Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women.
Animals ; Female ; Mice ; CA1 Region, Hippocampal/metabolism* ; Cell Adhesion Molecules/metabolism* ; CRF Receptor, Type 1/metabolism* ; Memory Disorders/etiology* ; Mice, Inbred C57BL ; Nectins/genetics* ; Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors* ; Recognition, Psychology/physiology* ; Stress, Psychological/complications*

Corticotrophin-releasing factor (CRF) plays a major role in coordinating stress responses. We aimed to test whether blocking endogenous CRF activity can prevent the stress-induced dilation of intercellular spaces in esophageal mucosa. Eighteen adult male rats were divided into 3 groups: 1) a non-stressed group (the non-stressed group), 2) a saline-pretreated stressed group (the stressed group), 3) and an astressin-pretreated stressed group (the astressin group). Immediately after completing the experiments according to the protocol, distal esophageal segments were obtained. Intercellular space diameters of esophageal mucosa were measured by transmission electron microscopy. Blood was sampled for the measurement of plasma cortisol levels. Mucosal intercellular spaces were significantly greater in the stressed group than in the non-stressed group. Mucosal intercellular spaces of the astressin group were significantly smaller than those of the stressed group. Plasma cortisol levels in the stressed group were significantly higher than in the non-stressed group. Pretreatment with astressin tended to decrease plasma cortisol levels. Acute stress in rats enlarges esophageal intercellular spaces, and this stress-induced alteration appears to be mediated by CRF. Our results suggest that CRF may play a role in the pathophysiology of reflux-induced symptoms or mucosal damage.
Animals ; Corticotropin-Releasing Hormone/*antagonists & inhibitors/metabolism/pharmacology ; Esophagus/anatomy & histology/*drug effects ; Extracellular Space/*drug effects ; Hydrocortisone/blood ; Male ; Mucous Membrane/anatomy & histology/*drug effects ; Neuroprotective Agents/pharmacology ; Peptide Fragments/*pharmacology ; Rats ; Rats, Wistar ; *Stress, Psychological/blood/physiopathology

Major classes of medication in asthma management include bronchodilating beta2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human beta2 adrenergic receptors. In addition, genetic variation in beta2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.
Adrenal Cortex Hormones ; Asthma ; Cholinergic Antagonists ; Genes, vif ; Genetic Variation ; Humans ; Pharmacogenetics ; Receptors, Adrenergic ; Receptors, Corticotropin-Releasing Hormone ; Receptors, Leukotriene

This study was performed in order to assess whether acute stress can increase mast cell and enterochromaffin (EC) cell numbers, and proteinase-activated receptor-2 (PAR2) expression in the rat colon. In addition, we aimed to investigate the involvement of corticotrophin-releasing factor in these stress-related alterations. Eighteen adult rats were divided into 3 experimental groups: 1) a saline-pretreated non-stressed group, 2) a saline-pretreated stressed group, and 3) an astressin-pretreated stressed group. The numbers of mast cells, EC cells, and PAR2-positive cells were counted in 6 high power fields. In proximal colonic segments, mast cell numbers of stressed rats tended to be higher than those of non-stressed rats, and their PAR2-positive cell numbers were significantly higher than those of non-stressed rats. In distal colonic segments, mast cell numbers and PAR2-positive cell numbers of stressed rats were significantly higher than those of non-stressed rats. Mast cell and PAR2-positive cell numbers of astressin-pretreated stressed rats were significantly lower than those of saline-pretreated stressed rats. EC cell numbers did not differ among the three experimental groups. Acute stress in rats increases mast cell numbers and mucosal PAR2 expression in the colon. These stress-related alterations seem to be mediated by release of corticotrophin-releasing factor.
Animals ; Colon/*metabolism ; Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism/pharmacology/*physiology ; Enterochromaffin Cells/cytology ; Male ; Mast Cells/*cytology/immunology/metabolism ; Peptide Fragments/pharmacology ; Rats ; Rats, Wistar ; Receptor, PAR-2/*metabolism ; Restraint, Physical ; *Stress, Physiological

OBJECTIVETo observe the role of NB127914, a CRF R1 receptor antagonist, in the regulation of neonatal sleep/wake cycle.

METHODSRat pups were surgically implanted with electrodes at postnatal day(PN) 13. At PN 14, 6 hours polysomnographic recording data were continuously collected before and after administration of various doses of NBI 27914, atropine and the same amount of saline.

RESULTSCompared with baseline, rapid eye movement (REM) sleep was significantly reduced and was replaced primarily by non-REM (NREM) sleep in all groups treated with NBI, but not with dimethyl sulfoxide/saline. Atropine suppressed REM sleep significantly and increased wakefulness simultaneously.

CONCLUSIONBlockage of corticotropin-releasing factor (CRF) R1 receptors deprives neonatal rat REM sleep.

Aniline Compounds ; pharmacology ; Animals ; Female ; Male ; Polysomnography ; Pyrimidines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Corticotropin-Releasing Hormone ; antagonists & inhibitors ; Sleep, REM ; drug effects ; physiology ; Wakefulness ; drug effects ; physiology

Animals ; Brain ; metabolism ; Dehydroepiandrosterone ; therapeutic use ; Depressive Disorder, Major ; drug therapy ; metabolism ; physiopathology ; Humans ; Metyrapone ; therapeutic use ; Mifepristone ; therapeutic use ; Psychotic Disorders ; drug therapy ; metabolism ; physiopathology ; Pyrimidines ; therapeutic use ; Receptors, Corticotropin-Releasing Hormone ; antagonists & inhibitors ; Receptors, Glucocorticoid ; antagonists & inhibitors ; metabolism