Socioemotional health is positively correlated with improved cognitive and physical aging. Despite known sex differences in socioemotional behaviors and the trajectory of aging, the interactive ...effects between sex and aging on socioemotional outcomes are poorly understood. We performed the most comprehensive assessment of sex differences in socioemotional behaviors in C57Bl/6J mice across aging to date. Compared to males, females exhibited decreased anxiety-like behavior and social preference but increased social recognition. With age, anxiety-like behavior, cued threat memory generalization, and social preference increased in both sexes. To investigate potential neural mechanisms underlying these behavioral changes, we analyzed transcriptional neuropathology markers in the ventral hippocampus and found age-related changes in genes related to activated microglia, angiogenesis, and cytokines. Sex differences emerged in the timing, direction, and magnitude of these changes, independent of reproductive senescence in aged females. Interestingly, female-specific upregulation of autophagy-related genes correlated with age-related behavioral changes selectively in females. These novel findings reveal critical sex differences in trajectories of ventral hippocampal aging that may contribute to sex- and age-related differences in socioemotional outcomes.
•Sex differences in avoidance behavior, social preference, and social recognition.•Age-related changes in avoidance behavior, social preference, and emotional memory.•Sex differences in the trajectory of transcriptional aging in the ventral hippocampus.•Female-specific relationship between autophagy genes and socioemotional behavior.•No impact of reproductive senescence on behavior or transcription in aged females.
Abstract Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and data from recent genetic studies suggest a link between PD and gut inflammation. We therefore undertook the ...present survey to investigate whether gastrointestinal inflammation occurs in PD patients. Nineteen PD patients and 14 age-matched healthy controls were included. For each PD patients, neurological and gastrointestinal symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively and cumulative lifetime dose of L-dopa was calculated. Four biopsies were taken from the ascending colon during the course of a total colonoscopy in controls and PD patients. The mRNA expression levels of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, interleukin-6 and interleukin-1 beta) and glial marker (Glial fibrillary acidic protein, Sox-10 and S100-beta) were analyzed using real-time PCR in two-pooled biopsies. Immunohistochemical analysis was performed on the two remaining biopsies using antibodies against phosphorylated alpha-synuclein to detect Lewy pathology. The mRNA expression levels of pro-inflammatory cytokines as well as of two glial markers (Glial fibrillary acidic protein and Sox-10) were significantly elevated in the ascending colon of PD patients with respect to controls. The levels of tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin-1 beta and Sox-10 were negatively correlated with disease duration. By contrast, no correlations were found between the levels of pro-inflammatory cytokines or glial markers and disease severity, gastrointestinal symptoms or cumulative lifetime dose of L-dopa. There was no significant difference in the expression of pro-inflammatory cytokines or glial marker between patients with and without enteric Lewy pathology. Our findings provide evidence that enteric inflammation occurs in PD and further reinforce the role of peripheral inflammation in the initiation and/or the progression of the disease.
There is growing evidence supporting a role of extracellular alpha‐synuclein in the spreading of Parkinson's disease (PD) pathology. Recent pathological studies have raised the possibility that the ...enteric nervous system (ENS) is one of the initial sites of alpha‐synuclein pathology in PD. We therefore undertook this survey to determine whether alpha‐synuclein can be secreted by enteric neurons. Alpha‐synuclein secretion was assessed by immunoblot analysis of the culture medium from primary culture of ENS. We show that alpha‐synuclein is physiologically secreted by enteric neurons via a conventional, endoplasmic reticulum/Golgi‐dependent exocytosis, in a neuronal activity‐regulated manner. Our study is the first to evidence that enteric neurons are capable of secreting alpha‐synuclein, thereby providing new insights into the role of the ENS in the pathophysiology of PD.
Current evidence suggests that extracellular alpha‐synuclein is critically involved in the spread of Parkinson's disease. As the enteric nervous system is affected early in Parkinson's disease, we undertook this research to investigate whether enteric neurons are capable of secreting alpha‐synuclein. Using primary culture of enteric nervous system, we show that alpha‐synuclein is physiologically secreted by enteric neurons in an activity‐regulated manner. Our results reinforce the assumption that the enteric nervous system might be implicated in the pathophysiology of Parkinson's disease.
Read the Editorial Highlight for this article on doi: 10.1111/jnc.12191.
Wistar rat dams exposed to limited nesting stress (LNS) from post-natal days (PND) 2 to 10 display erratic maternal behavior, and their pups show delayed maturation of the ...hypothalamic-pituitary-adrenal axis and impaired epithelial barrier at PND10 and a visceral hypersensitivity at adulthood. Little is known about the impact of early life stress on the offspring before adulthood and the influence of sex. We investigated whether male and female rats previously exposed to LNS displays at weaning altered corticosterone, intestinal permeability, and microbiota.
Wistar rat dams and litters were maintained from PND2 to 10 with limited nesting/bedding materials and thereafter reverted to normal housing up to weaning (PND21). Control litters had normal housing. At weaning, we monitored body weight, corticosterone plasma levels (enzyme immunoassay), in vivo intestinal to colon permeability (fluorescein isothiocyanate-dextran 4 kDa) and fecal microbiota (DNA extraction and amplification of the V4 region of the 16S ribosomal RNA gene).
At weaning, LNS pups had hypercorticosteronemia and enhanced intestinal permeability with females > males while body weights were similar. LNS decreased fecal microbial diversity and induced a distinct composition characterized by increased abundance of Gram positive cocci and reduction of fiber-degrading, butyrate-producing, and mucus-resident microbes.
