La actividad de las neuronas piramidales de la corteza prefrontal (CPF) está regulada por receptores ionotrópicos excitatorios (AMPA, KA y NMDA) e inhibitorios (GABAA). Las entradas sinápticas en dichos receptores son esenciales para el funcionamiento de las redes corticales. Sin embargo, los receptores monoaminérgicos juegan un papel esencial en la modulación fina de dichas entradas sinápticas. Los fármacos antipsicóticos clásicos y atípicos ejercen su acción fundamentalmente a través de su interacción con receptores dopaminérgicos de la familia D2 (clásicos) así como serotoninérgicos 5-HT2A (atípicos). Además, todos ellos poseen gran afinidad por los receptores adrenérgicos Alfa-1. Es por ello que la presente Tesis se ha centrado en su mayor parte en el estudio detallado de la distribución regional y celular de receptores monoaminérgicos en un área clave para la esquizofrenia como es la CPF.Así, los resultados de esta Tesis muestran que una gran proporción (entre un 40 y un 80%, dependiendo del área cortical) de neuronas glutamatérgicas de la CPF expresan el ARNm tanto del receptor serotoninérgico 5-HT1A como del 5-HT2A. Ambos se encuentran presentes en todas las regiones de la parte medial de la CPF (infralímbica, prelímbica, cingulada y motora secundaria) tanto en capas superficiales como profundas, siendo el 5-HT1A más abundante en capas profundas (V-VI) y el 5HT2A en capas más superficiales (III-V). Nuestros datos también indican una modulación serotoninérgica de las neuronas GABAérgicas de CPF a través de los receptores 5HT1A y 5HT2A. El ARNm de estos receptores se expresa en un 10-30% de las interneuronas GABAérgicas de las diferentes áreas de la CPF medial, a excepción del 5-HT2A en capa VI, donde este receptor se expresa en menor proporción. Este trabajo muestra también la presencia del ARNm del receptor serotoninérgico 5-HT3 en interneuronas GABAérgicas de CPF de rata, en una proporción de 40, 18, 6, 8% en capas I, II-III, V y VI, respectivamente. Además, la estimulación fisiológica de los núcleos del rafe excitó neuronas probablemente GABAérgicas en las áreas cingulada y prelímbica de la CPF de rata in vivo. Estas excitaciones fueron bloqueadas por la administración i.v. de los antagonistas del receptor 5-HT3 ondansetron y tropisetron.En este trabajo examinamos también la expresión celular de los receptores Alfa-1-adrenérgicos en neuronas piramidales y GABAérgicas en CPF y su colocalización con los receptores serotoninérgicos 5-HT2A. Los adrenoceptores Alfa-1 se expresaron en una alta proporción de neuronas piramidales (62-85%) y GABAérgicas (52-79%) en CPF medial y coexpresaron con el 80% de las células positivas para el 5-HT2A. Además, mediante las técnicas de co-inmunoprecipitación y FRET, se demostró la interacción heterodimérica entre el receptor serotoninérgico 5-HT2A con cada uno de los subtipos del receptor Alfa-1-adrenérgico. Se examinó también la expresión de los ARNm de los receptores dopaminérgicos D1 y D2 en neuronas piramidales y GABAérgicas en la CPF de rata. Los ARNm de ambos receptores se expresaron predominantemente en capas V-VI de la CPF medial, las áreas cingulada y motora así como en áreas ventrales de la CPF. Las neuronas que expresaron el receptor D1 fueron más abundantes que las que expresaron el receptor D2. Algunas neuronas piramidales y GABAérgicas expresaron densidades muy altas del ARNm del receptor D1. Los receptores D1 se expresaron por una mayor proporción de células GABAérgicas que piramidales mientras que lo contrario ocurrió en el caso de los receptores D2. La administración sistémica de fenciclidina (PCP), utilizada como modelo farmacológico de esquizofrenia, aumentó marcadamente la expresión de c-fos en una gran proporción de neuronas piramidales (50%) de CPF. Este aumento se dio tanto en el nivel de expresión celular como en el número de células que expresaron este marcador de actividad neuronal. Las interneuronas GABAérgicas de CPF sin embargo, no experimentaron un aumento de la expresión de c-fos tras la administración de PCP. Por otra parte, la PCP aumentó la frecuencia de descarga del 45% de las neuronas piramidales registradas en CPF y la redujo en el 33% de éstas. Además, la administración sistémica de PCP redujo marcadamente la sincronía cortical en el rango de frecuencia delta (0.3-4 Hz), resultando en una descarga aleatoria de las neuronas piramidales. Ambos efectos (aumento de la expresión de c-fos y aumento de la excitablilidad neuronal) fueron revertidos por fármacos antipsicóticos. La administración sistémica de fenciclidina (PCP) produjo además un aumento de la expresión del marcador de actividad neuronal c-fos en varias áreas corticales y subcorticales, entre ellas, en los núcleos talámicos con una mayor conexión recíproca con la CPF, los núcleos mediodorsal y centromedial. Otras áreas subcorticales aferentes a la CPF, como el hipocampo ventral o la amígdala no aumentaron significativamente su expresión de c-fos tras la administración de PCP. Tampoco lo hicieron las interneuronas GABAérgicas del núcleo reticular del tálamo, encargado del control inhibitorio del resto de los núcleos talámicos. El aumento de expresión de c-fos en las neuronas glutamatérgicas de las áreas mencionadas fue revertido por la aplicación del antipsicótico atípico clozapina.

