Treatment Outcomes of Patients with Orbital Inflammatory Diseases: Should Steroids Still Be the First Choice?

Objective: To clarify the therapy response in orbital inflammatory diseases (OID), we analyzed the treatment effects of steroid therapy, the use of disease-modifying antirheumatic drugs (DMARDS), and biologicals in our tertiary referral center cohort. Methods: We collected the clinical and demographic data of all patients treated for non-specific orbital inflammation (NSOI) (n = 111) and IgG4-ROD (n = 13), respectively at our center from 2008 to 2020 and analyzed them with descriptive statistics. NSOI were sub-grouped according to the location into either idiopathic dacryoadenitis (DAs) (n = 78) or typical idiopathic orbital myositis (n = 32). Results: Mean age at first clinical manifestation was significantly different between subgroups (IOI: 49.5 ± 18, IgG4-ROD: 63.2 ± 14, p = 0.0171). Among all examined OID, 63 patients (50%) achieved full remission (FR) with corticosteroids (NSOI 53%/IgG4-ROD 31%). In contrast, classic myositis showed a significantly higher response (76%). Disease-modifying drugs (DMARDS) for myositis accomplished only 33% FR (NSOI 57%) and 66% did not respond sufficiently (NSOI 43%). The biologic agent (Rituximab) was significantly more efficient: 19 of 23 patients (82%) achieved full remission and only 4 (17%) did not respond fully and needed orbital irradiation or orbital decompressive surgery.

[Graves' orbitopathy as the cause of diplopia in old age-Differences between young and old]. / Endokrine Orbitopathie als Ursache einer Diplopie im Senium ­ Unterschiede zwischen Jung und Alt.

BACKGROUND: Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue. PATIENTS AND METHODS: The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 ≤50 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses. RESULTS: Younger patients (n = 484) presented significantly more frequently with milder EO (53% vs. 33%, p < 0.0001), whereas older patients (n = 448) more frequently suffered from moderate or severe forms (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310° vs. 330°, both p < 0.0001, CAS 2.1 vs. 1.7, p = 0.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR = 0.12, 95 % CI 0.1-0.2, p < 0.0001), followed by orbital irradiation and age. CONCLUSION: In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age.

Repeated Lacrimal Gland Biopsies.

PURPOSE: To examine the indications for repeated lacrimal gland biopsies, and the rate of detection of a new diagnosis. METHODS: A single-center, retrospective review of patients who underwent more than 1 lacrimal gland biopsy, either ipsilateral or contralateral, between 2000 and 2022. RESULTS: One hundred and twenty-three patients (80 female; 65%) had repeated lacrimal gland biopsy. The commonest diagnosis on initial biopsy was chronic nonspecific dacryoadenitis (NSD) (49/123; 40%). Indications for repeated biopsy were uncertainty in making a histopathological diagnosis (16/123; 13%), poorly-responsive or recurrent ipsilateral disease (61/123; 50%), new or continued/worsening contralateral disease (30 patients; 24%), and planned tumor resection after initial biopsy (16/123; 13%). Of the 40 patients (33%) with a different histopathological diagnosis after repeated lacrimal biopsy, 4 (10%) had lymphoma, initially reported as NSD (4/49 with NSD; 8%), and 7/40 (18%) (14% of the 49 NSD patients) were reclassified as having specific inflammations (including 2 with granulomatous polyangiitis); of the 7 having reclassification as a specific dacryoadenitis, 6/7 had ipsilateral disease failing to respond to primary treatment, and 1/7 had new onset or progression of contralateral disease. All histology after the primary biopsy of 16 patients with lacrimal gland malignancies retained the same tissue diagnosis. CONCLUSION: Repeated biopsy for lacrimal gland disease in this study revealed a diagnosis of malignancy in 20%, including lymphoma in 8% of those initially diagnosed with NSD. There was a 14% rate of diagnostic progression from "non-specific" dacryoadenitis to a more specific inflammatory disease.

Rare periorbital, pseudocystic metastasis of squamous cell carcinoma of the bladder: Case report and review of the literature.

