High Exploratory Phenotype Rats Exposed to Environmental Stressors Present Memory Deficits Accompanied by Immune-Inflammatory/Oxidative Alterations: Relevance to the Relationship Between Temperament and Mood Disorders.

Camila Nayane De Carvalho Lima,Marta Maria De França Fonteles,Danielle S Macedo,Adriano José Maia Chaves Filho,David F De Lucena,João Quevedo,Gabriel Rodrigo Fries,Silvania Maria Mendes Vasconcelos,Francisco Eliclécio Rodrigues Da Silva,Ana Isabelle De Gois Queiroz,Francisca Cléa F De Sousa,Adriana Mary Nunes Costa Okamura

doi:10.3389/fpsyt.2019.00547

Abstract

Low-exploratory (LE) and high-exploratory (HE) rodents mimic human depressive and hyperthymic temperaments, respectively. Mood disorders (MD) may be developed by the exposure of these temperaments to environmental stress (ES). Psychiatric symptoms severity in MD patients is related to the magnitude of memory impairment. Thus, we aimed at studying the consequences of the exposure of LE and HE male Wistar rats, during periadolescence, to a combination of ES, namely, paradoxical sleep deprivation (PSD) and unpredictable stress (US), on anxiety-related behavior in the plus maze test, working (WM) and declarative memory (DM) performance. We also evaluated hippocampal immune-inflammatory/oxidative, as consequences of ES, and prevention of ES-induced alterations by the mood-stabilizing drugs, lithium and valproate. Medium exploratory (ME) control rats were used for comparisons with HE- and LE-control rats. We observed that HE-controls presented increased anxiolytic behavior that was significantly increased by ES exposure, whereas LE-controls presented increased anxiety-like behavior relative to ME-controls. Lithium and valproate prevented anxiolytic alterations in HE+ES rats. HE+ES- and LE+ES-rats presented WM and DM deficits. Valproate and lithium prevented WM deficits in LE-PSD+US rats. Lithium prevented DM impairment in HE+ES-rats. Hippocampal levels of reduced glutathione (GSH) increased four-fold in HE+ES-rats, being prevented by valproate and lithium. All groups of LE+ES-rats presented increased levels of GSH in relation to controls. Increments in lipid peroxidation in LE+ES- and HE+ES-rats were prevented by valproate in HE+ES-rats and by both drugs in LE+ES-rats. Nitrite levels were increased in HE+ES- and LE+ES-rats (five-fold increase), which was prevented by both drugs in LE+ES-rats. HE+ES-rats presented a two-fold increase in the inducible nitric oxide synthase (iNOS) expression that was prevented by lithium. HE+ES-rats showed increased hippocampal and plasma levels of interleukin (IL)-1β and IL-4. Indoleamine 2, 3-dioxygenase 1 (IDO1) was increased in HE+ES- and LE+ES-rats, while tryptophan 2,3-dioxygenase (TDO2) was increased only in HE+ES-rats. Altogether, our results showed that LE- and HE-rats exposed to ES present distinct anxiety-related behavior and similar memory deficits. Furthermore, HE+ES-rats presented more brain and plasma inflammatory alterations that were partially prevented by the mood-stabilizing drugs. These alterations in HE+ES-rats may possibly be related to the development of mood symptoms.

Highlights

The relationship between personality and mood disorders has been studied for decades
In the analysis of the interaction between “exploratory activity” and “stress exposure,” we observed that high exploratory (HE)-control rats presented a significant increase in the % of time in open arms in relation to low exploratory (LE)-control rats (P = 0.0038) and that the exposure of HE-rats to paradoxical sleep deprivation (PSD)+unpredictable stressors (US) caused a significant 1.4-fold increase in the % of time spent in the open arms relative to HE-control rats {HE-PSD+US vs. HE-control, P < 0.0001; two-way ANOVA interaction: [F(1, 31) = 12.59, P = 0.0016]}
We evaluated the expression of inducible nitric oxide synthase (iNOS), because it is increased in an inflammatory environment, and based on the fivefold increase in nitrite levels detected in the hippocampus of LE-PSD+US rats

Summary

Introduction

The relationship between personality and mood disorders has been studied for decades. The personality model proposed by Cloninger [2] and its derived instruments have been widely applied to mood disorders [3, 4]. According to Cloninger’s model, temperament is the emotional core of personality and represents the basic pattern of response to emotional stimuli that is heritable and moderately stable through life. NS and HA are dimensions evolutively conserved in humans and mammals and greatly influence exploratory behavior. This behavior consists of a complex act that allows the collection of information about the environment and increases the chances to find food, mating partner, shelter, and, lately, of survival [6, 7]

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Conclusion