RESUMO
Las alteraciones morfológicas encefálicas en individuos que padecen alcoholismo crónico explican los severos trastornos neurocognitivos, principalmente amnésicos anterógrados, y neuropsiquiátricos debido al carácter neurotóxico y déficits nutricionales que genera. El objetivo fue describir la morfología del cuerpo calloso y los cuerpos mamilares en dependientes al alcohol y su relación volumétrica otras áreas cerebrales. Se estudiaron morfológica y morfométricamente con resonancia magnética los cerebros de 26 masculinos, edades 29 a 51 años, con diagnóstico de trastorno por consumo de alcohol tipo dependencia (DSM IV). Fueron criterios de exclusión: patologías hepáticas, autoinmunes, neurológicas centrales y antecedentes neurológicos no relacionados con el consumo, traumatismo craneoencefálico o neurocirugías previas. Se cuantificó la volumetría (método ROI) de: corteza prefrontal, hipocampo, cuerpo amigdalino, tálamo y cuerpos mamilares; y la morfometría bidimensional de las regiones del cuerpo calloso (métodos de Witelson y de Clarke). El procedimiento fue sometido a pruebas estadísticas y cumplió con los reparos ético-legales vigentes. Todos los volúmenes de pacientes dependientes fueron menores. Se registró según severidad reducción volumétrica significativa en corteza prefrontal, cuerpo mamilar, hipocampo y tálamo izquierdos, seguidos por el cuerpo amigdalino derecho. La superficie con mayor afectación del cuerpo calloso fue el 1/3 anterior. Se determinaron correlaciones entre la afectación de los cuerpos mamilares y el cuerpo calloso con estructuras subcorticales. El compromiso del cuerpo calloso y los cuerpos mamilares presentó correlación con la afectación del hipocampo, cuerpo amigdalino y tálamo, y una estrecha relación con el tiempo y cantidad de consumo. Estas alteraciones morfométricas son indicadores de severidad cognitiva y alteración comportamental.
Brain morphological abnormalities in individuals with severe chronic alcoholism explains the severe neurocognitive disorders, namely neuropsychiatric and anterograde amnesia, due to the neurotoxic nature and nutritional deficits generated. The objective of the present study was to describe in alcohol dependent subjects, the morphology of the corpus callosum and mammillary bodies and volume ratio in other brain areas. We used morphological and morphometric magnetic resonance imaging to study the brains of 26 men, ages 29-51 years diagnosed with alcohol dependence type disorder (DSM IV). Exclusion criteria were: liver diseases, autoimmune and central neurological disorders, as well as a neurological history not related to consumption, prior traumatic brain injury or brain surgery. Volumes were quantified by (ROI method) for the following: prefrontal cortex, hippocampus, amygdaloid body, thalamus and mammillary bodies, and the two-dimensional morphometry of corpus callosum regions (Witelson and Clarke methods). The procedure was subject to statistical tests and current legal ethical standards. Our results showed all patients dependent volumes were lower. In accordance with severity, significant volume reduction was recorded in prefrontal cortex, mammillary body, left hippocampus and thalamus, followed by the right amygdaloid body. The most affected area of the corpus callosum was the anterior third. Correlations were determined between the involvement of the mammillary bodies and the corpus callosum with subcortical structures. The relation of the corpus callosum and mammillary bodies correlated with the involvement of the hippocampus, amygdala and thalamus body, and are closely related to the amount of time and consumption of alcohol. These morphometric changes are indicative of severe cognitive and behavioral impairment.
Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Alcoolismo/patologia , Corpo Caloso/patologia , Imageamento por Ressonância Magnética , Corpos Mamilares/patologiaRESUMO
The dorsal premammillary nucleus (PMd) is one of the most responsive hypothalamic sites during exposure to a predator or its odor, and to a context previously associated with a predatory threat; and lesions or pharmacological inactivation centered therein severely reduced the anti-predatory defensive responses. Previous studies have shown that beta adrenergic transmission in the PMd seems critical to the expression of fear responses to predatory threats. In the present study, we have investigated the putative sources of catecholaminergic inputs to the PMd. To this end, we have first described the general pattern of catecholaminergic innervation of the PMd by examining the distribution and morphology of the tyrosine hydroxylase (TH) immunoreactive fibers in the nucleus; and next, combining Fluoro Gold (FG) tracing experiments and TH immunostaining, we determined the putative sources of catecholaminergic inputs to the nucleus. Our results revealed that the PMd presents a moderately dense plexus of catecholaminergic fibers that seems to encompass the rostral pole and ventral border of the nucleus. Combining the results of the FG tract-tracing and TH immunostaining, we observed that the locus coeruleus was the sole brain site that contained double FG and TH immunostained cells. In summary, the evidence suggests that the locus coeruleus is seemingly a part of the circuit responding to predatory threats, and, as shown by the present results, is the sole source of catecholaminergic inputs to the PMd, providing noradrenergic inputs to the nucleus, which, by acting via beta adrenoceptor, seems to be critical for the expression of anti-predatory responses.
