The hypocretin/orexin (HCRT) system is associated with compulsive stimulant drug use, involving both HCRT-receptor 1 (-R1) and HCRT-receptor 2 (-R2). Few studies, however, have examined the role of HCRT-R2 or combined HCRT-R1/2 on compulsive methamphetamine (METH) taking behavior. In this study, we examined the effects of HCRT-R1, -R2, and -R1/2 antagonists on compulsive METH self-administration, as modeled by escalated intake in adult male Wistar rats allowed extended access to METH. Three cohorts of rats were allowed either short (1h; ShA; n=7-10/cohort) or long (6h; LgA; n=7-9/cohort) access to METH intravenous self-administration for 14 sessions (fixed ratio 1 schedule). Each cohort was then systemically administered a single- or dual-HCRT-R antagonist 30 min prior to METH self-administration testing: cohort 1, selective HCRT-R1 antagonist (RTIOX-276; RTI-R1; 0, 10, and 20 mg/kg); cohort 2, selective HCRT-R2 antagonist (JNJ-10397049; JNJ-R2; 0, 10, and 20 mg/kg); and cohort 3, dual HCRT-R1/2 antagonist (Suvorexant; SUV-R1/2; 0, 30, and 60 mg/kg). RTI-R1 elicited a dose-dependent reduction in METH intake in LgA, but not ShA, in the first hour. Administration of JNJ-R2 had no effect on METH intake in the first hour in neither ShA nor LgA rats, but reduced METH intake during the full 6 h session at the lowest dose. SUV-R1/2 administration had no effect on METH intake in ShA rats, but showed significant attenuation of METH-taking at the highest dose in both the first hour and full 6h session for LgA rats. Locomotor activity was significantly reduced following RTI-R1 and SUV-R1/2 in ShA rats only. To further explore the role that HCRT plays in METH dependence after a period of abstinence, we used a shRNA-encoding adeno-associated viral vector (AAV) to silence Hcrt in a separate cohort of previously-escalated METH-dependent rats. Following an initial escalation phase, and prior to a 3-week period of drug abstinence, rats were injected with either a control scramble-RNA AAV (AAV-Scram; n= 4) or a Hcrt-knockdown AAV (AAV-HCRT-KD; n= 5). AAV-Scram rats showed a significant decrease in METH self-administration post-abstinence, and a subsequent increase in METH-taking following a re-escalation period. In contrast, AAV-HCRT-KD rats showed a significant attenuation of METH self-administration following the re-escalation period. Combined, these results suggest HCRT neurotransmission at both HCRT-R1 and -R2 may contribute to compulsive METH-taking behavior.

No description available.

Abuse of psychostimulants including cocaine and new synthetic formulations remains an international public health problem and economic burden. Addiction develops consequential to positive and negative drives that underlie “getting” and “staying” high. Dopamine (DA), arising from ventral tegmental area (VTA), projects to ventral striatal targets to encode reward signals and reward prediction. Mesolimbic DA is implicated in both the immediate rewarding effects of psychostimulants, and its hypoactivity underlies negative affect as drug levels decline. Accordingly, modulating inputs to midbrain DA possesses capacity to mediate positive/rewarding and negative/aversive effects of drugs. Hypocretin/orexin (hcrt/ox) is a family of excitatory hypothalamic peptides that projects widely throughout the central nervous system including to VTA DA cells, and hcrt/ox mediates brain reward function and motivation for self-administered drugs. Notably, the first-in-class hcrt/ox receptor antagonist (suvorexant) was approved for management of insomnia in the summer of 2014. Also within the past decade, the caudal division of VTA (termed “tail of VTA” and “rostromedial tegmental nucleus [RMTg]”) was detailed for its ability to negatively regulate VTA DA. Functionally, stimulation of the GABA-producing RMTg population encodes aversion and responds to aversive cues. Curiously, anatomy work depicts the hypothalamus as a principal input to the RMTg although the cellular phenotypes and functions of hypothalamic projections to RMTg have not been fully resolved. Work in this thesis was designed to map hcrt/ox projections to VTA and RMTg in effort to understand functionally-relevant topographical arrangement. In preliminary assessments, we test for the first time the ability of suvorexant to modulate reward and reinforcement associated with psychostimulant use in rats. Additionally, we profile how self-administered cocaine and “bath salt” synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) influence affective states in rats by measuring ultrasonic vocalizations (USVs) and