Observer's adrenal corticosterone secretion involvement in vicarious fear conditioning.

Vicarious learning represents a far-reaching value for the survival of social animals. Adrenal hormones are known to affect many forms of learning, yet the roles of adrenal hormones in vicarious learning remain unexplored. This study was undertaken to assess whether observation-stimulated corticosterone (CORT) secretion may affect the magnitude of a vicarious fear conditioning. Mouse observers were individually subjected to an observational compartment next to the training compartment wherein three their cage-mate demonstrators received (1) 5 days of 15 randomly-scheduled footshocks (0.5 mA, 2 s in duration over a 30 min session) (G1); (2) a 30-min presentation of vanilla odors (G2); or (3) footshock delivery and vanilla odors in combination (G3). Demonstrator mice receiving G3 training session and their respective observer mice were found to exhibit greater training-induced and slightly greater observation-stimulated CORT secretion, greater vanilla odors-induced fear responses (FR) and conditioned place aversion (CPA), as compared with the observers vicariously learning from demonstrators receiving G1 or G2 sessions. Observers held in their home cages during demonstrators' trainings and those receiving null demonstrator (No Demonstrator) failed to exhibit vanilla odors-induced FR. Moreover, observers undergoing adrenalectomy (ADX) and G3 sessions exhibited lower vanilla odors-induced FR and CPA as compared to sham surgical (Sham) observers observing G3 sessions. Furthermore, systemic metyrapone injections (50 and 100 mg/kg) prior to daily vicarious G3 training session resulted in decreases in vanilla odors-induced FR and CPA magnitudes in observers. Finally, CORT (1 mg/kg)-pretreated G2 observers failed to display odors-induced FR escalation. These results, taken together, suggest that observation-stimulated CORT secretion is necessary for reliable establishment of vicarious fear conditioning in observer mice.

Neonatal isolation decreases cued fear conditioning and frontal cortical histone 3 lysine 9 methylation in adult female rats.

Early life stress is thought to enhance adult susceptibility to stress and stress-related mood disorders. In this study, fear-potentiated startle was used to model the acquisition of a traumatic event-related memory in female rats experiencing early life stress. Daily 1-hr maternal and sibling separation throughout day 2-9 postpartum (D2-9 PP) caused a decrease in the fear-potentiated startle, but not acoustic startle baseline, in adult female rats. The separation procedure did not affect corticosterone secretion but produced an increase in serum estradiol concentration. Moreover, the separation procedure did not affect histone 3 lysine 9 (H3K9) acetylation but decreased H3K9 mono- and tri-methylation in frontal cortices. Treatment with 5-aza-2'-deoxycytidine (AZA) (5mg/kg at alternative days from D2PP to D9PP or 10mg/kg at D5PP and D9PP), a DNA methylation inhibitor, did not affect the separation-decreased fear-potentiated startle. Treatment with valproic acid (VPA), a histone deacetylase inhibitor, at 3 dosing regimens (300mg/kg at D2-9PP; 100mg/kg at D2-4PP, 200mg/kg at D5-7PP, 300mg/kg at D8-9PP; 100mg/kg at D2-5PP, 200mg/kg at D6-9PP) prior to daily separation reversed such a decrease in fear-potentiated startle. The lowest effective VPA dosing regimen used (100mg/kg at D2-5PP, 200mg/kg at D6-9PP) reversed the separation-decreased H3K9 mono- and tri-methylation in frontal cortices. Eight-day VPA (300mg/kg/day) and AZA (5mg/kg/day) administrations starting at D28PP were ineffective in altering the separation-decreased fear-potentiated startle. We, hereby, suggest that decreased frontal cortical H3K9 mono- and tri-methylation may be involved in early life separation-decreased fear memory of adult rats.

Local proteins associated with methamphetamine-induced nigrostriatal dopaminergic neurotoxicity.

The present study aimed to examine the proteins involved in the methamphetamine (MA)-induced nigrostriatal dopaminergic toxicity. Infusion of anisomycin into striatum and substantia nigra both abolished the MA-induced striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) depletions, indicating a critical role of local protein synthesis in determining such dopaminergic toxicity. Moreover, local protein synthesis blockade reversed this neurotoxicity via a temperature-independent mechanism. We then employed a proteomic approach, two-dimensional gel electrophoresis (2-DE) in conjunction with mass spectrometry analysis, to identify the protein candidates associated with the MA-induced neurotoxicity. In striatal samples, 2-DE analysis revealed that the intensities of nine protein spots were altered by MA treatment. Mass spectrometry analysis allowed us to identify five proteins, including an up-regulated protein, alpha-synuclein, and four down-regulated proteins, ATPase, F-actin capping protein beta subunit, ubiquitin carboxy-terminal hydrolase/PGP 9.5, and peroxidase. MA-altered expression levels of alpha-synuclein and ubiquitin carboxy-terminal hydrolase/PGP 9.5 in striata were confirmed by western blotting analysis. Taken together, these results suggest that local up-regulation of alpha-synuclein and down-regulation of ubiquitin carboxy-terminal hydrolase/PGP 9.5 could be linked to the MA-induced dopaminergic terminal toxicity.