Characterization of a novel subtype of hippocampal interneurons that express corticotropin‐releasing hormone

A subset of corticotropin‐releasing hormone (CRH) neurons was previously identified in the hippocampus with unknown function. Here we demonstrate that hippocampal CRH neurons represent a novel subtype of interneurons in the hippocampus, exhibiting unique morphology, electrophysiological properties, molecular markers, and connectivity. This subset of hippocampal CRH neurons in the mouse reside in the CA1 pyramidal cell layer and tract tracing studies using AAV‐Flex‐ChR2‐tdTomato reveal dense back‐projections of these neurons onto principal neurons in the CA3 region of the hippocampus. These hippocampal CRH neurons express both GABA and GAD67 and using in vitro optogenetic techniques, we demonstrate that these neurons make functional connections and release GABA onto CA3 principal neurons. The location, morphology, and importantly the functional connectivity of these neurons demonstrate that hippocampal CRH neurons represent a unique subtype of hippocampal interneurons. The connectivity of these neurons has significant implications for hippocampal function. © 2015 Wiley Periodicals, Inc.     

Ethanol Modulates Corticotropin Releasing Hormone Release From the Rat Hypothalamus: Does Acetaldehyde Play a Role?

Background and Methods: Ethanol (EtOH) activates hypothalamic–pituitary–adrenal (HPA) axis, resulting in adrenocorticotropin hormone, glucocorticoid release, and in modifications of the response of the axis to other stressors. The initial site of EtOH action within the HPA system seems to be the hypothalamus. Thus, to determine the mechanisms responsible for these effects, we investigated: (i) whether EtOH was able to release corticotrophic releasing hormone (CRH) from incubated hypothalamic explants; (ii) whether acetaldehyde (ACD), its first metabolite formed in the brain by catalase activity, might play a role in EtOH activity. To this aim, rat hypothalamic explants were incubated with: (i) medium containing EtOH at 32.6 × 10³ μM; (ii) different concentration of ACD (1, 3, 10, and 30 μM); (iii) EtOH plus 3amino‐1,2,4‐triazole (3AT, 32 × 10³ μM) an inhibitor of cerebral catalase; (iv) ACD plus D‐penicillamine (DP, 50.3 × 10³ μM) an ACD‐trapping agent. CRH levels were evaluated by a radioimmunoassay. Results: Incubation with EtOH induced a 7‐fold increase in CRH secretion, with respect to basal levels; ACD was able to stimulate CRH release in a dose‐dependent manner; the inhibition of cerebral catalase by 3AT blocked EtOH‐induced CRH outflow; the inactivation of ACD by DP reverted the ACD‐stimulating effect on CRH secretion. Conclusions: These data show that both EtOH and acetaldehyde are able to increase hypothalamic CRH release from the rat hypothalamus and that acetaldehyde itself appears to be the mediator of EtOH activity.     

木姜叶柯总黄酮胶囊的成型工艺

目的:探讨木姜叶柯总黄酮胶囊的成型工艺。方法:以休止角、吸湿率、临界相对湿度、堆密度为考察指标,筛选木姜叶柯总黄酮胶囊的成型工艺条件。结果:以微粉硅胶为辅料,用量为10%,临界相对湿度66%,选用0号胶囊,可满足木姜叶柯总黄酮胶囊剂装填要求。结论:该成型工艺合理可行。     

Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology

Exposure to childhood trauma may induce persistent changes in Hypothalamic-Pituitary-Adrenal (HPA)-axis functioning even in the absence of current psychopathology. Because previous studies did not systematically exclude subjects with lifetime psychiatric morbidity, prevalent psychopathology may have confounded the association. In this study we investigated whether women exposed to childhood trauma, but without a history of psychiatric disorders, show alterations in HPA-axis functioning. We included 10 women exposed to significant childhood trauma and 12 non-exposed women. All women were between 29 and 64 years old, mentally and physically healthy, and without current or lifetime psychopathology. HPA-axis functioning was assessed as 1) basal activity with salivary cortisol patterns over 8 time points on two consecutive sampling days and 2) plasma cortisol and adrenocorticotropic hormone (ACTH) reactivity over 7 time points after the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) challenge test. Basal salivary cortisol output did not differ between trauma-exposed compared to non-exposed women. Significantly blunted plasma cortisol and ACTH responses in response to dex/CRH administration were found in the trauma-exposed compared to the non-exposed women (F(1,20) = 5.08, p = 0.04 and F(1,20) = 5.23, p = 0.03 respectively). Adjusting for age, body mass index (BMI), oral contraceptive use, and menopausal status, somewhat weakened the associations for cortisol as well as ACTH (F(1,16) = 3.30, p = 0.09) and F(1,16) = 2.17, p = 0.16 respectively), but for cortisol absolute differences in point estimates were largely unaffected. Although basal cortisol patterns were similar in the two groups, exposure to childhood trauma seemed to be related to a blunted HPA-axis reactivity in women who were free of current or lifetime psychopathology.     

