The rat posterodorsal medial amygdala (MePD) expresses receptors for gonadal hormones and integrates sex steroid-sensitive subcortical networks. Male-female differences are found in the morphology, connectivity, and local neuropil structure of MePD. For example, dendritic spine density is sexually-dimorphic and changes with the estrous cycle and following gonadal hormones manipulations. Due to its connectivity, the MePD may affect emotionally-loaded social behaviors, according to a former Newman's seminal proposition. Unilateral fiber-sparing ibotenic acid damage of the MePD does not impair male sexual behavior. However, microinjecting glutamate and histamine into the right MePD facilitates ejaculation. Further, MePD-lesioned rats are not different from normal rats in anxiety-like behavior as evaluated by the elevated plus maze test or innate fear test induced by a live cat. In another study, an adapted model for inducing aggressive behavior in rats by a brief period of restraint prior to the resident-intruder paradigm was used to study Fos-immunoreactivity in the MePD. Following stressful stimulation (restraint) or the restraint and fight condition, but not after aggression alone, Fos-immunoreactivity was detected in the MePD. Microinjecting the inhibitory neuropeptide somatostatin into the right MePD notably reduces fighting behavior without affecting locomotion. Overall, these data indicate that sex steroids and local neurochemical stimulatory/inhibitory transmitters modulate the MePD and reinforce the idea that this area is a node for modulating social behavior neural networks.

In this case a mother and three of her four sons living in southern England are affected. The mother’s At III level measured as progressive At III (chromogenic substrate) was 51% heparin cofactor 61% and by immunological assay 53%. Three sons have At III levels of 48%, 55%. and 56%, (progressive), 43%, 54% and 51% (heparin eofarctor), and 53%, 57% and 51% (immunological) respectively. By a clotting assay the sons were found to have values of 60%, 56% and 63% Crossover immmunoelectrophoresis against At III antisera in the presence of heparin (Sas et al, 1975) showed no difference from normal, distinguishing this form of deficiency from Antithrombin Budapest. A sister of the mother and four other members of the family had normal At III levels. All members of the family had normal levels of α1 antitrypsin and α-2 macroglobulin as measured by the radial immunodiffusion technique.Clinically all the At III deficient sons have had recurrent DVT and have grade IV post phlebitic legs. One son has also had in addition, an inferior vena cava thrombosis (at age of 8 years) and mesenteric thrombosis (at age of 30 years). The development of a thrombosis at age 8 may illustrate that symptoms of At III deficiency may not be confined only 8 adulthood. Affected members of the family are at present: on a regimen of self administered low-dose subcutaneous heparin.

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Background Intestinal microbiota, diet, and the immune system have been proposed to contribute to the development of inflammatory bowel diseases (IBD). The aryl hydrocarbon receptor (AhR) is a critical regulator of intestinal immunity and mucosal barrier homeostasis that is activated by agonists such as host and microbial tryptophan metabolites. IBD patients have altered microbiota and reduced AhR agonists in intestinal content resulting in the downregulation of AhR. These findings necessitate further study to understand how diet-microbiota interactions contribute to intestinal inflammation. Purpose To study the influence of intestinal microbiota on tryptophan metabolism, AhR activation, and colitis severity. Method 8- to 10-week-old germ-free C57BL/6 mice were colonized with cecal content of mice harbouring specific pathogen-free (SPF) or a limited and well-defined altered Schaedler flora (ASF) microbiota. Germ-free mice were used as controls. Three weeks following colonization, mucosal injury was induced in a subset of mice with dextran sulfate sodium (DSS) in drinking water for five days followed by two days of water recovery. Activation of AhR was measured in stool using an in vitro AhR luciferase reporter assay. Stool AhR agonists were determined using high-performance liquid chromatography coupled to high-resolution mass spectrometry. Colonic expression of AhR pathway genes Cyp1a1, Il22, Ahrr, Ahr, and Il17 was evaluated by RT-qPCR. Susceptibility to colitis was assessed by analysing stool consistency and stool blood, colonic microscopic damage, immune infiltration by immunohistochemistry, and pro-inflammatory gene expression (NanoString). Fecal microbiota was analysed by 16S rRNA gene sequencing (Illumina). Result(s) AhR agonists, AhR activation in vitro, and AhR pathway gene expression were elevated in mice colonized with SPF microbiota in comparison to mice colonized with ASF microbiota and germ-free mice. In ASF-colonized mice, DSS induced more severe inflammation than in SPF-colonized mice, as demonstrated by worsened mucosal injury, greater weight loss, and softer stools. SPF-colonized mice developed less mucosal immune cell infiltration and pro-inflammatory gene signaling. Conclusion(s) Our findings suggest that intestinal microbiota composition determines the metabolic capacity to degrade tryptophan into agonists that homeostatically activate AhR. When mucosal injury is induced, mice with elevated microbiota-derived AhR agonists and AhR activation develop less severe mucosal injury and signs of colitis. This study presents a useful tool for evaluating dietary and microbial therapies in the context of a microbiota with impaired tryptophan metabolism. Please acknowledge all funding agencies by checking the applicable boxes below CCC, CIHR Disclosure of Interest None Declared

Background The intestinal microbiota, diet, and the immune system have all been proposed to contribute to the development of inflammatory bowel disease (IBD). The aryl hydrocarbon receptor (AhR) is a critical regulator of intestinal immunity and mucosal barrier homeostasis that is activated by agonists such as diet-derived microbial tryptophan (Trp) metabolites. Increasing evidence suggests that IBD patients have reduced AhR agonists in intestinal content resulting in the downregulation of AhR-regulated genes. In mice, impaired Trp metabolism and AhR signaling translate to increased intestinal inflammation and injury during colitis. This finding highlights the utility of Trp dietary intervention to reduce the onset and progression of inflammation and injury in IBD. Aims To optimize a Trp-enriched diet formulation to increase AhR activation and reduce intestinal inflammation and injury in mouse models of colitis. Methods Three diet types with elevated Trp were explored: (1) free amino acid diet with added Trp, (2) purified protein diet with added Trp, and (3) purified high protein diet. Following three weeks of diet consumption by C57BL/6 mice, mucosal injury was induced with 2% dextran sulfate sodium in drinking water (DSS) before sacrifice. Susceptibility to colitis was assessed by analyzing stool consistency and blood, microscopic damage, immune infiltration by immunohistochemistry, and pro-inflammatory gene expression (NanoString). Activation of AhR was measured in feces using an in vitro AhR luciferase reporter assay. Colonic expression of AhR pathway genes Cyp1a1, Il22, Ahrr, and Il17 was evaluated by RT-qPCR. Fecal microbiota was analyzed by 16S rRNA gene sequencing (Illumina). Results AhR activation in vitro and colonic AhR pathway gene expression were elevated in mice fed diets containing added Trp (1 & 2) in comparison to mice fed a high protein diet (3). While all DSS-treated mice developed colitis, mice fed a purified protein diet with added Trp (2) were protected from severe colitis and developed less microscopic damage, immune cell infiltration, and pro-inflammatory gene signalling. Enriched Trp concentrations in the form of free amino acid (1) and high protein (3) diets were not associated with protection from inflammation and injury during colitis. Conclusions Our findings suggest that the addition of Trp to a conventional diet (2) may increase microbial tryptophan metabolites to ameliorate colitis severity and intestinal homeostasis through AhR activation. Despite having similar Trp concentrations, a Trp-enriched free amino acid diet (1) and a high protein diet (3) do not improve colitis severity. Thus, both the diet formulation and the availability of Trp should be considered when designing dietary interventions for the treatment of colitis through AhR activation. Funding Agencies CCC, CIHRFarncombe Family Digestive Health Research Institute, Douglas Family Chair in Gastroenterology Research, Biocodex Microbiota Foundation