Neurobiological Disease Research Articles

"Mourning" a lost opportunity.

"Mourning" a lost opportunity.

Whole-brain mapping of behaviourally induced neural activation in mice.

The ability to visualize behaviourally evoked neural activity patterns across the rodent brain is essential for understanding the distributed brain networks mediating particular behaviours. However, current imaging methods are limited in their spatial resolution and/or ability to obtain brain-wide coverage of functional activity. Here, we describe a new automated method for obtaining cellular-level, whole-brain maps of behaviourally induced neural activity in the mouse. This method combines the use of transgenic immediate-early gene reporter mice to visualize neural activity; serial two-photon tomography to image the entire brain at cellular resolution; advanced image processing algorithms to count the activated neurons and align the datasets to the Allen Mouse Brain Atlas; and statistical analysis to identify the network of activated brain regions evoked by behaviour. We demonstrate the use of this approach to determine the whole-brain networks activated during the retrieval of fear memories. Consistent with previous studies, we identified a large network of amygdalar, hippocampal, and neocortical brain regions implicated in fear memory retrieval. Our proposed methods can thus be used to map cellular networks involved in the expression of normal behaviours as well as to investigate in depth circuit dysfunction in mouse models of neurobiological disease.

Neurobiological disease etiology and inheritance: an epigenetic perspective

Epigenetic marks in mammals are essential to properly control the activity of the genome. They are dynamically regulated during development and adulthood, and can be modulated by environmental factors throughout life. Changes in the epigenetic profile of a cell can be positive and favor the expression of advantageous genes such as those linked to cell signaling and tumor suppression. However, they can also be detrimental and alter the functions of important genes, thereby leading to disease. Recent evidence has further highlighted that some epigenetic marks can be maintained across meiosis and be transmitted to the subsequent generation to reprogram developmental and cellular features. This short review describes current knowledge on the potential impact of epigenetic processes activated by environmental factors on the inheritance of neurobiological disease risk. In addition, the potential adaptive value of epigenetic inheritance, and relevant current and future questions are discussed.

Blockade of SOCE protects HT22 cells from hydrogen peroxide-induced apoptosis

Oxidative stress is an established event in the pathology of neurobiological diseases. Previous studies indicated that store-operated Ca2+ entry (SOCE) has been involved in oxidative stress. The present study was carried out to investigate the effects of SOCE inhibition on neuronal oxidative stress injury induced by hydrogen peroxide (H2O2) in HT22 cells, a murine hippocampal neuronal model. H2O2 insult induced significant intracellular Ca2+ overload, mitochondrial dysfunction and cell viability decrease. Inhibition of SOCE by pharmacological inhibitor and STIM1 RNAi significantly alleviated intracellular Ca2+ overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and eventually inhibited H2O2-induced cell apoptosis. These findings suggest that SOCE inhibition exhibited neuroprotection against oxidative stress induced by H2O2 and SOCE might be a useful therapeutic target in neurobiological disorders.

Epigenetic studies in Alzheimer's disease: Current findings, caveats, and considerations for future studies

Alzheimer's disease (AD) is a sporadic, chronic neurodegenerative disease, usually occurring late in life. The last decade has witnessed tremendous advances in our understanding about the genetic basis of AD, but a large amount of the variance in disease risk remains to be explained. Epigenetic mechanisms, which developmentally regulate gene expression via modifications to DNA, histone proteins, and chromatin, have been hypothesized to play a role in other complex neurobiological diseases, and studies to identify genome-wide epigenetic changes in AD are currently under way. However, the simple brute-force approach that has been successfully employed in genome-wide association studies is unlikely to be successful in epigenome-wide association studies of neurodegeneration. A more academic approach to understanding the role of epigenetic variation in AD is required, with careful consideration of study design, methodological approaches, tissue-specificity, and causal inference. In this article, we review the empirical literature supporting a role for epigenetic processes in AD, and discuss important considerations and future directions for this new and emerging field of research.

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

Esquizofrenia é uma severa doença neurobiológica com fatores genéticos e ambientais desempenhando um papel na fisiopatologia. Diversas regiões cerebrais têm sido implicadas no processo da doença e estão conectadas em complexos circuitos neuronais. Nos níveis molecular e celular, a conectividade afetada entre essas regiões, envolvendo mielinização disfuncional dos axônios neuronais, bem como as alterações no nível sináptico e metabolismo energético levando a distúrbios na plasticidade sináptica, são os maiores achados em estudos post-mortem. Estudos de microarranjos investigando a expressão gênica contribuíram para os achados de alterações em vias complexas em regiões cerebrais relevantes na esquizofrenia. Além disso, estudos utilizando microdissecção e captura a laser permitiram a investigação da expressão gênica em grupos específicos de neurônios. Entretanto, deve ser mantido em mente que em estudos post-mortem, confusos efeitos de medicação, qualidade de RNAm, bem como capacidade de mecanismos regenerativos neuroplásticos do cérebro em indivíduos com história de vida de esquizofrenia, podem influenciar o complexo padrão de alterações no nível molecular. Apesar dessas limitações, estudos transcriptômicos livres de hipóteses em tecido cerebral de pacientes esquizofrênicos oferecem uma possibilidade única para aprender mais sobre os mecanismos subjacentes, levando a novas ópticas da fisiopatologia da doença.

