39 research outputs found
Distribution of Alarin Immunoreactivity in the Mouse Brain
Alarin is a 25 amino acid peptide that belongs to the galanin peptide family. It is derived from the galanin-like peptide gene by a splice variant, which excludes exon 3. Alarin was first identified in gangliocytes of neuroblastic tumors and later shown to have a vasoactive function in the skin. Recently, alarin was demonstrated to stimulate food intake as well as the hypothalamic–pituitary–gonadal axis in rodents, suggesting that it might be a neuromodulatory peptide in the brain. However, the individual neurons in the central nervous system that express alarin have not been identified. Here, we determined the distribution of alarin-like immunoreactivity (alarin-LI) in the adult murine brain. The specificity of the antibody against alarin was demonstrated by the absence of labeling after pre-absorption of the antiserum with synthetic alarin peptide and in transgenic mouse brains lacking neurons expressing the GALP gene. Alarin-LI was observed in different areas of the murine brain. A high intensity of alarin-LI was detected in the accessory olfactory bulb, the medial preoptic area, the amygdala, different nuclei of the hypothalamus such as the arcuate nucleus and the ventromedial hypothalamic nucleus, the trigeminal complex, the locus coeruleus, the ventral chochlear nucleus, the facial nucleus, and the epithelial layer of the plexus choroideus. The distinct expression pattern of alarin in the adult mouse brain suggests potential functions in reproduction and metabolism
Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia
Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies
Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa
In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN
The Anorexia Nervosa Genetics Initiative (ANGI): overview and methods
This manuscript version is made
available under the CC-BY-NC-ND 4.0 license:
http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This author accepted manuscript is made available following 12 month embargo from date of publication (October 2018) in accordance with the publisher’s archiving policyBackground
Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.
Methods
ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H.
Results
Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable.
Conclusions
Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection.Please refer to published article
Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes
publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc
Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa
Galanin-like peptide (GALP) is a target for regulation by leptin in the hypothalamus of the rat
Galanin-like peptide (GALP), which was recently isolated from the porcine
hypothalamus, shares sequence homology with galanin and binds with high
affinity to galanin receptors. To study the distribution and regulation of
GALP-expressing cells in the brain, we cloned a 120 base-pair cDNA
fragment of rat GALP and produced an antisense riboprobe. In situ
hybridization for GALP mRNA was then performed on tissue sections
throughout the forebrain of adult ovariectomized female rats. We found
GALP mRNA-containing cells in the arcuate nucleus (Arc), caudal
dorsomedial nucleus, median eminence and the pituitary. Because GALP mRNA
in the Arc appeared to overlap with the known distribution of leptin
receptor mRNA, we tested the hypothesis that GALP expression is regulated
by leptin. Using in situ hybridization, we compared the number of GALP
mRNA-containing cells among groups of rats that were fed ad lib or fasted
for 48 h and treated with either leptin or vehicle. Fasting reduced the
number of identifiable cells containing GALP mRNA in the Arc, whereas the
treatment of fasted animals with leptin produced a 4-fold increase in the
number of cells expressing GALP message. The presence of GALP mRNA in the
hypothalamus and pituitary and its regulation by leptin suggests that GALP
may have important neuroendocrine functions, including the physiological
regulation of feeding, metabolism, and reproduction
Distribution and regulation of galanin-like peptide (GALP) in the hypothalamus of the mouse
Galanin-like peptide (GALP) is a newly discovered molecule whose
expression in the brain is confined to the arcuate nucleus and median
eminence. In the rat, cellular levels of GALP mRNA are reduced by fasting
and reversed by peripheral administration of leptin. The purpose of this
investigation was 1) to clone and map the distribution of GALP mRNA in the
brain of the mouse; 2) to compare the pattern and magnitude of GALP mRNA
expression in the leptin-deficient obese (ob/ob) mouse with that of
wild-type controls; and 3) to examine the effects of leptin delivered into
the brain on the expression of GALP mRNA in the ob/ob mouse. We report the
sequence of a mouse GALP cDNA and show that GALP mRNA is expressed in the
arcuate nucleus, median eminence, infundibular stalk, and the
neurohypophysis of this species. The expression of GALP mRNA in the brain
was markedly reduced in the ob/ob mice, compared with wild-type animals.
Intracerebroventricular infusion of leptin to ob/ob mice increased both
the number of GALP mRNA-expressing neurons and their content of GALP mRNA,
compared with vehicle-treated controls. These observations demonstrate
that GALP mRNA is induced by leptin through a direct action on the brain
Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq
The mammalian cerebral cortex supports cognitive functions such as sensorimotor integration, memory, and social behaviors. Normal brain function relies on a diverse set of differentiated cell types, including neurons, glia, and vasculature.Here,we have used large-scale single-cell RNA sequencing (RNA-seq) to classify cells in themouse somatosensory cortex and hippocampal CA1 region.We found 47 molecularly distinct subclasses, comprising all known major cell types in the cortex.We identified numerous marker genes, which allowed alignment with known cell types, morphology, and location.We found a layer I interneuron expressing Pax6 and a distinct postmitotic oligodendrocyte subclass marked by Itpr2. Across the diversity of cortical cell types, transcription factors formed a complex, layered regulatory code, suggesting amechanism for the maintenance of adult cell type identity