Evidence for hypothalamic dysregulation in mouse models of anorexia as well as in humans

Eating disorders constitute major medical health problems in the western world. Even though little is known about the molecular mechanisms behind abnormal eating behavior, it has become clear that the central nervous system (CNS), particularly the hypothalamus, plays a significant role. The anorexic anx/anx mouse is a unique model for studying food intake and energy expenditure. The anx mutation is linked to marked alterations in hypothalamic distributions of signal substances known to have potent regulatory roles in the control of food intake. Another mouse model that displays an anorectic phenotype similar to the anx/anx mouse is the Contactin KO mouse. This model displays very similar hypothalamic alterations as seen in the anx/anx mouse, arguing for a role of these specific hypothalamic changes in an anorectic phenotype. In human eating disorders, hypothalamic systems corresponding to those defective in mouse models could be compromised since autoantibodies against melanocortin peptides have been detected in anorectic and bulimic patients. These findings represent research avenues that may lead to a better understanding of eating disorders and development of targeted therapeutic approaches.     

The nosological status of early onset anorexia nervosa

BACKGROUND: Although cases of early onset anorexia nervosa have been described, there has been no systematic comparison of early onset cases with classic cases of later onset, or with other forms of early onset eating disturbance. METHOD: A consecutive series of patients referred to two specialist child and adolescent eating disorder services with a clinical diagnosis of eating disorder (N = 126) was systematically assessed using a child version of the Eating Disorder Examination (EDE) and the K-SADS interview. RESULTS: Of 86 patients with a diagnosis of eating disorder of early onset, 38 received a clinical diagnosis of anorexia nervosa (AN). The remainder were mainly diagnosed as having food avoidance emotional disorder (25 patients) and selective eating (17 patients). Six received other diagnoses (bulimia nervosa, or functional dysphasia). These 48 patients were combined to form a group of early onset non-AN eating disturbance. In terms of specific eating disorder psychopathology and general psychopathology, the early onset AN group was very similar to the late onset AN sample. When the two early onset groups were compared, there was a marked difference between them in terms of eating disorder psychopathology. A discriminant function analysis using the EDE information produced a clear discrimination, with the EDE restraint and shape concern subscales doing most of the discrimination work. CONCLUSIONS: The specific psychopathology of AN of early onset is very similar to that of classic adolescent onset AN. Other forms of early onset eating disorder do not evidence this specific psychopathology.     

Cystamine and ethyl-eicosapentaenoic acid treatment fail to prevent malonate-induced striatal toxicity in mice

Cystamine has demonstrated neuroprotective activity in a variety of studies, and is currently being evaluated in a human clinical trial in Huntington's disease (HD). Cystamine treatment of various genetic models of HD demonstrated protection against neurodegeneration and/or improvement in behavior. Given the need for a rapid screening tool for HD therapeutics, we assessed the potential therapeutic benefits of cystamine in a short-term acute toxicity murine model of striatal cell death. Cystamine did not provide neuroprotection against bilateral intrastriatal malonate injections in mice as measured by lesion size, loss of striatal volume, or decreased striatal neuronal counts. Similar results were obtained for treatment with another potential therapeutic agent that was protective in genetic mouse models of HD, the essential fatty acid ethyl-eicosapentaenoic acid. Our findings suggest that this toxic model is not reflective or predictive of findings in genetic mouse models, and may not be useful as a preclinical screen for HD therapeutics.     

Experimental animal models for rheumatoid arthritis

Rheumatoid Arthritis (RA) is an autoimmune systemic disorder of unknown etiology and is characterized by chronic inflammation and synovial infiltration of immune cells. RA is associated with decreased life expectancy and quality of life. The research on RA is greatly simplified by animal models that help us to investigate the complex system involving inflammation, immunological tolerance and autoimmunity. The animal models of RA with a proven track record of predictability for efficacy in humans include: collagen type II induced arthritis in rats as well as mice, adjuvant induced arthritis in rats and antigen induced arthritis in several species. The development of novel treatments for RA requires the interplay between clinical observations and studies in animal models. However, each model features a different mechanism driving the disease expression; the benefits of each should be evaluated carefully in making the appropriate choice for the scientific problem to be investigated. In this review article, we focus on animal models of arthritis induced in various species along with the genetic models. The review also discussed the similarity and dissimilarities with respect to human RA.     