These data indicate that chronic exposure to LNS during the first week post-natally has sustained effects monitored at weaning including hypercorticosteronemia, a leaky gut, and dysbiosis. These alterations may impact on the susceptibility to develop visceral hypersensitivity in adult rats and have relevance to the development of irritable bowel syndrome in childhood.
A few studies indicate that limited nesting stress (LNS) alters maternal behavior and the hypothalamic pituitary adrenal (HPA) axis of dams and offspring in male Sprague Dawley rats. In the present ...study, we evaluated the impact of LNS on maternal behavior in Wistar rats, and on the HPA axis, glycemia and in vivo intestinal permeability of male and female offspring. Intestinal permeability is known to be elevated during the first week postnatally and influenced by glucocorticoids. Dams and neonatal litters were subjected to LNS or normal nesting conditions (control) from days 2 to 10 postnatally. At day 10, blood was collected from pups for determination of glucose and plasma corticosterone by enzyme immunoassay and in vivo intestinal permeability by oral gavage of fluorescein isothiocyanate-dextran 4kDa. Dams exposed to LNS compared to control showed an increase in the percentage of time spent building a nest (118%), self-grooming (69%), and putting the pups back to the nest (167%). LNS male and female pups exhibited a reduction of body weight by 5% and 4%, adrenal weights/100g body weight by 17% and 18%, corticosterone plasma levels by 64% and 62% and blood glucose by 11% and 12% respectively compared to same sex control pups. In male LNS pups, intestinal permeability was increased by 2.7-fold while no change was observed in females compared to same sex control. There was no sex difference in any of the parameters in control pups except the body weight. These data indicate that Wistar dams subjected to LNS during the first postnatal week have an altered repertoire of maternal behaviors which affects the development of the HPA axis in both sexes and intestinal barrier function in male offspring.
Background
Water avoidance stress (WAS) induces a naloxone‐independent visceral analgesia in male rats under non‐invasive conditions of monitoring. The objective of the study was to examine the role ...of brain CRF signaling in acute stress‐induced visceral analgesia (SIVA).
Methods
Adult male Sprague‐Dawley rats were chronically implanted with an intracerebroventricular (ICV) cannula. The visceromotor response (VMR) to graded phasic colorectal distension (CRD: 10, 20, 40, 60 mm Hg, 20 seconds, 4 minutes intervals) was monitored using manometry. The VMR to a first CRD (baseline) was recorded 5 minutes after an ICV saline injection, followed 1 hour later by ICV injection of either CRF (30, 100, or 300 ng and 1, 3, or 5 μg/rat) or saline and a second CRD, 5 minutes later. Receptor antagonists against CRF1/CRF2 (astressin‐B, 30 μg/rat), CRF2 (astressin2‐B, 10 μg/rat), oxytocin (tocinoic acid, 20 μg/rat), or vehicle were injected ICV 5 minutes before CRF (300 ng/rat, ICV) or 15 minutes before WAS (1 hour).
Key Results
ICV CRF (100 and 300 ng) reduced the VMR to CRD at 60 mm Hg by −36.6% ± 6.8% and −48.7% ± 11.7%, respectively, vs baseline (P < 0.001), while other doses had no effect and IP CRF (10 µg/kg) induced visceral hyperalgesia. Astressin‐B and tocinoic acid injected ICV induced hyperalgesia and prevented the analgesic effect of ICV CRF (300 ng/rat) and WAS, while astressin2‐B only blocked WAS‐induced SIVA.
Conclusions & Inferences
These data support a role for brain CRF signaling via CRF2 in SIVA in a model of WAS and CRD likely mediated by the activation of brain oxytocin pathway.
Recent reports indicate that WAS induces a naloxone‐independent visceral analgesia in male rats under non‐invasive conditions of monitoring, but the underlying brain neurochemical mechanisms are still unknown. When injected intracerebroventricularly (ICV) at low nanogram range doses, CRF induced a CRF1 receptor‐mediated visceral analgesic response to colorectal distension that was prevented by ICV oxytocin antagonist. Similarly, acute WAS recruits endogenous CRF and oxytocin to induce SIVA. Increasing the understanding of the neurochemical coding by which stress promotes visceral analgesia and how their dysfunction leads to visceral hyperalgesia may help developing new therapeutic modalities for patients with functional gastrointestinal disorders who exhibit abnormal endogenous pain modulation.
Sacral nerve stimulation (SNS) is recognized for its efficiency and safety for anal incontinence, preventing high morbidity. Evidence from the literature suggests extending SNS to diseases associated ...with problems of intestinal barrier permeability. The aim of this study was to highlight clinical evidence of the beneficial impact of SNS in a refractory proctitis case report.
A permanent SNS was performed successfully in a patient with proctitis after implantation of the neuromodulator. Despite immunosuppressive drugs, the patient was experiencing mucus and blood discharge, pain, and fecal incontinence. To relieve fecal incontinence, SNS was tested without modification of medications. Disease activity, endoscopic and histologic score, ex vivo barrier permeability, expression of inflammatory cytokines (transforming growth factor-β, tumor necrosis factor α, Interleukin-6, Interleukin-8), and junctional proteins (ZO-1, claudin-1, occludin) were assessed before and after SNS to observe the impact of SNS other than for incontinence.
After a 3-week period of temporary stimulation, the patient experienced significant improvement with a decrease in fecal incontinence and disease activity scores. Both endoscopic and histologic scores showed improvement. The rectal barrier permeability decreased with SNS, whereas junctional protein mRNA expression transiently increased. Clinical and histologic improvement was sustained over time. After 18 months of permanent stimulation, the patient remained improved by SNS.
This work demonstrates the relevance to explore further indications of SNS beyond fecal incontinence.
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