Central to human intelligence, visual categorization is a skill that is both remarkably fast and accurate. Although there have been numerous studies in primates regarding how information flows in inferiortemporal (ITC) and prefrontal (PFC) cortices during online discrimination of visual categories, there has been little comparable research on the human cortex. To bridge this gap, this thesis explores how visual categories emerge in prefrontal cortex and the ventral stream, which is the human homologue of ITC. In particular, cortical spatiotemporal plasticity in visual category learning was investigated using behavioral experiments, magnetoencephalographic (MEG) imaging, and statistical machine learning methods. From a theoretical perspective, scientists from work on non-human primates have posited that PFC plays a primary role in the encoding of visual categories. Much of the extant research in the cognitive neuroscience literature, however, emphasizes the role of the ventral stream. Despite their apparent incompatibility, no study has evaluated these theories in the human cortex by examining the roles of the ventral stream and PFC in online discrimination and acquisition of visual categories. To address this question, I conducted two learning experiments using visually-similar categories as stimuli and recorded cortical response using MEG—a neuroimaging technique that offers a millisecond temporal resolution. Across both experiments, categorical information was found to be available during the period of cortical activity. Moreover, late in the learning process, this information is supplied increasingly in the ventral stream but less so in prefrontal cortex. These findings extend previous theories by suggesting that the ventral stream is crucial to long-term encoding of visual categories when categorical perception is proficient, but that PFC jointly encodes visual categories early on during learning. From a methodological perspective, MEG is limited as a technique because it can lead to false discoveries in a large number of spatiotemporal regions of interest (ROIs) and, typically, can only coarsely reconstruct the spatial locations of cortical responses. To address the first problem, I developed an excursion algorithm that identified ROIs contiguous in time and space. I then used a permutation test to measure the global statistical significance of the ROIs. To address the second problem, I developed a method that incorporates domainspecific and experimental knowledge in the modeling process. Utilizing faces as a model category, I used a predefined “face” network to constrain the estimation of cortical activities by applying differential shrinkages to regions within and outside this network. I proposed and implemented a trial-partitioning approach which uses trials in the midst of learning for model estimation. Importantly, this renders localizing trials more precise in both the initial and final phases of learning. In summary, this thesis makes two significant contributions. First, it methodologically improves the way we can characterize the spatiotemporal properties of the human cortex using MEG. Second, it provides a combined theory of visual category learning by incorporating the large time scales that encompass the course of the learning.

The midbrain dopamine system is involved in many aspects of purposeful behaviour and, when compromised, can have devastating effects on movement and cognition as seen in diseases like Parkinson's. In the healthy brain, dopamine neurons are thought to play particularly important roles in learning by signalling errors in reward prediction. The objective of this thesis was to investigate the diversity in the functional properties of the midbrain dopamine system, and how this is altered through genetic variation of relevance to Parkinson's and development of cell phenotype. This objective was addressed with a combination of behavioural experiments, in vivo single-cell recording and labelling (both in anaesthetised as well as awake rodents), immunofluorescence labelling, retrograde tracing and stereology. In a first set of experiments, it was demonstrated that chronic as well as acute genetic challenges can alter the firing patterns of midbrain dopamine neurons. Using a novel bacterial artificial chromosome-transgenic rat model, it was shown that the R1441C mutation in human leucine-rich repeat kinase 2, which is linked to Parkinson's, leads to motor deficits and an age-dependent reduction in the in vivo firing variability and burst firing of substantia nigra pars compacta (SNc) dopamine neurons. These findings help reveal processes of early, pre-degenerative