Female adolescents with anorexia nervosa and their parents: a case-control study of exercise attitudes and behaviours

BACKGROUND: Few studies of physical activity in patients with anorexia nervosa (AN) have included a suitable control group. Nor has such research considered the influence of parents' activity on that of their children. Our first prediction was that adolescents with AN would be significantly more active than healthy controls both prior to, and during, the progression of their disorder. We also expected that the activity levels of parents and their daughters would be correlated, and that this relationship would be stronger in patient than control families. Finally, we expected that the AN parents would be more active and report a greater commitment to exercise than the control parents. METHOD: In a case-control design, we employed multiple indicators of physical activity from adolescent females and their parents, using longitudinal, retrospective, self-report measurements. RESULTS: AN patients were significantly more active than controls both during the course of their disorder and prior to its onset. Parents' activity related to their daughter's activity, but this relationship was not stronger in the parents of the patients. CONCLUSIONS: Future research is needed to determine whether the relationship between parents' and children's activity levels reflects environmental or genetic influences, or a combination of both factors. The important observation of a significant increase in patients' activity levels at least a year prior to diagnosis of the disorder suggests that enhanced physical activity may play a role in the development of the disorder. This may also serve as an early warning sign of a subclinical eating disorder in adolescent girls.     

A genetic basis for shared autoimmunity in mouse models

Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.     

Dissection of behavior and psychiatric disorders using the mouse as a model

Mouse genetic models have played an important role in the elucidation of molecular pathways underlying human disease. This approach is becoming an increasingly popular way to study the genetic underpinning of psychiatric disorders. Genes within candidate regions for susceptibility to psychiatric illness can be evaluated through the phenotypic assessment of mutants mapped to the corresponding regions in the mouse genome. Alternatively, one can search for mouse mutants displaying characteristics that might correspond to physiological and behavioral markers of a psychiatric disorder, sometimes referred to as endophenotypes. Mice with anomalies in these traits can be generated by targeted mutagenesis in known genes (gene-based mutagenesis or reverse genetics), or can be identified among progeny of mice in a random mutagenesis screen (phenotype-based mutagenesis or forward genetics). In this review, we discuss recently generated behavioral mutants in the mouse. We also give an overview of several robust and commonly used behavioral phenotypes, their relevance to human disease and lessons learned from recent successes in mouse behavioral genetics.     

Anorexia nervosa: obsessive-compulsive disorder,obsessive-compulsive personality disorder,or neither?

Anorexia nervosa (AN) is a severe and often chronic disorder with uncertain aetiology and poor prognosis. New approaches to the understanding of the disorder are needed in order to aid the development of more effective treatments. Several authors have suggested that AN has a considerable overlap with obsessive-compulsive disorder (OCD) and that this may reflect common neurobiological, genetic, or psychological elements. However, more recent studies have suggested that AN may have a closer relationship with obsessive-compulsive personality traits such as those found in obsessive-compulsive personality disorder (OCPD). In this paper, evidence for links between the three conditions is reviewed, suggestions for further research are outlined and possible implications for the treatment of AN are presented.     

Therapeutic targeting of signaling pathways in muscular dystrophy

Muscular dystrophy refers to a group of genetic diseases that cause severe muscle weakness and loss of skeletal muscle mass. Although research has helped understanding the molecular basis of muscular dystrophy, there is still no cure for this devastating disorder. Numerous lines of investigation suggest that the primary deficiency of specific proteins causes aberrant activation of several cell signaling pathways in skeletal and cardiac muscle leading to the pathogenesis of muscular dystrophy. Studies using genetic mouse models and pharmacological approaches have provided strong evidence that the modulation of the activity of specific cell signaling pathways has enormous potential to improving the quality of life and extending the life expectancy in muscular dystrophy patients. In this article, we have outlined the current understanding regarding the role of different cell signaling pathways in disease progression with particular reference to different models of muscular dystrophy and the development of therapy.     

Stepped care treatment for eating disorders

A stepped care approach would link different patient needs to therapeutic modalities that range from simple advice to intensive inpatient care. Brief methods, including self-help and psychoeducation, may be effective for a subset of patients with bulimia nervosa and binge eating disorder. Identifying this subset remains a challenge. It is unclear how patients who fail to respond to evidence-based, first-line treatments should be treated. Given the absence of data on effective treatment of anorexia nervosa (AN), discussion of a stepped care approach is speculative. Because AN typically demands expert and sustained treatment, the lower levels of stepped care models are inapplicable for these patients. A stepped care approach poses methodological challenges for clinical research and raises important clinical issues, such as when to switch from 1 level of treatment to another.     

An assessment of the genetic toxicology of novel boron‐containing therapeutic agents

Boron‐containing compounds are being studied as potential therapeutic agents. As part of the safety assessment of these therapeutic agents, a battery of genetic toxicology studies was conducted. The battery included a bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay in peripheral human lymphocytes, and an in vivo rat micronucleus study. The following compounds represent some of the boron‐containing compounds that have been advanced to human clinical trials in various therapeutic areas. The borinic picolinate, AN0128, is an antibacterial compound with anti‐inflammatory activity that has been studied in clinical trials for acne and the treatment of mild to moderate atopic dermatitis. AN2690 (tavaborole) is a benzoxaborole in Phase 3 clinical trials for the topical treatment of onychomycosis, a fungal infection of the toenails and fingernails. Another benzoxaborole derivative, AN2728, a phosphodiesterase‐4 (PDE4) inhibitor, is in Phase 2 clinical trials for the treatment of atopic dermatitis. AN2898, also a PDE4 inhibitor, has been studied in clinical trials for atopic dermatitis and psoriasis. AN3365 is a leucyl‐tRNA synthetase inhibitor that has been in clinical development for the treatment of various Gram‐negative bacterial infections. These five representative compounds were negative in the three genotoxicity assays. Furthermore, AN2690 has been studied in mouse and rat 2‐year bioassays and was not found to have any carcinogenic potential. These results demonstrate that it is possible to design boron‐based therapeutic agents with no genetic toxicology liabilities. Environ. Mol. Mutagen. 54:338–346, 2013. © 2013 Wiley Periodicals, Inc.     

Association between serotonin transporter gene polymorphism and eating disorders outcome: a 6-year follow-up study

Eating disorder patients show different long-term outcomes, and trait-related alterations of serotonergic function, which might be related with the serotonin transporter (5-HTT) gene. We studied the relationships between 5-HTTLPR polymorphism, eating specific and general psychopathology and the long-term outcome of anorexia nervosa (AN) and bulimia nervosa (BN) patients. We evaluated the distribution of the functional 5-HTTLPR polymorphism in a series of 201 Italian, Caucasian, eating disorder patients (113 with AN and 88 with BN binge/purging (BP subtype) and in 150 Caucasian unrelated controls. Prior to starting an individual cognitive behavior therapy, a clinical assessment was performed by means of the structured clinical interview for DSM-IV axis I disorders and several self-report questionnaires. This assessment was repeated at the end of treatment, 3 years after the end of treatment and 3 years after the first follow-up. Diagnostic changes between AN and BN were frequent (28.3%), and the presence of depressive disorders was associated with a higher rate of diagnostic crossover during the follow-up period. The S-allele of the 5-HTTLPR genotype increases the risk susceptibility for both depressive comorbidity (OR?=?4.23; 95% CI, 1.45-12.37) and diagnostic crossover during the follow-up period in AN patients (OR = 5.04; 95% CI, 1.69-14.98). Logistic regression analyses confirmed these findings, when the interaction between genotype and psychiatric comorbidity as predictors of diagnostic instability in AN patients were taken into account. No significant association was found between 5-HTTLPR genotype and recovery. The S-allele of the 5-HTTLPR genotype increases the risk for depressive disorders comorbidity, and moderates the long-term outcome of anorectic patients.     

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.     

Mouse models of autism spectrum disorders: the challenge for behavioral genetics

Autism is a severe neurodevelopmental disorder, which typically emerges early in childhood. The core symptoms of autism include deficits in social interaction, impaired communication, and aberrant repetitive behavior, including self-injury. Despite the strong genetic component for the disease, most cases of autism have not been linked to mutations in a specific gene, and the etiology of the disorder has yet to be established. At the present time, there is no generally accepted therapeutic strategy to treat the core symptoms of autism, and there remains a critical need for appropriate animal models and relevant behavioral assays to promote the understanding and treatment of the clinical syndrome. Challenges for the development of valid mouse models include complex genetic interactions underlying the high heritability of the disease in humans, diagnosis based on deficits in social interaction and communication, and the lack of confirmatory neuropathological markers to provide validation for genetic models of the disorder. Research focusing on genes that mediate social behavior in mice may help identify neural circuitry essential for normal social interaction, and lead to novel genetic animal models of the autism behavioral phenotype.     

Genetic studies of neuropsychiatric disorders in Costa Rica: a model for the use of isolated populations

The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive-compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.     

SPG4基因的遗传学研究

遗传性痉挛性截瘫(hereditary spastic paraplegia,HSP),又称为家族性Strümpell-Lorrain病,是一种具有临床及遗传高度异质性的神经系统遗传病,患病率为2/10万～9.6/10万,表现为缓慢进展的双下肢无力及痉挛性截瘫.根据遗传方式不同HSP可分为常染色体显性遗传、常染色体隐性遗传和X-连锁隐性遗传,以常染色体显性遗传最常见.目前已经发现40个HSP基因位点,已克隆19个疾病基因.其中spastin基因突变所致的遗传性痉挛性截瘫4型(spastic paraplegia-4,SPG4)约占常染色体显性遗传的HSP的40%.基因检测是诊断该病的金标准,有助于早期诊断、症状前诊断及产前诊断.动物模型的研究对揭示HSP的分子病理机制有重要作用,本文就SPG4基因的遗传学研究作一概述.     

Comorbidity of bipolar and eating disorders: distinct or related disorders with shared dysregulations?

BACKGROUND: The co-occurrence of bipolar and eating disorders, though of major clinical and public health importance, remains relatively unexamined. METHODS: In reviewing the literature on this comorbidity, we compared bulimia, anorexia nervosa, bulimia nervosa, binge eating disorders and bipolar disorders on phenomenology, course, family history, biology, and treatment response. RESULTS: Epidemiological studies show an association between subthreshold bipolar disorder and eating disorders in adolescents, and between hypomania and eating disorders, especially binge eating behavior, in adults. Of the clinical studies, most show that patients with bipolar disorder have elevated rates of eating disorders, and vice versa. Finally, the phenomenology, course, comorbidity, family history, and pharmacologic treatment response of these disorders show considerable overlap on all of these parameters. In particular, on phenomenologic grounds--eating dysregulation, mood dysregulation, impulsivity and compulsivity, craving for activity and/or exercise--we find many parallels between bipolar and eating disorders. Overall, the similarities between these disorders were more apparent when examined in their spectrum rather than full-blown expressions. LIMITATIONS: Despite an extensive literature on each of these disorders, studies examining their overlap across all these parameters are relatively sparse and insufficiently systematic. CONCLUSIONS: Nonetheless, the reviewed literature leaves little doubt that bipolar and eating disorders--particularly bulimia nervosa and bipolar II disorder--are related. Although several antidepressants and mood stabilizers have shown promise for eating disorders, their clinical use when these disorders co-exist with bipolarity is still very much of an art. We trust that this review will stimulate more rigorous research in their shared putative underlying psychobiologic mechanisms which, in turn, could lead to more rational targeted treatments.     

A neurodevelopmental model for anorexia nervosa

This paper integrates genetic and biological data on aetiological risk for anorexia nervosa (AN) with cognitive and psychosocial explanatory models. We have reviewed clinical and basic science data from each of these domains and then used a developmental perspective to formulate a multifactorial threshold model. By positioning interpersonal stress as a central component of this model, psychological, social and biological conceptualisations of AN can be used to generate a data driven, neurodevelopmental hypothesis for the aetiology of this complex disorder.     

New In Vitro Models to Study Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a complex multifactorial disorder, characterized by motor neuron loss with involvement of several other cell types, including astrocytes, oligodendrocytes and microglia. Studies in vivo and in in vitro models have highlighted that the contribution of non‐neuronal cells to the disease is a primary event and ALS pathogenesis is driven by both cell‐autonomous and non‐cell autonomous mechanisms. The advancements in genetics and in vitro modeling of the past 10 years have dramatically changed the way we investigate the pathogenic mechanisms involved in ALS. The identification of mutations in transactive response DNA‐binding protein gene (TARDBP), fused in sarcoma (FUS) and, more recently, a GGGGCC‐hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) and their link with familial ALS have provided new avenues of investigation and hypotheses on the pathophysiology of this devastating disease. In the same years, from 2007 to present, in vitro technologies to model neurological disorders have also undergone impressive developments. The advent of induced pluripotent stem cells (iPSCs) gave the field of ALS the opportunity to finally model in vitro not only familial, but also the larger part of ALS cases affected by sporadic disease. Since 2008, when the first human iPS‐derived motor neurons from patients were cultured in a petri dish, several different techniques have been developed to produce iPSC lines through genetic reprogramming and multiple direct conversion methods have been optimised. In this review, we will give an overview of how human in vitro models have been used so far, what discoveries they have led to since 2007, and how the recent advances in technology combined with the genetic discoveries, have tremendously widened the horizon of ALS research.