We present the case of a man in his fifties with a history of bladder carcinoma who presented with a large periorbital cystic lesion that was found to be a metastasis. Bladder carcinomas are a very rare cause of peri-/orbital metastasis. The primary tumor in this case predominately showed squamous cell differentiation and small areas of adenoid differentiation. To our knowledge only one previous case of orbital metastasis from squamous cell carcinoma of the bladder has been reported. Cyst formation in bladder cancer metastasis has not been reported and is very rare for orbital metastases in general. The pathogenesis of metastatic cyst development is not fully understood and may vary from case to case. A biopsy of an atypical cyst is indicated.

Treatment of periocular lentigo maligna with topical 5% Imiquimod: a review.

Lentigo Maligna is a benign subtype of melanoma in situ and can progress to lentigo maligna melanoma, which is invasive. Complete surgical excision is the gold standard of treatment but requires large margins. If affecting the peri-ocular region, surgical excision leads to extensive defects, complex reconstructions, and functional impairment of the protection of the ocular surface. Here we review the reported literature about the use of Imiquimod 5% topical cream for lentigo maligna of the eyelid, the treatment outcomes, side effects and tolerance. In addition, the side effects of imiquimod treatment of non-LM lesions are described to help better inform the decision-making process. Treatment for peri-ocular Lentigo maligna showed a 56-86% complete treatment response and a 90% tolerability rate. However, reported treatment protocols vary and histopathological confirmation of clearance was only obtained in 56%. Further studies are required to determine the optimal treatment protocol to maximise clearance rates. Overall, Imiquimod was well tolerated in the peri-ocular area.

Total Full-Thickness Upper Eyelid Reconstruction: Combination of Mustardé Eyelid Switch Flap with a Bipedicled Periosteal and Tenzel Flap Technique.

INTRODUCTION: In recent decades, two techniques for large full-thickness upper eyelid reconstruction have been described, the Cutler-Beard lid sharing flap and the Mustardé eyelid switch flap. In the literature, modifications are being introduced to improve those techniques. Here, we present our approach for the reconstruction of total full-thickness upper eyelid defects and compare it with these established upper lid reconstruction techniques. METHODS: Three patients presented with upper eyelid tumors and required extensive excision resulting in total full-thickness upper eyelid defects. Reconstruction consisted of a two-stage procedure: a Mustardé eyelid switch flap was performed followed by division of the rotation flap and lateral canthoplasty using a periosteal bipedicled flap and Tenzel flap. Patients were followed-up every 3 months for at least 1 year. During every preoperative and postoperative check-up, palpebral fissure height, levator function, margin reflex distance, and presence of lagophthalmos were measured. RESULTS: Histopathological examination revealed a Merkel cell carcinoma in two cases and a Basal cell carcinoma in one case. Postoperatively, all patients showed a stable reconstructed upper eyelid with preserved motility and satisfying aesthetic results when compared to the fellow eye. In one case, a lagophthalmos of 1.5 mm was observed, which was treated conservatively to prevent exposure keratopathy. CONCLUSION: The eyelid switch flap combined with a bipedicled periosteal and a Tenzel flap is a good alternative for the reconstruction of total upper eyelid defects with the advantage of leaving the contralateral eye untouched. It achieves satisfying anatomical results, including an upper eyelid margin with eyelashes and well-matched skin color.

Transcriptome and chromatin alterations in social fear indicate association of MEG3 with successful extinction of fear.

Social anxiety disorder is characterized by a persistent fear and avoidance of social situations, but available treatment options are rather unspecific. Using an established mouse social fear conditioning (SFC) paradigm, we profiled gene expression and chromatin alterations after the acquisition and extinction of social fear within the septum, a brain region important for social fear and social behaviors. Here, we particularly focused on the successful versus unsuccessful outcome of social fear extinction training, which corresponds to treatment responsive versus resistant patients in the clinics. Validation of coding and non-coding RNAs revealed specific isoforms of the long non-coding RNA (lncRNA) Meg3 regulated, depending on the success of social fear extinction. Moreover, PI3K/AKT was differentially activated with extinction success in SFC-mice. In vivo knockdown of specific Meg3 isoforms increased baseline activity of PI3K/AKT signaling, and mildly delayed social fear extinction. Using ATAC-Seq and CUT&RUN, we found alterations in the chromatin structure of specific genes, which might be direct targets of lncRNA Meg3.

GDF15 promotes simultaneous astrocyte remodeling and tight junction strengthening at the blood-brain barrier.