dysfunction in dopamine neurons in Parkinson's. Similar effects on firing variability and burst firing of SNc dopamine neurons were found in a mouse model with conditional knock- out of the transcription factors Forkhead box A1 and A2 (FoxA1/2) in midbrain dopamine neurons. These findings indicate that FoxA1/2 are not only crucial for the early development of dopamine neurons, but also their function in the mature brain. In a second set of experiments in wildtype mice, it was demonstrated that midbrain dopamine neurons (located in SNc and ventral tegmental area) show diverse expression of the molecular markers Calbindin, Calretinin, Aldh1a1, Sox6, Girk2, SatB1 and Otx2. It was found that selective expression of these markers is of use for discriminating between midbrain dopamine neurons that project to dorsal striatum or nucleus accumbens. To elucidate whether the diverse molecular marker expression would map onto dopamine neurons whose firing correlates with distinct behavioural events, midbrain dopamine neurons were recorded and labelled in head-fixed awake mice either exposed to neutral sensory stimuli or performing a classical conditioning paradigm. The population activity of midbrain dopamine neurons was not modulated by neutral sensory stimuli. Interestingly, fewer than 50% of identified dopamine neurons showed phasic firing increases following reward- predicting cue and/or reward delivery, despite the common assumption that most (if not all) midbrain dopamine neurons signal reward prediction errors. Instead, firing was modulated by other explanatory factors, such as licking, or showed no modulation during the task. Response types of midbrain dopamine neurons were not correlated with their anatomical location nor the selective or combinatorial expression of the markers Aldh1a1, Calbindin and Sox6. In conclusion, the first set of experiments identified how different genetic burdens can alter the in vivo firing of midbrain dopamine neurons, and provide new insights into how circuits can change in pathological or compensatory ways at early disease stages in Parkinson's. The second set of experiments revealed striking heterogeneity of midbrain dopamine neurons in the intact system, and established further a functional diversity in the response types of identified midbrain dopamine neurons that is only partially consistent with canonical reward prediction error signalling.

Orientador: José Roberto Fioretto / Resumo: A Síndrome do Desconforto Respiratório Agudo (SDRA) cursa com alta morbi-mortalidade apesar dos avanços no entendimento de sua fisiopatologia e tratamento. A terapia ventilatória baseia-se na proteção pulmonar, sendo a ventilação oscilatória de alta frequência (VOAF) uma opção de método protetor. A posição prona (PP) é terapia adjuvante que possibilita homogeneização da distribuição do volume corrente (VC) e promove recrutamento alveolar. O objetivo do estudo foi investigar o efeito da posição prona associada à VOAF e ventilação mecânica convencional (VMC) protetora sobre a oxigenação, inflamação, dano oxidativo e histologia pulmonares, comparando-a à posição supina em ambos os modos ventilatórios. Foram instrumentados 75 coelhos com traqueostomia e acessos vasculares. A lesão pulmonar aguda (LPA) foi induzida por lavagem traqueal de salina aquecida (30mL/Kg, 38°C). Os animais foram então aleatorizados em cinco grupos (n=15): 1) GC (Controle): animais sadios em VMC protetora basal; 2) GVMS: animais com LPA em VMC protetora e posição supina; 3) GVMP: animais com LPA em VMC protetora e posição prona; 4) GVAFS: animais com LPA em VOAF e posição supina; 5) GVAFP: animais com LPA em VOAF e posição prona. Após, foram submetidos a quatro horas de VMC protetora (modo pressão regulada-volume controlado, PEEP 10 cmH2O, VC 6mL/kg, Ti 0,5s, FR 40 rpm e FiO2 1) ou VOAF (MAP 15 mmHg, FR 10Hz, amplitude 22 e FiO2 1). O nível de significância foi de 5%. Após a indução, os grupos apresentaram... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Acute Respiratory Distress Syndrome (ARDS) presents with high morbidity and mortality despite advances in the understanding of its pathophysiology and treatment. Ventilatory therapy is based on the intention of injuring less, with high frequency oscillatory ventilation (HFOV) being a protective method option. Prone position (PP) is an adjuvant therapy that enables homogenization of volume tidal (VT) distribution and promotes alveolar recruitment. The aim of this study was to investigate the effects of prone position associated with HFOV and protective conventional mechanical ventilation (CMV) on oxygenation and lung inflammation, oxidative damage and histology, comparing