The locomotor activity of the reindeer is separated into a diurnal and a nocturnal phase which, in turn, consists of a  number of short-term activity bursts. The onset and termination  of diurnal and nocturnal activity are largely in synchrony  with sunrise and sunset. Since the diurnal phase is  longer, total activity is dependent on the photoperiod. Total  activity as well as the number of activity bursts is greater  in Jùne with continuous daylight than in December with 6  hours daylight. In winter, reindeer spent less time feeding  but more time ruminating and resting *than in summer. Synchronization  between individuals was also greatest in winter. It  is concluded that the described changes in the activity  pattern are due to an endogenous component and that this component  further controls food consumption and energy balance  of the reindeer.  Seasonal variations in behavioural patterns are described.  Several specific rutting behavioürs, sexual and agonostic,  emerge in the male during the prerut and persist until after  the rut. The preorbital gland is enlarged and secretory activity  is evident. The rut is cha'tabterized by the sudden appearance  of an odour in the breath of mature males followed a few  later by a strong odour in the urine. These odours persist for  a short time during the most intense period of rut. The amount  of androgen rizes sharply and reaches peak concentrations in  late September - early October, decreasing thereafter. The  described behavioural cues occur with a certain constancy in  time in concecutive seasons.  A quantification of the amounts of secretory epithelia in preorbital,  interdigital, caudal and tarsal glands reveals that  only the preorbital gland is subjected to any seasonal and  sexual variation. The apocrine epithelium in this gland is  most developed in mature males during the rutting season and  seems to be dependent upon the presence of an elevated androgen  concentration. The tarsal gland is the least developed  gland while the interdigital and caudal glands are more welldeveloped  and structurally complex. Scattered apocrine glands  are only developed on the legs, the ventral body, oral angle  and in the rump patch. / digitalisering@umu

O estudo de mosquitos é extremamente importante, pois muitos são considerados vetores de diversos patógenos transmissíveis ao homem. Aedes aegypti e Aedes albopictus são responsáveis por transmitir arbovírus, como os da dengue, chikungunya, zika e febre amarela urbana, no mundo. Neste trabalho foram empregados Ae. aegypti e Ae. albopictus para: analisar a atividade locomotora de machos, fêmeas virgens e fêmeas inseminadas naturalmente; comparar a atividade locomotora de fêmeas injetadas intratoracicamente com extrato de glândulas acessórias (AG) de machos co e heteroespecíficos; e verificar a taxa de inseminação de fêmeas injetadas com glândulas acessórias de machos co e heteroespecíficos, quando são posteriormente expostas a seus machos coespecíficos. Os mosquitos foram coletados em ovitrampas instaladas no Parque Municipal do Piqueri, Zona Leste da cidade de São Paulo, durante o outono e a primavera de 2015 e outono de 2016. Após a emergência dos adultos, estes foram transferidos para quatro gaiolas matrizes separadas por espécie e sexo, dos quais obtivemos machos e fêmeas virgens de cada espécie. Em outras duas gaiolas foram agrupadas por espécie, 40 fêmeas e 40 machos para cópula por 24 horas para obtermos fêmeas inseminadas naturalmente. Posteriormente, todos os mosquitos foram transferidos para uma incubadora por quatro dias para análise da atividade locomotora. Na comparação de fêmeas injetadas com glândulas acessórias, foram extraídas as glândulas de machos de Ae. aegypti e Ae. albopictus e estas injetadas intratoracicamente em fêmeas co e heteroespecíficas. Todas as fêmeas injetadas foram transferidas para uma incubadora por três dias. Para a análise dos dados foram utilizados os testes estatísticos F e T e ANOVA. Após a atividade locomotora, as fêmeas injetadas foram expostas a seus machos coespecíficos e posteriormente tiveram suas espermatecas dissecadas para verificar a presença de espermatozoides a fim de analisar a taxa de inseminação. Nos machos, fêmeas virgens e fêmeas inseminadas naturalmente de Ae. aegypti e