Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

Galina T Shishkina,Ekaterina V Babluk,Veta V Bulygina,Tatyana S Kalinina,Nikolay N Dygalo,Dmitry A Lanshakov,Michael Bader

doi:10.1371/journal.pone.0143978

Galina T Shishkina, Ekaterina V Babluk + Show 5 more

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https://doi.org/10.1371/journal.pone.0143978

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Abstract

Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

Highlights

The world around us is not constant, and the organism has to adapt to changing conditions [1]
The study by McEuen et al [10] showed that mice displaying signs of cell death in the raphe after chronic stress failed to exhibit the increases in TPH2 and anti-apoptotic factors during the stress experience found in mice resilient to stress
Compared with the control unstressed animals, when measured at 24 h after the last swim stress exposure, the midbrain bcl-xl mRNA level did not change after the first swim session, was significantly increased after the second swim and significantly decreased after chronic swim stress for 14 days [effect of stress: F(3,29) = 5.676, p < 0.01] (Fig 2A)

Summary

Introduction

The world around us is not constant, and the organism has to adapt to changing conditions [1]. Numerous data indicate that gene and protein expression of TPH, the rate limiting enzyme for 5-HT synthesis, may be affected in the raphe nuclei, where cell bodies of 5-HT neurons are located, by stressful stimuli as well as by glucocorticoids, the levels of which are elevated under stress. The differences in TPH responses to these stimuli, in addition to dependence on the raphe region investigated, duration of stress exposure, genetic background and other experimental peculiarities [22, 23], may be related to variations in expression of cell survival proteins. Most investigations of the modulation of brain anti-apoptotic protein expression by these factors have been done in the hippocampus and cortical areas [24,25,26,27,28,29,30,31]

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