Probability learning is the ability to establish a relationship between stimulus and outcomes based on occurrence probabilities using repetitive feedbacks. Participants learn the task according to the cue-outcome relationship, and try to gain in depth understanding of this relationship throughout the experiment. While learning is at the highest level, people rely on their working memory. In this study 20 participants were presented a probability learning task, and their prefrontal cortex activity was measured with functional Near-Infrared Spectroscopy. It was hypothesized that as participants gain more knowledge of the probabilities they will learn cue-outcome relationships and therefore rely less on their working memory. Therefore as learning precedes a drop in the fNIRS signal is expected. We obtained results confirming our hypothesis: Significant negative correlation between dorsolateral prefrontal cortex activity and learning was found. Similarly, response time also decreased through the task, indicating that as learning precedes participants made decisions faster. Participants used either the frequency matching or the maximization strategy in order to solve the task in which they had to decide whether the blue or the red color was winning. When they use the frequency matching strategy they chose blue at the rate of winning for the blue choice. When they use the maximization strategy they chosed blue almost always. Our task was designed such that the frequency for blue to win was 80%. We had hypothesized that the people in frequency matching and maximization groups would show working memory differences which could be observed from the fNIRS signal. However, we were unable to detect this type of behavioral difference in the fNIRS signal. Overall, our study showed the relationship between probability learning and working memory as depicted by brain activity in the dorsolateral prefrontal cortex which widely known as the central executive component of working memory.

Abnormal connectivity of the intrinsic anticorrelated networks, the task-negative network (TNN) and task-positive network (TPN), is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings offer an opportunity to further understand illness susceptibility and pathophysiology. We hypothesized that schizophrenic patients would demonstrate hyperconnectivity in the intrinsic networks and that similar, but less pronounced, hyperconnectivity would be evident in the networks of the unaffected siblings. Resting-state functional magnetic resonance images were obtained from schizophrenic patients (n=25), their unaffected siblings (n=25), and healthy controls (n=25). The posterior cingulate cortex/precuneus (PCC/PCu) and right dorsolateral prefrontal cortex (DLPFC) were used as seed regions to identify the TNN and TPN. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to the intrinsic networks of the three subject groups. In the TNN, schizophrenic patients alone demonstrated hyperconnectivity between the PCC/PCu and left inferior temporal gyrus and between the ventral medial prefrontal cortex and the right lateral parietal cortex. Both schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. In the TPN, schizophrenic patients showed hyperconnectivity between the left DLPFC and right inferior frontal gyrus relative to unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls. Resting-state hyperconnectivity of the intrinsic networks may underlie the pathophysiology of schizophrenia by disrupting network coordination. Similar, though milder, hyperconnectivity in unaffected siblings of schizophrenic patients may contribute to their cognitive deficits and increased risk to develop schizophrenia.

Decades of research have demonstrated that people sometimes provide self-evaluations that emphasize their most flattering qualities. Different theoretical accounts have been offered to explain the mechanisms underlying positively-biased self-evaluation. Some researchers theorize that positively-biased self-evaluations arise from a self-protection motivation because positivity biases increase in situations of heightened self-esteem threat. Alternative views question whether self-protection motivation is a necessary or even dominant source of positivity bias by demonstrating that positively-biased self-evaluations occur even when threat is not heightened, and that a general judgment approach leads to positivity biases in some domains but also to negativity biases in other domains. One reason for this gap in knowledge is that behavioral measures are limited in their ability to resolve whether the processes underlying positively-biased self-evaluation are the same or different depending on contextual motivators. Neuroimaging methods are well suited to examine whether different mechanisms underlie similar behaviors, specifically similar positively-biased responses in different contexts. The four studies presented here explore the neural mechanisms of positively-biased self-evaluation by first identifying a core set of neural regions associated with positivity bias (Study 1A and 1sB), examining whether a heightened self-protection motivation changes the engagement of those neural systems (Study 2), and specifying the precise mechanisms supported by those regions (Study 3). Studies 1A and 1B revealed evidence for a neural system comprised of medial and lateral orbitofrontal cortex (OFC) and, to a lesser extent dorsal anterior cingulate (dACC) that was modulated by positivity bias. Study 2 found that a heightened self-protection motivation changes the engagement of medial OFC in positively-biased self-evaluation. Finally, Study 3 found evidence that medial OFC may support a common mechanism in positively-biased judgment that is implemented differently as a function of the motivational context. Taken together, these studies represent a first step toward developing a neural model of positively-biased self-evaluation. The findings provide some preliminary evidence that positivity biases may represent distinct processes in different motivational contexts. This dissertation sets the stage for future work to examine how specific positively-biased cognitive mechanisms may be supported by specific neural systems and computations as a function of motivational contexts. / text