Ae. albopictus, o padrão da atividade locomotora foi diurno e bimodal no outono e na primavera. Em Ae. aegypti machos a atividade foi mais evidente no outono e em Ae. albopictus na primavera. Nas fêmeas de Ae. aegypti virgens a atividade foi mais evidente que nas inseminadas naturalmente em ambas as estações. Nas fêmeas de Ae. albopictus não houve diferença na atividade das virgens e inseminadas. Nas fêmeas de Ae. aegypti injetadas com AG a atividade locomotora foi diurna, com padrão unimodal e menos marcada. Nas fêmeas de Ae. albopictus injetadas com AG não houve diferença. Na taxa de inseminação, somente Ae. albopictus fêmeas injetadas com AG heteroespecíficas apresentaram espermatozoides após cópula coespecífica. Este estudo contribui para compreensão do comportamento de mosquitos vetores como Ae. aegypti e Ae. albopictus / The study of mosquitoes is extremely important, since many are considered vectors of several pathogens transmissible to man. Aedes aegypti and Aedes albopictus are responsible for transmitting arboviruses, such as dengue, chikungunya, zika and urban yellow fever, in the world. This study employed Ae. aegypti and Ae. albopictus to: analyze the locomotor activity of males, virgin females and females naturally inseminated; compare the locomotor activity of females injected intratoracically with extract of accessory glands (AG) of co and heterospecific males; and verify the rate of insemination of females injected with accessory glands of co and heterospecific males when later exposed to their co-specific males. The mosquitoes were collected in ovitraps installed in Piqueri Municipal Park, East of São Paulo city, during the autumn and spring of 2015 and autumn of 2016. After the emergence of adults, they were transferred to four cages, separated by species and sex from which we obtained virgin males and females of each species. In the other two cages, they were grouped by species, 40 females and 40 males for mating during 24 hours to obtain naturally inseminated females. Thereafter, all the mosquitoes were transferred to an incubator for four days to the locomotor activity analysis. In the comparison of females injected with accessory glands, the male glands of Ae. aegypti and Ae. albopictus were extracted and injected intratoracically into co and heterospecific females. All injected females were transferred to an incubator for three days. For the analysis, the statistical tests F and T and ANOVA were used. After the locomotor activity, the injected females were exposed to their co-specific males and later had their spermathecas dissected to verify the presence of spermatozoa in order to analyze the insemination rate. In males, virgin and naturally inseminated females of Ae. aegypti and Ae. albopictus, the pattern of locomotor activity was diurnal and bimodal in autumn and spring. Aedes aegypti males activity was more evident in autumn and in Ae. albopictus in spring. In virgin females of Ae. aegypti the activity was more evident than in the naturally inseminated in both seasons. In females of Ae. albopictus, there was no difference in the activity of virgin and inseminated. In females of Ae. aegypti injected with AG the locomotor activity was diurnal, with a unimodal and less marked pattern. In the females of Ae. albopictus injected with AG there was no difference. In the insemination rate, only Ae. albopictus females injected with heterospecific AGs presented spermatozoa after coespecific mating. This study contributes to the understanding of mosquito vectors behavior such as Ae. aegypti and Ae. albopictus

O estudo de mosquitos é extremamente importante, pois muitos são considerados vetores de diversos patógenos transmissíveis ao homem. Aedes aegypti e Aedes albopictus são responsáveis por transmitir arbovírus, como os da dengue, chikungunya, zika e febre amarela urbana, no mundo. Neste trabalho foram empregados Ae. aegypti e Ae. albopictus para: analisar a atividade locomotora de machos, fêmeas virgens e fêmeas inseminadas naturalmente; comparar a atividade locomotora de fêmeas injetadas intratoracicamente com extrato de glândulas acessórias (AG) de machos co e heteroespecíficos; e verificar a taxa de inseminação de fêmeas injetadas com glândulas acessórias de machos co e heteroespecíficos, quando