it with the supine position in both ventilatory modes. Seventy five rabbits were submitted to tracheostomy and vascular accesses. ALI was induced by tracheal infusion of heated saline (30mL/kg, 38° C). The subjects were then ramdomized in five groups (n=15): 1) CG (Control): healthy animals in basal protective CMV; 2) MVSG: animals with ALI in protective CMV and supine position; 3) MVPG animals with ALI in protective CMV and prone position; 4) HFSG: animals with ALI in HFOV and supine position; 5) HFPG: animals with ALI in HFOV and prone position. After that, they were submitted to four hours of protective VMC (PRV mode, PEEP 10 cmH2O, VC 6ml/kg, Ti 0,5s, FR=40 rpm and FiO2 1) or HFOV (MAP 15 mmHg, FR 10 Hz, amplitude 22 and FiO2 1). The level of significance was 5%. After induction, the groups presented simi... (Complete abstract click electronic access below) / Doutor

O sistema serotoninérgico há muito tempo vem sendo relacionado ao comportamento agressivo e particularmente o subtipo de receptor 5-HT1A está envolvido na modulação da agressividade. Estudos prévios utilizando agonistas que atuam seletivamente sobre estes receptores demonstraram tanto redução como aumento da agressão. Sabe-se que estes receptores são encontrados em diversas regiões encefálicas onde atuam como auto e heteroreceptores, apresentando diferentes funções, dependendo de sua localização. Heteroreceptores 5-HT1A, além de outras regiões, são encontrados no córtex pré-frontal, uma região encefálica particularmente importante no controle inibitório de comportamentos agressivos e impulsivos. O objetivo do presente estudo foi verificar os possíveis efeitos antiagressivos da microinjeção do agonista seletivo dos receptores 5-HT1A, F15599, na região ventro-orbital do córtex pré-frontal de camundongos machos da linhagem CF-1, previamente submetidos ao protocolo de provocação social, caracterizado por elevar os níveis de agressividade a padrões considerados violentos. Nossos resultados mostraram que a microinjeção das menores doses de F15599 (0,03 e 0,1 μg) reduziu significativamente a frequência de mordidas além de ocorrer uma tendência à redução da frequência de ataques laterais para o grupo de animais que recebeu a dose de 0,03 μg. Estes efeitos anti-agressivos não foram acompanhados por alterações nos demais elementos comportamentais relacionados à agressividade: perseguir o intruso, cheirar o intruso e sacudir a cauda. Também não foram observadas alterações na duração dos elementos comportamentais não agressivos caminhar e rearing. Ocorreu aumento apenas na duração do comportamento de grooming para o grupo de animais que recebeu a dose de 0,03 μg do agonista. Os resultados do presente estudo confirmaram o envolvimento da região VO do CPF e do sistema serotoninérgico, mais precisamente do subtipo de receptor 5-HT1A na modulação da agressividade exacerbada. / The serotonergic system has long been linked to aggressive behavior and particularly 5-HT1A receptor subtype is involved in modulation of aggressiveness. Previous studies using agonists that act selectively on these receptors showed both reduction and increased aggression. It is known that these receptors are found in several brain regions where they act as auto and heteroreceptors, with different functions, depending on their location. 5-HT1A heteroreceptors, as well as other regions, are found in the prefrontal cortex (PFC), a brain region particularly important in the inhibitory control of aggressive and impulsive behaviors. The aim of this study was to investigate the possible anti-aggressive effects of microinjections of F15599, a selective 5-HT1A agonist, in the ventral orbital prefrontal cortex (VO PFC) of CF-1 male mice, previously submitted to social instigation, characterized by increasing aggression to high levels. Our results showed that the microinjection of the lower doses of F15599 (0.03 and 0.1 μg) significantly reduced attack bite frequency. Furthermore, there was a tendency to reduce sideway threats for the group that received 0.03 μg agonist microinjection. These anti-aggressive effects were not accompanied by changes in other elements of the behavioral repertoire related to aggression: pursuit the intruder, sniff the intruder and tail rattle. There were also no changes observed in the duration of nonaggressive behavioral repertoire elements, walking and rearing. Only for grooming behavior was an increased duration observed for the group that received 0.03 μg agonist dose. The results of this study confirmed the involvement of VO PFC and serotonergic system, specifically de 5- HT1A receptor subtype, in the modulation of escalated aggressive behavior.