Association Between Obsessive Compulsive Disorder And Tumor Necrosis Factor-Α Gene –308 (G>A) And –850 (C>T) Polymorphisms In Turkish Children

Obsessive compulsive disorder (OCD) is a neurobiological disease characterized with obsessions and compulsions. Obsessive compulsive disorder occurs with an autoimmune mechanism after Group A β hemolytic streptococcus (GABHS) infection. Tumor necrosis factor (TNF) is an important cytokine, as well as having an important role in the apoptosis mechanism of autoimmune diseases. It is expressed by the TNF-α gene. The aim of this study was to examine the relationship between the TNF-α gene promoter region −308 (G>A) and −850 (C>T) polymorphisms and OCD. In this study, ages of the OCD patients and the control group ranged between 4 and 12 years. We studied two patient groups, one included childhood onset OCD patients (n = 49) and the control group was composed of healthy children (n = 58). Patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria and with Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (KSAD-S-PL) version. For identifying the polymorphisms, polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and polyacrylamide gel electrophoresis (PAGE) methods were used.For the −308 polymorphism, 45 of 49 OCD patients’ results were completed, and for the −850 polymorphism, 47 of 49 OCD patients’ results were completed. According to our statistical results, there is a positive relationship between OCD and the −308 polymorphism (p <0.001) but no association between OCD and the −850 polymorphism (p = 0.053). There is no positive relationship between antistreptolysin O (ASO) titers and the −308 polymorphism (p = 0.953) but there is an important significance between the −850 polymorphism and ASO (p = 0.010). There is no positive relationship between gender of patients and OCD (p = 0.180) and no positive association between ASO and gender (p = 0.467). According to our results, we hypothesize that we can propose the mutant AA genotype for the −308 polymorphism, and that the mutant CT genotype for the −850 polymorphism may be used as molecular indicators for OCD.

Identification of subgroups among fibromyalgia patients

This paper presents some hypotheses concerning the identification of homogeneous subgroups among fibromyalgia (FM) patients in order to improve the management of the disease. It also reviews the available literature about this subject. Three methods for subgrouping are discussed according to clinical features, biomarkers, and gait analysis. Clinical subgrouping based on cluster analysis has been used for the identification of homogeneous subgroups of patients and, more recently, homogeneous clinical features. So far, longitudinal studies using clinical subgroups to direct treatment and predict outcome are still required. Biomarkers in FM, which is a neurobiological disease, are of promising interest, nevertheless currently, none of them can be used to subgroup FM patients. Due to the fact that cortical and subcortical mechanisms of gait control share some cognitive functions which are involved in FM, gait markers have been proposed to evaluate and to subgroup FM patients, in clinical settings. Three out of 4 core FM symptoms are linked to gait markers. Kinesia measured by means of cranio-caudal power is correlated to pain, and could be proposed to assess pain behavior (kinesiophobia). Stride frequency, which is linked to physical component, allows the identification of a hyperkinetic subgroup. Moreover, SF has been correlated to fatigue during the 6 minute walking test. Stride regularity, which expresses the unsteadiness of gait, is correlated to cognitive dysfunction in FM. Decreased stride regularity allows the recognition of a homogeneous subgroup characterized by an increased anxiety and depression, and decreased cognitive functions. These results need further studies to be validated and so used in the daily clinical practice.

The Purpose in Chronic Addiction

I argue that addiction is not a chronic, relapsing, neurobiological disease characterized by compulsive use of drugs or alcohol. Large-scale national survey data demonstrate that rates of substance dependence peak in adolescence and early adulthood and then decline steeply; addicts tend to “mature out” in their late twenties or early thirties. The exceptions are addicts who suffer from additional psychiatric disorders. I hypothesize that this difference in patterns of use and relapse between the general and psychiatric populations can be explained by the purpose served by drugs and alcohol for patients. Drugs and alcohol alleviate the severe psychological distress typically experienced by patients with comorbid psychiatric disorders and associated problems. On this hypothesis, consumption is a chosen means to ends that are rational to desire: Use is not compulsive. The upshot of this explanation is that the orthodox view of addiction as a chronic, relapsing neurobiological disease is misguided. I delineate five folk psychological factors that together explain addiction as purposive action: strong and habitual desire; willpower; motivation; functional role; and decision and resolve. I conclude by drawing lessons for research and effective treatment.