são posteriormente expostas a seus machos coespecíficos. Os mosquitos foram coletados em ovitrampas instaladas no Parque Municipal do Piqueri, Zona Leste da cidade de São Paulo, durante o outono e a primavera de 2015 e outono de 2016. Após a emergência dos adultos, estes foram transferidos para quatro gaiolas matrizes separadas por espécie e sexo, dos quais obtivemos machos e fêmeas virgens de cada espécie. Em outras duas gaiolas foram agrupadas por espécie, 40 fêmeas e 40 machos para cópula por 24 horas para obtermos fêmeas inseminadas naturalmente. Posteriormente, todos os mosquitos foram transferidos para uma incubadora por quatro dias para análise da atividade locomotora. Na comparação de fêmeas injetadas com glândulas acessórias, foram extraídas as glândulas de machos de Ae. aegypti e Ae. albopictus e estas injetadas intratoracicamente em fêmeas co e heteroespecíficas. Todas as fêmeas injetadas foram transferidas para uma incubadora por três dias. Para a análise dos dados foram utilizados os testes estatísticos F e T e ANOVA. Após a atividade locomotora, as fêmeas injetadas foram expostas a seus machos coespecíficos e posteriormente tiveram suas espermatecas dissecadas para verificar a presença de espermatozoides a fim de analisar a taxa de inseminação. Nos machos, fêmeas virgens e fêmeas inseminadas naturalmente de Ae. aegypti e Ae. albopictus, o padrão da atividade locomotora foi diurno e bimodal no outono e na primavera. Em Ae. aegypti machos a atividade foi mais evidente no outono e em Ae. albopictus na primavera. Nas fêmeas de Ae. aegypti virgens a atividade foi mais evidente que nas inseminadas naturalmente em ambas as estações. Nas fêmeas de Ae. albopictus não houve diferença na atividade das virgens e inseminadas. Nas fêmeas de Ae. aegypti injetadas com AG a atividade locomotora foi diurna, com padrão unimodal e menos marcada. Nas fêmeas de Ae. albopictus injetadas com AG não houve diferença. Na taxa de inseminação, somente Ae. albopictus fêmeas injetadas com AG heteroespecíficas apresentaram espermatozoides após cópula coespecífica. Este estudo contribui para compreensão do comportamento de mosquitos vetores como Ae. aegypti e Ae. albopictus / The study of mosquitoes is extremely important, since many are considered vectors of several pathogens transmissible to man. Aedes aegypti and Aedes albopictus are responsible for transmitting arboviruses, such as dengue, chikungunya, zika and urban yellow fever, in the world. This study employed Ae. aegypti and Ae. albopictus to: analyze the locomotor activity of males, virgin females and females naturally inseminated; compare the locomotor activity of females injected intratoracically with extract of accessory glands (AG) of co and heterospecific males; and verify the rate of insemination of females injected with accessory glands of co and heterospecific males when later exposed to their co-specific males. The mosquitoes were collected in ovitraps installed in Piqueri Municipal Park, East of São Paulo city, during the autumn and spring of 2015 and autumn of 2016. After the emergence of adults, they were transferred to four cages, separated by species and sex from which we obtained virgin males and females of each species. In the other two cages, they were grouped by species, 40 females and 40 males for mating during 24 hours to obtain naturally inseminated females. Thereafter, all the mosquitoes were transferred to an incubator for four days to the locomotor activity analysis. In the comparison of females injected with accessory glands, the male glands of Ae. aegypti and Ae. albopictus were extracted and injected intratoracically into co and heterospecific females. All injected females were transferred to an incubator for three days. For the analysis, the statistical tests F and T and ANOVA were used. After the locomotor activity, the injected females were exposed to their co-specific males and later had their spermathecas dissected to verify the presence of spermatozoa in order to analyze the insemination rate. In males, virgin and naturally inseminated females of Ae. aegypti and Ae. albopictus, the pattern of locomotor activity was diurnal and bimodal in autumn and spring. Aedes aegypti males activity was more evident in autumn and in Ae. albopictus in spring. In