Perivascular astrocyte processes (PAP) surround cerebral endothelial cells (ECs) and modulate the strengthening of tight junctions to influence blood-brain barrier (BBB) permeability. Morphologically altered astrocytes may affect barrier properties and trigger the onset of brain pathologies. However, astrocyte-dependent mediators of these events remain poorly studied. Here, we show a pharmacologically driven elevated expression and release of growth/differentiation factor 15 (GDF15) in rat primary astrocytes and cerebral PAP. GDF15 has been shown to possess trophic properties for motor neurons, prompting us to hypothesize similar effects on astrocytes. Indeed, its increased expression and release occurred simultaneously to morphological changes of astrocytes in vitro and PAP, suggesting modulatory effects of GDF15 on these cells, but also neighboring EC. Administration of recombinant GDF15 was sufficient to promote astrocyte remodeling and enhance barrier properties between ECs in vitro, whereas its pharmacogenetic abrogation prevented these effects. We validated our findings in male high anxiety-related behavior rats, an animal model of depressive-like behavior, with shrunk PAP associated with reduced expression of the junctional protein claudin-5, which were both restored by a pharmacologically induced increase in GDF15 expression. Thus, we identified GDF15 as an astrocyte-derived trigger of astrocyte process remodeling linked to enhanced tight junction strengthening at the BBB.

Chemogenetic activation of oxytocin neurons: Temporal dynamics, hormonal release, and behavioral consequences.

Chemogenetics provides cell type-specific remote control of neuronal activity. Here, we describe the application of chemogenetics used to specifically activate oxytocin (OT) neurons as representatives of a unique class of neuroendocrine cells. We injected recombinant adeno-associated vectors, driving the stimulatory subunit hM3Dq of a modified human muscarinic receptor into the rat hypothalamus to achieve cell type-specific expression in OT neurons. As chemogenetic activation of OT neurons has not been reported, we provide systematic analysis of the temporal dynamics of OT neuronal responses in vivo by monitoring calcium fluctuations in OT neurons, and intracerebral as well as peripheral release of OT. We further provide evidence for the efficiency of chemogenetic manipulation at behavioral levels, demonstrating that evoked activation of OT neurons leads to social motivation and anxiolysis. Altogether, our results will be profitable for researchers working on the physiology of neuroendocrine systems, peptidergic modulation of behaviors and translational psychiatry.

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis.

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.

Oxytocin Regulates Stress-Induced Crf Gene Transcription through CREB-Regulated Transcription Coactivator 3.

The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor (CRF), whose transcription is controlled by CREB and its cofactors CRTC2/3 (TORC2/3). Phosphorylated CRTCs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. As the stress response is attenuated by oxytocin (OT), we tested whether OT interferes with CRTC translocation and, thereby, Crf expression. OT (1 nmol, i.c.v.) delayed the stress-induced increase of nuclear CRTC3 and Crf hnRNA levels in the paraventricular nucleus of male rats and mice, but did not affect either parameter in the absence of the stressor. The increase in Crf hnRNA levels at later time points was parallel to elevated nuclear CRTC2/3 levels. A direct effect of Thr(4) Gly(7)-OT (TGOT) on CRTC3 translocation and Crf expression was found in rat primary hypothalamic neurons, amygdaloid (Ar-5), hypothalamic (H32), and human neuroblastoma (Be(2)M17) cell lines. CRTC3, but not CRCT2, knockdown using siRNA in Be(2)M17 cells prevented the effect of TGOT on Crf hnRNA levels. Chromatin-immunoprecipitation demonstrated that TGOT reduced CRTC3, but not CRTC2, binding to the Crf promoter after 10 min of forskolin stimulation. Together, the results indicate that OT modulates CRTC3 translocation, the binding of CRTC3 to the Crf promoter and, ultimately, transcription of the Crf gene. SIGNIFICANCE STATEMENT: The neuropeptide oxytocin has been proposed to reduce hypothalamic-pituitary-adrenal (HPA) axis activation during stress. The underlying mechanisms are, however, elusive. In this study we show that activation of the oxytocin receptor in the paraventricular nucleus delays transcription of the gene encoding corticotropin releasing factor (Crf), the main regulator of the stress response. It does so by sequestering the coactivator of the transcription factor CREB, CRTC3, in the cytosol, resulting in reduced binding of CRTC3 to the Crf gene promoter and subsequent Crf gene expression. This novel oxytocin receptor-mediated intracellular mechanism might provide a basis for the treatment of exaggerated stress responses in the future.