Assuntos
Catecolaminas/fisiologia , Locus Cerúleo/citologia , Corpos Mamilares/citologia , Vias Neurais/citologia , Animais , Axônios/fisiologia , Axônios/ultraestrutura , Comportamento Animal/fisiologia , Medo/fisiologia , Locus Cerúleo/fisiologia , Masculino , Corpos Mamilares/fisiologia , Vias Neurais/fisiologia , Ratos , Ratos WistarRESUMO
The dorsal premammillary nucleus (PMd) is a hypothalamic structure that plays a pivotal role in the processing of predatory threats. Lesions of this nucleus virtually eliminate the expression of defensive responses to predator exposure. However, little is known about the neurotransmitters responsible for these behavioral responses. Since PMd neurons express ionotropic glutamate receptors and exposure to predators have been shown to activate nitric oxide (NO) producing cells in this region, the aim of this study was to verify the involvement of glutamate and NO-mediated neurotransmission in defensive reactions modulated by the PMd. We tested in male Wistar rats the hypothesis that intra-PMd injection of the NMDA receptor antagonist, AP7, or the NO synthase inhibitor, N-propyl-L-arginine (NP), would attenuate behavioral responses induced by cat exposure. Our results showed that both AP7 and NP significantly attenuated the behavioral responses induced by the live cat. These results suggest that the NMDA/NO pathway plays an important role in the behavioral responses mediated by the PMd.
Assuntos
Mecanismos de Defesa , Medo , Corpos Mamilares/fisiologia , N-Metilaspartato/metabolismo , Óxido Nítrico/metabolismo , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Arginina/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Gatos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Corpos Mamilares/efeitos dos fármacos , Ratos , Ratos Wistar , Estatísticas não ParamétricasRESUMO
In the present work, we sought to mimic the internal state changes in response to a predator threat by pharmacologically stimulating the brain circuit involved in mediating predator fear responses, and explored whether this stimulation would be a valuable unconditioned stimulus (US) in an olfactory fear conditioning paradigm (OFC). The dorsal premammillary nucleus (PMd) is a key brain structure in the neural processing of anti-predatory defensive behavior and has also been shown to mediate the acquisition and expression of anti-predatory contextual conditioning fear responses. Rats were conditioned by pairing the US, which was an intra-PMd microinjection of isoproterenol (ISO; ß-adrenoceptor agonist), with amyl acetate odor-the conditioned stimulus (CS). ISO (10 and 40 nmol) induced the acquisition of the OFC and the second-order association by activation of ß-1 receptors in the PMd. Furthermore, similar to what had been found for contextual conditioning to a predator threat, atenolol (ß-1 receptor antagonist) in the PMd also impaired the acquisition and expression of OFC promoted by ISO. Considering the strong glutamatergic projections from the PMd to the dorsal periaqueductal gray (dPAG), we tested how the glutamatergic blockade of the dPAG would interfere with the OFC induced by ISO. Accordingly, microinjections of NMDA receptor antagonist (AP5, 6 nmol) into the dPAG were able to block both the acquisition, and partially, the expression of the OFC. In conclusion, we have found that PMd ß-1 adrenergic stimulation is a good model to mimic predatory threat-induced internal state changes, and works as a US able to mobilize the same systems involved in the acquisition and expression of predator-related contextual conditioning.
Assuntos
Condicionamento Clássico/fisiologia , Medo/psicologia , Corpos Mamilares/fisiologia , Receptores Adrenérgicos beta/metabolismo , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Análise de Variância , Animais , Atenolol/farmacologia , Butoxamina/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Corpos Mamilares/efeitos dos fármacos , Microinjeções , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Odorantes , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Wistar , Valina/análogos & derivados , Valina/farmacologiaRESUMO
There is increasing evidence that early adverse experience contributes to the development of stress susceptibility, and increases the onset of stress-related psychiatric disorders in stressful environments in adulthood. This study addressed whether or not prolonged maternal separation, a well-established model of early stress, affects adult limbic areas related to the regulation of the hypothalamic-pituitary-adrenal axis in exposure to chronic variable stress in adulthood. Rats were subjected to daily maternal separation for 4.5h during postnatal days 1-21. As adults, the animals were exposed to a variable chronic stress paradigm of 24 days. Persistent changes were assessed in glucocorticoid receptor density and Fos activity in the anterodorsal thalamic nuclei, mammillary nuclei and retrosplenial cortex. Immunohistochemical analysis revealed that adult maternally separated animals had increased levels of c-Fos immunoreactivity in the anterodorsal thalamic nuclei as well as in the mammillary nuclei compared to normal non-maternally separated animals. Chronic variable stress in maternally separated and non-maternally separated animals diminished glucocorticoid receptor density in the anterodorsal thalamic nuclei but not in the rest of the nuclei analyzed. These results indicate that c-Fos immunoreactivity as well as glucocorticoid receptor expression in the anterodorsal thalamic nuclei and mammillary nuclei exhibit long-term alterations in adult rats following repeated maternal separation and subsequent stress exposure. Recognition of these adaptations helps to define the brain regions and neural circuitry associated with persistent alterations induced by early life environment and the development of stress-associated disorders.