Les capacités attentionnelles sont nécessaires à la plupart des tâches de la vie quotidienne. Au cours du vieillissement normal, ces habiletés se modifient. De même, les études suggèrent que l’activité neurofonctionnelle du réseau fronto-pariétal qui sous-tend les capacités attentionnelles diffère entre les individus âgés et de jeunes adultes. Par contre, les changements en contexte du vieillissement du réseau fronto-pariétal ventral, aussi appelé le réseau attentionnel ventral, ont été peu investigués. Une telle question doit être soulevée dans le contexte où les plus récents modèles décrivant les changements fonctionnels associés au vieillissement rapportent que des possibles transformations neurofonctionnelles peuvent survenir au niveau intrahémisphérique et interhémisphérique. Le but de cet ouvrage est de déterminer comment le vieillissement normal affecte le réseau attentionnel ventral et de décrire la nature des changements qui peuvent survenir sur les axes intra et interhémisphériques. Pour y parvenir, la méthode de connectivité fonctionnelle fut privilégiée puisqu’elle permet de quantifier l’interaction neurofonctionnelle entre diverses régions composant un réseau fonctionnel. La première étude de cette thèse a permis de décrire les modifications de connectivité fonctionelle intrahémisphériques du réseau attentionnel ventral en comparant des adultes jeunes et âgés lorsqu’ils réalisent une tâche d’attention sélective en imagerie par résonance magnétique. Sur le plan comportemental, les individus âgés répondaient significativement plus lentement et commettaient davantage d’erreurs que le groupe composé de jeunes adultes. Les résultats de connectivité fonctionnelle montrent que le degré d’intégration de la connectivité fonctionnelle intrahémisphérique est globalement plus élevé chez les individus âgés dans l’ensemble des régions fronto-pariétales composant ce réseau. De plus, il semble que les aires antérieures du réseau, soit les aires préfrontales et insulaires, sont moins intégrées chez les individus âgés, alors que les zones pariétales, temporales et cérébelleuses le sont davantage. Le degré d’intégration de la connectivité est également plus élevé chez les adultes âgés entre les régions postérieures et antérieures. Ainsi, les résultats de cette étude suggèrent que la dynamique des régions antérieures et postérieures du réseau attentionnel ventral est modifiée au cours du vieillissement normal et que les régions postérieures occupent au sein de ce réseau un rôle plus important avec l’âge. Cette hyperconnectivité des aires pariétales pourrait représenter une stratégie de compensation intrahémisphérique (i.e. recrutement de régions additionnelles en postérieur) qui aurait cependant atteint un certain plateau puisque bien que les âgés réussissent à réaliser la tâche, ils performent significativement plus faiblement que de jeunes adultes. La seconde étude s’est intéressée aux modifications de connectivité interhémisphériques du même réseau fonctionnel en comparant le degré de connectivité fonctionnelle entre des individus jeunes et âgés. De manière similaire à l’étude 1, sur le plan comportemental les individus âgés répondaient significativement plus lentement et commettaient plus d’erreurs que les jeunes adultes. En ce qui concerne la dimension inter-hémisphérique du réseau, les résultats des analyses de connectivité montrent que le degré d’intégration des régions hémisphériques gauches fronto-pariétales et temporales est plus faible pour les participants âgés que pour les participants jeunes. Au contraire, les régions frontales, pariétales, temporales et sous-corticales de l’hémisphère droit sont plus intégrées. Par ailleurs, les résultats montrent également que le degré d’intégration interhémisphérique est plus élevé chez les individus âgés. Ainsi, cette étude suggère que le degré de connectivité fonctionnelle entre les régions hémisphériques droites du réseau attentionnel ventral augmente au cours du vieillissement, suggérant ainsi une amplification de la latéralisation de ce réseau vers l’hémisphère droit avec l’âge. Cette étude montre également que malgré une augmentation de la latéralisation du VAN à droite, celle-ci s’accompagne d’une augmentation du degré de connectivité fonctionnelle interhémisphérique qui pourrait être envisagée comme une tentative de compensation interhémisphérique (i.e. recrutement des régions homologues) qui aurait atteint toutefois un certain plateau car même si les âgés réussissent