comparing patterns of responding. Subsequently, we test the ability of suvorexant to influence MDPV-taking and affective changes that promote self-administration. Finally, we utilize direct-site pharmacology to assess the degree to which hcrt/ox transmission within VTA and RMTg contributes to motivated responding for and affective processing of self-administered cocaine across two doses. Specifically, we hypothesized that intra-VTA suvorexant would suppress drug-taking by reducing the rewarding value of self-administered cocaine, whereas intra-RMTg hcrt/ox peptide injection would suppress drug-taking by increasing aversive value of self-administered cocaine. We observed that systemic suvorexant effectively reduces motivated cocaine-taking, and that this reduction relates in part to reductions in subjective reward of self-administered cocaine as interpreted by reductions in positively-valenced 50-kHz USVs. Retrograde tracing supports that hcrt/ox projects to both VTA and RMTg without discernible topographical arrangement. Target-site pharmacology finds that intra-VTA suvorexant has no appreciable effects on motivated cocaine-taking but tends to elevate 50-kHz USVs during the pre-drug “anticipation” time epoch in low-dose cocaine self-administering rats (0.375 mg/kg/inf). While intra-RMTg hcrt/ox pre-treatment sparsely affected USVs, 0.3 nmol/hemisphere hcrt/ox significantly enhanced cocaine-taking in low-dose cocaine self-administering rats, and, in high-dose (0.750 mg/kg/inf) cocaine self-administering rats, intra-RMTg hcrt/ox significantly suppressed responding when pre-treated with 1.0 and 3.0 nmol/hemisphere. Collectively, studies within this thesis promote the use of hcrt/ox receptor antagonists as adjunct pharmacotherapy in managing psychostimulant use disorders, although the circuitries through which aberrant motivated behaviors are modulated are not entirely clear. Future work will need to be performed to understand how hcrt/ox transmits to neurochemically-defined cell populations residing within VTA and RMTg—these pathways are recruited for processing stimuli as “rewarding” and “aversive” which are critical contributors in the development of substance use disorders and other psychiatric disorders characterized by dysregulated reward processing. / Biomedical Sciences

Submitted by Bruna Rodrigues (bruna92rodrigues@yahoo.com.br) on 2016-09-21T12:17:25Z No. of bitstreams: 1 DissMCV.pdf: 1396676 bytes, checksum: d3fa0ce7f0f0504dfe6926528b1e7366 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-09-21T18:23:20Z (GMT) No. of bitstreams: 1 DissMCV.pdf: 1396676 bytes, checksum: d3fa0ce7f0f0504dfe6926528b1e7366 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-09-21T18:23:27Z (GMT) No. of bitstreams: 1 DissMCV.pdf: 1396676 bytes, checksum: d3fa0ce7f0f0504dfe6926528b1e7366 (MD5) / Made available in DSpace on 2016-09-21T18:23:33Z (GMT). No. of bitstreams: 1 DissMCV.pdf: 1396676 bytes, checksum: d3fa0ce7f0f0504dfe6926528b1e7366 (MD5) Previous issue date: 2015-10-16 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / The orexins are hypothalamic neuropeptides involved in an array of functions such as regulation of sleep/wake states and chemoreception to CO2/pH. The Locus coeruleus (LC) is a chemosensitive site and expresses an extensive population of orexin receptor 1 (OX1R). Here we tested the hypothesis that OX1Rs located in the LC participate in the ventilatory response to hypercapnia in a vigilance state and diurnal cycle-dependent manner. To this end, we performed unilateral injections of SB-334867 (OX1R antagonist, 5 mM) into the LC of male Wistar rats and evaluated the ventilatory response to 7% CO2 during wakefulness and sleep in the dark and light phase of the diurnal cycle. Hypercapnia induced an increase in ventilation in all groups compared to normocapnic values. However, the injection of (SB-334867) promoted an attenuation of the hypercapnic chemorreflex during wakefulness, due to changes in VT. In addition, microinjection of SB-334867 decreases the wakefulness time during dark phase. We suggest that projections of orexin-containing neurons to the LC contribute, via OX1Rs, to the hypercapnic chemoreflex during wakefulness in the dark phase. / As orexinas são neuropeptídeos hipotalâmicos envolvidos em uma variedade de funções, tais como, na regulação do ciclo sono-vigília e na quimiorecepção ao CO2 / pH. O locus coeruleus (LC) é um núcleo quimiossensível e expressa uma extensa população de receptor de orexina 1 (OX1R). Portanto, nós testamos a hipótese de que OX1Rs localizados no LC participam da