate PUFA levels in D2R-expressing neurons selectively (including iMSNs), was sufficient to reverse alterations in electrophysiological properties of MSNs induced by n-3 PUFA deficiency. Moreover, the selective expression of FAT1 in D2-expressing neurons – but not in D1-expressing neurons – reversed the motivational deficit observed in n-3 PUFA deficient mice. We demonstrated the existence of a causal link between modifications in PUFA levels in a discrete neuronal population and behavioral alterations. Overall, this study suggests that altered PUFA levels, observed in some psychiatric disorders, could directly participate in the development of symptoms such as avolition or apathy.

Rxry est l’un des récepteurs nucléaires impliqués dans la signalisation à l’acide rétinoïque. L’ablation de Rxry chez les souris provoque le développement de comportements de type dépressifs - désespoir et d’anhédonie. De tels déficits pouvaient être normalisés par des anti-dépresseurs tels que la fluoxetine, suggérant donc l’importance de telles données pour la recherche sur la dépression.Nous avons trouvé que le NAcSh est une structure impliquée dans le contrôle par Rxry des comportements motivés étant donné que la ré-expression de Rxry dans cette structure par le virus normalise les déficits comportementaux chez les souris Rxry-/-. Nous avons démontré que le récepteur Drd2 qui est sous-exprimé dans le NAcSh des souris Rxry-/- est nécessaire dans le contrôle des comportements affectifs étant donné que le blocage des activités du Drd2 par infusion de raclopride dans le NAcSh empêche le rétablissement du phénotype Rxry-/- par le virus AAV2-RxryCette observation est étayée par le rétablissement fonctionnel des déficits comportementaux par injection de virus ou traitement à la fluoxetine qui augmentent l’expression du Drd2 dans le NAcSh chez les souris Rxry-/-. Ces données sont la première démonstration que les récepteurs aux rétinoides sont impliqués dans le contrôle des comportements affectifs chez la souris.Nous avons observé que l’ablation de Rxry provoquent une hyperactivité du NAcSh. Nous avons observé des phénomènes similaires dans un modèle de stresse par défaite sociale. L’existence de telle corrélation dans deux modèles animaux distincts de comportements dépressifs suggère que l’hyperactivité du NacSh pourrait être un phénomène commun sous-tendant la dépression. / Rxry is one of nuclear receptors involved in retinoic acid signalling. Ablation of this receptor in mice leads to development of depressive-like behaviours - despair and anhedonia. Importantly, such deficits could be normalized by antidepressant, fluoxetine chronic treatment, suggesting thus the relevance of such data for research into depression. We identified that NAcSh is a key structure implicated in Rxry control of motivated behaviours as virus mediated re-expression of Rxry in this brain region normalized behavioural deficits of Rxry-/- mice. We demonstrated that dopaminergic D2 receptor – Drd2, which is underexpressed in the NAcSh of Rxry-/- mice is necessary for Rxry control of affective behaviours since blocking of Drd2 activities by infusion of raclopride into the NAcSh prevented AAV2-Rxry mediated rescue of Rxry-/- phenotype. This observation was further supported by functional rescue of behavioral deficits by virus mediated or chronic fluoxetine treatment increase of Drd2 expression in the NAcSh of Rxry-/- mice. Such data provide the first evidence that retinoid receptors are implicated in the control of affective behaviours in mice.We also identified that molecular changes caused by Rxry ablation lead to hyperactivity of the NAcSh. Importantly, we observed similar phenomenon in etiologically different model of depression – social defeat stress model. Existence of such correlation in two distinct animal models of depressive behaviours, suggests that NAcSh hyperactivity might be a common phenomenon underlying depression.

No description available.