à réaliser la tâche, leur niveau de performance reste significativement plus faible que les jeunes. En somme, ce travail a permis de contribuer à notre compréhension de l’impact du vieillissement sur le réseau attentionnel ventral sur l’axe intrahémisphérique et interhémisphérique. Cet ouvrage lance de nouvelles pistes d’investigation dans ce domaine et pourrait éventuellement mener à l’élaboration d’interventions susceptibles de promouvoir une santé cognitive optimale lors du vieillissement. / Attention is necessary for most of daily life’s tasks. During aging, these cognitive abilities are changed. Studies suggest that the neurofunctional activity of the frontoparietal network, which upholds the attentional capacities, differ between young and older adults. However, age-related changes of the ventral frontoparietal network, also called the ventral attention network, have been less investigated. Such question has to be raised in context of recent models of neurofunctional changes in aging, who report possible functional transformation that could occur both at the intrahemispheric and interhemispheric levels. The goal of the present thesis is to determine how aging affects the ventral attention network and describe the nature of such changes that can occur on the intrahemispheric and interhemispheric axis. To do so, functional connectivity methods were favoured because of their capacity to measure the neurofunctional interaction between the regions of a network. The first study of the present thesis has allowed describing the age-related intrahemispheric modifications of functional connectivity in this network by comparing young and older adults while they respond on a selective attention task during a functional magnetic resonance imagery scan. On the task, aged adults performed significantly slower and made more errors than the young adults. At the functional connectivity level, the results show higher level of the functional connectivity between all frontoparietal regions of this network for the older group. Further, the integration level of functional connectivity in anterior regions of the network seems to be less integrated for the older participants, while posterior regions have more neurofunctional signal dependency. Also, the level of integration of functional connectivity is higher in older adults between anterior and posterior regions. Thus, results from this study suggest that the anterior and posterior regions of the ventral attention network interact differently during aging and that the posterior regions play a more important role with age in this network. This hyperconnectivity in the parietal regions could represent an unsuccessful intrahemispheric compensation attempt (i.e. recruitment of additional regions in posterior part of the brain) since older adults perform significantly less well than younger adults. The second study has investigated interhemispheric alterations of functional connectivity in the same functional network by comparing young and older adults. Like in the first study, younger adults were faster to respond on task and were more accurate. Regarding the neurofunctional lateralization of the network, the degree of functional connectivity is lower in older adults for the left hemisphere’s frontoparietal and temporal regions. However, older adults have a higher degree of functional connectivity in the right frontal, parietal, temporal and subcortical regions of the same network. Also, the results also show that the interhemispheric integration level is superior for the older adults. Thus, this study suggests that the level of functional connectivity with the right hemisphere’s regions of the ventral attention network increases with age, which could suggest an age-related lateralization of this network towards the right hemisphere. In this context, increased interhemispheric functional connectivity could be interpreted as a failed interhemispheric compensation attempt (i.e. recruitment of homologous regions) since the performance of older adults on task was significantly lower than younger adults. In short, this work has allowed contributing to our understanding of the impact of aging on the ventral attention network both on the intrahemispheric and interhemispheric axis. These various results bring up new hypothesis that needs to be investigated in further studies and eventually that could lead to the establishment of intervention that promote an optimal healthy cognitive aging.