resposta ventilatória à hipercapnia no estado de vigília de maneira dependente do ciclo claro e escuro. A participação da neurotransmissão orexinérgica do LC na resposta ventilatória à hipercapnia foi avaliada por meio da microinjeção do antagonista de receptor-1 OXR- 1 (SB-334867, 5 mM) no LC de ratos Wistar não anestesiados durante o sono e a vigília nas fases clara e escura. Nossos resultados demonstraram que a hipercapnia induz um aumento significativo da ventilação em todos os grupos comparado aos valores de ventilação na normocapnia. No entanto, na fase escura, a microinjeção do SB-334867 promoveu uma atenuação do quimiorreflexo hipercápnico durante a vigília, mas não durante o sono devido à diminuição do volume corrente VT. Adicionalmente, a microinjeção do SB-334867 diminui o tempo que os animais passam acordados em normocapnia na fase escura. Portanto, nossos dados sugerem que as projeções orexinérgicas para o LC atuando em OXR-1 exercem uma modulação excitatória na resposta ventilatória ao CO2 durante a vigília na fase escura. / 2014/00330-3

L'histamine(HA) et l'orexine(Ox) jouent des rôles distincts/complémentaires dans l'éveil(Ev) associés à la locomotion, l'exploration, la motivation & l'anticipation. La régulation de l'Ev dépend donc des activités comportementales instantanées et de la participation diverse des systèmes d'éveil. Par une approche intégrée, cette thèse se focalise sur le rôle d'HA et Ox dans l'Ev lié à l'attirance sexuelle (Sexual Arousal), une condition sine qua non pour la reproduction.La présence de la souris femelle entraîne une augmentation de l'Ev chez le mâle. Celle-ci n'est pas significative si un autre mâle est présent. Cet effet dépend d'hormones sexuelles car les souris femelles ovariectomisées ou prétraitées par un antagoniste d'œstrogènes n'entrainent pas d'Ev chez les mâles, alors que les mâles prétraités par un antagoniste d'androgènes n'ont plus cette augmentation. L'inhibition de la synthèse d'HA ou du récepteur Ox1 abolit l'augmentation de l'Ev. Celle-ci est préservée chez la souris sans HA ou sans Ox mais absente chez la souris sans les deux. Ainsi, les systèmes à HA & à Ox, pilotés par les hormones sexuelles, jouent un rôle clé dans Sexual Arousal. Un déficit chronique en HA ou Ox serait compensé par des mécanismes adaptatifs, qui deviennent insuffisants lors de la délétion des deux systèmes. J'ai aussi participé à des études sur : 1) le rôle du récepteur H1 dans l'Ev exploratoire; 2) les neurones à HA, cible de l'acide ursodésoxycholique; 3) les connexines & le mode d'action du modafinil.Cette thèse contribue à qualifier le rôle synergique d'HA & Ox dans le contrôle des multiples facettes de l'Ev & soutient l'hypothèse que le contrôle de l'Ev est comportement-dépendant / Our previous work showed that histamine (HA) and orexin (Ox) neurons play distinct, but complementary roles in wakefulness(W) associated with locomotion, exploration, motivation and anticipation, leading to the hypothesis that the regulation of W, a highly heterogeneous brain state, depends on the instantaneous ongoing behavioral activities and diverse participation of various arousal systems. Using an integrative approach, this thesis focused on the role of HA and Ox in sexual arousal, a prerequisite for reproduction.The presence of a female mouse elicited in a male a marked increase in W. This increase was not significant if another male was introduced. Ovariectomized or estrogen receptor antagonist-treated female mice did not elicit sexual arousal in males. Male mice pretreated with an androgen receptor antagonist did not show any increased W facing a female. Acute inhibition of HA synthesis or Ox1-receptor antagonist abolished sexual arousal. Whereas sexual arousal was intact in knockout(KO) mice lacking either HA or Ox, it was totally absent in double KO mice. Thus, both the HA and Ox systems, driven by sex hormones, promote sexual arousal. Chronic HA or Ox loss could be compensated by up-regulated adaptive mechanisms, which became ineffective when both systems were deleted.During my thesis, I was also involved in the studies of 1) role of HA H1-receptor in W associated with exploration; 2) HA neurons as target of ursodeoxycholic acid; 3) astroglial connexins and modafinil mode of action.This thesis contributes to qualify the synergistic role of HA and Ox in controlling the multiple facets of W and supports the hypothesis that the control of W is behavior-dependent