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Behavioral studies have documented impaired working memory in childhood brain tumor survivors; however, neural mechanisms have yet to be identified using fMRI. The current study investigated BOLD response differences between twenty survivors (Mean age=23.1(4.14), 55% female) and twenty age- and gender-matched controls from the start to the end of a twenty minute 3-back task. There were no differences in task performance between groups or over time. Effects of practice were present in left prefrontal regions, with both groups showing decreases in activation as the task progressed. There were qualitative and quantitative differences in the brain regions that survivors recruited relative to controls in bilateral prefrontal (including the dorsolateral prefrontal cortex) and parietal cortices. Findings suggest that areas under top-down control of the dorsolateral prefrontal cortex become less activated with practice, and that survivors may require more top-down processing and attentional control to perform at similar levels to healthy controls.

The philosophical and scientific studies of consciousness are two disciplines having much to learn from one another. On the one hand, a science of consciousness involves taking an objective approach to what is essentially a subjective phenomenon, giving rise to tricky conceptual and methodological issues, ones an analytic philosopher is perhaps best equipped to handle. On the other hand, a wealth of data now exists concerning the neural basis of consciousness. Such data, interpreted properly, can confirm or disconfirm philosophical views on consciousness, helping adjudicate debates thus far intractable. This dissertation explores some ways in which the philosophy and science of consciousness can be of mutual benefit to one another.

No description available.

Prior work has shown important effects of the early life environment on development of adult stress response systems in both rats and humans. The present thesis is based on experiments that attempt to explore: 1) adolescent stress responding at hormonal and behavioural levels, and 2) the effects of repeated adolescent stressor exposure on adult stress responding (hormonal and behavioural) and levels of dopamine receptors expressed in prefrontal cortex, using both male and female rats. Defensive behaviours exhibited during stressor exposure and post-stress levels of circulating corticosterone were quantified as behavioural and hormonal measures of stress responding, respectively. In the first study, responses were compared among groups of adolescent rats exposed repeatedly to one of two different types of cat odour stressor stimuli (J-cloth coated in hair/dander or cat collar previously worn by a cat) or control stimuli, and long-term outcomes were examined in adulthood. Adolescent rats showed behavioural responses to both stressor stimuli, but behavioural inhibition was more consistent using repeated cat collar exposure, and this treatment resulted in long-term increases in anxiety-like behaviour in adulthood, whereas a stress-induced adolescent corticosterone elevation was observed only in the group that received exposure to the J-cloth stimuli. In the second study, adolescent and adult rats were compared directly using repeated exposure to the cat collar stressor or control stimuli. Adolescents were found to be more sensitive to the effects of the stressor stimuli, relative to adults. Finally, in the third study, repeated exposure to the J-cloth stressor or control stimuli was used, and stressor-exposed females showed elevated baseline corticosterone levels prior to the final exposure. Furthermore, stressor-exposed males and females showed lower levels of the D2 dopamine receptor in infralimbic and dorsopeduncular cortices of the prefrontal cortex in adulthood. In addition, these studies together provide evidence that sex differences in corticosterone levels emerge during the adolescent period. It may be concluded that adolescence should be considered a sensitive developmental timeframe for stress response programming.

Neural changes in the forelimb cortex were studied at Postnatal (P) 10, 15, 20, 25, 30, and 100 days. Six biological markers of brain development, cortical thickness, Layer III pyramidal cell morphology, glial fibrillary acidic protein (GFAP), myelination, c-fos activity and Acetylcholinesterase (AChE) were correlated with the behavioural development of reaching, bimanual coordination, postural adjustment, and defensive feeding behaviours. The behaviours were filmed from P15 until P30 and then also in adulthood. For the behaviours there was a gradual development of the skilled patterns of paw and digit use seen in adults as well as in the patterns of movements in postural adjustment, carry behaviours and dodging and robbing type behaviours. The development of the adult patterns of movement were correlated to the morphological and biochemical changes in the cortex. The results suggest that the maturation of skilled movements depends upon anatomical and neurochemical maturation of the neocortex as well as upon learning. / x, 132 leaves : ill. ; 28 cm.