Prolactin-derived vasoinhibins increase anxiety- and depression-related behaviors.

The hormone prolactin (PRL) regulates neuroendocrine and emotional stress responses. It is found in the hypothalamus, where the protein is partially cleaved to vasoinhibins, a family of N-terminal antiangiogenic PRL fragments ranging from 14 to 18kDa molecular masses, with unknown effects on the stress response. Here, we show that the intracerebroventricular administration of a recombinant vasoinhibin, containing the first 123 amino acids of human PRL that correspond to a 14kDa PRL, exerts anxiogenic and depressive-like effects detected in the elevated plus-maze, the open field, and the forced swimming tests. To investigate whether stressor exposure affects the generation of vasoinhibins in the hypothalamus, the concentrations of PRL mRNA, PRL, and vasoinhibins were evaluated in hypothalamic extracts of virgin female rats immobilized for 30min at different time points after stress onset. The hypothalamic levels of PRL mRNA and protein were higher at 60min but declined at 360min to levels seen in non-stressed animals. The elevation of hypothalamic PRL did not correlate with the stress-induced increase in circulating PRL levels, nor was it modified by blocking adenohypophyseal PRL secretion with bromocriptine. A vasoinhibin having an electrophoretic migration rate corresponding to 17kDa was detected in the hypothalamus. Despite the elevation in hypothalamic PRL, the levels of this hypothalamic vasoinhibin were similar in stressed and non-stressed rats. Stress reduced the rate of cleavage of PRL to this vasoinhibin as shown by the incubation of recombinant PRL with hypothalamic extracts from stressed rats. These results suggest that vasoinhibins are potent anxiogenic and depressive factors and that stress increases PRL levels in the hypothalamus partly by reducing its conversion to vasoinhibins. The reciprocal interplay between PRL and vasoinhibins may represent an effective mechanism to regulate anxiety and depression.

Short-term psychosocial stress protects photoreceptors from damage via corticosterone-mediated activation of the AKT pathway.

Apoptotic death of photoreceptors in hereditary retinal degenerations can be prevented by neuroprotective molecules. Here, we report that adrenal glucocorticoids (GC) released during psychosocial stress protect photoreceptors from apoptosis after light damage. Psychosocial stress is known to be the main type of stressor humans are exposed to and was induced here in mice by 10h of chronic subordinate colony housing (CSC). Photoreceptor damage was generated by subsequent exposure to white light. Short-term psychosocial stress prior to illumination significantly reduced the number of apoptotic photoreceptors, an effect that was absent in adrenalectomized (ADX) mice. The neuroprotective effect was completely restored in ADX mice substituted with GC. Moreover, phosphorylation of retinal AKT increased following CSC or exogenous GC treatment, an effect that was again absent in ADX mice exposed to CSC. Finally, inhibition of AKT signaling with triciribine blocked the stress- and GC-mediated neuroprotective effects on photoreceptors. In summary, we provide evidence that 1) short-term psychosocial stress protects photoreceptors from light-induced damage and 2) the protective effect is most likely mediated by GC-induced activation of the AKT signaling pathway.

Reduced plasma oxytocin levels in female patients with borderline personality disorder.

The neuropeptide oxytocin is involved in social cognition and interaction across species and plays a crucial role in the regulation of affiliative behaviors. Oxytocin levels in cerebrospinal fluid (CSF), but also in plasma or urine, have been shown to be negatively associated with childhood traumata, aggressive behavior, and suicide attempts. Recently, an altered activity of the oxytocin system has been discussed to play a prominent role in borderline personality disorder (BPD), which is thought to be closely related to traumatic experiences in childhood and is characterized by (para)suicidal behaviors as well as aggressive outbursts. In the present study, we compared plasma oxytocin levels of women with and without BPD in the follicular phase and assessed the relationship between oxytocin concentrations and childhood traumata. Women diagnosed with BPD had significantly reduced oxytocin concentrations, even after controlling for estrogen, progesterone, and contraceptive intake. In addition, plasma oxytocin correlated negatively with experiences of childhood traumata, in particular with emotional neglect and abuse. The results of mediation analyses do not support a model of oxytocin being a prominent mediator in the link between childhood trauma and BPD. Thus, the findings indicate dysregulations in the oxytocin system of patients diagnosed with BPD with more longitudinal research being necessary to disentangle the relationship between childhood adversities, oxytocin system, and psychopathology.

