17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger. Following cocaine self-administration and extinction, female rats were ovariectomized to isolate estrogen effects on reinstatement. Although neither peak proestrus levels of the primary estrogen 17β-estradiol (E2; 10 μg/kg, i.p., 1-h pretreatment) nor a subthreshold cocaine dose (1.25 mg/kg, i.p.) alone were sufficient to reinstate drug-seeking behavior, pretreatment with E2 potentiated reinstatement to the ordinarily subthreshold cocaine dose. Furthermore, E2 microinfusions revealed that E2 (5 μg/0.3 μl, 15-min pretreatment) acts directly within the prelimbic prefrontal cortex (PrL-PFC) to potentiate reinstatement. As E2 has been implicated in endocannabinoid mobilization, which can disinhibit PrL-PFC projection neurons, we investigated whether cannabinoid type-1 receptor (CB1R) activation is necessary for E2 to potentiate reinstatement. The CB1R antagonist AM251 (1 or 3 mg/kg, i.p., 30-min pretreatment) administered prior to E2 and cocaine suppressed reinstatement in a dose-dependent manner. Finally, PrL-PFC AM251 microinfusions (300 ng/side, 15-min pretreatment) also suppressed E2-potentiated reinstatement. Together, these results suggest that E2 can augment reactivity to an ordinarily subthreshold relapse trigger in a PrL-PFC CB1R activation-dependent manner

The resilience framework as a strategy to combat stress-related disorders

Consistent failure over the past few decades to reduce the high prevalence of stress-related disorders has motivated a search for alternative research strategies. Resilience refers to the phenomenon of many people maintaining mental health despite exposure to psychological or physical adversity. Instead of aiming to understand the pathophysiology of stress-related disorders, resilience research focuses on protective mechanisms that shield people against the development of such disorders and tries to exploit its insights to improve treatment and, in particular, disease prevention. To fully harness the potential of resilience research, a critical appraisal of the current state of the art — in terms of basic concepts and key methods — is needed. We highlight challenges to resilience research and make concrete conceptual and methodological proposals to improve resilience research. Most importantly, we propose to focus research on the dynamic processes of successful adaptation to stressors in prospective longitudinal studies.In preparing this Perspective, U.B. was supported by the Deutsche Forschungsgemeinschaft (DFG CRC 1193, subproject C06); G.A.B. by the United States-Israel Binational Science Foundation (project 2013067), David and Maureen O’Connor, and the Rockefeller Foundation (2012-RLC 304); A.C. by DFG CRC 1193, subproject C04; E.B. by the European Union’s Horizon 2020 Programme (EU H2020/705217); C.J.F. by DFG CRC 1193, subprojects C03 and C06, DFG FI 848/5-1, and the European Research Council (ERC-CoG 617891); I.G.-L. by the National Institute of Mental Health (K01MH102415); S.G. by DFG CRC 1193, subproject B05; E.J.H. by the ERC (ERCCoG682591); R.K. by DFG CRC 1193, subprojects B01 and C01, and the State of Rhineland- Palatinate (project 1080, MARP); K.L. by DFG CRC 1193, subproject Z03, and the State of Rhineland-Palatinate (project 1080, MARP); B.L. by DFG CRC 1193, subprojects A02, B03, and Z02; M.B.M. by DFG CRC 1193, subprojects A03 and Z02; R.J.M. by the Swiss National Science Foundation (SNF 100014-143398; project no. un 8306); A.R. by DFG CRC 1193, subprojects C07 and Z03, and EU H2020/2014-2020 (643051 (MiND) and 667302 (CoCA)); K.R. by the ERC (ERC_StG2012_313749) and the NWO (NWO VICI no. 453-12-001); B.P.F.R. by the NWO (NWO VENI no. 916-11-086); D.S. by the SNF (SNF 100014-143398, project no. un 8306); O.T. by DFG CRC 1193, subproject C04, and the State of Rhineland-Palatinate (project 1080, MARP); A.-L.v.H. by the Royal Society (DH150176); C.H.V. by the Netherlands Brain Foundation (Fellowship F2013(1)-216) and the NWO (NWO VENI no. 451-13-001); T.D.W. by the National Institute of Health (NIH); M.We. by DFG CRC 1193, subprojects C05 and C07; and M.Wi. by DFG CRC 1193, subproject C04

