The molecular mechanisms that control the range and stability of emotions are unknown, yet this knowledge is critical for understanding mood disorders, especially bipolar illness. Here, we show glucocorticoid receptor (GR) modulates these features emotional responsiveness. We generated transgenic mice overexpressing GR specifically in forebrain. These display a significant increase anxiety-like depressant-like behaviors relative to wild type. Yet, they also supersensitive antidepressants...

The rat corticotropin releasing hormone (CRH) gene has been isolated and characterized by DNA sequence analysis. exhibits a structural organization similar to that of the human CRH gene. nucleotide encoding entire precursor is located on second exon, while exon I encodes 5′-untranslated region them RNA. Analysis homology between genes reveals several highly conserved regions including peptide-encoding 5′-flanking sequence. RNA blot analysis demonstrates mRNA can be observed in numerous brain...

Although numerous stress-related molecules have been implicated in vulnerability to psychiatric illness, especially major depression and anxiety disorders, the role of brain mineralocorticoid receptor (MR) stress, depression, affective function is not well defined. MR a steroid hormone that detects circulating glucocorticoids with high affinity has primarily controlling their basal level circadian rhythm. To specifically address hypothalamic-pituitary-adrenal axis activity anxiety-related...

The molecular mechanisms involved in the regulation of expression rat CRH gene have been examined pheochromocytoma (PC-12) cells transiently transfected with a chimeric containing 1.4 kilobases 5′-flanking DNA fused to bacterial reporter encoding chloramphenicol acetyltransferase. Cyclic AMP analogs and activators adenylate cyclase positively regulate this PC-12 cells, inducing acetyltransferase activity more than 15-fold. sequence required for response cAMP has localized 59 base pair region...

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor-beta family factors, was first identified by its ability to promote survival midbrain dopaminergic neurons in culture. We demonstrate that GDNF treatment several neuroblastoma lines leads dose-dependent tyrosine phosphorylation RET receptor and other members are not able activate receptor. cells also results increased transcription an Elk luciferase reporter gene, suggesting activates...

Corticotropin-releasing hormone (CRH) is widely recognized as the primary mediator of neuroendocrine and behavioral responses to stress, including stress-induced anxiety. The biological activity CRH other mammalian CRH-like peptides, such urocortin, may be modulated by CRH-binding protein (CRH-BP). To assess directly CRH-BP function, we created a mouse model deficiency gene targeting. Basal adrenocorticotropic corticosterone levels are unchanged in CRH-BP-deficient mice, animals demonstrate...

A novel protein tyrosine phosphatase [homologue of vaccinia virus H1 gene clone 5 (hVH-5)] was cloned; it shared sequence similarity with a subset phosphatases that regulate mitogen-activated kinase. The catalytic region hVH-5 expressed as fusion and shown to hydrolyze p-nitrophenylphosphate inactivate kinase, thus proving possessed activity. unique proline-rich distinguished from other closely related phosphatases. Another feature predominantly in the adult brain, heart, skeletal muscle. In...

CRH mRNA was detected by in situ hybridization histochemistry numerous regions of the adult mouse brain, including most prominently paraventricular nucleus (PVN) hypothalamus, inferior olivary nucleus, and Barrington's nucleus. After adrenalectomy, steady state levels increased 1.7-fold, specifically PVN, consistent with reports negative glucocorticoid regulation expression rat PVN. Ontogenetic analysis fetal neonatal brain demonstrated complex, amygdaloid primordia on embryonic day 13.5. In...

A new family of neuronal survival factors comprised glial cell line-derived neurotrophic factor (GDNF) and neurturin has recently been described (Kotzbauer, P. T., Lampe, A., Heuckeroth, R. O., Golden, J. P., Creedon, D. J., Johnson, E. M., Jr., Milbrandt, (1997) <i>Nature</i> 384, 467–470). These molecules, which are related to transforming growth factor-β, important in embryogenesis the distinct populations. molecules signal through a novel receptor system that includes Ret tyrosine...

Cyclic AMP regulates a variety of cellular responses through activation the catalytic subunit cAMP-dependent protein kinase. The cDNAs for two isoforms subunit, Cα and Cβ, were placed into expression vectors, their ability to stimulate transcription human enkephalin promoter was examined in transiently transfected CV-1 cells. Expression vectors Cβ that directed by cytomegalovirus produced up 350- 200-fold increases chloramphenicol acetyltransferase activity, respectively, when cotransfected...

Mutations in Prophet of PIT1 (Prop1), one several homeodomain transcription factors that are required for the development anterior pituitary gland, predominant cause MPHD (multiple hormone deficiency) humans. We show deletion Prop1 mice causes severe hypoplasia with failure entire Pit1 lineage and delayed gonadotrope development. The deficiencies secondary endocrine problems a high rate perinatal mortality due to respiratory distress. Lung atelectasis mutants correlates reduced levels NKX2.1...

The negative glucocorticoid regulation of CRH gene expression is a critical control element in the hypothalamic-pituitary-adrenal axis. In this study, molecular mechanisms mediating repression cAMP-induced CRH-reporter AtT-20 cells have been examined. these cells, dexamethasone decreases forskolin-induced activity dose-dependent manner. This mediated by receptor (GR) and does not require ongoing protein synthesis. Several binding sites for GR DNA-binding domain were identified within...

Maternal behavior and anxiety are potently modulated by the brain corticotropin-releasing factor (CRF) system postpartum. Downregulation of CRF in limbic regions is essential for appropriate maternal an adaptive response. Here, we focus our attention on arguably most important region behavior, hypothalamic medial preoptic area (MPOA). Within MPOA, mRNA receptor subtype 1 (protein: CRFR1, gene: Crhr1) was more abundantly expressed than 2 CRFR2, Crhr2), however expression Crhr1, Crhr2...

The dorsal striatum (DS) is implicated in behavioral and neural processes including action control reinforcement. Alcohol alters these rodents, it believed that the development of alcohol use disorder involves changes DS dopamine signaling. In nonhuman primates, can be divided into caudate putamen subregions. As part a collaborative effort examining effects long-term self-administration rhesus macaques, we examined signaling using fast-scan cyclic voltammetry. We found chronic resulted...

Corticotropin-releasing hormone (CRH) is the primary hypothalamic releasing factor that mediates mammalian stress response. The CRH-binding protein (CRH-BP) secreted from corticotropes, pituitary CRH target cells, suggesting CRH-BP may modulate hypothalamic-pituitary-adrenal (HPA) axis activity by preventing receptor stimulation. Transgenic mice were generated constitutively express elevated levels of in anterior gland. RNA and analyses confirmed elevation CRH-BP. Basal plasma concentrations...

Membrane depolarization is a critical element of neuronal signaling.In this study, the biochemical and molecular mechanisms involved in transcriptional regulation corticotropin-releasing hormone (CRH) gene by were investigated.In PC-12 cells, potassium-induced membrane increased expression CRH-reporter construct CAMP-dependent manner.This synergistic activation was mediated via calcium influx, predominantly L-type channels, calmodulin.RNase protection assays demonstrated levels transcripts...

Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of lifespan. This contributes cognitive deficits observed during aging. In addition, aging associated with dysregulation limbic–hypothalamic–pituitary–adrenal (LHPA) axis, leading a delayed termination response. delay, in turn, increases exposure glucocorticoids and exacerbates likelihood damage. Here we asked whether similar effects could emerge at an early age as result genetic variations level...