Functional networks activated by controllable and uncontrollable stress in male and female rats.

The ability of an individual to reduce the intensity, duration or frequency of a stressor is a critical determinant of the consequences of that stressor on physiology and behavior. To expand our understanding of the brain networks engaged during controllable and uncontrollable stress and to identify sex differences, we used functional connectivity analyses of the immediate early gene product Fos in male and female rats exposed to either controllable or uncontrollable tail shocks. Twenty-eight regions of interest (ROI) were selected from the structures previously evinced to be responsible for stress response, action-outcome learning, or sexual dimorphism. We found that connectivity across these structures was strongest in female rats without control while weaker connectivity was evident in male rats with control over stress. Interestingly, this pattern correlates with known behavioral sex differences where stressor controllability leads to resilience in male but not female rats. Graph theoretical analysis identified several structures important to networks under specific conditions. In sum, the findings suggest that control over stress reshapes functional connectivity.

Monoacylglycerol lipase alpha inhibition alters prefrontal cortex excitability and blunts the consequences of traumatic stress in rat.

Neural activity within the ventromedial prefrontal cortex (vmPFC) is a critical determinant of stressor-induced anxiety. Pharmacological activation of the vmPFC during stress protects against stress-induced social anxiety suggesting that altering the excitatory/inhibitory (E/I) tone in the vmPFC may promote stress resilience. E/I balance is maintained, in part, by endogenous cannabinoid (eCB) signaling with the calcium dependent retrograde release of 2-arachidonoylglycerol (2-AG) suppressing presynaptic neurotransmitter release. We hypothesized that raising 2-AG levels, via inhibition of its degradation enzyme monoacylglycerol lipase (MAGL) with KML29, would shift vmPFC E/I balance and promote resilience. In acute slice experiments, bath application of KML29 (100 nM) augmented evoked excitatory neurotransmission as evidenced by a left-shift in fEPSP I/O curve, and decreased sIPSC amplitude. In whole-cell recordings, KML29 increased resting membrane potential but reduced the after depolarization, bursting rate, membrane time constant and slow after hyperpolarization. Intra-vmPFC administration of KML29 (200ng/0.5µL/hemisphere) prior to inescapable stress (IS) exposure (25, 5s tail shocks) prevented stress induced anxiety as measured by juvenile social exploration 24 h after stressor exposure. Conversely, systemic administration of KML29 (40 mg/kg, i.p.) 2 h before IS exacerbated stress induced anxiety. MAGL inhibition in the vmPFC may promote resilience by augmenting the output of neurons that project to brainstem and limbic structures that mediate stress responses.