Combining brief recall and ketamine treatment prevents stress-primed methamphetamine memory reinstatement via heightening mPFC GABA activity.

This study aimed to assess whether brief recall of methamphetamine (MA) memory, when combined with ketamine (KE) treatment, may prevent stress-primed MA memory reinstatement. Combining 3-min recall and KE facilitated MA memory extinction and resistance to subsequent stress-primed reinstatement. Such combination also produced glutamate metabotropic receptor 5 (mGluR5) upregulation in animals' medial prefrontal cortex (mPFC) γ-amino-butyric acid (GABA) neuron. Accordingly, chemogenetic methods were employed to bi-directionally modulate mPFC GABA activity. Following brief recall and KE-produced MA memory extinction, intra-mPFC mDlx-Gi-coupled-human-muscarinic-receptor 4 (hM4Di)-infused mice receiving compound 21 (C21) treatment showed eminent stress-primed reinstatement, while their GABA mGluR5 expression seemed to be unaltered. Intra-mPFC mDlx-Gq-coupled-human-muscarinic-receptor 3 (hM3Dq)-infused mice undergoing C21 treatment displayed MA memory extinction and resistance to stress-provoked reinstatement. These results suggest that combining a brief recall and KE treatment and exciting mPFC GABA neuron may facilitate MA memory extinction and resistance to stress-primed recall. mPFC GABA neuronal activity plays a role in mediating brief recall/KE-produced effects on curbing the stress-provoked MA seeking.

Male Stressed Mice Having Behavioral Control Exhibit Escalations in Dorsal Dentate Adult-Born Neurons and Spatial Memory.

An escapable (ES)/inescapable stress (IS) paradigm was used to study whether behavioral control and repeated footshock stressors may affect adult neurogenesis and related cognitive function. Male stressed mice having behavioral control (ES) had a short-term escalation in dorsal dentate gyrus (DG) neurogenesis, while similarly stressed mice having no such control had unaltered neurogenesis as compared to control mice receiving no stressors. Paradoxically, ES and IS mice had comparable stress-induced corticosterone elevations throughout the stress regimen. Appetitive operant conditioning and forced running procedures were used to model learning and exercise effects in this escapable/inescapable paradigm. Further, conditioning and running procedures did not seem to affect the mice's corticosterone or short-term neurogenesis. ES and IS mice did not show noticeable long-term changes in their dorsal DG neurogenesis, gliogenesis, local neuronal density, apoptosis, autophagic flux, or heterotypic stress responses. ES mice were found to have a greater number of previously labeled and functionally integrated DG neurons as compared to IS and control mice 6 weeks after the conclusion of the stressor regimen. Likewise, ES mice outperformed IS and non-stressed control mice for the first two, but not the remaining two, trials in the object location task. Compared to non-stressed controls, temozolomide-treated ES and IS mice having a lower number of dorsal DG 6-week-old neurons display poor performance in their object location working memory. These results, taken together, prompt us to conclude that repeated stressors, albeit their corticosterone secretion-stimulating effect, do not necessary affect adult dorsal DG neurogenesis. Moreover, stressed animals having behavioral control may display adult neurogenesis escalation in the dorsal DG. Furthermore, the number of 6-week-old and functionally-integrated neurons in the dorsal DG seems to confer the quality of spatial location working memory. Finally, these 6-week-old, adult-born neurons seem to contribute spatial location memory in a use-dependent manner.

Stress while lacking of control induces ventral hippocampal autophagic flux hyperactivity and a depression-like behavior.

BACKGROUND: Stressed animals may perform depression-like behavior insomuch as stress-provoking blood-brain barrier (BBB) disruption, central immune activation, and autophagic flux changes. This study was undertaken to assess whether adult mice having (executive) vs. lacking (yoke) of behavioral control in otherwise equivalent stress magnitude condition, may display differences in their BBB integrity, ventral hippocampal (VH) interleukin-6 (IL-6) and autophagic flux level and VH-related depression-like behavior. To further understand the causative relation of enhanced autophagic flux and stress-primed depression-like behavior, we assessed the effects of bilateral intra-VH 3-methyladenine (3-MA), an autophagic flux inhibitor, infusion in stressed mice. METHODS: Adult mice used had comparable genetic background and housing condition. Executive/yoke pairs of mice received a 10-day (1 h/day) footshock stressor regimen. Throughout the regimen, the ongoing footshock was terminated immediately contingent on the executive mouse', while irrelevant to the respective yoke mouse' voluntary behavior, or lasting for 7 s. Each dyad's cage-mate receiving no such regimen served as no stressor controls. RESULTS: Yoke mice displayed disrupted BBB integrity (escalated Evans blue extravasation and decreased VH ZO-1, claudin-5 expression), increases in VH autophagic flux (increased LC3II/LC3I and decreased p62) and immobility duration in forced swimming test. Most of these indices remained unaltered in executive mice. Administration of 3-MA did not affect immobility duration in control mice, while prevented the increases in immobility duration in yoke mice. CONCLUSIONS: (1) stress susceptibility may be determined by their differences in stress-coping results; (2) VH autophagic flux increase plays a permissive role in priming the stressed animals susceptible to exhibit depression-like behavior.

Social disruption-induced stress pre-exposure aggravates, while the presence of conspecifics diminishes, acetic acid-induced writhing.

RATIONALE AND OBJECTIVE: This study was undertaken to assess the modulating effects of (1) pre-exposure to repeated social disruption and (2) group testing on writhing associated with visceral pain induced by intraperitoneal administration of acetic acid. MATERIALS AND METHODS: Six consecutive days of social disruption were used to prime for stress, while group testing referred to 3 mouse cage-mates receiving the acetic acid-induced writhing test as a group. RESULTS: Social disruption-induced stress-pre-exposed mice displayed a greater number acid-induced writhes compared to mice not receiving the pre-exposure. However, mice displayed fewer acid-induced writhes in a triad group vs. individually, suggesting group-mediated writhing-reducing effects. Likewise, group testing prevented the stress pre-exposure escalation in acid-induced writhes. Additional studies revealed that the stress-pre-exposed mice had increased expression in accumbal TRPV1 receptors. Systemic (0.25 mg/kg) and bilateral intra-accumbal (0.2 ng/0.2 µl/side) administration of SB366791, a TRPV1 receptor antagonist, reliably prevented the stress pre-exposure escalation in acid-induced writhing; SB366791 treatment alone did not affect acid-induced writhing, stress pre-exposure anxiety-like behavior, or the group testing effects. Furthermore, lower neuronal activation was found in the medial septal nucleus in group vs. individual tested mice. Intra-medial septum (0.2 µg/0.5 µl) infusion with bicuculline, a GABAA receptor antagonist, effectively prevented group-mediated writhing-reducing effects, but not individual acid-induced writhing effects. CONCLUSIONS: These findings suggest that social disruption-induced stress pre-exposure may upregulate accumbal TRPV1 receptor expression and consequently aggravate acid-induced writhing. Group testing prevents such stress pre-exposure escalation of acid-induced writhing most likely by strengthening the GABAergic inhibition on local neural activity in the medial septum.

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.