Orientador: Ricardo Nunes de Souza / Banca: Cleopatra da Silva Planeta / Banca: Hélio Zangrossi Junior / Banca: Marcus Lira Brandão / Banca: Francisco Silveira Guimarães / Resumo: Quando os animais são confrontados com estímulos ambientais ameaçadores como a exposição ao predador ou estímulos como altura, iluminação e estímulos nociceptivos, exibem reações de defesa coordenadas e específicas. Nas últimas décadas, observa-se um crescente interesse pela utilização de estímulos naturalísticos para o estudo das bases neurais de emoções como o medo e ansiedade. Nesse contexto, o teste de exposição ao rato (RET), um novo modelo etológico de interação presa-predador, utilizando camundongos (presa) e ratos (predador), foi desenvolvido para avaliar a expressão de diferentes comportamentos defensivos na presa. Entretanto, poucos estudos foram conduzidos com esse modelo no intuito de investigar as bases neurais das respostas defensivas de camundongos expostos ao rato. Adicionalmente, evidências da literatura destacam que o hipocampo ventral (HV) e o complexo amidalóide (CA) parecem contribuir diferencialmente na modulação de respostas defensivas frente a estímulos proximais (predador) ou potenciais. Assim, o presente estudo foi conduzido para investigar o papel do HV e do CA nas respostas defensivas de camundongos exibidas diante do predador (rato) e do contexto associado ao predador. Para tal, o presente estudo foi dividido em quatro etapas. Na primeira delas, investigamos se o estresse da exposição ao predador no RET altera a secreção de corticosterona em camundongos e determinamos a magnitude e a duração desta secreção. Na segunda etapa, avaliamos o papel do HV e do CA, através da injeção local do agonista de receptores GABAA muscimol (0,1 μg/0,1 μl), na mediação de respostas comportamentais defensivas de camundongos expostos ao RET (situação proximal) e comparamos com aquelas apresentadas durante a exposição ao labirinto em cruz elevado (LCE - situação potencial). Subsequentemente, investigamos se camundongos expostos... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: When animals are confronted with environmental threatening situations such as exposure to a predator as well as to height, high illumination and nociceptive stimuli they exhibit defensive behaviors. Over the past decades there has been a growing interest by the neuroscientists in the use of naturalistic stimuli to the study of the neural systems of the emotions such as fear and anxiety. In this context, the Rat Exposure Test (RET) which is a new ethological model of prey-predator interaction using mice (prey) and rats (predator) was developed in order to evaluate the expression of different defensive behaviors in the prey. However few studies using this model have been carried out with the objective of investigating the neural systems of the defensive behaviors in mice exposed to rats. In addition, evidence in literature has shown that the ventral hippocampus (VH) and the amygdaloid complex (AC) contribute differentially in the modulation of defensive behaviors during exposure to either potential or immediate stimuli (predator). Thus, the present study was aimed at investigating the role of VH and AC in the modulation of defensive behaviors of mice when exposed to predators (rats) as well as the predatory context. The experiment comprised four parts: (i) to investigate both whether stress regarding the exposure to the predator alters the corticosterone secretion in mice and to determine the magnitude and the duration of this secretion; (ii) the role of VH and AC was evaluated through local microinjection of the GABAA receptor agonist muscimol (0,1 μg/0,1 μl) in the modulation of defensive behavioral responses of mice exposed to RET (proximal aversive situation). The responses then were compared to those presented during to the exposure to the elevated plus-maze (EPM - potential aversive situation); (iii) to investigate whether mice exposed to natural predator (rat) in RET exhibit... (Complete abstract click electronic access below) / Doutor