The goal of this dissertation was to investigate the role of μ-opioid receptors in the mechanism of ethanol-stimulated dopamine release in the nucleus accumbens shell (NAcS) of rats. The underlying hypothesis is that blockade of the μ-opioid receptors leads to an attenuation of ethanol-stimulated mesolimbic dopamine release. We prepared ethanol-naïve male Long Evans rats (n = 95) for intravenous (i.v.) drug administration and in vivo microdialysis (in awake, freely moving animals), and analyzed our samples using HPLC and GC for dopamine and ethanol detection, respectively. In one set of experiments, we looked at the effects of naltrexone, a non-selective opioid antagonist, on ethanol-stimulated mesolimbic dopamine release. First of all, we checked to see if naltrexone affected basal dopamine levels in the NAcS. Thereafter, we looked for a dose of naltrexone (i.v.) that was effective in suppressing the release of dopamine in the NAcS evoked by morphine (1 mg/kg, i.v.). Subsequently, we checked to see if doses of naltrexone that inhibited morphine-evoked dopamine were also effective in attenuating dopamine release due to ethanol (1g/kg, 10% w/v, i.v.). To do this, we pretreated rats with naltrexone doses, followed 20 min later by morphine, ethanol or saline (all drugs were administered i.v.). In another set of experiments, we looked at the effect of β-funaltrexamine, a selective μ-opioid antagonist, on ethanol-stimulated dopamine release in the NAcS. Similarly to the previous set of experiments, we looked for a dose of β-funaltrexamine (s.c.) that was effective in suppressing the release of dopamine the NAcS evoked by morphine (1 mg/kg, i.v.), and checked to see if this dose of β-funaltrexamine was also effective in attenuating ethanol-stimulated dopamine release in the NAcS. For the β- funaltrexamine experiments, rats were pretreated with β-funaltrexamine (s.c.) 20- 25 h before i.v. infusions of saline, morphine and ethanol. Morphine increased dopamine release in the NAcS. Naltrexone and β- funaltrexamine significantly attenuated morphine-evoked dopamine release. Also, ethanol increased dopamine release in the NAcS. Naltrexone and β- funaltrexamine, at doses effective in attenuating morphine-evoked dopamine release, suppressed the prolongation, but not the initiation of dopamine release in the NAcS due to ethanol. Naltrexone and β-funaltrexamine did not affect the peak concentration and clearance of ethanol in the brain. The conclusion of this study is that the μ-opioid receptors are involved in a delayed component of ethanol-stimulated dopamine release in the NAcS in ethanol-naïve rats. This is the first study to show that the ethanol-stimulated dopamine response consists of a delayed μ-opioid mechanism. / text

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.

O comportamento maternal (CM) em mamíferos tem características específicas. O período logo após o parto é particularmente sensível a alterações fisiológicas que podem modular a expressão deste comportamento importante. Mudanças comportamentais observadas em animais doentes são consideradas comportamento doentio (CD). A exposição ao LPS, uma endotoxina derivada da parede de uma bactéria gran negativa, durante a gravidez pode causar doenças mentais. A fim de investigar, uma possível relação entre CM e CD, os animais foram tratados com LPS. Para o estudo do CM e agressivo, quarenta ratas foram divididos em quatro grupos, dois controles e dois grupos experimentais, com dez animais cada. O grupo experimental recebeu 100µg/kg de LPS por via i.p, e grupo controle o veículo de endotoxina, após quarenta e oito horas de administração de LPS, ou seja, no quinto dia de lactação, as observações começaram. Para escolha deste dia, ratas virgens e ratas lactantes foram divididas em quatro grupos, dois controles e dois experimentais, com dez fêmeas cada. O peso corporal, consumo de água, ração, e a temperatura corporal foram medidas para cento e vinte horas. As fêmeas do grupo controle foram observadas da mesma forma, mas foram tratados com o veículo do LPS. Observamos que: 1) Em ratas virgens e lactantes o tratamento com LPS modificou a temperatura e peso corporal, consumo de água e ração; 2) No período de lactação houve redução da latência para busca do primeiro filhote. Na prole verificou-se que: 3) Houve alteração no padrão de vocalização dos filhotes cujas mães foram expostas ao LPS no terceiro dia de lactação; 4) houve alteração no burst e fagocitose de enutrofilos no vigésimo primeiro dia de lactação após desafio com a endotoxina indicativo de maior resposta ao LPS. Concluiu-se que a exposição de ratos ao LPS facilita o comportamento maternal, mas promove alterações na sua prole relacionadas à interação entre mãe-filhote e aumento na resposta a um desafio imunológico. / Maternal behavior (MB) in mammals has specific characteristics. The time period just after parturition is particularly sensitive to physiological changes that can modulate the expression of this important behavior. Behavioral changes observed in sick animals, are considered as sick behavior (SB). Exposure to LPS, an endotoxin derived from the wall of a gran negative bacteria, during pregnancy might cause mental diseases. In order to investigate, a possible relationship between MB and SB, animals were treated with LPS. For the study of MB and maternal aggressive behavior, 40 rats were divided in 4 groups, 2 control and 2 experimental groups. The experimental group received 100µg/kg LPS by ip, and control group the vehicle of endotoxin, after 48 hours of LPS administration the observations of SB began. For choice these days, 20 virgin and 20 lactating rats were divided in 4 groups, 2 control and 2 experimental. They received ip 100µg/kg. Body weight, water and feed consumption, and body temperature were measured for 120h. Control females were observed in the same way, but they were treated with vehicle of LPS. The results showed that: 1) In 48 hours after the LPS treatment, virgin and lactating rats showed increased body temperature, loss of body weight, increased water consumption and decreased food consumption, 2) In 48 hours after the treatment with LPS, lactating rats showed reduced latency to retrieve the first pup to the nest. In the offspring of mothers treated with LPS it was found that: 3) Pups form mothers treated with LPS on the 5th day of lactation showed changes in the vocalization pattern; 4) Those pups showed changes in oxidative burst and phagocytosis on 21th day of lactation. It is concluded that exposure of rats to LPS promoted changes in the in the interaction between mother and pups.

