Stress-induced anxiety and differential activation of related limbic areas in mice

Author(s)

Fernanda Daher Pitta

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (PCARP/BC)
• Defense date: 2017-10-19

Examining board members

Rosana Mattioli; Silvio Morato de Carvalho; Carlos Cesar Crestani; Raquel Vecchio Fornari; Ricardo Luiz Nunes de Souza

• Advisor: Rosana Mattioli; Claudia Maria Padovan

Abstract

Chronic exposure to socio-environmental stressors leads to a myriad of long-term alterations in affective, cognitive and physiological levels, which typifies prevalent neuropsychiatric disorders. Importantly, chronic variable stress (CVS) is an experimental model for anxiety- and depressive-like disorders based on the random, intermittent, and uncertain exposure to various stressors. Some individuals also show a remarkable ability to adapt and actively cope and persist in the face of such unpredictable and uncontrollable events. Histamine is a sensitive indicator of stressful experiences and modulates the activation of neuroendocrine stress response to influence defensive reactions. However, little is known about the role of histamine on CVS model. While the behavioral profile of CUS-stressed mice is also contradictory, we investigated whether (1) two widely used mouse strains were susceptible to stress-related responses; (2) histaminergic neurotransmission is involved on stress-induced anxiety; (3) L-histidine (LH) chronic treatment combined to CVS changes Fos expression in limbic areas. To test the impact of the CVS protocol on depressive-like responses, the performance of non-stressed (NST) and stressed (ST) Swiss animals was analyzed in the two-way avoidance task and in the tail suspension test. No increased passive immobility was detected, but the ST group did display hyperreactivity in the avoidance task. Next, the effects of CVS on anxiety were examined in the elevated plus maze (EPM). Remarkably, stressed C57Bl/6 developed anxiogenic responses, while Swiss mice displayed a heterogeneous behavioral profile in the EPM. These results indicate that 2-week-long CVS regimen consistently induces anxiogenic-like response in adult C57Bl/6 mice, while Swiss animals seem to be resilient. Additionally, CVS-induced anxiety is not reversed or potentialized by the chronic administration of LH, but the histamine precursor appears to be a potential stressor per se. Importantly, a hypoactivation of the prelimbic and infralimbic cortical areas was related to the chronic stress condition, with no main effects of the pharmacological treatment. EPM induced Fos+ expression was detected in the lateral, basolateral and central subnuclei, without differential activation of these amygdaloid subnuclei provoked by CVS and/or histaminergic stimulation. The present evidences corroborate the concept that stress responses can be genetic- and experience-dependent, resulting in resilience or maladaptation of a particular strain. Also, stress-induced anxiety could be related to a hypoactivation of the medial prefrontal cortex, important brain region in regulating the defensive behaviors and HPA stress response. (AU)

• FAPESP's process: 13/10761-9 - Involvement of neural histamine in learned helplessness, aversive memory and postnatal neurogenesis of mice
• Grantee: Fernanda Daher Pitta
• Support Opportunities: Scholarships in Brazil - Doctorate