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-04-09T00:26:04Z No. of bitstreams: 1 StefanoPupeJohann_TESE.pdf: 36592987 bytes, checksum: f44357f3110776cf9f7cb628b2d65a95 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-04-09T00:36:11Z (GMT) No. of bitstreams: 1 StefanoPupeJohann_TESE.pdf: 36592987 bytes, checksum: f44357f3110776cf9f7cb628b2d65a95 (MD5) / Made available in DSpace on 2016-04-09T00:36:12Z (GMT). No. of bitstreams: 1 StefanoPupeJohann_TESE.pdf: 36592987 bytes, checksum: f44357f3110776cf9f7cb628b2d65a95 (MD5) Previous issue date: 2015-03-20 / Os neurocientistas tem uma diversidade de perspectivas com as quais podem classificar diferentes partes do c?rebro. Com o surgimento de t?cnicas baseadas na gen?tica, como a optogen?tica, se torna cada vez mais importante identificar se um grupo de c?lulas, definidas atrav?s de morfologia, fun??o ou posi??o anat?mica possui um padr?o caracter?stico de express?o de um ou mais promotores gen?ticos. Isso permitiria melhores formas de estudar essas popula??es de neur?nios definidas geneticamente. Neste trabalho, eu apresento uma discuss?o te?rica e tr?s estudos experimentais nos quais essa foi a principal quest?o sendo abordada. O Estudo I discute as quest?es envolvidas em selecionar um promotor para estudar estruturas e subpopula??es na ?rea Tegmental Ventral. O Estudo II caracteriza uma subpopula??o de c?lulas na ?rea Tegmental Ventral que compartilha a express?o de um promotor, que ? anatomicamente muito restrita, e que induz avers?o quando estimulada. O Estudo II utiliza uma estrat?gia similar para investigar a subpopula??o no n?cleo subtal?mico que expressa PITX2 e VGLUT2 que, quando inativada, causa hiperlocomo??o. O Estudo IV explora o fato de que um grupo de c?lulas previamente identificadas no Hipocampo Ventral expressa CHRNA2, e indica que essa subpopula??o pode ser necess?ria e suficiente para o estabelecimento do ritmo teta (2-8 Hz) no Hipocampo Ventral de camundongos anestesiados. Todos esses estudos foram guiados pela mesma estrat?gia de identificar um promotor gen?tico capaz de permitir o controle de uma popula??o de neur?nios identificada geneticamente, e eles demonstram as diferentes formas em que essa abordagem pode generar novas descobertas. / Neuroscientists have a variety of perspectives with which to classify different parts of the brain. With the rise of genetic-based techniques such as optogenetics, it is increasingly important to identify whether a group of cells, defined by morphology, function or anatomical location possesses a distinct pattern of expression of one or more genetic promoters. This would allow for better ways to study of these genetically defined subpopulations of neurons. In this work, I present a theoretical discussion and threeexperimental studies in which this was the main question being addressed. Paper I discusses the issues involved in selecting a promoter to study structures and subpopulations in the Ventral Tegmental Area. Paper II characterizes a subpopulation of cells in the Ventral Tegmental Area that shares the expression of a promoter and is anatomically very restricted, and induces aversion when stimulated. Paper III utilizes a similar strategy to investigate a subpopulation in the subthalamic nucleus that expresses PITX2 and VGLUT2 which, when inactivated, causes hyperlocomotion. Paper IV exploits the fact that a previously identified group of cells in the ventral hippocampus expresses CHRNA2, and indicates that this population may be necessary and sufficient for the establishment of the theta rhythm (2-8 Hz) in the Local Field Potential of anesthetized mice. All of these studies were guided by the same strategy of characterizing and studying the role of a genetically defined subpopulation of cells, and they demonstrate the different ways in which this approach can generate new discoveries.