Le système olfactif partage de nombreux liens moléculaires, neuroanatomiques et fonctionnels avec le système de régulation de l’homéostasie énergétique. L’exploration de ces interactions nous a conduit à démontrer que la détection olfactive est modulée par les états alimentaires et métaboliques : des animaux affamés présentent une meilleure sensibilité olfactive que des animaux rassasiés. Cette modulation persiste chez les rats Zucker fa/fa obèses et disparaît chez les rats LouC résistants à l’obésité. Les hormones et les neuropeptides impliqués dans la régulation de l’homéostasie énergétique apparaissent comme de bons candidats pour expliquer l’influence des états alimentaires et métaboliques sur la détection olfactive. Afin de tester directement leur action sur la détection olfactive, nous avons évalué les rôles de l’Orexine A, un neuropeptide hypothalamique orexigène, ainsi que de la leptine et de l’insuline, deux hormones d’adiposité périphériques, sur la capacité de détection olfactive de rats Wistar. Ainsi, nous avons démontré que l’injection ICV d’orexine A induit une augmentation de la détection olfactive. A l’inverse, les injections ICV de leptine et d’insuline induisent une diminution de la détection olfactive. Les récepteurs de l’orexine A, de l’insuline et de la leptine sont largement exprimés au niveau du système olfactif. En particulier, les récepteurs de l’insuline présentent une régionalisation marquée et sont très abondants au niveau de plusieurs catégories cellulaires du bulbe olfactif, le premier relais central de l’information olfactive. Nous avons également montré que la quantité d’insuline bulbaire variait en fonction de l’état alimentaire tandis que la densité des récepteurs n’était pas modifiée. L’ensemble de ces données, corroboré par d’autres travaux de la littérature, suggère que les hormones et les neuropeptides impliqués dans la régulation de l’homéostasie énergétique jouent également un rôle majeur dans la régulation de la fonction olfactive. Les molécules orexigènes, libérées en état de faim et de carence énergétique, augmentent la détection olfactive et participent à l’initiation du comportement alimentaire. A l’inverse, les molécules anorexigènes libérées en état de rassasiement et d’abondance énergétique, diminuent la détection olfactive et conduisent à l’arrêt de la prise alimentaire. La compréhension des mécanismes qui sous-tendent les interactions entre l’odorat et la régulation de la prise alimentaire et de la masse corporelle pourrait permettre à terme d’évaluer l’importance de la perception sensorielle de la nourriture lors de la mise en place de troubles du comportement alimentaire. / Olfaction is closely linked to energy homeostasis regulation. The olfactory system shares several molecular, anatomical and functional links with brain areas and peripheral organs involved in food intake and body weight regulations. We demonstrated that the feeding state modulates olfactory detection: fasted rats display better olfactory sensitivity that satiated ones. This modulation is also observed in Obese Zucker fa/fa rats. However, obesity-resistant LouC rats do not modulate their olfactory detection according to the feeding state. Peripheral hormones and neuropeptides involved in energy homeostasis regulation might be responsible for olfactory detection modulation. To examine this hypothesis, we evaluated the respective roles of Orexin A, a hypothalamic orexigenic neuropeptide; as well as leptin and insulin, two peripheral adiposity hormones; on olfactory detection. We demonstrated that central administration of Orexin A increases olfactory detection; whereas central administration of leptin or insulin decreases olfactory detection. Orexin A, leptin and insulin receptors are widely expressed in the olfactory system. We further demonstrated that insulin receptors were abundantly expressed in discrete olfactory bulb areas and in several neuron types of the olfactory bulb network. The whole of these data, supported by several reports, suggest that hormones and neuropeptides classically involved in energy homeostasis regulation extend their roles to olfactory detection modulation. Indeed, orexigenic signals released upon fasting or in conditions of energy depletion increase olfactory detection which participate in meal initiation. By contrast, anorexigenic signals released during refeeding or in conditions of energy abundance decrease olfactory detection which participate in meal termination. With the ever rising incidence of metabolic disorders, elucidating the cross-talks between olfaction and energy homeostasis regulation is of critical relevance to better understand and manage the etiology of altered food-intake behaviours.

