Immune mechanisms in stress response: from vulnerability to pharmacological intervention

Abstract

It is known that exposure to stress can produce different psychopathologic domains through the modulation of specific brain mechanisms. In our studies, we have used two different stress paradigms, namely prenatal stress (PNS) and Chronic Mild Stress (CMS), to investigate the contribution of immune mechanisms to the short and long-term changes associated with such adverse experiences. We also investigated the potential effects of chronic treatment with the antipsychotic drug lurasidone in normalizing such alterations in the CMS model. In both experimental paradigms, we found that only a sub-group of animals develops a pathologic phenotype, with emotional dysregulation including anhedonia, anxiety, and reduced sociability. Such vulnerability was associated with an increased inflammatory response as well as with an up-regulation of different microglial markers (Complement C3/C4, Cd11b, CD68) in the hippocampal subregions. Interestingly, treatment with the antipsychotic drug lurasidone was able to normalize the up-regulation of microglial markers while buffering the expression of proinflammatory cytokines in the CMS paradigm, an effect that may ultimately promote resilience. Our preclinical studies show that exposure to stress has harmful effects on emotional behavior at different life stages. The vulnerability to stress may be driven, among other mechanisms, by significant alterations of immune-inflammatory mechanisms within selected brain regions, such as the dorsal and ventral hippocampus. The ability of chronic treatment with the antipsychotic drug lurasidone to counteract such changes, in addition to the ability in regulating different synaptic mechanisms, may represent an important element for its clinical effectiveness in the treatment of different psychiatric disorders.