The transmission of sex pheromone-mediated signals is essential for goldfish reproduction. However, the neural pathways underlying this reproductive signalling pathway in the goldfish brain is not well described. Lesioning experiments have shown previously that two brain areas, the preoptic area (POA) and the ventral telencephali pars ventralis (Vv) in particular, are important for reproduction. We used patch clamp electrophysiology to study the electrical activities of POA and Vv neurons. Based on the intrinsic properties of these neurons, we suggest there are five different functional classes of POA neurons and a single class of Vv neurons. In addition, by electrically stimulating the olfactory bulb (OB), we were able to show that this primary sensory structure makes monosynaptic glutamatergic connections with both POA and Vv neurons. While electrophysiology measures signalling events occurring at short time scales on the order of milliseconds to minutes, we were also interested in studying sex pheromone signalling in the goldfish brain over a long time scale. Thus, we describe changes in gene expression in male goldfish exposed to waterborne sex pheromones (17alpha,20beta dihydroxy-4-pregene-3-one and Prostaglandin-F2alpha) over 6 hours. We perform cDNA microarrays on Prostaglandin-F2alpha-treated fish to study the rapid modulation of transcription and define the signalling pathways affected. Our microarrays showed that 71 genes were differentially regulated (67 up and 4 down). Through gene ontology enrichment analysis, we found that these genes were involved in various biological processes such as RNA processing, neurotransmission, neuronal development, apoptosis, cellular metabolism and sexual reproduction. RT-PCRs were performed to validate our microarrays and to facilitate direct comparisons of the effects of the two sex pheromones, 17alpha,20beta dihydroxy-4-pregene-3-one and Prostaglandin-F2alpha. By combining electrophysiology and gene expression analyses, we were able to study sex-pheromone signalling on two different time scales. One short, occurring on the order of milliseconds to minutes, that involves electrical activities in the brain through the glutamatergic amino-3-hydroxy-5-methylisoxazole-4-propionate and N-methyl-D-aspartate receptors; and the other long occurring several hours later that involves changes in the gene expression levels of calmodulin and ependymin among other genes underlying neuroplasticity. Reproductive neuroplasticity in the goldfish may therefore require the activation of glutamatergic receptors which then activate downstream signals like calmodulin and ependymin to transform the sex pheromones-mediate signal into gene expression.

Master of Science / Department of Biology / Tonia L. Von Ohlen / The Drosophila embryonic nervous system develops from an array of neural precursor cells called, neuroblasts. These neuroblasts give rise to all the cell types that populate the mature central nervous system (CNS). The CNS originates from a bilateraly symmetric neurectoderm that is subdivided into three domains along the dorso-ventral (DV) axis. One of these domains is defined by the expression of the Homeodomain protein ventral nervous system defective (vnd). Regulation of neuroblast designation is very precise and controlled. Extensive research has been done on neuroblast formation along the anteroposterior axis, most of which indicates that neuroblast selection within a cluster of neurectodermal cells is controlled by segmentation genes. However, much more research is required to elucidate the function of genes along the DV axis. Early studies indicate that vnd is required for neuroblast formation in the ventral column. Here, we show that vnd function, but not expression, is dependent on MAPK activity downstream of Drosophila EGF-R (DER). Specifically, we show that vnd activity is eliminated in EGF-R mutant embryos in a stage specific manner by evaluating vnd’s ability to inhibit intermediate neuroblast defective (ind), muscle segment homeobox (msh), and the newly identified neural tube development player, neu3. Finally, we show that DER functionality in the ventral column is entirely dependent on the processing protein rhomboid (rho) in later stage embryos.