Comparison of corticosterone responses to acute stressors: chronic jugular vein versus trunk blood samples in mice.

A commonly used method for obtaining blood samples from mice is decapitation. However, there is an obvious need for repeated blood sampling in mice under stress-free conditions. Here, we describe a simple technique to repeatedly collect blood samples from conscious, freely moving mice through a chronically implanted jugular vein catheter. Furthermore, we compare plasma corticosterone (CORT) concentrations in samples obtained through the catheter 1 day after surgery with samples taken from trunk blood obtained under basal or acute stress conditions. CORT concentrations in repeated 100-µl venous blood samples were found to be similar to trunk blood samples both under basal conditions and after stressor exposure collected at identical time points (at 5, 15, and 60 min). Using both techniques, we demonstrate a progressive increase in CORT levels until 15 min after termination of stressor exposure and a decrease towards baseline values 60 min later. Anxiety-related behavior, as assessed on the elevated plus maze 3-4 days after surgery, did not differ between catheterized and non-catheterized mice. Our results provide evidence for application of jugular vein catheterization as a technique for repeated blood sampling in conscious laboratory mice. Use of this technique will greatly reduce the number of animals required for experiments involving endocrine endpoints.

Chronic psychosocial stress increases the risk for inflammation-related colon carcinogenesis in male mice.

Patients with inflammatory bowel diseases (IBDs) have a higher risk of developing colorectal cancer (CRC) than the general population. Furthermore, chronic psychosocial stress increases the likelihood of developing IBD and multiple types of malignant neoplasms, including CRC. Here, for the first time, we investigate the effects of chronic psychosocial stress in male mice on an artificially induced CRC, by employing the chronic subordinate colony (CSC) housing paradigm in combination with the reliable azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC model. Colonoscopy revealed that CSC mice showed accelerated macroscopic suspect lesions. In addition, more CSC mice developed low-grade dysplasia (LGD) and/or high-grade dysplasia (HGD) in the colonic tissue compared to the single-housed control mice (SHC). CSC mice showed an increased number of Ki67+ and a decreased number of terminal deoxynucleotidyl transferase dUTP nick end labeling epithelial cells in colonic tissue. Colonic liver receptor homolog-1 (LRH-1), cyclooxygenase II (COXII), tumor necrosis factor, forkhead box P3 (FoxP3) mRNA as well as colonic ß-catenin, COXII, and LRH-1 protein expression were also increased in CSC compared with SHC mice. Although the number of CD4+ Th cells was increased, a tendency toward a decreased colonic interferon-γ (IFN-γ) mRNA expression was observed. Furthermore, despite an increased percentage of CD3+ cells and CD3+/FoxP3+ double-positive cells within mesenteric lymph node cells of CSC mice, IFN-γ secretion from these cells was unaffected. Altogether, our results suggest that chronic psychosocial stress increases the risk for AOM/DSS-induced and, thus, inflammation-related CRC. Finally, assessment of additional time points may test whether the shift from tumor-protective Th1 cell to regulatory T-cell immunity represents a consequence of increased carcinogenesis or a causal factor involved in its development.

Yes, I am ready now: differential effects of paced versus unpaced mating on anxiety and central oxytocin release in female rats.

Sexual activity and partner intimacy results in several positive consequences in the context of stress-coping, both in males and females, such as reduced state anxiety in male rats after successful mating. However, in female rats, mating is a rewarding experience only when the estrous female is able to control sexual interactions, i.e., under paced-mating conditions. Here, we demonstrate that sex-steroid priming required for female mating is anxiolytic; subsequent sexual activity under paced mating conditions did not disrupt this anxiolytic priming effect, whereas mating under unpaced conditions increased anxiety-related behavior. In primed females, the release of the neuropeptide oxytocin (OT) within the hypothalamic paraventricular nucleus was found to be elevated and to further increase during paced, but not unpaced mating. Central administration of an OT receptor antagonist partly prevented priming/mating-induced anxiolysis indicating the involvement of brain OT in the anxiolysis triggered by priming and/or sexual activity.These findings reveal that the positive consequences of mating in females are dependent on her ability to control sexual interactions, and that brain OT release is at least in part the underlying neurobiological correlate.