virgin females of Ae. aegypti the activity was more evident than in the naturally inseminated in both seasons. In females of Ae. albopictus, there was no difference in the activity of virgin and inseminated. In females of Ae. aegypti injected with AG the locomotor activity was diurnal, with a unimodal and less marked pattern. In the females of Ae. albopictus injected with AG there was no difference. In the insemination rate, only Ae. albopictus females injected with heterospecific AGs presented spermatozoa after coespecific mating. This study contributes to the understanding of mosquito vectors behavior such as Ae. aegypti and Ae. albopictus

The diversification of eutherian mammals following the end-Cretaceous mass extinction was a critical period in evolutionary history. The Palaeocene is marked by the proliferation of archaic mammals which exhibit a mosaic of primitive and derived anatomies and whose phylogenetic affinities with extant mammals remain contentious. Consequently, macroevolutionary studies assessing the timing and recovery of eutherian mammals following the end-Cretaceous mass extinction are inhibited by our relatively poor knowledge of the mammals which thrived during the Palaeocene. One group of Palaeocene mammals in particular, the ‘Condylarthra’ have proven especially enigmatic and, as historically conceived, includes families of ungulate-grade mammals some of which are considered the ancestral stock from which modern perissodactyls and artiodactyls arose. The Periptychidae are a distinctive ‘condylarth’ family and were among the first mammals to appear after the extinction. As such they constitute an excellent empirical case study towards resolving the evolutionary relationships and understanding the palaeobiology of Palaeocene mammals. The overarching aim of this thesis has been to generate a comprehensive higher-level phylogenetic hypothesis of Periptychidae and shed light on the species-level interrelationships of taxa historically identified as periptychids and other ‘condylarth’ exemplars. This aim has been achieved by the undertaking a comprehensive anatomical re-description of the archetypal periptychid, Periptychus carinidens, based on a wealth of new fossils recovered from the San Juan Basin in New Mexico, USA. The anatomical information described in this thesis has also facilitated a greater understanding of ecology and functional morphology of Periptychus and its kin. Periptychus carinidens was a medium-sized, robust, stout-limbed animal that was mediportal and adopted a plantigrade mode of locomotion. The cranial and dental anatomy of Periptychus is broadly concurrent with the inferred plesiomorphic eutherian condition albeit more robust in its overall construction. The broad facial region, tall sagittal and nuchal crests and distinctive dentition with strong enamel crenulations and compressive wear are likely indicative of durophagous diet made up of dense, fibrous, plant-based food stuffs. The postcranial skeleton of Periptychus is a miscellany of morphologies with often paradoxical functional implications. Despite its robustness, Periptychus retained a moderately high degree of multiaxial movement and dexterity in its limbs with prominent muscle attachment sites indicative of powerful, non-rapid limb movements. Well-developed manual and digital flexors and extensors are further indicative of some scansorial and fossorial capability. Periptychus and other Palaeocene mammals are characterised by their robust anatomy and tend to lack any obvious extant analogues impeding our understanding of eutherian ecological diversity during the Palaeocene and the roles of many so-called ‘archaic’ mammals. Multivariate analyses on a dataset of functionally significant limb measurements show that Palaeocene mammals exhibit a distinct and more constrained range of locomotor ability defined by their prevalent robust morphology. However, there are subtle distinctions between archaic taxa indicating ecomorphical diversity possibly due to niche partitioning, that are not easily comparable to extant mammals. This suggests that, far from being generalized ancestral stock, Palaeocene taxa were experimenting with their own unique locomotor styles. The extinction of many archaic groups at the end of the Palaeogene is associated with a trend towards increasingly open habitats, which was less conducive to the survivorship of robust, ambulatory mammals. The anatomy of Periptychus combines a basic early placental body plan with numerous unique specialisations in its dental, cranial and postcranial anatomy that not only exemplify the ability of mammals to adapt and evolve following catastrophic environmental upheaval but provide a prime exemplar by which to tackle the taxonomic and systematic conundrum that is ‘Condylarthra’. A cladistic analysis was conducted to determine the phylogenetic affinities of Periptychidae within Placentalia. 