Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: Early experiences affect the vulnerability to adolescent-onset depression and determine antidepressant efficacy

Adolescence is a critical developmental phase during which adverse experiences, such as a lack of appropriate social interactions, increase the vulnerability to major depression and raise the risk of antidepressant treatment-resistance in adulthood. In addition, adolescent adverse experiences have been shown to have a gender-dependent effect, with girls being more susceptible to mental illness than boys. However, the biological processes underlying both the onset of psychopathology, including the sex-dependent vulnerability, and the lack of response to antidepressant treatments have not been identified yet. To investigate such biological processes, we have performed three independent studies. Study 1. We aimed at identifying the neural bases of adolescent-onset depression and sex-dependent vulnerability. Special attention was paid to neural plasticity and immune function that recently have been critically involved in this psychopathology. To this aim, we exposed C57BL/6 male and female mice either to standard laboratory housing (i.e., controls) or to social isolation during adolescence and phenotyped their behavioral and hormonal responses. Our results show that isolation leads to depressive- and anxiety-like phenotype and reduced neural plasticity and inflammatory markers in both sexes, though affecting different behavioral domains: females showed more marked impairments in the emotional domain, while males displayed alterations in the cognitive domain and stress response. These findings suggest that social experiences in adolescence represent a key factor in the neurodevelopment of both sexes and that the sex-differences in vulnerability to depression could be, at least in part, ascribed to biological factors and not to cultural and social influences. The aim of Study 2 was to explore the role of the interplay between the environment and SSRIs in the recovery from adolescent-onset depression-like phenotype. According to recent findings, we hypothesized that a supportive environment is critical for recovery and antidepressant treatment can further enhance such beneficial action. To test this hypothesis, C57BL/6 male mice have been exposed to social isolation from weaning to adulthood to induce a depressive-like phenotype. We then compared the efficacy of the exposure to an enriched environment, the administration of selective serotonin reuptake inhibitor (SSRI) fluoxetine, and their combination to treat depression-like adult mice. The control group consisted of mice not exposed to social isolation during adolescence and socially housed. We assessed the effects of the different treatment strategies on the cognitive and emotional domains and stress hormone levels. Our results showed that environmental enrichment alone or in combination with fluoxetine, but not fluoxetine alone, counterbalanced the detrimental effects of isolation on the depression-like phenotype. Our findings outline the relevance of environmental interventions alone or in combination with SSRI to treat adolescence-onset depression and confirm that SSRIs do not univocally lead to recovery but amplify the influence of the environment on the emotional response. With Study 3, we explored the influence of the subjective experience of the environment as a determinant of SSRI treatment outcome. Since the quality of the living environment determines SSRI outcome and depends not only on its objective features but also on the subjective experience of it, we hypothesized that the latter plays a key role in determining antidepressant efficacy. To test this hypothesis, we generated two experimental groups of CD-1 male mice that reportedly show different subjective views of the environment, as they differently reacted at emotional and social levels to the same environmental stimuli. These distinct socioemotional profiles were generated by rearing mice either in standard laboratory conditions (SN) or in a communal nest (CN). Twenty-one days of fluoxetine produced different effects in the two groups, increasing offensive and anxious responses in SN while producing opposite effects in CN mice. BDNF regulation was modified accordingly. These results indicate that the subjective experience of the environment determines fluoxetine outcome. In a translational perspective, our findings point out the need to consider not only the objective quality but also the subjective experience of the patient’s living environment to develop effective personalized therapeutic approaches in psychiatry.