Publicação
The role of IFNγ in higher brain function: in health and under chronic stress
| Resumo: | The neuroimmunology field is at an exciting stage due to a set of revolutionary discoveries challenging the now old-fashioned dogma of the brain being “protected” from the peripheral immune system action. Immune components such as T lymphocytes and the cytokines they produce, once regarded as detrimental to the brain, are now considered integrant parts of the healthy nervous system since their regulated actions control immune surveillance but also modulate higher brain functions. The cytokine interferon-gamma (IFNγ), produced mainly by T lymphocytes, is a potent pro-inflammatory molecule, whose levels are altered in many neuropsychiatric and neurodegenerative diseases. Though studies assessing the effects of this cytokine, when administered into the brain, have shown that it affects different cellular and synaptic mechanisms underlying behavioural dimensions, it is still unclear whether this is a collateral damage of the inflammatory response or if IFNγ indeed plays a role in the modulation of non-pathological brain function. As so, we sought to explore the role of this cytokine in the modulation of brain function in physiological conditions and also after exposure to chronic stress – a paradigm known to trigger the development of psychiatric complications and also accelerate neurodegenerative processes. In the first part of the thesis (2nd Chapter) we demonstrate that, in a healthy brain, the absence of IFNγ enhances dorsal hippocampus plasticity and associated cognitive function. At the structural level, an enlargement of the dorsal hippocampus volume contrasted with the absence of alterations observed in the ventral part, highlighting that the effects of this cytokine are more selective for cognitive behaviours. Moreover, the absence of this cytokine amplifies neuroplastic phenomena in the dorsal hippocampus, namely neurogenesis, size of neuronal dendritic arborisations and presynaptic functioning, most likely contributing for the enhanced cognitive performance. On the 3rd chapter, we demonstrate that there are gender-differences on the behavioural phenotype of IFNγ KO mice, and discuss the possible association of estrogen and the IFNγ expression in the central nervous system. In the following chapter (4th Chapter) we describe the optimisation of a chronic unpredictable stress (CUS) paradigm for use in C57BL/6 mice, a strain with higher resistance to stress. This mice model of stress-related disorders exhibits, beyond the stress-related neuroendocrine and behavioural alterations, mild changes in thymic cellular populations and relevant splenic myeloid cellular alterations, with an increased number of neutrophils as the most striking change. At last (5th Chapter), we discuss the contributory role of IFNγ for the development of the immune maladaptive response to chronic stress. By submitting mice to the optimized CUS protocol, it was observed that mRNA levels of Ifnγ are elevated in the brain, specifically in the medial prefrontal and orbitofrontal cortices. Moreover, exposure to chronic stress leads to an increase of the adrenergic innervation of the spleen as to alterations on the percentage of neutrophils and monocytes/macrophages populations in the spleen. Importantly, the absence of this cytokine blunts the stress-related changes on these cell populations in the spleen. The recognition of the proinflammatory cytokine – IFNγ, as a negative regulator of hippocampal plasticity and associated cognitive function, together with its contributory role for the stress-related immune dysfunction, suggests that this cytokine may articulate the complex network that underlies the inflammatory component of neuropsychiatric disorders. |
|---|---|
| Autores principais: | Monteiro, Susana Isabel Gonçalves |
| Assunto: | IFNγ cognition neuroimmunology chronic stress neutrophils cognição neuroimunologia stress crónico neutrófilos |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | português |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | The neuroimmunology field is at an exciting stage due to a set of revolutionary discoveries challenging the now old-fashioned dogma of the brain being “protected” from the peripheral immune system action. Immune components such as T lymphocytes and the cytokines they produce, once regarded as detrimental to the brain, are now considered integrant parts of the healthy nervous system since their regulated actions control immune surveillance but also modulate higher brain functions. The cytokine interferon-gamma (IFNγ), produced mainly by T lymphocytes, is a potent pro-inflammatory molecule, whose levels are altered in many neuropsychiatric and neurodegenerative diseases. Though studies assessing the effects of this cytokine, when administered into the brain, have shown that it affects different cellular and synaptic mechanisms underlying behavioural dimensions, it is still unclear whether this is a collateral damage of the inflammatory response or if IFNγ indeed plays a role in the modulation of non-pathological brain function. As so, we sought to explore the role of this cytokine in the modulation of brain function in physiological conditions and also after exposure to chronic stress – a paradigm known to trigger the development of psychiatric complications and also accelerate neurodegenerative processes. In the first part of the thesis (2nd Chapter) we demonstrate that, in a healthy brain, the absence of IFNγ enhances dorsal hippocampus plasticity and associated cognitive function. At the structural level, an enlargement of the dorsal hippocampus volume contrasted with the absence of alterations observed in the ventral part, highlighting that the effects of this cytokine are more selective for cognitive behaviours. Moreover, the absence of this cytokine amplifies neuroplastic phenomena in the dorsal hippocampus, namely neurogenesis, size of neuronal dendritic arborisations and presynaptic functioning, most likely contributing for the enhanced cognitive performance. On the 3rd chapter, we demonstrate that there are gender-differences on the behavioural phenotype of IFNγ KO mice, and discuss the possible association of estrogen and the IFNγ expression in the central nervous system. In the following chapter (4th Chapter) we describe the optimisation of a chronic unpredictable stress (CUS) paradigm for use in C57BL/6 mice, a strain with higher resistance to stress. This mice model of stress-related disorders exhibits, beyond the stress-related neuroendocrine and behavioural alterations, mild changes in thymic cellular populations and relevant splenic myeloid cellular alterations, with an increased number of neutrophils as the most striking change. At last (5th Chapter), we discuss the contributory role of IFNγ for the development of the immune maladaptive response to chronic stress. By submitting mice to the optimized CUS protocol, it was observed that mRNA levels of Ifnγ are elevated in the brain, specifically in the medial prefrontal and orbitofrontal cortices. Moreover, exposure to chronic stress leads to an increase of the adrenergic innervation of the spleen as to alterations on the percentage of neutrophils and monocytes/macrophages populations in the spleen. Importantly, the absence of this cytokine blunts the stress-related changes on these cell populations in the spleen. The recognition of the proinflammatory cytokine – IFNγ, as a negative regulator of hippocampal plasticity and associated cognitive function, together with its contributory role for the stress-related immune dysfunction, suggests that this cytokine may articulate the complex network that underlies the inflammatory component of neuropsychiatric disorders. |
|---|