O núcleo motor do trigêmeo (Mo5) está cercado por um anel de neurônios pré-motores localizados na região h. Estudos demonstram que neurônios que inervam o Mo5 estão distribuídos no tronco encefálico e no prosencéfalo. Após implante de traçador retrógrado no Mo5, verificamos células retrogradamente marcadas no núcleo mesencefálico do trigêmeo (Me5), na região h e em núcleos prosencefálicos como o central da amígdala (CeA), a área hipotalâmica lateral (LH) e o parasubtalâmico (PSTh). Para confirmação, realizamos injeção de traçador anterógrado e investigamos, também, a neuroquímica das projeções. Neurônios do CeA que se projetam para o Mo5 recebem inervação de fibras imunorreativas ao fator liberador de corticotrofina (CFR-ir) e/ou à tirosina hidroxilase (TH-ir); alguns neurônios da LH que se projetam para o Mo5 são imunorreativos à orexina (ORX) e alguns neurônios do PSTh que se projetam para o Mo5 são innervados por fibras TH-ir. O Me5 recebe grande inervação do CeA e moderada da LH e do PSTh, possuindo grande aferência de fibras imunorreativas ao CRF, ORX e TH / The trigeminal motor nucleus (Mo5) is surrounded by a ring of premotor neurons defined as the h region. Studies have shown that neurons innervating the Mo5 are located in brainstem and in forebrain nuclei. Through the injection of the retrograde tracer cholera toxin b subunit/CTb in the Mo5, we found retrograde labeled neurons in the brainstem including the h region and the mesencephalic trigeminal nucleus (Me5), and in forebrain nuclei such as the central nucleus of amygdala (CeA), the lateral hypothalamic area (LH) and the parasubthalamic nucleus (PSTh). As control, we injected the anterograde tracer biotin dextran amine and found that these areas project direct or indirectly via the h region or the Me5 to the Mo5. Some CeA neurons that project to the Mo5 receive corticotrophin releasing factor (CRF) and tyrosine hydroxylase (TH) innervation, some LH neurons that project to Mo5 express orexin, and PSTh neurons that project to the Mo5 receive TH innervation. The Me5 is also innervated by CeA, LH and PSTh neurons and by CRF, orexin and TH immunoreactive fibers

Made available in DSpace on 2015-07-22T20:50:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-03-30. Added 1 bitstream(s) on 2015-08-11T03:26:11Z : No. of bitstreams: 1 Publico-12803.pdf: 1327527 bytes, checksum: 4fb071f9df6c6a7299fea37a3cbfb20a (MD5) / As orexinas são dois neuropeptídeos, orexina-A e orexina-B, derivados do mesmo gene precursor (pré-pro-orexina), produzidos em alguns milhares de neurônios localizados na área perifornicial do Hipotálamo lateral. Apesar de ter uma produção restrita ao hipotálamo, os neurônios orexinérgicos projetam-se amplamente para todo o cérebro regulando uma série de funções endócrinas e homeostáticas. Evidências recentes, no entanto, mostram o envolvimento do sistema da orexina no circuito de recompensa. Neste estudo avaliamos o envolvimento do sistema da orexina na sensibilização comportamental induzida por etanol. No experimento 1 foi utilizado o modelo de sensibilização comportamental e os animais do grupo salina, agudo (uma administração de EtOH) e crônico (7 administrações de EtOH) foram tratados durante 14 dias para verificar o desenvolvimento de sensibilização comportamental; após o término do tratamento os animais foram perfundidos e a imunorreatividade de duplas marcações para orexina e c-Fos foi avaliada pela técnica de imunohistoquímica. No experimento 2 foi utilizado o modelo de sensibilização comportamental para verificar se o antagonista de receptor do tipo 1 da orexina, SB 334867, bloqueia esse fenômeno. No primeiro experimento não houve diferença estatística entre os grupos salina, agudo e crônico quanto à ORX+c-Fos-IR; porém os animais tratados cronicamente com EtOH apresentaram uma tendência de aumento da dupla marcação de