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

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.

IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats

“…While FPI did not impact rat learning ability on the Barnes maze at 14-17 DPI, it did cause memory disruption. The lack of learning deficits after FPI is in keeping with previous reports (Fitzgerald et al, 2022;Krishna et al, 2017;Lima, Camila Nayane de Carvalho et al, 2019) and not unexpected. FPI-induced memory deficits were not as marked on the short-term probe trial as they were on the long-term probe.…”

“…This pattern of behavior is indicative of increased anxiety (Himanshu et al, 2020;Knight et al, 2021) and is consistent with reports of increased anxiety-like behaviors in rats after FPI demonstrated in a variety of tests (Bao et al, 2012;Fucich et al, 2019;Almeida-Suhett et al, 2014). Increased IDO1 activity has been linked with anxious behaviours in response to environmental stress (Lima, Camila Nayane de Carvalho et al, 2019), and IDO1 inhibition following an inflammatory challenge significantly reduced previously present anxious behaviours (Salazar et al, 2012). This may be related to the ability of QuinA to severely disrupt dopaminergic metabolism in the amygdala and mesolimbic system (Kurachi et al, 2000).…”

IDO‐1 inhibition improves outcome after fluid percussion injury in adult male rats

“…While FPI did not impact rat learning ability on the Barnes maze at 14-17 DPI, it did cause memory disruption. The lack of learning deficits after FPI is in keeping with previous reports (de Carvalho Lima et al, 2019;Fitzgerald et al, 2022;Krishna et al, 2017) and not unexpected. FPI-induced memory deficits were not as marked on the shortterm probe trial as they were on the long-term probe.…”

“…This pattern of behavior is indicative of increased anxiety (Himanshu et al., 2020; Knight et al., 2021) and is consistent with reports of increased anxiety‐like behaviors in rats after FPI demonstrated in a variety of tests (Almeida‐Suhett et al., 2014; Bao et al., 2012; Fucich et al., 2019). Increased IDO1 activity has been linked with anxious behaviors in response to environmental stress (de Carvalho Lima et al., 2019), and IDO1 inhibition following an inflammatory challenge significantly reduced previously present anxious behaviors (Salazar et al., 2012). This may be related to the ability of QuinA to severely disrupt dopaminergic metabolism in the amygdala and mesolimbic system (Kurachi et al., 2000).…”

Temperament, Plasticity, and Emotions in Defensive Behaviour of Paca (Mammalia, Hystricognatha)

“…We predicted that we would find stable variation in our temperament measures amongst pacas, as observed in other captive wild mammals (e.g., Pecari tajacu and Tayassu pecari [ 39 ]). We also predicted that individuals that were bolder and less disturbed in challenge tests would also be less affected by the MDTB, show a smaller physiological stress response, and make fewer “pessimistic” decisions in the JBT, because links between behavioural and physiological responses to challenge have been observed in other rodents [ 40 , 41 , 42 ]. We also expected to see plasticity of responding during the duration of the MDTB, because pacas exhibit behavioural flexibility [ 18 , 43 ].…”