Chronic Addiction, Compulsion, and the Empirical Evidence

Pickard (2012) provides a strong critique of the definition of addiction as a “chronic, relapsing, neurobiological disease characterized by compulsive use of drugs or alcohol.” We agree with Pickar...

Psychopharmacology of Addiction

Addiction is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development. Developments in the psychopharmacology of addiction is much slower than the other disciplines of psychiatry. For a long time, social and behavioral therapeutic approaches are the only choices for the treatment of addictive disorders. Disulfiram was the only pharmacological agent approved for addiction treatment until the end of 20th century. Pharmacological treatment options available for treatment have grown along with our understanding of the neurobiological mechanisms underlying the development and persistence of addiction. Several new medications like naltrexone, acamprosate, methadone and buprenoprhine have been approved for the treatment of alcohol and opioid use disorders ever since. Based on ever-increasing information about neurotransmitter and receptors, many studies have been performed concerning craving and relapse prevention in recent years. Besides many other pharmacological agents have been focus of new researches for treatment of different types of addiction. The aim of this article is to briefly review the literature on psychopharmacology of addictive disorders and recent developments in this area.

Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines

Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction for prescription medication, or a natural source of food to fight various infections and diseases. Genetics has played a role in identifying various interactions between existing drugs and side effects. In addition, various food allergies have been identified with children in recent years, suggesting genetic associations between certain populations carrying specific genetic alleles. The recent availability of genomic data and our increased understanding of the effects of genetic variations permit a quantitative examination of the contribution of genetic variation to efficacy or toxicity of compounds derived from natural sources. The identification of target molecules relevant for diseases allows screening for natural products capable of inhibiting targets which can lead to the development of rational treatment of various diseases including neurobiological disorders, cancer, osteoporosis, and cardiovascular diseases. This allows for more opportunities to predict the response of individual patients. Identification of genetic variations that arose as a consequence of naturally occurring compounds will help identify gene alleles, or protein ligands that can affect the pharmacodynamic and pharmacokinetics of the natural products in question. In addition, diet modification and precautions to food products can be identified to help consumers limit or increase certain food intake. Understanding the molecular mechanisms underlying these interactions and their modification by genetic variation is expected to result in the development of new drugs that optimize individual health. We expect that strategies for individualized therapies will lead to improved results for patients.

Coinciding revolutions: how discovery of non-coding DNA and RNA can change our understanding of addiction.

Coinciding revolutions: how discovery of non-coding DNA and RNA can change our understanding of addiction.

Predictive factors for familiality in a Danish clinical cohort of children with Tourette syndrome

Tourette syndrome (TS) is a chronic, neurobiological disease, characterized by the presence of motor and vocal tics and it is often accompanied by associated symptoms. The two best-known co-morbidities are Obsessive-Compulsive Disorder (OCD) and Attention Deficit Hyperactivity Disorder (ADHD). The fact that TS aggregates strongly in families suggests that family members share either genetic and/or environmental risk factors contributing to TS. Numerous studies have been performed to examine the familiality in TS, but clear-cut factors to predict hereditability in TS have not been found yet. We have examined a large Danish clinical cohort of children with TS ( N = 307). Validated diagnostic instruments were used to assess the presence of co-morbidities in the children with TS. A three-generation pedigree was drawn for all the probands and through reports from the family, a family history and the frequency of affected relatives was noted. The rates of tics, symptoms of OCD, and ADHD among relatives are similar to the rates found in other countries and are higher than in the general population. Although the role of sex in determining the phenotype has to be examined more thoroughly, we found that male relatives were more likely to have tics and female relatives were more likely to have symptoms of OCD. When comparing the relatives to male patients with relatives to female patients, there were no differences in the rates of symptoms, apart from symptoms of ADHD that were more frequent in second-degree relatives to female patients. The severity of tics and the presence of co-morbidity did not seem to predict the familiality of TS and its associated symptoms.

