Evidence for a Role of srGAP3 in the Positioning of Commissural Axons within the Ventrolateral Funiculus of the Mouse Spinal Cord

Slit-Robo signaling guides commissural axons away from the floor-plate of the spinal cord and into the longitudinal axis after crossing the midline. In this study we have evaluated the role of the Slit-Robo GTPase activating protein 3 (srGAP3) in commissural axon guidance using a knockout (KO) mouse model. Co-immunoprecipitation experiments confirmed that srGAP3 interacts with the Slit receptors Robo1 and Robo2 and immunohistochemistry studies showed that srGAP3 co-localises with Robo1 in the ventral and lateral funiculus and with Robo2 in the lateral funiculus. Stalling axons have been reported in the floor-plate of Slit and Robo mutant spinal cords but our axon tracing experiments revealed no dorsal commissural axon stalling in the floor plate of the srGAP3 KO mouse. Interestingly we observed a significant thickening of the ventral funiculus and a thinning of the lateral funiculus in the srGAP3 KO spinal cord, which has also recently been reported in the Robo2 KO. However, axons in the enlarged ventral funiculus of the srGAP3 KO are Robo1 positive but do not express Robo2, indicating that the thickening of the ventral funiculus in the srGAP3 KO is not a Robo2 mediated effect. We suggest a role for srGAP3 in the lateral positioning of post crossing axons within the ventrolateral funiculus

Histamine Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling

Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H2 receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases

The research landscape of tuberous sclerosis complex–associated neuropsychiatric disorders (TAND)—a comprehensive scoping review

Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. Methods The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. Results Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). Conclusions Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified

Table_1_Family and developmental history of female versus male adolescents with ADHD: diagnosis-specific overlap, few gender/sex differences.xlsx

BackgroundGender and sex differences in the development of children and adolescents are commonly found in the psychiatric examination. Family and developmental history is an important part of the clinical diagnostic interview, the basic examination technique. Attention-deficit/hyperactivity disorder (ADHD) is associated with diagnosis-specific markers in family and development history. However, it is unclear to what extent ADHD-specific signs and narratives differ between females and males. The aim of this study was to assess and to compare the family and developmental history profiles of female versus male adolescents with ADHD.MethodsData were collected using the clinical diagnostic interview technique from parents of female and male patients diagnosed with ADHD (ICD-10  F90.0, F90.1 and F98.8) between the ages of 12 and 17  years (n = 92). The two groups were matched in pairs for sex, IQ and ICD-10 diagnosis (F90.0, F90.1 and F98.8). Interview data were operationalized in three categories: 0 - physiological marker, 1 - subclinical marker, 2 - clinical marker. The two groups were compared with two-way ANOVA.ResultsInformation about female in comparison to male adolescents were reported in the parental interview with few differences.ConclusionOur study suggests that family and developmental history of the neurodevelopmental disorder ADHD is only poorly influenced by gender or sex.</p

Data_Sheet_1_Family and developmental history of female versus male adolescents with ADHD: diagnosis-specific overlap, few gender/sex differences.PDF

BackgroundGender and sex differences in the development of children and adolescents are commonly found in the psychiatric examination. Family and developmental history is an important part of the clinical diagnostic interview, the basic examination technique. Attention-deficit/hyperactivity disorder (ADHD) is associated with diagnosis-specific markers in family and development history. However, it is unclear to what extent ADHD-specific signs and narratives differ between females and males. The aim of this study was to assess and to compare the family and developmental history profiles of female versus male adolescents with ADHD.MethodsData were collected using the clinical diagnostic interview technique from parents of female and male patients diagnosed with ADHD (ICD-10  F90.0, F90.1 and F98.8) between the ages of 12 and 17  years (n = 92). The two groups were matched in pairs for sex, IQ and ICD-10 diagnosis (F90.0, F90.1 and F98.8). Interview data were operationalized in three categories: 0 - physiological marker, 1 - subclinical marker, 2 - clinical marker. The two groups were compared with two-way ANOVA.ResultsInformation about female in comparison to male adolescents were reported in the parental interview with few differences.ConclusionOur study suggests that family and developmental history of the neurodevelopmental disorder ADHD is only poorly influenced by gender or sex.</p

Table_2_Family and developmental history of female versus male adolescents with ADHD: diagnosis-specific overlap, few gender/sex differences.xlsx

BackgroundGender and sex differences in the development of children and adolescents are commonly found in the psychiatric examination. Family and developmental history is an important part of the clinical diagnostic interview, the basic examination technique. Attention-deficit/hyperactivity disorder (ADHD) is associated with diagnosis-specific markers in family and development history. However, it is unclear to what extent ADHD-specific signs and narratives differ between females and males. The aim of this study was to assess and to compare the family and developmental history profiles of female versus male adolescents with ADHD.MethodsData were collected using the clinical diagnostic interview technique from parents of female and male patients diagnosed with ADHD (ICD-10  F90.0, F90.1 and F98.8) between the ages of 12 and 17  years (n = 92). The two groups were matched in pairs for sex, IQ and ICD-10 diagnosis (F90.0, F90.1 and F98.8). Interview data were operationalized in three categories: 0 - physiological marker, 1 - subclinical marker, 2 - clinical marker. The two groups were compared with two-way ANOVA.ResultsInformation about female in comparison to male adolescents were reported in the parental interview with few differences.ConclusionOur study suggests that family and developmental history of the neurodevelopmental disorder ADHD is only poorly influenced by gender or sex.</p

What happened to the concept of adolescence crisis?

Children and adolescents' mental health risk and resilience arise from a complex interplay of factors on several socio-ecological levels. However, little is known about the factors that shape the mental health of refugee youth living in refugee camps close to ongoing conflict. We conducted a cross-sectional study with a representative sample of 217 Burundian refugee children aged 7-15 and their mothers residing in refugee camps in Tanzania to investigate associations between risk, protective and promotive factors from various ecological levels (individual, microsystem, exosystem), and children's post-traumatic stress disorder (PTSD) symptoms, internalizing and externalizing problems, and prosocial behavior. Data were collected using structured clinical interviews and analyzed using multiple regression models. Exposure to violence across all contexts and engagement coping were risk factors for PTSD symptoms and internalizing problems, while only violence by mothers seemed to increase children's vulnerability for externalizing problems. A differential impact of violence exposures on prosocial behavior was observed. Higher-quality friendships appeared to protect youth from PTSD symptoms and externalizing problems, while they also promoted children's prosocial behavior, just as mothers' social support networks. Prevention and intervention approaches should integrate risk, protective and promotive factors for refugee youth's mental health across multiple ecological contexts and take into account context-specific and adaptive responses to war and displacement

Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage gated calcium channels (LVGCC) and has been shown previously to selectively interfere with the extinction, but not the acquisition, of fear memory. We studied here the effect of retrograde and anterograde shifts of nifedipine application, with respect to an extinction training, on the extinction of fear conditioning. Subcutaneous injection of 30 mg/kg nifedipine, at least up to 4 h before the extinction session, significantly impaired extinction, as did intraperitoneal injection of 15 mg/kg nifedipine, at least up to 2 h before extinction training. However, the injection of nifedipine also induced a strong and protracted stress response. The pharmacokinetics of nifedipine suggest that it was mainly this stress response that triggered the specific inhibition of extinction, not the blockade of LVGCC in the brain. Our results support recent findings that stress selectively interferes with the extinction, but not the acquisition, of fear memory. They also indicate that a pharmacological approach is not sufficient to study the role of brain LVGCC in learning and memory. Further research using specific genetically modified animals is necessary to delineate the role of LVGCC in fear memory extinction