Estradiol-Mediated Spine Changes in the Dorsal Hippocampus and Medial Prefrontal Cortex of Ovariectomized Female Mice Depend on ERK and mTOR Activation in the Dorsal Hippocampus

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Estradiol-Mediated Spine Changes in the Dorsal Hippocampus and Medial Prefrontal Cortex of Ovariectomized Female Mice Depend on ERK and mTOR Activation in the Dorsal Hippocampus

Dendritic spine plasticity underlies the formation and maintenance of memories. Both natural fluctuations and systemic administration of 17β-estradiol (E(2)) alter spine density in the dorsal hippocampus (DH) of rodents. DH E(2) infusion enhances hippocampal-dependent memory by rapidly activating extracellular signal-regulated kinase (ERK)-dependent signaling of mammalian target of rapamycin (mTOR), a key protein synthesis pathway involved in spine remodeling. Here, we investigated whether infusion of E(2) directly into the DH drives spine changes in the DH and other brain regions, and identified cell-signaling pathways that mediate these effects. E(2) significantly increased basal and apical spine density on CA1 pyramidal neurons 30 min and 2 h after infusion. DH E(2) infusion also significantly increased basal spine density on pyramidal neurons in the medial prefrontal cortex (mPFC) 2 h later, suggesting that E(2)-mediated activity in the DH drives mPFC spinogenesis. The increase in CA1 and mPFC spine density observed 2 h after intracerebroventricular infusion of E(2) was blocked by DH infusion of an ERK or mTOR inhibitor. DH E(2) infusion did not affect spine density in the dentate gyrus or ventromedial hypothalamus, suggesting specific effects of E(2) on the DH and mPFC. Collectively, these data demonstrate that DH E(2) treatment elicits ERK- and mTOR-dependent spinogenesis on CA1 and mPFC pyramidal neurons, effects that may support the memory-enhancing effects of E(2). SIGNIFICANCE STATEMENT Although systemically injected 17β-estradiol (E(2)) increases CA1 dendritic spine density, the molecular mechanisms regulating E(2)-induced spinogenesis in vivo are largely unknown. We found that E(2) infused directly into the dorsal hippocampus (DH) increased CA1 spine density 30 min and 2 h later. Surprisingly, DH E(2) infusion also increased spine density in the medial prefrontal cortex (mPFC), suggesting that estrogenic regulation of the DH influences mPFC spinogenesis. Moreover, inhibition of ERK and mTOR activation in the DH prevented E(2) from increasing DH and mPFC spines, demonstrating that DH ERK and mTOR activation is necessary for E(2)-induced spinogenesis in the DH and mPFC. These findings provide novel insights into the molecular mechanisms through which E(2) mediates dendritic spine density in CA1 and mPFC

Muscle tissue adaptations of high-altitude natives to training in chronic hypoxia or acute normoxia

Twenty healthy high-altitude natives, residents of La Paz, Bolivia (3,600 m), participated in 6 wk of endurance exercise training on bicycle ergometers, 5 times/wk, 30 min/session, as previously described in normoxia- trained sea-level natives (H. Hoppeler, H. Howald, K. E. Conley, S. L. Lindstedt, H. Claassen, P. Vock, and E. R. Weibel. J. Appl. Physiol. 59: 320- 327, 1985). A first group of 10 subjects was trained in chronic hypoxia (HT; barometric pressure = 500 mmHg; inspired O2 fraction = 0.209); a second group of 10 subjects was trained in acute normoxia (NT; barometric pressure 500 mmHg; inspired O2 fraction = 0.314). The workloads were adjusted to ~70% of peak O2 consumption (V̇O2(peak)) measured either in hypoxia for the HT group or in normoxia for the NT group. (V̇O(2peak)) determination and biopsies of the vastus lateralis muscle were taken before and after the training program. (V̇O(2peak)) in the HT group was increased (14%) in a way similar to that in NT sea-level natives with the same protocol. Moreover, (V̇O(2peak)) in the NT group was not further increased by additional O2 delivery during the training session. HT or NT induced similar increases in muscle capillary-to-fiber ratio (26%) and capillary density (19%) as well as in the volume density of total mitochondria and citrate synthase activity (45%). It is concluded that high-altitude natives have a reduced capillarity and muscle tissue oxidative capacity; however, their training response is similar to that of sea-level residents, independent of whether training is carried out in hypobaric hypoxia or hypobaric normoxia