O núcleo acumbens (Acb) é envolvido em comportamentos adaptativos e emocionais. A maioria dos neurônios do Acb são neurônios de projeção (MSNs) que contém a fosfoproteína DARPP-32 e são modulados por distintos tipos de interneurônios. Há pouca informação sobre os receptores de glutamato (Glu) expressos no Acb. Este estudo investiga, através de técnicas de imunohistoquímica, a distribuição e co-localização de marcadores do sistema dopaminérgico, dos receptores de Glu do tipo AMPA (GluR1-GluR4) e NMDAR1 e marcadores de interneurônios. Nossos resultados mostram que o Acb possui uma neuroquímica semelhante ao estriado dorsal. Porém, detectamos uma distribuição distinta de alguns dos marcadores no Acb. Os estudos de co-localização revelam que quase todos os neurônios no Acb expressam GluR2/3 ou GluR2. Em contraste, GluR1 e GluR4 são fracamente expressas e co-localizam com parvalbumina. Esses resultados indicam que GluR2 e GluR2/3 são expressas em MSNs DARPP-32+ e na maioria dos interneurônios do Acb enquanto GluR1 e GluR4 são exclusivamente expressas em interneurônios. / The nucleus accumbens is involved in adaptive and emotional behaviors. The majority of neurons in the Acb are projection neurons that express the phosphoprotein DARPP-32 and are modulated by distinct types of interneurons. There is little information about the glutamate receptors expressed in the Acb. This study investigates by immunohistochemical methods the distribution and co-localization of markers of the dopaminergic system, AMPA (GluR1-4) and NMDAR1 type Glu receptor subunits and specific markers of interneurons. Our results show that the neurochemistry of the Acb is similar to that of the dorsal striatum. However, we detected a distinct distribution of some markers in the Acb. Our co-localization studies reveal that almost all neurons of the Acb express GluR2/3 or GluR2. In contrast, GluR1 and GluR4 are weakly expressed and are co-localized with parvalbumin. These results indicate that GluR2 and GluR2/3 are expressed by MSNs DARPP-32+ and by the majority of interneurons of the Acb, whereas GluR1 and GluR4 are exclusively expressed by interneurons.

