Stress exposure is known not only to be a risk factor for the development of psychiatric disorders itself, but also to exacerbate other medical conditions, prompting structural and functional changes that can eventually evolve from a normal adaptive body reaction to a pathological state (Gradus, 2017). On this basis, the aim of my PhD project was to investigate at preclinical level how and by which molecular mechanisms stress exposure can leave a signature in the individual, thus increasing the susceptibility of the central nervous system (CNS) to stress-related disorders or aggravating the outcome of illnesses occurring later in life. To achieve this goal, I took advantage of a “double hit” approach that implies that a ‘first hit’, mostly during critical periods of development, disrupts the ontogeny of neural systems and establishes a vulnerability to a ‘second hit’ later in life. Among the multiple mechanisms involved in stress- susceptibility, I have focused my analyses on neuroplasticity, neuroinflammation and oxidative damage. Moreover, considering that one of the most crucial variables of stress response extent is when the individual experiences it, I have investigated the long-lasting impact of stress occurring in different time windows. Specifically, I firstly focused on the gestational period, a so-called “window of vulnerability” (Briscoe et al., 2016) since the exposure to adverse events during pregnancy has been shown to impact not only on maternal health but also to have a deep long-lasting influence on the offspring neurodevelopment, leading to enhanced susceptibility to diseases and dysfunctions during adulthood (Zucchi et al., 2013; Coe and Lubach, 2005; Entringer et al., 2015). Therefore, in the first part of my project I examined the long-term effects of stress occurring during the intrauterine life on the clinical manifestations of a well-established animal model of multiple sclerosis, the Experimental Autoimmune Encephalomyelitis (EAE), a chronic and inflammatory condition characterized by loss of myelin (Robinson et al., 2014). My results 1 demonstrated that gestational stress induced a marked increase in the severity of EAE symptoms in the adult mouse. Further, I highlighted an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE animals. These behavioral and molecular alterations were paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination (Murray and Holmes, 2011). Furthermore, since patients affected by stress-related disorders present deficit in the neuroplastic mechanisms that are normally set in motion in response to external challenging stimuli (Wang et al., 2017), I investigated the influence of stress in utero on the response to a second challenge in adulthood, exposing prenatally stressed mice to a further acute stress. The molecular analyses in the hippocampus revealed that fetal stress resulted not only in increased activation of the immune system itself, but also in an impairment of the proper responsiveness of the redox machinery to the second stress. I then focused on adolescence, a sensitive period for brain development and thus also for environmental stimuli including stress. Social stress, such as bullying or subordination, is among the most prevalent stressors throughout adolescence and is strongly related to an enhanced susceptibility to diseases and dysfunctions later in adulthood (Lupien et al., 2009). Moreover, adolescents are more prone to brain concussion, and indeed 15/19-year age juvenile are experiencing the highest rates of incidence of traumatic brain injury (TBI) (Kimbler et al., 2011). As such, I spent 6 months as a visiting PhD student at the laboratory of Brain Injury, Neuroinflammation and Cognitive Function headed by Professor Susanna Rosi at the University of California, San Francisco, to investigate if and how exposure to social stress during adolescence can alter the TBI outcome. Specifically, in this part of the PhD project, adolescent mice were exposed to the social defeat stress 2 protocol before being injured with a new model of TBI, the repetitive closed-head impact model of engineered rotational acceleration (CHIMERA). The results highlighted that stressed mice developed anxiety-like features, regardless the concussions, while stress and brain injury have a reciprocal influence in the NOR test, where only mice that were both stressed and exposed to TBI did not display impairment in the ability to recognize the novel object. Paralleled to these behavioral effects, we didn’t find differences in hippocampal microglia activation. Lastly, I have investigated stress exposure during adulthood, focusing on the potential long-lasting impact of a chronic stress paradigm -known to induce psychiatric-like phenotype in preclinical model- in altering the responsiveness to a second acute challenge after a recovery period of 3 weeks. The molecular analyses, focused on modulators of the oxidative balance, demonstrated that the second hit was able to strongly induce the gene expression of Sulfiredoxin 1 (Srxn1) and Metallothionein-1a (Mt-1a), two antioxidant genes. This beneficial effect set in motion to cope with the sudden challenging situation was impaired by the previous exposure to chronic stress. Interestingly, chronic treatment with the antipsychotic lurasidone partially restored the appropriate acute responsiveness. The results obtained during my PhD project by using the double hit approach in different periods of life, indicate neuroinflammation, altered oxidative balance and impaired neuroplasticity as common molecular targets underlying the impact of a previous stress in shaping the vulnerability to further adverse conditions, providing new information on the etiopathogenesis of stress-related diseases.
|Titolo:||STRESS EXPOSURE ACROSS LIFESPAN SHAPES THE CNS SUSCEPTIBILITY TO FURTHER ADVERSE EVENTS: PRECLINICAL EVIDENCE USING A DOUBLE HIT APPROACH|
|Supervisori e coordinatori interni:||CATAPANO, ALBERICO LUIGI|
|Data di pubblicazione:||11-dic-2019|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||STRESS EXPOSURE ACROSS LIFESPAN SHAPES THE CNS SUSCEPTIBILITY TO FURTHER ADVERSE EVENTS: PRECLINICAL EVIDENCE USING A DOUBLE HIT APPROACH / M.s. Paladini ; tutor: M.A. Riva ; co-tutor: R. Molteni ; coordinatore: A.L. Catapano. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2019 Dec 11. ((32. ciclo, Anno Accademico 2019.|
|Digital Object Identifier (DOI):||10.13130/paladini-maria-serena_phd2019-12-11|
|Appare nelle tipologie:||Tesi di dottorato|