neurônios orexinérgicos indicando que o desenvolvimento da sensibilização comportamental produz ativação desses neurônios; além disso, os animais tratados cronicamente com etanol desenvolveram a sensibilização comportamental. No segundo experimento, o SB 334867 bloqueou a expressão deste fenômeno, indicando que o sistema orexinérgico parece influenciar de maneira importante o processo de sensibilização comportamental, já que a administração sistêmica do SB334867 bloqueou a expressão da sensibilização comportamental aos efeitos estimulantes do etanol em camundongos machos. / Orexins are two neuropeptides, orexin-A and orexin-B, derived from the same precursor gene (pre-pro-orexin) produced by a few thousand neurons located in the perifornical area of the lateral hypothalamus. Despite having a restricted production, orexinergic neurons project widely to brain structures that regulate a number of endocrine and homeostatic functions. Recent evidence suggests the involvement of the orexin system in the reward circuit. We evaluated the role of this system in ethanol-induced behavioral sensitization. In Experiment 1 was used the behavioral sensitization model (development), in which animals were chronically treated for 14 days with saline, acute ethanol after saline treatment or with ethanol (seven administration) to induce behavioral sensitization; at the end of the treatment animals were perfused and immunohistochemistry technique was used to determine double staining for orexin and c-Fos (ORX+c-Fos-IR). In Experiment 2 behavioral sensitization was induced and SB 334867, an orexin-1 receptor antagonist, was used to examine whether it could block the expression of this phenomenon. The results of Experiment 1 showed no statistical difference among the groups (saline, acute and chronic) as to ORX+c-Fos-IR, although animals chronically treated with EtOH exhibited an trend to more double staining of orexin neurons indicating that this treatment regimen activates this neuropeptide system. In the second experiment, SB 334867 blocked the expression of this phenomenon. The orexin system seems to influence the process of behavioral sensitization, since systemic administration of SB 334867 blocked the expression of this phenomenon induced by a stimulant dose of ethanol in male mice. / TEDE / BV UNIFESP: Teses e dissertações

O núcleo motor do trigêmeo (Mo5) está cercado por um anel de neurônios pré-motores localizados na região h. Estudos demonstram que neurônios que inervam o Mo5 estão distribuídos no tronco encefálico e no prosencéfalo. Após implante de traçador retrógrado no Mo5, verificamos células retrogradamente marcadas no núcleo mesencefálico do trigêmeo (Me5), na região h e em núcleos prosencefálicos como o central da amígdala (CeA), a área hipotalâmica lateral (LH) e o parasubtalâmico (PSTh). Para confirmação, realizamos injeção de traçador anterógrado e investigamos, também, a neuroquímica das projeções. Neurônios do CeA que se projetam para o Mo5 recebem inervação de fibras imunorreativas ao fator liberador de corticotrofina (CFR-ir) e/ou à tirosina hidroxilase (TH-ir); alguns neurônios da LH que se projetam para o Mo5 são imunorreativos à orexina (ORX) e alguns neurônios do PSTh que se projetam para o Mo5 são innervados por fibras TH-ir. O Me5 recebe grande inervação do CeA e moderada da LH e do PSTh, possuindo grande aferência de fibras imunorreativas ao CRF, ORX e TH / The trigeminal motor nucleus (Mo5) is surrounded by a ring of premotor neurons defined as the h region. Studies have shown that neurons innervating the Mo5 are located in brainstem and in forebrain nuclei. Through the injection of the retrograde tracer cholera toxin b subunit/CTb in the Mo5, we found retrograde labeled neurons in the brainstem including the h region and the mesencephalic trigeminal nucleus (Me5), and in forebrain nuclei such as