Progressive hippocampal alterations in stress-induced major depression and novel therapeutic strategies
[eng] Major depression disorder (MDD) is a serious, frequent, and recurrent mental illness that affects millions of people worldwide. One of the most important environmental risk factors associated with DM is chronic stress. Although stress and depression affect various brain regions, the hippocampu...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223148 |
| Acceso en línea: | https://hdl.handle.net/2445/223148 http://hdl.handle.net/10803/695208 |
| Access Level: | acceso abierto |
| Palabra clave: | Depressió psíquica Estrès Hipocamp (Cervell) Etologia Mental depression Stress Hippocampus (Brain) Animal behavior |
| Sumario: | [eng] Major depression disorder (MDD) is a serious, frequent, and recurrent mental illness that affects millions of people worldwide. One of the most important environmental risk factors associated with DM is chronic stress. Although stress and depression affect various brain regions, the hippocampus plays a key role in this pathology. Due to the pathophysiological complexity of DM, current treatments are ineffective in 30% of patients and are often associated with significant side effects. Therefore, the design of more effective therapeutic strategies is necessary. Hence, in this thesis we wanted to elucidate the effects of stress in mice, determine pathological mechanisms in the hippocampus and modulate them using different strategies. Firstly, the results obtained have shown that the effects of stress on behavior is progressive, since prolonged periods of stress are needed to see a robust behavioral effect. We then determined which specific neuronal subtypes play a fundamental role in the stress response. The results obtained have identified that CA1 of the hippocampus is highly sensitive to the duration of stress and that Egr1 in superficial pyramidal neurons plays a crucial role in the sequelae induced by chronic stress. In addition, proteomic studies performed in the hippocampus have highlighted that Sirt1 is a complex and interesting molecule involved in depression caused by chronic stress, the levels of which are increased with stress. In addition, in this thesis we tried to modulate the microbiota-intestine-brain axis through combined photobiomodulation. The results obtained have shown that simultaneous photobiomodulation of the abdomen and head is beneficial in chronically stressed mice as it produces improvements at the behavioral level, in dendritic spines, in microbiota dysbiosis and in Sirt1 levels, among others. Finally, we determined the role of GSK3β in depression caused by chronic stress. The results obtained demonstrate that the inhibition of GSK3β through the administration of meridianins, a marine natural product with bioactive properties, is beneficial as it induces behavioral improvements. In conclusion, the hippocampal pathogenic mechanisms demonstrated in this thesis provide a new understanding of the pathophysiology of stress-induced major depression. In addition, we propose several cutting-edge strategies to try to reverse stress- induced alterations at different levels: behavioral, cellular, and molecular. |
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