Dorsal-ventral (DV) polarity in the Drosophila embryo is defined by spatially regulated activation of the transmembrane receptor Toll, which is uniformly distributed throughout the early embryo's plasma membrane. Ventral activation of Toll is accomplished through the local production of its activating ligand, a processed C-terminal fragment of the Spätzle protein, which is generated in the last step of a proteolytic cascade involving the sequentially-acting proteases Gastrulation Defective (GD), Snake and Easter. Pipe protein, a homologue of vertebrate glycosaminoglycan modifying enzymes, which is expressed during oogenesis in ventral follicle cells adjacent to the developing oocyte, is believed to control the ventrally restricted processing of Spätzle. pipe expression and the sulfation of its enzymatic target in the ventral follicle cells leads to the formation of a stable ventral cue, embedded in the eggshell. Recently the Pipe enzymatic target has been identified as several protein components of the vitelline membrane, the inner layer of the eggshell. Prior to this work, an important piece of information missing from our understanding of Drosophila DV patterning was the identity of the initial step in the protease cascade that requires Pipe activity. Here, I show that the processing of Snake is independent of Pipe activity, while the processing of Easter requires Pipe function, indicating that Easter processing by Snake is the key proteolytic step that is controlled by Pipe activity and presumably the first cleavage event that is spatially regulated. A second key gap in our understanding of Drosophila embryonic DV patterning concerned the role of GD in the protease cascade. While GD is the protease that cleaves and activates Snake, the existence of two distinct classes of complementing gd alleles has suggested that GD provides another, distinct function. Investigations described here indicate that the second function of GD is to promote the ability of activated Snake to process Easter, independent of its Snake-processing function. Finally, I provide evidence for the formation of protein complexes containing various components of the serine protease cascade, which suggest that conformational changes in the complexes, which act to promote productive interactions between the proteins, are an important aspect of their activation. / text

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

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

Personen unterscheiden sich in dem, wie sie sich im Allgemeinen fühlen. Das Ziel dieser Dissertation ist es, die Prozesse, die diesen Personenunterschieden zugrunde liegen, zu verstehen. Es wurden insbesondere die affektiven Prozesse affektive Reaktivität und Emotionsregulation untersucht. In drei Studien wurden die folgenden Forschungsfragen untersucht: (1) Haben Personen mit höherem subjektiven Wohlbefinden einen stärkeren Anstieg in positivem Affekt, wenn sie auf positive Stimuli im Labor reagieren oder ihre positiven Emotionen hochregulieren? (2) Welches sind die neuronalen Korrelate, die diesen kurzfristigen Veränderungen in positivem Affekt zugrunde liegen, insbesondere während der Hochregulation positiver Emotionen? (3) Hängt ein höheres subjektives Wohlbefinden mit einer stärkeren oder geringeren Reaktion auf positive Ereignisse im Alltag zusammen? Die Befunde haben gezeigt, dass ein stärkerer Anstieg in positivem Affekt (durch eine stärkere Reaktion auf positive Ereignisse oder durch das Hochregulieren positiver Emotionen) nicht mit einem höheren subjektiven Wohlbefinden zusammenhängt. Stattdessen hatten Personen mit einem höheren subjektiven Wohlbefinden eine geringere Reaktivität auf positive Ereignisse im Alltag. Auf der neuronalen Ebene spiegelten sich die Veränderungen in positivem Affekt durch eine verstärkte neuronale Aktivierung in emotionsbezogenen Regionen (insbesondere des ventralen Striatums) wieder, sowie durch eine Deaktivierung in einem fronto-parietalen Kontrollnetzwerk. Ein Zusammenhang von neuronaler Aktivierung und Veränderungen in positivem Affekt im Alltag wurde nicht gefunden. Die Arbeit dieser Dissertation zeigt, dass nicht besonders intensives positives Erleben, sondern eher weniger Schwankungen in momentanen positiven Affekt wichtig für das Wohlbefinden sind. Darüber hinaus zeigt diese Dissertation die Wichtigkeit auf verschiedene Analyseebenen und Untersuchungsmethoden in die Erforschung von affektivem Erleben zu integrieren. / This dissertation investigates the affective processes – affective reactivity and emotion regulation – underlying short-term changes in positive affective experiences and their relation to interindividual differences in subjective well-being. The main research objectives that were addressed in the empirical studies of this dissertation concerned (1) whether stronger increases in positive affect when reacting to and when up-regulating in response to positive stimuli in the laboratory relate to higher subjective well-being, (2) which brain regions underlie changes in positive affective experiences, particularly during the up-regulation of positive emotions, and (3) whether enhanced or reduced affective reactivity to positive events in daily life relates to higher subjective well-being. Findings showed that greater increases in positive affect were not related to higher subjective well-being, both when investigated in the laboratory and in daily life. Instead, people with higher levels of subjective well-being showed reduced affective reactions to positive events in daily life, pointing to the importance of a relative greater emotional stability. At the neural level, changes in positive affective experiences were mirrored by increased activations in emotion-related (e.g., ventral striatum) regions as well as deactivation in a fronto-parietal control network. These neural activations were not related to changes in positive affective experiences in daily life. The work in this dissertation indicates that not the experience of particularly intense positive affective states, but rather less fluctuation in momentary positive affective experiences seems to be essential to the overall composition of subjective well-being. The present dissertation further emphasizes the need to integrate different methods in the study of emotion. Concluding, this dissertation advances our understanding of the processes underlying subjective well-being.

