Postpartum Oxytocin Treatment via the Mother Reprograms Long-Term Behavioral Disorders Induced by Early Life Stress on the Plasma and Brain Metabolome in the Rat.

The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior, is characterized by a metabolic profile that is reminiscent of the "metabolic syndrome". We aimed to identify plasma metabolomic signatures linked to long-term programming induced by PRS in aged male rats. This study was conducted in the plasma and frontal cortex. We also investigated the reversal effect of postpartum carbetocin (Cbt) on these signatures, along with its impact on deficits in cognitive, social, and exploratory behavior. We found that PRS induced long-lasting changes in biomarkers of secondary bile acid metabolism in the plasma and glutathione metabolism in the frontal cortex. Cbt treatment demonstrated disease-dependent effects by reversing the metabolite alterations. The metabolomic signatures of PRS were associated with long-term cognitive and emotional alterations alongside endocrinological disturbances. Our findings represent the first evidence of how early life stress may alter the metabolomic profile in aged individuals, thereby increasing vulnerability to CNS disorders. This raises the intriguing prospect that the pharmacological activation of oxytocin receptors soon after delivery through the mother may rectify these alterations.

Corticotropin-Releasing Hormone: Biology and Therapeutic Opportunities.

In 1981, Wylie Vale, Joachim Spiess, Catherine Rivier, and Jean Rivier reported on the characterization of a 41-amino-acid peptide from ovine hypothalamic extracts with high potency and intrinsic activity stimulating the secretion of adrenocorticotropic hormone and ß-endorphin by cultured anterior pituitary cells. With its sequence known, this neuropeptide was determined to be a hormone and consequently named corticotropin-releasing hormone (CRH), although the term corticotropin-releasing factor (CRF) is still used and preferred in some circumstances. Several decades have passed since this seminal contribution that opened a new research era, expanding the understanding of the coding of stress-related processes. The characterization of CRH receptors, the availability of CRH agonists and antagonists, and advanced immunocytochemical staining techniques have provided evidence that CRH plays a role in the regulation of several biological systems. The purpose of this review is to summarize the present knowledge of this 41-amino-acid peptide.

Postweaning social isolation and autism-like phenotype: A biochemical and behavioral comparative analysis.

Adolescence is a critical period for brain development. In most mammalian species, disturbances experienced during adolescence constitute a risk factor for several neuropsychiatric disorders. In this study, we compared the biochemical and behavioral profile induced by postweaning social isolation (PWSI) in inbred C57BL/6 N mice with that of BTBR mice, a rodent model of autism spectrum disorders. Male C57BL/6 N mice were either housed in groups of four or isolated from weaning (postnatal day 21) for four weeks before experimental analyses. After weaning, male BTBR mice were housed four per cage and analyzed at 48 days of age. PWSI reduced hippocampal levels of type 2 metabotropic glutamate (mGlu2) receptors, and glucocorticoid and mineralocorticoid receptors. A similar reduction was seen in group-housed BTBR mice. Plasma corticosterone levels in basal conditions were not influenced by PWSI, but were increased in BTBR mice. Social investigation (total and head sniffing) and the number of ultrasonic vocalizations were reduced in both PWSI mice and age-matched group-housed BTBR mice, indicating a lower social responsiveness in both groups of mice. These results suggest that absence of social stimuli during adolescence induces an endophenotype with social deficit features, which mimics the phenotype of a mouse model of autism spectrum disorders.

Risk Factors for Alzheimer's Disease: Focus on Stress.

In vulnerable individuals, chronic and persistent stress is an established risk factor for disorders that are comorbid with Alzheimer's disease (AD), such as hypertension, obesity and metabolic syndrome, and psychiatric disorders. There are no disease-modifying drugs in the treatment of AD, and all phase-3 clinical trials with anti-amyloid drugs (e.g., ß- or γ-secretase inhibitors and monoclonal antibodies) did not meet the primary endpoints. There are many reasons for the lack of efficacy of anti-amyloid drugs in AD, the most likely being a late start of treatment, considering that pathophysiological mechanisms underlying synaptic dysfunction and neuronal death begin several decades before the clinical onset of AD. The identification of risk factors is, therefore, an essential step for early treatment of AD with candidate disease-modifying drugs. Preclinical studies suggest that stress, and the resulting activation of the hypothalamic-pituitary-adrenal axis, can induce biochemical abnormalities reminiscent to those found in autoptic brain samples from individuals affected by AD (e.g., increases amyloid precursor protein and tau hyperphosphorylation). In this review, we will critically analyze the current knowledge supporting stress as a potential risk factor for AD.