the central nucleus of amygdala (CeA), the lateral hypothalamic area (LH) and the parasubthalamic nucleus (PSTh). As control, we injected the anterograde tracer biotin dextran amine and found that these areas project direct or indirectly via the h region or the Me5 to the Mo5. Some CeA neurons that project to the Mo5 receive corticotrophin releasing factor (CRF) and tyrosine hydroxylase (TH) innervation, some LH neurons that project to Mo5 express orexin, and PSTh neurons that project to the Mo5 receive TH innervation. The Me5 is also innervated by CeA, LH and PSTh neurons and by CRF, orexin and TH immunoreactive fibers

La maladie de Huntington est une pathologie héréditaire qui se caractérise par une dégénérescence sélective des neurones striataux de la voie indirecte des ganglions de la base. Chez les patients ainsi que chez les souris modèles de la pathologie, en plus des symptômes moteurs, cognitifs et psychiatriques, des troubles du sommeil peuvent aussi apparaitre dès la phase pré-symptomatique. L’étude électrophysiologique in vivo des souris transgéniques R6/1a, en outre, révélé en début de phase symptomatique l’apparition du rythme pathologique β observé principalement durant le sommeil. Ces travaux de thèses ont donc eut pour but d’étudier le lien entre les modifications d’activités de réseaux cérébraux, les troubles du sommeil et l’émergence du rythme β ainsi que l’implication de ces anomalies dans les perturbations comportementales observées chez les souris R6/1. Notre étude de l’imagerie c-Fos a montré une hyperactivation de la voie frontostriatale chez ces souris, et ceci uniquement au stade pré-symptomatique sans aucune modification d’activation de la voie indirecte. Notre étude pharmacogénétique a démontré que la modification d’activité de ces neurones de projection striataux pouvait modifier l’alternance veille/sommeil mais ne pouvaient générer le rythme β. Enfin, notre étude pharmacologique a établit le lien entre le dysfonctionnement du système orexinergique et l’émergence du rythme β chez les souris R6/1. Ces travaux ont permis de mieux décrire des modifications d’activités de réseaux associées aux différents stades de la pathologie, en particulier au stade présymptomatique, et leurs contributions aux troubles du sommeil et l’émergence du rythme β. / Huntington’s disease (HD) is an inherited pathology that causes selective degeneration ofindirect striatal pathway neurons of the basal ganglia. In addition to the classic motor,cognitive and psychiatric symptoms, patients and mouse models of HD develop sleepdisorders, which can appear at as early as pre-symptomatic stage. Furthermore, in vivoelectrophysiological study of R6/1 transgenic mice revealed a unique and pathological βrhythm that appear at early symptomatic stage and which is mainly observed during sleep.The aim of this thesis work was to examine the link between changes in cerebral networkactivities, sleep disturbances and β rhythm, and to determine the contribution of theseabnormalities to the behavioral disturbances observed in R6/1 mice. Our neuroimaging study of the marker of neuronal activity c-Fos showed a hyperactivation of frontostriatal pathway at pre-symptomatic stage without any activity changes of the vulnerable indirect pathway neurons. Our pharmacogenetic study demonstrated that changes of striatal projection neuronal activity can modify sleep/wake behaviors, without inducing the pathological β rhythm. Finally, our pharmacological study established a link between orexinergic system dysfunction and β rhythm emergence in R6/1 mice. Our data, therefore, described further the natures of altered neural circuit activity associated with different disease stages, in particular pre-motor symptomatic period, and the importance of these alterations for sleep disturbances as well as β rhythm appearance in transgenic HD mice.