O sistema serotoninérgico há muito tempo vem sendo relacionado ao comportamento agressivo e particularmente o subtipo de receptor 5-HT1A está envolvido na modulação da agressividade. Estudos prévios utilizando agonistas que atuam seletivamente sobre estes receptores demonstraram tanto redução como aumento da agressão. Sabe-se que estes receptores são encontrados em diversas regiões encefálicas onde atuam como auto e heteroreceptores, apresentando diferentes funções, dependendo de sua localização. Heteroreceptores 5-HT1A, além de outras regiões, são encontrados no córtex pré-frontal, uma região encefálica particularmente importante no controle inibitório de comportamentos agressivos e impulsivos. O objetivo do presente estudo foi verificar os possíveis efeitos antiagressivos da microinjeção do agonista seletivo dos receptores 5-HT1A, F15599, na região ventro-orbital do córtex pré-frontal de camundongos machos da linhagem CF-1, previamente submetidos ao protocolo de provocação social, caracterizado por elevar os níveis de agressividade a padrões considerados violentos. Nossos resultados mostraram que a microinjeção das menores doses de F15599 (0,03 e 0,1 μg) reduziu significativamente a frequência de mordidas além de ocorrer uma tendência à redução da frequência de ataques laterais para o grupo de animais que recebeu a dose de 0,03 μg. Estes efeitos anti-agressivos não foram acompanhados por alterações nos demais elementos comportamentais relacionados à agressividade: perseguir o intruso, cheirar o intruso e sacudir a cauda. Também não foram observadas alterações na duração dos elementos comportamentais não agressivos caminhar e rearing. Ocorreu aumento apenas na duração do comportamento de grooming para o grupo de animais que recebeu a dose de 0,03 μg do agonista. Os resultados do presente estudo confirmaram o envolvimento da região VO do CPF e do sistema serotoninérgico, mais precisamente do subtipo de receptor 5-HT1A na modulação da agressividade exacerbada. / The serotonergic system has long been linked to aggressive behavior and particularly 5-HT1A receptor subtype is involved in modulation of aggressiveness. Previous studies using agonists that act selectively on these receptors showed both reduction and increased aggression. It is known that these receptors are found in several brain regions where they act as auto and heteroreceptors, with different functions, depending on their location. 5-HT1A heteroreceptors, as well as other regions, are found in the prefrontal cortex (PFC), a brain region particularly important in the inhibitory control of aggressive and impulsive behaviors. The aim of this study was to investigate the possible anti-aggressive effects of microinjections of F15599, a selective 5-HT1A agonist, in the ventral orbital prefrontal cortex (VO PFC) of CF-1 male mice, previously submitted to social instigation, characterized by increasing aggression to high levels. Our results showed that the microinjection of the lower doses of F15599 (0.03 and 0.1 μg) significantly reduced attack bite frequency. Furthermore, there was a tendency to reduce sideway threats for the group that received 0.03 μg agonist microinjection. These anti-aggressive effects were not accompanied by changes in other elements of the behavioral repertoire related to aggression: pursuit the intruder, sniff the intruder and tail rattle. There were also no changes observed in the duration of nonaggressive behavioral repertoire elements, walking and rearing. Only for grooming behavior was an increased duration observed for the group that received 0.03 μg agonist dose. The results of this study confirmed the involvement of VO PFC and serotonergic system, specifically de 5- HT1A receptor subtype, in the modulation of escalated aggressive behavior.

