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Identifier 000427455
Title Inflammatory stress and adult neurogenesis
Alternative Title Φλεγμονώδες στρες και ενήλικη νευρογένεση
Author Γαμπιεράκης, Ιωάννης Αλέξανδρος
Thesis advisor Χαραλαμπόπουλος, Ιωάννης
Reviewer Καραλή, Αικατερίνη
Καραγωγέως, Δόμνα
Abstract Inflammatory bowel disease (IBD), which comprises Crohn’s disease (CD) and Ulcerative Colitis (UC), is a chronic gastrointestinal inflammatory condition with characteristic relapsing remitting phases. As the incidence of IBD is growing worldwide, new aspects of the pathophysiology of the disease and associated comorbidities are being recognized. Notably, increased incidence of psychiatric disorders and cognitive impairment has been observed in IBD patients that, together with the chronic inflammation, contribute to compromised quality of life. Emerging evidence suggests an intriguing interaction between the gut, brain and the immune systems, while any dysregulation in this communication is considered to affect the balance between central nervous system (CNS) homeostasis and neuropathology. Nevertheless, the impact of peripheral inflammatory processes, such as, those occurring in the context of IBD, on cognitive function and behavior and the specific immunological mechanisms involved remain incompletely understood. Hippocampus is a key brain region implicated in cognitive processes, mood regulation and the pathophysiology of mood disorders. In addition, hippocampus is one of the brain regions with demonstrated active neurogenesis throughout life. The Neural Stem Cells (NSCs) niche in the Dentate Gyrus (DG) of the hippocampus is strongly associated with the modulation of cognitive processes, such as, pattern separation and cognitive flexibility, mediating the behavioral effects of stress and of depression therapy. As a result, dysregulation of hippocampal neurogenesis leads to memory and learning deficits and has been associated with the onset of depression and anxiety disorders. A rapidly growing number of experimental and clinical findings suggest that systemic peripheral inflammation can modify synaptic plasticity and neuronal activity with associated, long-term behavioural changes. In fact, chronic neuroinflammation or peripheral inflammatory processes can disrupt the differentiation, maturation, migration and functional integration of new neurons in the hippocampal circuitry. Notably, traumatic brain injury or prolonged infusion of lipopolysaccharide (LPS), resulted in compromised integration of newborn neurons and decreased expression of the immediate early gene Arc, a marker of neuronal activity. Altered expression of Arc in mature and newborn neurons of the DG was highly correlated with the activation of microglia, while it also led to disruption of the regulated process of DG sparse coding as well as changes in memory function and mood. Interestingly, studies assessing hippocampus-dependent cognitive functions of IBD patients provided evidence of deficits in cognitive flexibility tasks, as evidenced by poor performance in the Subtle Cognitive Impairment test (SCIT). Moreover, structural changes in the hippocampal and para-hippocampal regions have been also revealed by functional magnetic resonance imaging (fMRI) studies in IBD patients, indicative of the association of this disease with hippocampal dysfunctions. Soluble factors produced in the periphery, even of high molecular weight, such as, inflammatory cytokines, can reach the brain, affect microglial responses and modulate cognition. Pertinent to intestinal inflammation, enhanced excitability and diminished long term-potentiation (LTP) and depression (LTD) were found in the hippocampus of mice with colitis, together with signs of activated microglia and increased release of pro-inflammatory cytokines. Microglia and astrocytes play a pivotal role in the regulation of different steps in the neurogenesis process and, depending on their state of activation, can exert protective or inhibitory effects on the lineage of adult neural stem cells. Despite the increasing evidence on the effects of peripheral inflammatory processes in cognition and behavior, our understanding of the effects of acute and chronic intestinal inflammation on microglia and their potential link to hippocampal neurogenesis remains very limited. Seminal studies have documented that innate immune memory underlies long term microglia responses and the associated neuropathology. For example, systemic administration of repeated doses of lipopolysaccharide (LPS) induced an initial training of microglia, which was followed by the establishment of immune tolerance that lasted up to six months. Further, in response to a secondary inflammatory stimulus, such as Alzheimer’s- or stroke-induced pathology, distinct effects of trained versus tolerant microglia have been shown, with exacerbation or alleviation of the manifestations of the disease by the former and the latter, respectively. In the present study, we characterized the effects of experimental acute and chronic colitis, induced by administration of dextran sodium sulfate (DSS) in mice, on microglia activation and hippocampal neurogenesis. Our results showed that during acute DSS-induced colitis hippocampal microglia is activated, as evidenced by increased percentages of pro-inflammatory M1-like microglia and infiltration of inflammatory myeloid cells, along with elevated levels of pro-inflammatory cytokines, in the hippocampus. Microglia was induced in the neurogenic niche of the hippocampus along with increased astrogliosis. These findings were accompanied by enhanced neurogenesis, however with cell cycle deficits of proliferating neural progenitor cells. In contrast, microglia acquired an anti-inflammatory phenotype during chronic DSS colitis, as reflected by increased percentages of M2-like microglia, along with heightened levels of the anti-inflammatory cytokine IL-10, concomitant with decreased infiltration of myeloid cells and a marked reduction in pro-inflammatory cytokines. These findings were accompanied by deficits in the migration and integration of newborn neurons in the functional circuitry of the DG. Overall, our findings reveal that distinct immune pathways are induced during acute and chronic experimental colitis in the hippocampus, accompanied with changes in the neurogenic niche functions. These findings highlight potential underlying mechanisms that could exploited for the design of novel treatment modalities for better management of the off-site brain symptomatology found in IBD.
Language English
Subject Chemically induced colitis
Κολίτιδα χημικά επαγώμενη
Issue date 2020-03-24
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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