HPA-axis regulation at in-patient admission is associated with antidepressant therapy outcome in male but not in female depressed patients

A concatenation of data implicates a hyperactivity of the hypothalamus pituitary adrenal (HPA)-axis in the pathogenesis of depression and its normalization as a necessary predecessor of clinical response to antidepressant drugs. In addition, regulation of the HPA-axis has been shown to be dependent on sex hormones. We therefore investigated gender differences in HPA-axis regulation in depression and its normalization during remission of clinical symptoms. We used the combined dexamethasone suppression/CRH stimulation (Dex-CRH) test to evaluate the degree of HPA-axis dysregulation in 194 in-patients with unipolar depression from the Munich Antidepressant Response Signature (MARS) study at both admission and discharge. The Hamilton Depression (HAM-D) Rating Scale was used to monitor clinical response to antidepressant treatment. For both genders, we observed a normalization of HPA-axis dysregulation in remitters but not in non-remitters, both after 5 weeks of treatment and at discharge. The pattern of HPA-axis normalization with remission of depressive symptoms, however, showed gender-specific differences. In male patients, remission after 5 weeks of in-patient treatment was associated with a significantly higher cortisol response in the Dex-CRH test at admission. In female patients, 5-week remitters and non-remitters had a comparable cortisol response at admission. Cortisol response at admission was not correlated with gonadal steroid levels at this time point and the results were similar for pre-menopausal women vs. post-menopausal women. Gender-associated biological characteristics, likely independent of circulating gonadal steroids, thus seem to influence HPA-axis regulation in depression. In male patients, a single measure of HPA-axis dysregulation at admission may serve as a predictor of response to antidepressant treatment in addition to the previously reported repeated measure of the Dex-CRH test.     

Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

Although brain pathways activated by sepsis may respond acutely to endotoxin administration, the long-term central response to sepsis is not known. We prepared male rats for hormonal sampling at the circadian nadir (AM) and peak (PM) after cecal ligation and puncture (CLP) or sham surgery. Diurnal variation of corticosterone was present on postoperative day (D) 3 and D4 after sham surgery but not after CLP. CLP increased Fos immunostaining in the nucleus of tractus solitarius (NTS), ventrolateral medulla, medullary raphe, parabrachial nucleus, hypothalamus, amygdala, bed nucleus of stria terminalis, and preoptic region. Fos responses were generally greatest on D1 but persisted to the AM of D4. The number of Fos-positive cell nuclei in the NTS on D3 and D4 did not differ but had greater variance on D3 than on D4 (P<0.01) with a divergent response in the PM of D3 that was correlated with plasma ACTH (r=0.927, P<0.01) but not with corticosterone. CLP increased CRH-staining intensity in the hypothalamic paraventricular neurons uniformly from D1 through D4 (P<0.01). Similar to Fos in NTS, this response was correlated with plasma ACTH (r=0.738, P<0.05) and adrenal size (r=0.730, P<0.05) in the PM of D3. Neuronal CRH became detectable after CLP in specific medullary areas on D1 and in the preoptic region on D3 and D4. Thus, the suppression of circadian variation by CLP was associated with central neural responses that increased in relation to plasma ACTH without apparent influence on the release of corticosterone.     

Agitated depression successfully treated with electroconvulsive therapy combined with steroid cover in a patient with Addison's disease

We report the case of a 70-year-old man with Addison's disease who developed severe agitated depression resulting in life-threatening medical conditions. The depression was treated safely with electroconvulsive therapy (ECT) combined with steroid cover. Administration of steroid cover just before each ECT session may increase safety of the ECT procedure in psychiatric patients with Addison's disease.     

Hypothalamic-pituitary-adrenal responses to 5-HT1A and 5-HT2A/C agonists are differentially altered in female and male rats prenatally exposed to ethanol

BACKGROUND: Prenatal ethanol exposure alters the development of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA hyper-responsiveness to stressors in adulthood. Prenatal ethanol exposure also alters the development and activity of the serotoninergic (5-HT) system. We have previously shown that 5-HT(1A) and 5-HT(2A/C) receptor-mediated behavioral and physiological function are altered in fetal ethanol-exposed offspring. As there are extensive interactions between the HPA axis and the 5-HT system, the present study tested the hypothesis that prenatal ethanol exposure would alter 5-HT(1A) and 5-HT(2A/C) receptor-mediated HPA function. METHODS: The 5-HT(1A) agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.2 mg/kg), and the 5-HT(2A/C) agonist, (+)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.3 mg/kg), or vehicle (1 mL/kg) were administered to adult female and male offspring from prenatal ethanol-exposed (E), pair-fed control (PF), and ad libitum-fed control (C) dams. The plasma concentration of adrenocorticotropin (ACTH) and corticosterone (CORT) were determined at 0, 15, 30, 60, and 120 minutes postinjection. In addition, corticotropin releasing hormone (CRH) mRNA expression in the paraventricular nucleus of the hypothalamus, and 5-HT(1A) and 5-HT(2A/C) receptor mRNA expression in the hippocampus and prefrontal cortex, respectively, were determined by in situ hybridization. RESULTS: Ethanol-exposed females showed a blunted ACTH response to 8-OH-DPAT at 15 and 30 minutes, and conversely, an increased ACTH response to DOI at all time points postinjection, compared with PF and C females. Differences among E, PF, and C males failed to reach significance. Centrally, however, DOI resulted in a trend toward lower CRH mRNA levels in E and PF compared with C females, but higher CRH mRNA levels in E compared with control males. There were no differences among prenatal groups in 5-HT(2A) receptor expression in the prefrontal cortex following either 8-OH-DPAT or DOI treatment. However, following 8-OH-DPAT, hippocampal 5-HT(1A) receptor expression was higher in E than in PF females in CA1, with a trend toward higher expression in E than in C females in CA2, whereas following DOI, a prenatal group by subfield interaction suggests lower 5-HT(1A) mRNA levels in E and PF compared with C females in CA1 and the dentate gyrus. CONCLUSIONS: These data are the first to demonstrate that prenatal ethanol exposure has differential long-term effects on 5-HT(1A)-mediated and 5-HT(2A)-mediated neuroendocrine function in females and males, and suggest a sex-specific ethanol-induced alteration in the interaction between the HPA axis and the serotonin system.     

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.