STRESS EXPOSURE ACROSS LIFESPAN SHAPES THE CNS SUSCEPTIBILITY TO FURTHER ADVERSE EVENTS: PRECLINICAL EVIDENCE USING A DOUBLE HIT APPROACH
Tesi di Dottorato
Data di Pubblicazione:
2019
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. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2019 Dec 11. 32. ciclo, Anno Accademico 2019. [10.13130/paladini-maria-serena_phd2019-12-11].
Abstract:
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
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
M.S. Paladini
Link alla scheda completa: