A burden of rare copy number variants in obsessive-compulsive disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway.

Association of autism diagnosis and polygenic scores with eating disorder severity.

Among individuals with eating disorders (ED), those with co-occurring autism are often considered to have more severe presentations and poorer prognosis. However, previous findings have been contradictory and limited by small sample size and/or cross-sectional assessment of autistic traits. We examine the hypothesis that autism diagnosis and autism polygenic score (PGS) are associated with increased ED severity in a large ED cohort using a broad range of ED severity indicators.

First genome-wide association study of esophageal atresia identifies three genetic risk loci at , //, and .

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci.

Study protocol of comprehensive risk evaluation for anorexia nervosa in twins (CREAT): a study of discordant monozygotic twins with anorexia nervosa.

Background: Anorexia nervosa (AN) is a severe disorder, for which genetic evidence suggests psychiatric as well as metabolic origins. AN has high somatic and psychiatric comorbidities, broad impact on quality of life, and elevated mortality. Risk factor studies of AN have focused on differences between acutely ill and recovered individuals.

Distribution of the voltage-gated sodium channel Na(v)1.7 in the rat: expression in the autonomic and endocrine systems.

It is generally accepted that the voltage-gated, tetrodotoxin-sensitive sodium channel, Na(V)1.7, is selectively expressed in peripheral ganglia. However, global deletion in mice of Na(V)1.

Patterned gene programs and target remodeling following axotomy at a major site for sensory innervation.

The genetic mechanisms that a target uses to reestablish the connections of regenerating axons were explored using oligonucleotide microarrays and real-time PCR. In normal and denervated mouse vibrissa follicles, patterns of genetic regulation were assessed in adjacent targets that normally receive different types of sensory and autonomic innervation. We show that a target remodeling occurs following axotomy involving reduced hair growth, altered hair follicle integrity and remodeling of the extracellular matrix.

Diverse dependencies of developing Merkel innervation on the trkA and both full-length and truncated isoforms of trkC.

This study demonstrates that innervation dependent on two different neurotrophin tyrosine kinase (trk) receptors can form the same types of sensory endings (Merkel endings) in the same target (Merkel cells of vibrissa follicles). Some endings transiently express trkA during their initial development, whereas others express trkC throughout their development. Consequently, elimination of kinase domains of either trkA or trkC each result in a partial loss of Merkel endings, whereas absence of kinase domains of both receptors results in a total loss.

Impairment of peripheral sensory innervation in senescence.

Sensorimotor disturbances are common among elderly and one of the main factors depreciating life quality in senescence. Mechanistically sensory deficits during aging include not only degenerative and regressive events but also phenotypic switches among sensory neurons as well as remodeling of sensory innervation. The pattern of changes suggests that an underlying mechanism is a sustained dependence of sensory neurons on target tissues, and that this dependence, at least in part, appears to be mediated through signaling by target-derived trophic factors.

Regulation of neurotrophin signaling in aging sensory and motoneurons: dissipation of target support?

A hallmark of senescence is sensorimotor impairment, involving locomotion and postural control as well as fine-tuned movements. Sensory and motoneurons are not lost to any significant degree with advancing age, but do show characteristic changes in gene-expression pattern, morphology, and connectivity. This review covers recent experimental findings corroborating that alterations in trophic signaling may induce several of the phenotypic changes seen in primary sensory and motoneurons during aging.

Attenuation of a caspase-3 dependent cell death in NT4- and p75-deficient embryonic sensory neurons.

Neuronal survival during the developmental period of naturally occurring cell death is mediated through a successful competition for limiting concentrations of neurotrophic factors, and the deprived neurons will die. New results show that induced death through the p75 neurotrophin receptor (p75(NTR)), a member of the p55TNF/Fas family of cell death receptors, may also influence survival during development. We find that eliminating p75(NTR) or neurotrophin 4 (NT4) in mice leads to a marked attenuation of apoptosis during the programmed cell death period of the trigeminal ganglion neurons, suggesting that NT4 can induce the death of these neurons through the p75(NTR).

Regulation of NGF-family ligands and receptors in adulthood and senescence: correlation to degenerative and regenerative changes in cutaneous innervation.

During development, a highly differential neurotrophin dependency is reported for various types of nerve endings in the whisker follicle. To what extent these dependencies extend and play a role in adulthood is largely unresolved. We show here, using in situ hybridization and immunohistochemistry that the expression of neurotrophins and trk/p75 receptors persists in adulthood.

Effects of aging and axotomy on the expression of neurotrophin receptors in primary sensory neurons.

Aging is accompanied by declined sensory perception, paralleled by widespread dystrophic and degenerative changes in both central and peripheral sensory pathways. Several lines of evidence indicate that neurotrophic interactions are of importance for a maintained plasticity in the adult and aging nervous system, and that changes in the expression of neurotrophins and/or their receptors may underpin senile neurodegeneration. We have here examined the expression of neurotrophin receptor (p75NTR, trkA, trkB, and trkC) mRNA and protein in intact and axotomized primary sensory neurons of young adult (3 months) and aged (30 months) rats.

A rapid and dynamic regulation of GDNF-family ligands and receptors correlate with the developmental dependency of cutaneous sensory innervation.

Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are members of the transforming growth factor-beta family and have been shown to elicit neurotrophic effects upon several classes of neurons including dopaminergic neurons, motoneurons, parasympathetic, sympathetic as well as primary sensory neurons. However, there is little information available on their roles in cutaneous innervation. Herein, we have studied the regulation of gdnf, ntn and the GDNF family receptors and examined their role in the development of facial cutaneous innervation in GDNF mutant mice.

Differential dependency of unmyelinated and A delta epidermal and upper dermal innervation on neurotrophins, trk receptors, and p75LNGFR.

The impact of the nerve growth factor (NGF) family of neurotrophins and their receptors was examined on the cutaneous innervation in the mystacial pads of mice. Ten sets of unmyelinated and thinly myelinated sensory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair follicles. Mystacial pads were analyzed from newborn to 4-week-old mice that had homozygous functional deletions of the genes for NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75.

Different distributions of the sensory and autonomic innervation among the microvasculature of the rat mystacial pad.

The regulation of the vasculature in the skin is a complex process involving both perivascular nerves and local endothelial-mediated control. In this study, the perivascular innervation in the mystacial pad of the rat was characterized based upon immunochemical and lectin binding characteristics and distribution. All of the innervation labeled with anti-protein gene product 9.

Alterations in mystacial pad innervation in the aged rat.

It is well established that sensory perception becomes impaired with advancing age and that, in parallel, dystrophy and degeneration of axons occur in sensory pathways. In this study, the impact of aging was examined in the mystacial pad, which receives a large variety of sensory nerve endings organized in a highly predictable pattern. Mystacial pad specimens from aged (30 months old) and young adult (2-3 months old) female Sprague-Dawley rats were processed, in parallel, for immunohistochemical analyses with antibodies against human neuronal cytoplasmic protein (protein gene product 9.

Overexpression of nerve growth factor in skin causes preferential increases among innervation to specific sensory targets.

The impact of increased levels of skin-derived nerve growth factor (NGF) neurotrophin on sensory and sympathetic innervation to the mouse mystacial pad and postero-orbital vibrissae was determined. Consistent with an approximate doubling of neuron number in trigeminal and superior cervical ganglia, many components of the sensory and sympathetic innervation were substantially enhanced. Although the increased number of neurons raised the possibility that all types of innervation were increased, immunohistochemical analysis indicated that enhanced NGF production had a differential effect upon sensory innervation, primarily increasing unmyelinated innervation.

Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR.

The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75.

Comprehensive immunofluorescence and lectin binding analysis of intervibrissal fur innervation in the mystacial pad of the rat.

The innervation of the intervibrissal fur in the mystacial pad of the rat and mouse was examined by immunofluorescence with a wide variety of antibodies for neuronal related structural proteins, enzymes, and peptides as well as for lectin binding histofluorescence with Griffonia simplicifolia (GSA). Anti-protein gene product 9.5 (PGP) immunofluorescence labeled all sets of axons and endings.

Comprehensive immunofluorescence and lectin binding analysis of vibrissal follicle sinus complex innervation in the mystacial pad of the rat.

The innervation of the vibrissal follicle sinus complexes (FSCs) in the mystacial pad of the rat was examined by lectin binding histofluorescence with the B subunit of Griffonia simplicifolia (GSA) and by immunofluorescence with a wide variety of antibodies for neuronal related structural proteins, enzymes, and peptides. Only anti-protein gene product 9.5 labeled all sets of innervation.