141 taxa were scored for 503 characters including 40 periptychid species and 63 novel characters. The dataset was analysed under parsimony optimality criteria and the resulting phylogeny shows a well resolved strict consensus topology with numerous well-supported relationships which help elucidate periptychid phylogeny. The analysis presented here finds Periptychidae as a monophyletic group to the exclusion of several purported periptychid taxa which are recovered with the ‘arctocyonid’, Baioconodon nordicum. The in-group relationships of Periptychidae are resolved to broadly support the subfamilial arrangement proposed by previous workers. Alticonus is recovered the most basal, unambiguous periptychid taxon. Ampliconus forms a paraphyletic stem from Alticonus to all other unequivocal periptychid taxa. Conacodontinae forms a clade which includes Auraria as the most basal taxon relative to Oxyacodon, which forms a paraphyletic stem to Conacodon. The hypsodont periptychids, Haploconus + Goleroconus form a clade, separate from both ‘Anisonchinae’ and Conacodontinae, both of which they have previously been affiliated to. ‘Anisonchinae’ forms a paraphyletic stem relative to Periptychinae. Mithrandir oligustus is the most basal ‘anisonchine’. Gillisonchus is generically distinct from both Mithrandir and ‘Anisonchus’ due to morphological similarities with Hemithlaeus and the Periptychinae. Periptychinae forms a well-supported clade with Hemithlaeus and Tinuviel resolved to be more closely related to Ectoconus than Periptychus + Carsioptychus. Periptychus is a member of Periptychinae and most closely related to Carsioptychus within Periptychini. The phylogeny reported here indicates that Periptychidae were an incredibly successful family during much of their early history and were particularly prolific during the middle Puercan. Most species were small to medium sized animals; however, members of Periptychinae attained large body sizes within less than half a million years of the end-Cretaceous mass extinction. Periptychids were prolific during early Puercan, but spent the majority of their evolutionary history exhibiting high turnover, with many short-lived species, with the notable exception of three genera: Anisonchus, Haploconus and Periptychus, which prevailed through the Torrejonian. These periptychids are among the most enduring Palaeocene taxa known and reiterate the importance of the Periptychidae in understanding the recovering and radiation of Placentalia following the end-Cretaceous mass extinction.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / O Transtorno do Déficit de Atenção e Hiperatividade (TDAH) é uma desordem neurocomportamental caracterizada por graus variados de desatenção, atividade motora excessiva e impulsividade. Sua etiologia não é completamente conhecida, porém, um grande número de evidências sugere que, além de fatores de risco genéticos, a exposição gestacional ao etanol e a altas doses de cafeína contribuem para a manifestação deste transtorno. O etanol, presente na composição de bebidas alcoólicas, e a cafeína, presente na composição de diversas bebidas (refrigerantes, chás, café, e energéticos), alimentos derivados do cacau e medicamentos estão entre as substâncias neuroativas mais consumidas no mundo. Apesar das evidências epidemiológicas do uso combinado de cafeína e etanol por gestantes, as interações entre estas substâncias têm recebido pouca atenção em estudos experimentais. Este fato é particularmente importante visto que alguns estudos apontam que cafeína é capaz de ampliar alguns aspectos importantes da ação de outras substâncias com potencial