Publicação
An imaging characterization of the adaptive and maladaptive response to chronic stress
| Resumo: | Stress is a constant presence in the daily life of all beings and one’s ability to adapt to challenging circumstances has a real impact in the chance of survival. The response to stressful stimuli is regulated primarily by the hypothalamic-pituitary-adrenal (HPA) axis, but several other areas of the brain as well as hormonal circuits are known to be involved. The chronic activation of these circuits leads to an overburden of the system, eventually causing a disruption of the homeostasis. Different subjects respond differently to similar stressors, with some presenting a more adaptive or resistant response to stress, delaying or avoiding the negative impacts, while others present a maladaptive or susceptible pattern of response to stress. This stress-led disruption of the homeostasis is often associated with different neuropsychiatric disorders, including depression or dementia, major causes of disability worldwide. Understanding the circuits involved in determining this differentiated response to stress is key to not only understand it but also to develop new diagnostic and treatment approaches for the associated disorders. This thesis describes the use of multimodal ultra high-field Magnetic Resonance Imaging to characterize the differences in the brain structure and function of different responders in a rodent model of stress, revealing biomarkers of this response as well as their temporal profiles. To do this, several processing pipelines and supporting resources were developed, here presented as the SIGMA processing workflows, atlases and templates. Moreover, to study the response to stress two different approaches are used, first characterizing the differences between two genetic lines known to respond differently to stress and second by classifying a population with a uniform genetic background according to their response. Our results reveal several structural, functional and metabolic differences in the brains of resistant and susceptible animals. In the white matter of resistant animals accentuated alterations in diffusion properties were found, suggesting the triggering of plasticity processes. In the gray matter an accentuated atrophy of several brain areas was found which included the dorsal hippocampus and the ventral tegmental area. Temporally these changes were restricted to the later periods of exposure, with minimal changes occurring during the early period of exposure to stress. Functionally, widespread networks of altered functional connectivity were found centered on the thalamus and connecting sensorial, cognitive and autonomic regions. The temporal profile of these changes revealed different patterns in the earlier and later periods of exposure where the initial time-points were found to be marked by profound functional changes that may be key in determining the eventual response to stress. Finally, we reveal how concentrations of several metabolites are altered in the dorsal hippocampus, predominantly as markers of neurotransmitter metabolism. These changes are associated with alterations in the functional circuitry of the hippocampus, increasing the functional connectivity with the amygdala, piriform cortex and thalamus in susceptible responders to stress. Some conclusions can be gathered from the results here presented. We have identified several MRI biomarkers of the response to stress, findings that highlight the potential for the use of this technique as support tool in the diagnosis of stress-associated disorders. Temporally, the initial functional changes predate other alterations and may be a key part of the pathophysiological process associated to stress-disorders. Functionally our results point to an important role of circuits involving the limbic system, as well as somatosensory areas, in determining the response to stress. |
|---|---|
| Autores principais: | Magalhães, Ricardo José da Silva |
| Assunto: | Ciências Médicas::Ciências da Saúde |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Stress is a constant presence in the daily life of all beings and one’s ability to adapt to challenging circumstances has a real impact in the chance of survival. The response to stressful stimuli is regulated primarily by the hypothalamic-pituitary-adrenal (HPA) axis, but several other areas of the brain as well as hormonal circuits are known to be involved. The chronic activation of these circuits leads to an overburden of the system, eventually causing a disruption of the homeostasis. Different subjects respond differently to similar stressors, with some presenting a more adaptive or resistant response to stress, delaying or avoiding the negative impacts, while others present a maladaptive or susceptible pattern of response to stress. This stress-led disruption of the homeostasis is often associated with different neuropsychiatric disorders, including depression or dementia, major causes of disability worldwide. Understanding the circuits involved in determining this differentiated response to stress is key to not only understand it but also to develop new diagnostic and treatment approaches for the associated disorders. This thesis describes the use of multimodal ultra high-field Magnetic Resonance Imaging to characterize the differences in the brain structure and function of different responders in a rodent model of stress, revealing biomarkers of this response as well as their temporal profiles. To do this, several processing pipelines and supporting resources were developed, here presented as the SIGMA processing workflows, atlases and templates. Moreover, to study the response to stress two different approaches are used, first characterizing the differences between two genetic lines known to respond differently to stress and second by classifying a population with a uniform genetic background according to their response. Our results reveal several structural, functional and metabolic differences in the brains of resistant and susceptible animals. In the white matter of resistant animals accentuated alterations in diffusion properties were found, suggesting the triggering of plasticity processes. In the gray matter an accentuated atrophy of several brain areas was found which included the dorsal hippocampus and the ventral tegmental area. Temporally these changes were restricted to the later periods of exposure, with minimal changes occurring during the early period of exposure to stress. Functionally, widespread networks of altered functional connectivity were found centered on the thalamus and connecting sensorial, cognitive and autonomic regions. The temporal profile of these changes revealed different patterns in the earlier and later periods of exposure where the initial time-points were found to be marked by profound functional changes that may be key in determining the eventual response to stress. Finally, we reveal how concentrations of several metabolites are altered in the dorsal hippocampus, predominantly as markers of neurotransmitter metabolism. These changes are associated with alterations in the functional circuitry of the hippocampus, increasing the functional connectivity with the amygdala, piriform cortex and thalamus in susceptible responders to stress. Some conclusions can be gathered from the results here presented. We have identified several MRI biomarkers of the response to stress, findings that highlight the potential for the use of this technique as support tool in the diagnosis of stress-associated disorders. Temporally, the initial functional changes predate other alterations and may be a key part of the pathophysiological process associated to stress-disorders. Functionally our results point to an important role of circuits involving the limbic system, as well as somatosensory areas, in determining the response to stress. |
|---|