O sistema serotoninérgico há muito tempo vem sendo relacionado ao comportamento agressivo e particularmente o subtipo de receptor 5-HT1A está envolvido na modulação da agressividade. Estudos prévios utilizando agonistas que atuam seletivamente sobre estes receptores demonstraram tanto redução como aumento da agressão. Sabe-se que estes receptores são encontrados em diversas regiões encefálicas onde atuam como auto e heteroreceptores, apresentando diferentes funções, dependendo de sua localização. Heteroreceptores 5-HT1A, além de outras regiões, são encontrados no córtex pré-frontal, uma região encefálica particularmente importante no controle inibitório de comportamentos agressivos e impulsivos. O objetivo do presente estudo foi verificar os possíveis efeitos antiagressivos da microinjeção do agonista seletivo dos receptores 5-HT1A, F15599, na região ventro-orbital do córtex pré-frontal de camundongos machos da linhagem CF-1, previamente submetidos ao protocolo de provocação social, caracterizado por elevar os níveis de agressividade a padrões considerados violentos. Nossos resultados mostraram que a microinjeção das menores doses de F15599 (0,03 e 0,1 μg) reduziu significativamente a frequência de mordidas além de ocorrer uma tendência à redução da frequência de ataques laterais para o grupo de animais que recebeu a dose de 0,03 μg. Estes efeitos anti-agressivos não foram acompanhados por alterações nos demais elementos comportamentais relacionados à agressividade: perseguir o intruso, cheirar o intruso e sacudir a cauda. Também não foram observadas alterações na duração dos elementos comportamentais não agressivos caminhar e rearing. Ocorreu aumento apenas na duração do comportamento de grooming para o grupo de animais que recebeu a dose de 0,03 μg do agonista. Os resultados do presente estudo confirmaram o envolvimento da região VO do CPF e do sistema serotoninérgico, mais precisamente do subtipo de receptor 5-HT1A na modulação da agressividade exacerbada. / The serotonergic system has long been linked to aggressive behavior and particularly 5-HT1A receptor subtype is involved in modulation of aggressiveness. Previous studies using agonists that act selectively on these receptors showed both reduction and increased aggression. It is known that these receptors are found in several brain regions where they act as auto and heteroreceptors, with different functions, depending on their location. 5-HT1A heteroreceptors, as well as other regions, are found in the prefrontal cortex (PFC), a brain region particularly important in the inhibitory control of aggressive and impulsive behaviors. The aim of this study was to investigate the possible anti-aggressive effects of microinjections of F15599, a selective 5-HT1A agonist, in the ventral orbital prefrontal cortex (VO PFC) of CF-1 male mice, previously submitted to social instigation, characterized by increasing aggression to high levels. Our results showed that the microinjection of the lower doses of F15599 (0.03 and 0.1 μg) significantly reduced attack bite frequency. Furthermore, there was a tendency to reduce sideway threats for the group that received 0.03 μg agonist microinjection. These anti-aggressive effects were not accompanied by changes in other elements of the behavioral repertoire related to aggression: pursuit the intruder, sniff the intruder and tail rattle. There were also no changes observed in the duration of nonaggressive behavioral repertoire elements, walking and rearing. Only for grooming behavior was an increased duration observed for the group that received 0.03 μg agonist dose. The results of this study confirmed the involvement of VO PFC and serotonergic system, specifically de 5- HT1A receptor subtype, in the modulation of escalated aggressive behavior.

The Basal Ganglia consist of a number of different nuclei that form a diverse circuitry of GABAergic, dopaminergic and glutamatergic neurons. This complex network is further organized in subcircuits that govern limbic and motor functions in humans and other vertebrates. Due to the interconnection of the individual structures, dysfunction in one area or cell population can affect the entire network, leading to synaptic and molecular alterations in the circuitry as a whole. The studies in this doctoral thesis aimed at characterizing restricted subpopulations of neurons in the Basal Ganglia circuitry and their importance in the wider function of the network. To this end, we identified subpopulations of neurons in the subthalamic nucleus (STN), substantia nigra (SN) and ventral tegmental area (VTA), characterized their molecular profile and investigated their physiological role in the circuitry. Within the mouse STN, reduction of glutamatergic neurotransmission in a subpopulation expressing Paired-like homeodomain transcription factor 2 (Pitx2) led to structural alterations in the nucleus as well as biochemical alterations of the dopaminergic system in the Nucleus accumbens (NAc) and changes in reward-related behavior. In the ventral midbrain, we identified and characterized novel marker genes selective to the VTA or SN. Of these, transient receptor potential cation channel subfamily V member 1 (TrpV1) marks a population of mainly glutamatergic neurons in the VTA which project to the NAc, while gastrin releasing peptide (Grp) is expressed in a population of dopaminergic neurons neuroprotected in Parkinson's disease. Furthermore, we discovered that disruption of glutamatergic co-release of dopaminergic neurons expressing dopamine transporter (DAT), diminishes fast EPSCs and glutamate release but does not affect the acquisition of reward-related behavioral tasks. To selectively quantify glutamate release from specific subpopulations, we devised a technique combining glutamate-amperometry and optogenetics. This was used to measure glutamate released from Pitx2-expressing synaptic terminals in the Globus pallidus as well as DAT- or TrpV1-expressing terminals in the NAc. In summary, this doctoral thesis has furthered understanding of the function and importance of specific subpopulations within the Basal Ganglia circuitry and provides a novel means to investigate glutamate in the intact rodent brain within clearly defined, restricted cell populations.