neurotóxico. Nesse estudo avaliamos os efeitos da co-exposição à cafeína e ao etanol durante o desenvolvimento na atividade locomotora em camundongos adolescentes. Para tanto, camundongos Suíços foram expostos do primeiro dia gestacional até o vigésimo primeiro dia pós-natal (PN21), a solução de cafeína 0,1g/L (Grupo CAF1, 10 ninhadas), a solução de cafeína 0,3g/L (Grupo CAF3, 10 ninhadas) ou tiveram acesso à água potável (Grupo CAF0, 10 ninhadas). Em dias alternados de PN2 a PN8, os animais de cada ninhada receberam uma injeção intraperitoneal de 0,25 l/g de etanol (grupo ETOH25), 0,5 l/g de etanol (grupo ETOH50) ou de solução salina (grupo ETOH0). Em PN30, a atividade locomotora foi avaliada por 15 minutos no teste de Campo Aberto. A análise dos níveis de etanol sérico, realizada em uma amostra independente de animais em PN8, indicou que, para as duas doses de etanol, a alcoolemia dos animais do grupo CAF3 foi significativamente maior do que as dos grupos CAF0 e CAF1, que não diferiram entre si. No teste de campo aberto, apenas os animais expostos ao etanol apresentaram aumento da atividade locomotora. Tanto o grupo ETOH25 quanto o grupo ETOH50 tiveram a atividade maior que o grupo ETOH0. A exposição à cafeína, por si só, não afetou a atividade locomotora dos animais nem potencializou os efeitos do etanol. No grupo CAF3, a atividade locomotora não foi afetada pela exposição ao etanol. Nossos dados confirmam o papel da exposição precoce ao etanol na manifestação da hiperatividade locomotora. Além disso, a exposição à cafeína durante o desenvolvimento pode exercer um papel protetor para a manifestação da hiperatividade locomotora induzida pela exposição precoce ao etanol. / The attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by varying degrees of inattention, excessive motor activity and impulsivity. This etiology is not fully known, but considerable evidence suggests that, in addition to genetic factors, exposure to ethanol and high doses of caffeine contribute to the manifestation of the disorder. Ethanol, which is present in all alcoholic beverages, and caffeine, which is present in many beverages (sodas, teas, coffee and energetic drinks), food derived from cacao and medications, are two of the most consumed neuroactive drugs in the world. In spite of the epidemiological evidence of the combined use of caffeine and ethanol by pregnant women, the interactions between these two drugs have received little attention in experimental studies. This fact is particularly important since some studies have shown that caffeine is capable of amplifying important aspects of the action of other substances that have neurotoxic potential. In the current study we analyzed the effects of co-exposure to caffeine and ethanol during development on the locomotor activity of pre-pubertal mice. In this sense, Swiss mice were exposed from the first gestational day to the 21st postnatal (PN21) day to one of three solutions: 1) a solution containing caffeine 0.1 g/L (group CAF1, 10 litters); 2) a solution containing caffeine 0.3g/L (group CAF3, 10 litters); 3) filtered tap water (group CAF0, 10 litters). Every other day, from PN2 to PN8, animals in each litter were i.p injected with one of the following solutions: 1) 0.25 l/g ethanol (group ETOH25); 2) 0.5 l/g ethanol (group ETOH50); 3) saline solution (group ETOH0). On PN30, locomotor activity was analyzed for 15 min in the open field. The analysis of the ethanol serum levels, which was carried out in an independent sample of animals at PN8, indicated that levels were significantly higher in the CAF3 group when compared to the other two groups, which did not differ between them. In the open field, the ethanol exposure caused a dose-dependent increase in the locomotor activity. The locomotor activity of the group ETOH0 was lower than that presented by the ETOH25 and the ETOH50 groups. The caffeine exposure was not capable of affecting the locomotor activity. In the group CAF3, the locomotor activity was not affected by the ethanol exposure. Our data corroborate previous studies in that it shows that precocious ethanol exposure results in locomotor hyperactivity. Furthermore, it is possible that caffeine exposure during development have a protective effect on deleterious effects of ethanol.

