A prefrontal-periaqueductal gray pathway differentially engages autonomic, hormonal, and behavioral features of the stress coping response.

Activation of autonomic and hypothalamo-pituitary-adrenal (HPA) systems occur interdependently with behavioral adjustments under varying environmental demands. Nevertheless, laboratory rodent studies examining the neural bases of stress responses have generally attributed increments in these systems to be monolithic, regardless of whether an active or passive coping strategy is employed. Using the shock probe defensive burying test (SPDB) to measure stress-coping features naturalistically in male and female rats, we identify a neural pathway whereby activity changes may promote distinctive response patterns of hemodynamic and HPA indices typifying active and passive coping phenotypes. Optogenetic excitation of the rostral medial prefrontal cortex (mPFC) input to the ventrolateral periaqueductal gray (vlPAG) decreased passive behavior (immobility), attenuated the glucocorticoid hormone response, but did not prevent arterial pressure and heart rate increases associated with rats' active behavioral (defensive burying) engagement during the SPDB. By contrast, inhibition of the same pathway increased behavioral immobility and attenuated hemodynamic output but did not affect glucocorticoid increases. Correlational analyses confirmed that hemodynamic increments occurred preferentially during active behaviors, and decrements during immobility epochs, whereas pathway manipulations, regardless of the directionality of effect, weakened the correlational relationship. Finally, neuroanatomical evidence indicated that the influence of the rostral mPFC-vlPAG pathway on coping response patterns are mediated predominantly through GABAergic neurons within vlPAG. These data highlight the importance of this prefrontal-midbrain connection in organizing stress-coping responses, and in coordinating bodily systems with behavioral output for adaptation to aversive experiences.Significance statement Organisms maximize fitness by exhibiting distinct stress-coping responses that are specific to a particular challenge. However, the neurobiology underlying cortical control over coping styles is poorly understood. We reveal a novel role for a prefrontal-to-ventrolateral periaqueductal gray pathway in regulating active versus passive stress-coping response patterns in rats. Optogenetic excitation of this pathway decreased behavioral passivity, attenuated stress-induced glucocorticoid increases, but did not prevent associated increases in autonomic output. Pathway inhibition increased behavioral passivity, attenuated autonomic output, but did not affect glucocorticoid increases. These data highlight the importance of this prefrontal-midbrain connection in organizing stress-coping responses, and in coordinating bodily systems with behavioral output for adaptation to aversive experiences.

Brain Transforming Growth Factor-ß Resists Hypertension Via Regulating Microglial Activation.

BACKGROUND AND PURPOSE: Hypertension is the major risk factor for stroke. Recent work unveiled that hypertension is associated with chronic neuroinflammation; microglia are the major players in neuroinflammation, and the activated microglia elevate sympathetic nerve activity and blood pressure. This study is to understand how brain homeostasis is kept from hypertensive disturbance and microglial activation at the onset of hypertension. METHODS: Hypertension was induced by subcutaneous delivery of angiotensin II, and blood pressure was monitored in conscious animals. Microglial activity was analyzed by flow cytometry and immunohistochemistry. Antibody, pharmacological chemical, and recombinant cytokine were administered to the brain through intracerebroventricular infusion. Microglial depletion was performed by intracerebroventricular delivering diphtheria toxin to CD11b-diphtheria toxin receptor mice. Gene expression profile in sympathetic controlling nucleus was analyzed by customized qRT-PCR array. RESULTS: Transforming growth factor-ß (TGF-ß) is constitutively expressed in the brains of normotensive mice. Removal of TGF-ß or blocking its signaling before hypertension induction accelerated hypertension progression, whereas supplementation of TGF-ß1 substantially suppressed neuroinflammation, kidney norepinephrine level, and blood pressure. By means of microglial depletion and adoptive transfer, we showed that the effects of TGF-ß on hypertension are mediated through microglia. In contrast to the activated microglia in established hypertension, the resting microglia are immunosuppressive and important in maintaining neural homeostasis at the onset of hypertension. Further, we profiled the signature molecules of neuroinflammation and neuroplasticity associated with hypertension and TGF-ß by qRT-PCR array. CONCLUSIONS: Our results identify that TGF-ß-modulated microglia are critical to keeping brain homeostasis responding to hypertensive disturbance.

Differential effects of long-term slow-pressor and subpressor angiotensin II on contractile and relaxant reactivity of resistance versus conductance arteries.

Vascular reactivity was evaluated in three separate arteries isolated from rats after angiotensin II (Ang II) was infused chronically in two separate experiments, one using a 14-day high, slow-pressor dose known to produce hypertension and the other using a 7-day low, subpressor but hypertensive-sensitizing dose. There were three new findings. First, there was no evidence of altered vascular reactivity in resistance arteries that might otherwise explain the hypertension due to the high Ang II or the hypertensive-sensitizing effect of the low Ang II dose. Second, the high Ang II dose exerted a novel differential effect on arterial contractile responsiveness to the sympathetic neurotransmitter, norepinephrine, depending on the level of sympathetic innervation. It clearly enhanced that responsiveness in the sparsely innervated aorta but not in small mesenteric resistance arteries or the proximal (conductance) portion of the caudal artery, both of which are densely innervated. This suggests that the increased expression of alpha adrenergic receptors after long-term exposure to Ang II as previously reported for aortic smooth muscle, is prevented in densely innervated arteries, likely due to long-term Ang II-mediated increase in sympathetic neural traffic to those vessels. Third, the same high dose of Ang II impaired aortic relaxation in response to the nitric oxide (NO) donor nitroprusside without impairing aortic endothelium-dependent relaxation. NO is the main relaxing substance released by aortic endothelium. Accordingly, it is possible that this dose of Ang II is also associated with enhanced release of and/or enhanced smooth muscle responsiveness to other endothelial relaxing substances in a compensatory capacity.

Aging affects isoproterenol-induced water drinking, astrocyte density, and central neuronal activation in female Brown Norway rats.

Age-dependent impairments in the central control of compensatory responses to body fluid challenges have received scant experimental attention, especially in females. In the present study, we found that water drinking in response to ß-adrenergic activation with isoproterenol (30 µg/kg, s.c.) was reduced by more than half in aged (25 mo) vs. young (5 mo) ovariectomized female Brown Norway rats. To determine whether this age-related decrease in water intake was accompanied by changes in central nervous system areas associated with fluid balance, we assessed astrocyte density and neuronal activation in the SFO, OVLT, SON, AP and NTS of these rats using immunohistochemical labeling for GFAP and c-fos, respectively. GFAP labeling intensity was increased in the SFO, AP, and NTS of aged females independent of treatment, and was increased in the OVLT of isoproterenol-treated rats independent of age. Fos immunolabeling in response to isoproterenol was reduced in both the SFO and the OVLT of aged females compared to young females, but was increased in the SON of female rats of both ages. Finally, fos labeling in the AP and caudal NTS of aged rats was elevated after vehicle control treatment and did not increase in response to isoproterenol as it did in young females. Thus, age-related declines in water drinking are accompanied by site-specific, age-related changes in astrocyte density and neuronal activation. We suggest that astrocyte density may alter the detection and/or processing of signals related to isoproterenol treatment, and thereby alter neuronal activation in areas associated with fluid balance.