Submitted by Leticia Schettini (leticia@ufrrj.br) on 2017-04-24T14:23:01Z No. of bitstreams: 1 2016 - Carlos Augusto dos Santos Sousa.pdf: 2340153 bytes, checksum: 5ef373f242c2c4700a9a9e55280bc62c (MD5) / Made available in DSpace on 2017-04-24T14:23:01Z (GMT). No. of bitstreams: 1 2016 - Carlos Augusto dos Santos Sousa.pdf: 2340153 bytes, checksum: 5ef373f242c2c4700a9a9e55280bc62c (MD5) Previous issue date: 2016-02-03 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Morphology studies provide knowledge that allow us to understand how animals interact with the natural environment or in captivity. In this context, the comparative anatomy of the formation of the brachial plexus awakens interest since the nineteenth century and remains one of the most intriguing topics of contemporary anatomy. The aim of this study was to describe the origin and the antimeric distribution of the brachial plexus nerves in Macaca mulatta, as well as the innervated muscles. Ten male rhesus monkeys (Macaca mulatta) were used, from the Non-human Primates? Breeding Department at the Laboratory Animals Breeding Centre (Cecal/Fiocruz), donated to the Animal Anatomy Department of the Rural Federal University of Rio de Janeiro (UFRRJ). The specimens were fixed in formaldehyde solution by infusion of 10% solution. They were subsequently wrapped in a low-density polythene container with 500 liters of formaldehyde 30% solution over a period of 12 months. After this period, they were washed in running water and subjected to X-ray examinations of the neck at the Small Animals Veterinary Hospital of the UFRRJ to characterize the number of cervical vertebrae. Then, they had both antimeres dissected aiming at the exposure of the origins and the nerves arising from the brachial plexus. Data were presented both in absolute frequency and in simple percentage. In 11 (55%) animals the resulting nerves were constituted by the connections between the ventral spinal branches C5, C6, C7, C8 and T1. In 5 (25%) animals, the participants roots were C4, C5, C6, C7, C8, T1 and T2. In 2 (10%) animals C5, C6, C7, C8, T1 and T2. In the other 2 (10%) animals the formation of the plexus was observed from C6, C7, C8, T1 and T2. The ventral branches formed three nerve trunks: cranial, middle and caudal. The suprascapular nerves, subscapular, axillary, musculocutaneous, radial, median, ulnar innervated the intrinsic muscles and the subclavian nerve innervated the thoracodorsal, medial cutaneous arm and forearm, long thoracic, cranial pectoral and caudal pectoral innervate extrinsic muscles. The results obtained in this study contribute to the comparative anatomy of primates and to the information for applied research, serving as basis for clinical and surgical procedures that uses this species as an animal model. / Estudos morfol?gicos fornecem conhecimentos que permitem entender o modo como os animais interagem com o ambiente natural ou em cativeiro. O objetivo desse estudo foi descrever a origem e a distribui??o antim?rica dos nervos do plexo braquial em Macaca mulatta, assim como dos m?sculos inervados. Foram utilizados 10 cad?veres de Macaca mulatta do sexo masculino, oriundos do Servi?o de Cria??o de Primatas N?o Humanos do Centro de Cria??o de Animais de Laborat?rio (Cecal/Fiocruz) doados a ?rea de Anatomia Animal da Universidade Federal Rural do Rio de Janeiro (UFRRJ). Os esp?cimes foram fixados com perfus?o de solu??o de formalde?do a 10%. Posteriormente, foram acondicionados em caixas de polietileno de baixa densidade com capacidade de 500 litros contendo solu??o de formalde?do a 30% por um per?odo de 12 meses. Ap?s este per?odo, foram lavados em ?gua corrente e submetidos a exames radiogr?ficos da regi?o cervical no Hospital Veterin?rio de Pequenos Animais da UFRRJ para a caracteriza??o do n?mero de v?rtebras cervicais. Em seguida, foram dissecados at? a exposi??o das origens e dos nervos oriundos do plexo braquial. Os dados foram representados em frequ?ncia absoluta e percentual simples. Em 11 (55%) os nervos resultantes foram constitu?dos das conex?es entre os ramos espinhais ventrais de C5, C6, C7, C8 e T1. Em 5 (25%) as ra?zes participantes foram C4, C5, C6, C7, C8, T1 e T2. Em 2 (10%) de C5, C6, C7, C8, T1 e T2. Em outros 2 (10%) verificamos a constitui??o do plexo a partir de C6, C7, C8, T1 e T2. Os ramos ventrais formaram tr?s troncos nervosos: cranial, m?dio e caudal. Os nervos supraescapular, subescapulares, axilar, musculocut?neo, radial, mediano, ulnar inervaram a musculatura intr?nseca e os nervos subcl?vios, toracodorsal, tor?cico longo, peitoral cranial e peitoral caudal inervaram a musculatura extr?nseca. Tamb?m foram registrados os nervos cut?neos oriundos do plexo braquial, sendo eles o nervo cut?neo medial do bra?o, nervo cut?neo medial do antebra?o e ramos para a musculatura cut?nea do tronco. Os dados descritos neste estudo contribuem para a anatomia comparada de primatas e fornecem informa??es para a pesquisa aplicada, servindo como base para procedimentos cl?nico-cir?rgicos em que venha a se utilizar esta esp?cie como modelo experimental.

Orientador: José Roberto fioretto / Banca: Mário Ferreira Carpi / Banca: Carlos Fernando Ronchi / Resumo: A Síndrome do Desconforto Respiratório Agudo (SDRA) cursa com alta mortalidade apesar do melhor entendimento de sua fisiopatologia e avanços no tratamento. A Ventilação Oscilatória de Alta Frequência (VOAF) é método protetor por utilizar baixos volumes correntes (VC). Existem terapias adjuvantes à ventilação, dentre as quais se destaca a posição prona, que possibilita homogeneização da distribuição do VC e promove recrutamento alveolar. O objetivo foi investigar o efeito da posição prona associada à VOAF sobre a oxigenação, inflamação, histologia e dano oxidativo pulmonares, comparando-a com a posição supina neste mesmo modo ventilatório em modelo experimental de lesão pulmonar aguda (LPA) induzida em coelhos. Trinta coelhos foram instrumentados com traqueostomia e acessos vasculares e ventilados. A LPA foi induzida por infusão traqueal de salina aquecida (30mL/Kg, 38°C). Os coelhos foram submetidos à VOAF e divididos em dois grupos (n=15), um ventilado em posição supina (GS) e outro em posição prona (GP). VOAF foi iniciada com pressão aérea média de 16 cmH2O, que foi diminuída a cada 30 minutos até 10-11 cmH2O. Nos últimos 30 minutos os coelhos foram reposicionados em posição supina. Parâmetros ventilatórios e hemodinâmicos foram registrados a cada 30 minutos durante 150 minutos. Os desfechos foram: oxigenação, avaliada pela relação PaO2/FiO2 e índice de oxigenação (IO); inflamação pulmonar, avaliada pela porcentagem de polimorfonucleares (PMN) no lavado broncoalveolar (BAL) e pelo nível de TNF-alfa medido no BAL e no tecido pulmonar nas áreas ventral e dorsal; estresse oxidativo tecidual pulmonar, determinado pelo método de peroxidação lipídica (malondialdeído); e lesão tecidual pulmonar, determinada por escore histológico de lesão por área pulmonar. O nível de significância avaliado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Acute respiratory distress syndrome (ARDS) has been associated to high mortality rate despite better understanding of its pathophysiology and advances in treatment. High-frequency oscillatory ventilation (HFOV) is a protective ventilatory method because of using low tidal volume (VT). There are also many adjunctive therapies, of which prone position is known to allow homogenization of VT distribution and to promote alveolar recruitment. The objective was to investigate the prone position