Our laboratory has reported neonatal quinpirole (D2/D3 agonist) treatment to rats increases dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. This model appears to have clinical relevance to schizophrenia, and smoking is common in this population. Male and female Sprague-dawley rats were neonatally treated with quinpirole from postnatal (P) days 1–21. After habituation from P30 to 32, animals were administered saline or nicotine (0.3, 0.5, or 0.7mg/kg free base) every other day from P33 to 49 and locomotor activity was assessed. Generally, animals neonatally treated with quinpirole and administered nicotine during adolescence demonstrated increased behavioral activity and/or sensitization compared to animals neonatally given saline and sensitized to nicotine as well as controls. However, animals neonatally treated with quinpirole and given the 0.7mg/kg dose of nicotine demonstrated elevated activity throughout testing but did not show sensitization, and only mild sex differences were reported. Therefore, microdialysis was performed on male rats sensitized to the 0.5mg/kg dose of nicotine, and results revealed that neonatal quinpirole sensitized dopamine overflow in response to nicotine to 500% above animals neonatally given saline and sensitized to nicotine at peak levels. In addition, neonatal quinpirole increased the accumbal BDNF in response to nicotine compared to all other groups, and nicotine alone also produced significant increases in striatal and accumbal BDNF. This study reveals that neonatal quinpirole enhanced adolescent nicotine sensitization, accumbal dopamine overflow, and BDNF protein in response to nicotine, which may be related to changes in the brain's reward system.

In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth we

The neurochemical changes occurring between the preweanling period and adolescence could be crucial for understanding the role development plays in the manifestation of psychotic behaviors. N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) fully attenuates the DA agonist-induced behaviors of adult rats, while potentiating the DA agonist-induced locomotor activity of preweanling rats. My specific hypotheses were as follows: (1) Systemically administered EEDQ would block the cocaine-induced locomotor activity of adult rats. (2) Systemically administered EEDQ would potentiate the cocaine-induced locomotion of preweanling rats. (3) EEDQ would increase the Emax values (a measure of D2 receptor sensitivity) of preweanling rats, but not adolescent or adult rats. And, (4) EEDQ would reduce dorsal striatal β-arrestin-2 (ARRB2) and GRK6 levels (measures of D2 receptor sensitivity) of preweanling rats. Behavioral results were as expected, because EEDQ attenuated the locomotion of adult and adolescent rats, while EEDQ potentiated locomotor activity of preweanling rats. EEDQ enhanced the GTPγS binding of preweanling rats, while depressing ARRB2 levels. These results are consistent with the overarching hypothesis that EEDQ causes DA supersensitivity in preweanling rats. Thus, it is here proposed that EEDQ inactivates a significant number of D2 receptors in preweanling rats, but that the remaining D2 receptors are supersensitive and capable of mediating a potentiated locomotor response.

Les systèmes neuromodulateurs jouent un rôle essentiel dans la mise en place et dansla régulation des réseaux moteurs spinaux afin d’adapter finement le rythme et le patronlocomoteur aux contraintes internes et externes de l’organisme. Il a été montré que desaltérations du fonctionnement de ces systèmes étaient impliquées dans de nombreusespathologies neurologiques. La sclérose latérale amyotrophique (SLA) est une maladieneurodégénérative caractérisée par la perte des neurones moteurs corticaux et spinaux. Bienque les symptômes de la SLA n’apparaissent qu’à l’âge adulte, de plus en plus d’élémentsamènent à penser que des modifications précoces des réseaux locomoteurs spinaux ont lieudès les stades précoces du développement chez un modèle animal de la SLA, la souris SOD1.C’est dans ce cadre général que nous avons émis l’hypothèse que des altérations précoces dessystèmes neuromodulateurs pourraient intervenir dans la physiopathologie de la SLA. Dansun premier temps, nous avons comparé la modulation monoaminergique des réseaux moteursspinaux en réalisant des enregistrements extracellulaires de l’activité locomotrice générée parla préparation de moelle épinière isolée chez la souris nouveau-née sauvage et SOD1. Nousnous sommes ensuite attachés en combinant des enregistrements électrophysiologiques extraetintracellulaires avec des techniques d’immunohistochimie et de biologie cellulaire à décrirela mise en place et l’évolution avec l’âge des synapses cholinergiques reçues par lesmotoneurones en provenance d’interneurones de la lamina X : les boutons en C. Enfin, nousavons initié une