Maternal behaviours are those that increase offspring survival. Estrogens affect maternal behaviour by activating Estrogen Receptors (ER) in the brain. Maternal brain plasticity was explored by characterizing the effects of exposure to a mixture of environmental pollutants on number of ERs. Following exposure to the toxicants during pregnancy and lactation, brains of female rats were collected, sectioned at 30 μm and immunohistochemistry for ERα performed. Immuno-positive cells in the mPOA, VTA and NAc were counted. A two way ANOVA revealed no main effect of Treatment on the number of immunopositive cells for all three brain regions. However, a significant difference between the High and Low Doses with the high dose reducing the number of ERα+ cells in the mPOA and VTA. Our work showcases the importance of studying the effects of multiple chemical co-exposures on the mother's brain, as maternal brain changes impact maternal behaviour consequently affecting offspring neurodevelopment.

O comportamento maternal (CM) em mamíferos tem características específicas. O período logo após o parto é particularmente sensível a alterações fisiológicas que podem modular a expressão deste comportamento importante. Mudanças comportamentais observadas em animais doentes são consideradas comportamento doentio (CD). A exposição ao LPS, uma endotoxina derivada da parede de uma bactéria gran negativa, durante a gravidez pode causar doenças mentais. A fim de investigar, uma possível relação entre CM e CD, os animais foram tratados com LPS. Para o estudo do CM e agressivo, quarenta ratas foram divididos em quatro grupos, dois controles e dois grupos experimentais, com dez animais cada. O grupo experimental recebeu 100µg/kg de LPS por via i.p, e grupo controle o veículo de endotoxina, após quarenta e oito horas de administração de LPS, ou seja, no quinto dia de lactação, as observações começaram. Para escolha deste dia, ratas virgens e ratas lactantes foram divididas em quatro grupos, dois controles e dois experimentais, com dez fêmeas cada. O peso corporal, consumo de água, ração, e a temperatura corporal foram medidas para cento e vinte horas. As fêmeas do grupo controle foram observadas da mesma forma, mas foram tratados com o veículo do LPS. Observamos que: 1) Em ratas virgens e lactantes o tratamento com LPS modificou a temperatura e peso corporal, consumo de água e ração; 2) No período de lactação houve redução da latência para busca do primeiro filhote. Na prole verificou-se que: 3) Houve alteração no padrão de vocalização dos filhotes cujas mães foram expostas ao LPS no terceiro dia de lactação; 4) houve alteração no burst e fagocitose de enutrofilos no vigésimo primeiro dia de lactação após desafio com a endotoxina indicativo de maior resposta ao LPS. Concluiu-se que a exposição de ratos ao LPS facilita o comportamento maternal, mas promove alterações na sua prole relacionadas à interação entre mãe-filhote e aumento na resposta a um desafio imunológico. / Maternal behavior (MB) in mammals has specific characteristics. The time period just after parturition is particularly sensitive to physiological changes that can modulate the expression of this important behavior. Behavioral changes observed in sick animals, are considered as sick behavior (SB). Exposure to LPS, an endotoxin derived from the wall of a gran negative bacteria, during pregnancy might cause mental diseases. In order to investigate, a possible relationship between MB and SB, animals were treated with LPS. For the study of MB and maternal aggressive behavior, 40 rats were divided in 4 groups, 2 control and 2 experimental groups. The experimental group received 100µg/kg LPS by ip, and control group the vehicle of endotoxin, after 48 hours of LPS administration the observations of SB began. For choice these days, 20 virgin and 20 lactating rats were divided in 4 groups, 2 control and 2 experimental. They received ip 100µg/kg. Body weight, water and feed consumption, and body temperature were measured for 120h. Control females were observed in the same way, but they were treated with vehicle of LPS. The results showed that: 1) In 48 hours after the LPS treatment, virgin and lactating rats showed increased body temperature, loss of body weight, increased water consumption and decreased food consumption, 2) In 48 hours after the treatment with LPS, lactating rats showed reduced latency to retrieve the first pup to the nest. In the offspring of mothers treated with LPS it was found that: 3) Pups form mothers treated with LPS on the 5th day of lactation showed changes in the vocalization pattern; 4) Those pups showed changes in oxidative burst and phagocytosis on 21th day of lactation. It is concluded that exposure of rats to LPS promoted changes in the in the interaction between mother and pups.