and HFOV association effects on oxygenation, inflammation, oxidative damage and lung histology, comparing to the supine position in this same ventilation mode, in experimental acute lung injury (ALI) induced in rabbits. Thirty rabbits were instrumented with tracheotomy and vascular catheters and ventilated. ALI was induced by tracheal infusion of warm saline (30mL/Kg, 38°C). Rabbits were submitted to HFOV and divided in two groups (n=15), one ventilated in supine position (SG), and the other in prone position (PG). HFOV was initiated with mean airway pressure of 16 cmH2O, which was decreased each 30 minutes until 10-11 cmH2O. In the last 30 minutes, all rabbits were repositioned to supine position. Ventilatory and hemodynamic parameters were recorded every 30 minutes for 150 minutes. The outcomes were: oxygenation, measured by PaO2/FiO2 ratio and oxygenation index (OI); lung inflammation, assessed by the percentage of polymorphonuclear cells (PMN) in bronchoalveolar lavage fluid (BAL) and by the level of TNF- alpha measured in BAL and in lung tissue, in ventral and dorsal areas; lung tissue oxidative stress, determined by the method of lipid peroxidation (malondialdehyde); and lung tissue damage, as determined by a histological score of injury, in each lung area. A significance level of 5% was... (Complete abstract click electronic access below) / Mestre

Nicotine has multiple behavioral effects as a result of its action in the central nervous system. Nicotine strengthens the behaviors that lead to nicotine administration (primary reinforcement), and this effect of nicotine depends on mesotelencephalic systems of the brain that are critical to goal directed behavior, reward, and reinforcement. Nicotine also serves as a ‘reinforcement enhancer’ – drug administration enhances behaviors that lead to other drug and nondrug reinforcers. Although the reinforcement enhancing effects of nicotine may promote tobacco use in the face of associated negative health outcomes, the neuroanatomical systems that mediate this effect of nicotine have never been described. The ventral tegmental area (VTA) is a nucleus that serves as a convergence point in the mesotelencephalic system, plays a substantial role in reinforcement by both drug and nondrug rewards and is rich in both presynaptic and postsynaptic nicotinic acetylcholine receptors (nAChRs). Therefore, these experiments were designed to determine the role of the VTA and nAChR subtypes in the reinforcement enhancing effect of nicotine. Transiently inhibiting the VTA with a gamma amino butyric acid (GABA) agonist cocktail (baclofen and muscimol) reduced both primary reinforcement by a visual stimulus and the reinforcement enhancing effect of nicotine, without producing nonspecific suppression of activity. Intra-VTA infusions of a high concentration of mecamylamine a nonselective nAChR antagonist, or methylycaconitine, an α7 nAChR antagonist, did not reduce the reinforcement enhancing effect of nicotine. Intra-VTA infusions of a low concentration of mecamylamine and dihydro-beta-erythroidine (DHβE), a selective antagonist of nAChRs containing the *β2 subunit, attenuated, but did not abolish, the reinforcement enhancing effect of nicotine. In follow-up tests replacing systemic nicotine injections with intra-VTA infusions (70mM, 105mM) resulted in complete substitution of the reinforcement enhancing effects – increases in operant responding were comparable to giving injections of systemic nicotine. These results suggest that *β2-subunit containing nAChRs in the VTA play a role in the reinforcement enhancing effect of nicotine. However, when nicotine is administered systemically these reinforcement enhancing effects may depend on the action of nicotine at nAChRs in multiple brain nuclei.