approche (1) comportementale sur le long terme de l’activité motrice dessouris SOD1 et (2) des capacités plastiques des synapses glutamatergiques reçues par lesmotoneurones en culture. L’ensemble de ces travaux, nous a permis de mettre en évidence desaltérations précoces et évolutives des principaux systèmes neuromodulateurs spinaux:cholinergique, dopaminergique et noradrénergique chez les animaux SOD1. Nos résultatsmontrent pour la première fois (1) qu’une dynamique complexe des récepteurs M2 sous lesboutons en C existe et que celle-ci est perturbée chez les souris SOD1 et (2) que lesmotoneurones ne sont pas les seuls neurones à dégénérer dans la moelle de ces animaux maisque les neurones cholinergiques de la lamina X situés dans les segments lombaires L2 sontaussi la cible de processus neurodégénératifs. / Neuromodulatory systems play a crucial role in the establishment and regulation ofspinal motor networks to finely adjust the locomotor rhythm and pattern to the internal andexternal constraints. It is now well admitted that alterations in neuromodulatory functions areinvolved in diverse neurologic disorders. Amyotrophic lateral sclerosis is a neurodegenerativedisease characterized by the specific loss of cortical and spinal motor neurons. A growingbody of evidence now suggests that although ALS syndromes occur in adulthood, alterationscan be detected as early as at the embryonic stages in the spinal cord of the rodent model ofALS, the SOD1 mouse. In this context, we hypothesized that early alterations in the spinalneuromodulatory systems may be involved in the pathophysiology of ALS. To answer thisquestion, in a first step, we compared the monoaminergic modulation of spinal network byrecording extracellularly the fictive locomotion produced in the in vitro spinal cordpreparation form newborn wild-type and SOD1 mice. By combining extra- intracellularrecordings with immunohistochemical and cellular biology technics, we aimed, in a secondstep, to investigate the cholinergic synapses arising onto motoneurons and their neuronalsource, the lamina X interneurons as a function of the mouse age. Finally, we initiated (1) aninnovative behavioural study of mouse motor habits and (2) an analysis of the synapticplasticity of glutamatergic synapses imping on motoneurons in culture. Altogether, our datademonstrated early and progressive changes of the major spinal neuromodulatory systems:cholinergic, dopaminergic and noradrenergic. Our data show for the first time that: (1) M2receptors undergo a complex dynamic under C-bouton that is completely disturbed in SOD1motoneurons and (2) motoneurons are not the only cellular subtype to degenerate in SOD1mice. Indeed, we found evidence that neurodegenerative processes also target lamina Xcholinergic interneurons in the SOD1 spinal cord.

The central complex is a prominent neuropil found in the middle of the insect brain. It is considered as a higher center for motor control and information processing. Multiple neuropeptides and neurotransmitters are produced in neurons of the central complex, however, distribution patterns and functional roles of signaling substances in this brain region are poorly known. Thus, this thesis focuses on the distribution of signaling substances and on modulatory roles of neuropeptides in the central complex of Drosophila. Immunocytochemistry in combination with GAL4/UAS technique was used to visualize various signaling substances in the central complex. We revealed different central-complex neurons expressing the neuropeptides; Drosophila tachykinin (DTK), short neuropeptide F (sNPF), myoinhibitory peptide (MIP), allatostatin A, proctolin, SIFamide, neuropeptide F and FMRFamide. Subpopulations of DTK, sNPF and MIP-expressing neurons were found to co-localize a marker for acetylcholine. In addition, five metabotropic neurotransmitter receptors were found to be expressed in distinct patterns. Comparison of receptor/ligand distributions revealed a close match in most of the structures studied. By using a video-tracking assay, peptidergic modulation of locomotor behavior was studied. Different DTK and sNPF-expressing neurons innervating the central complex were revealed to modulate spatial distribution, number of activity-rest phases and activity levels, suggesting circuit dependent modulation. Furthermore, neurosecretory cells in the Drosophila brain that co-express three types of neuropeptides were shown to modulate stress responses to desiccation and starvation. In summary, we have studied two different neuropeptides (DTK and sNPF) expressed in interneuronal circuits and neurosecretory cells of the Drosophila brain in more detail. We found that these neuropeptides display multiple actions as neuromodulators and circulating hormones, and that their actions depend on where they are released. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Manuscript.