Mucosal immunosuppression and epithelial barrier defects are key events in murine psychosocial stress-induced colitis.

Chronic psychosocial stress is a risk factor for many affective and somatic disorders, including inflammatory bowel diseases. In support chronic subordinate colony housing (CSC, 19 days), an established mouse model of chronic psychosocial stress, causes the development of spontaneous colitis. However, the mechanisms underlying the development of such stress-induced colitis are poorly understood. Assessing several functional levels of the colon during the initial stress phase, we show a pronounced adrenal hormone-mediated local immune suppression, paralleled by impaired intestinal barrier functions, resulting in enhanced bacterial load in stool and colonic tissue. Moreover, prolonged treatment with broad-spectrum antibiotics revealed the causal role of these early maladaptations in the development of stress-induced colitis. Together, we demonstrate that translocation of commensal bacteria is crucial in the initiation of stress-induced colonic inflammation. However, aggravation by the immune-modulatory effects of fluctuating levels of adrenal hormones is required to develop this into a full-blown colitis.

Attenuation of the neuronal stress responsiveness and corticotrophin releasing hormone synthesis after sexual activity in male rats.

Beneficial effects of sexual activity and mating on the responsiveness to environmental stress can be observed in humans and other mammalian species alike, but the underlying neurobiological mechanisms are largely unknown. Sexual activity and mating with a receptive female has recently been shown to reduce the subsequent emotional stress response via activation of the brain oxytocin system. Therefore, we investigated the neuronal and hormonal responses to an acute stressor (forced swimming) after mating in male rats. Attenuation of the stress-induced increase of c-fos and CRH mRNA expression within the hypothalamic paraventricular nucleus 4 h after mating revealed that sexual activity reduced neuronal reactivity in this region. However, this effect was independent of oxytocin as oxytocin receptor blockade, by central administration of an oxytocin receptor antagonist, after mating did not prevent the reduced expression of c-fos mRNA in response to stressor exposure. Mating itself stimulated corticotrophin (ACTH) and corticosterone secretion, which was absent in males after contact with an unreceptive female (non-mated group). However, ACTH and corticosterone responses to forced swimming applied either 45 min or 4 h after female contact were similar between mated and non-mated males. These findings provide evidence for a stress-protective effect of sexual activity and mating in male rats and for dissociation between neuronal and neuroendocrine stress responses.

Effects of chronic intracerebral prolactin on the oxytocinergic and vasopressinergic system of virgin ovariectomized rats.

Chronic intracerebroventricular (icv) infusion of prolactin (PRL) into the cerebral ventricles and mimicking central hyperprolactinemia in lactation has recently been shown to reduce anxiety and neuronal as well as neuroendocrine responses to acute stressor exposure. Here, we studied the effects of icv PRL on the activity of the oxytocin (OXT) and arginine vasopressin (AVP) systems of virgin female, ovariectomized, estradiol-substituted Wistar rats. Ovine PRL was delivered via osmotic minipumps at 0.01, 0.1 or 1 microg/h for 5 days. Under basal conditions, both plasma OXT and AVP concentrations were increased after chronic PRL treatment (1 microg/h). At hypothalamic level, this was accompanied by an increased c-fos and OXT mRNA expression within the supraoptic nucleus, the main source of plasma OXT, whereas AVP mRNA levels remained unchanged. No effect of PRL on c-fos or on nonapeptide mRNA expression was found in the hypothalamic paraventricular nucleus. Moreover, chronic PRL abolished the rise in plasma OXT induced by acute exposure to 30 min restraint stress in vehicle-treated rats. However, restraint stress did not significantly alter OXT or AVP mRNA expression in the hypothalamus of either vehicle- or PRL-treated animals. From these results we conclude that brain hyperprolactinemia alters the synthetic activity of OXT neurons and the secretory performance of OXT and AVP neurons within the hypothalamus, resulting in elevated plasma concentrations of both hormones under basal conditions. These changes are comparable to adaptations seen in the female peripartum period.