Il existe différents types de mémoire chez l’homme et l’animal. Chez les mammifères, on distingue principalement une mémoire relationnelle/spatiale reposant sur l’hippocampe et le cortex préfrontal, et une mémoire procédurale/indicée dépendante du striatum. Lors de nouveaux apprentissages, ces systèmes interagissent de manière coopérative et/ou compétitive en fonction de la nature de la tâche. S’il est connu que les émotions négatives et le niveau d’entraînement modulent ces interactions, peu de travaux ont étudié le rôle des récompenses dans la sélection et l’utilisation de ces deux formes principales de mémoire. Nous avons utilisé deux versions du test de discrimination spatiale dans un labyrinthe en Y afin de d’évaluer la mémoire spatiale d’une part, et la mémoire procédurale d’autre part. Nos résultats montrent que la stimulation pharmacologique du système de récompense par auto-injection de morphine au niveau de l’aire tegmentale ventrale (ATV), perturbe de manière spécifique l’apprentissage spatial reposant sur le fonctionnement hippocampo-préfrontal Ce déficit spatial s’accompagne d’une forte réduction de l’activité du facteur de transcription CREB (cAMP Response Element Binding) au sein de ce réseau. Au contraire, l’apprentissage indicé est préservé et l’activation de CREB est potentialisée par l’utilisation d’une récompense pharmacologique (injections de morphine). Nous mettons en évidence que la suractivation de la voie PKA/CREB, dans le striatum dorsal, est la cause de l’interférence observée lors de la formation de la mémoire spatiale. De plus, la stimulation répétée du système de récompense par la drogue lors de l’acquisition d’une stratégie indicée entraîne une persistance de l’activité réverbérante de la voie PKA/CREB dans le striatum dorsal. Cette persistance peut être révélée par l’utilisation préférentielle d’une stratégie indicée dans une nouvelle tâche ambigüe, le test de compétition en piscine de Morris. L’ensemble de ce travail éclaire, grâce aux effets différentiels de récompenses sensorielles et pharmacologiques sur l’apprentissage, la compréhension des interactions dynamiques entre les systèmes de mémoire. De plus, il suggère que l’hyperassociativité persistante consécutive à l’usage de drogue est à l’origine de déficits de type déclaratifs qui pourraient jouer un rôle clé dans l’installation d’un comportement addictif. / There are different forms of memory proceeded in human’s and animal’s brain. At least two major systems can be defined. A spatial/declarative form of memory relies on the hippocampus and prefrontal cortex, and secondly, a more rigid, procedural/cued type of memory supported by striatal circuitry. Learning requires cooperative and/or competitive interactions between memory systems, depending on the nature of the task. It is well established that negative emotions and training modulate these interactions. However, little is known about the role of rewards on the selection and formation of these forms of memory.Using two versions (spatial or cue) of a Y-maze discrimination task, we show that drug reward, but not food reward, disrupts spatial learning while sparing the cued task. The spatial memory deficit relies on an decrease of CREB (cAMP Response Element Binding) activity within the hippocampus and the prefrontal cortex. Inhibition of the PKA/CREB signalling pathway restored spatial learning, suggesting that striatal overactivation of this pathway is responsible for the spatial memory deficit. The cued learning strategy elicits a strong CREB activitiy within the dorsal striatum which is further increased by morphine injections. We propose that drug-induced activation of the DA reward system induces abnormal reverberating activity of the PKA/CREB signalling pathway within the dorsal striatum, eventually leading to a preferential use of a striatum-dependent strategy during a new ambiguous learning task, the water maze competition task.In conclusion, our results points to a key role of rewards in the modulation of learning systems. Furthermore, we provide evidence that drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment more flexible forms of memory.