Glyceraldehyde-3-Phosphate Dehydrogenase–Monoamine Oxidase B-Mediated Cell Death-Induced by Ethanol is Prevented by Rasagiline and 1-R-Aminoindan

The inhibitors of monoamine oxidase B (MAO B) are effectively used as therapeutic drugs for neuropsychiatric and neurodegenerative diseases. However, their mechanism of action is not clear, since the neuroprotective effect of MAO B inhibitors is associated with the blockage of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-death cascade, rather than the inhibition of MAO B. Here, we provide evidence that GAPDH potentiates the ethanol-induced activity of MAO B and brain cell toxicity. The levels of nuclear GAPDH and MAO B activity are significantly increased in brain-derived cell lines upon 75 mM ethanol-induced cell death. Over-expression of GAPDH in cells enhances ethanol-induced cell death, and also increases the ethanol-induced activation of MAO B. In contrast, the MAO B inhibitors rasagiline and selegiline (0.25 nM) and the rasagiline metabolite, 1-R-aminoindan (1 muM) decreases the ethanol-induced MAO B, prevents nuclear translocation of GAPDH and reduces cell death. In addition, GAPDH interacts with transforming growth factor-beta-inducible early gene (TIEG2), a transcriptional activator for MAO B, and this interaction is increased in the nucleus by ethanol but reduced by MAO B inhibitors and 1-R-aminoindan. Furthermore, silencing TIEG2 using RNAi significantly reduces GAPDH-induced MAO B upregulation and neurotoxicity. In summary, ethanol-induced cell death, attenuated by MAO B inhibitors, may result from disrupting the movement of GAPDH with the transcriptional activator into the nucleus and secondly inhibit MAO B gene expression. Thus, the neuroprotective effects of rasagiline or 1-R-aminoindan on ethanol-induced cell death mediated by a novel GAPDH-MAO B pathway may provide a new insight in the treatment of neurobiological diseases including alcohol-use disorders.

Inter-age variability of bona fide unvaried transcripts: Normalization of quantitative PCR data in ischemic stroke

BackgroundAging is a major risk factor for a variety of neurobiological diseases leading to variations of transcriptional expression in affected tissues. Reverse transcription of RNA followed by quantitative PCR is a powerful technique for detection and quantification of specific transcripts differentially expressed. An essential prerequisite for accurate interpretation of quantitative PCR data obtained from expression studies is an appropriate normalization process. Therefore we validated the expression of the most frequently used reference genes consisting of Gapdh and Actb as well as Hmbs, Hprt1 and Gusb in an animal model of mice in respect to two major influence factors, aging and ischemia. In the experimental settings we intended to reflect variations in both, the local and systemic immune response. ResultsThe consistency in gene expression of the tested transcripts was quantified based on standard deviation, correlation analysis and two algorithms available as Visual Basic Applications (VBA) termed GeNorm and Normfinder. Overall, the results of the study proofed the suitability of Actb in combination with Gapdh and with tissue-specific limitations Hmbs in brain and Gusb in white blood cells as the most stable transcripts for accurate normalization. We clearly demonstrated that both, the aging process per se and aging in combination with ischemia are confounding factors with respect to the expression stability of Hprt1. ConclusionsThe present study emphasizes the urgent need to validate the expression stability also from bona fide unvaried transcripts under specific conditions of investigation to ensure adequate normalization of qPCR data. Based on the expression stability, the use of Gapdh and Actb as highly abundant transcripts for normalization of qPCR data under conditions of aging and ischemia in a mouse model was evaluated. However, for low abundant genes the use of Hmbs in brain and Gusb in white blood cells is recommended.

Recent Developments in Studies of l-Stepholidine and its Analogs: Chemistry, Pharmacology and Clinical Implications

Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinson's disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.

Regional thinning of the cerebral cortex in schizophrenia: Effects of diagnosis, age and antipsychotic medication

Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty remains regarding cause, mechanism and progression of the alterations. It has been suggested that antipsychotic medication reduces total gray matter volumes, but results are inconsistent. In the present study differences in regional cortical thickness between 96 patients with a DSM-IV diagnosis of schizophrenia ( n = 81) or schizoaffective disorder ( n = 15) and 107 healthy subjects (mean age 42 years, range 17–57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and antipsychotic medication on variation in global and regional cortical thickness was explored. Thinner cortex among patients than controls was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the temporal cortex in the left hemisphere. No significant interaction effect of age and diagnostic group on variation in cortical thickness was demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.

Metabolic enzymes link morphine withdrawal with metabolic disorder

npgEnergy metabolism is a fundamental biological process that is vital for the survival of all species. Disorders in the metabolic system result in deficiency or redundancy of cer-tain nutrients, including carbohydrates, lipids, amino acids, etc. Abnormality of the energy metabolism system leads to a number of metabolic diseases, such as the metabolic syndrome. Broadly speaking, the term “metabolic diseases” now tends to be widened to the category that refers to all diseases with metabolism disorder. It is shown that many diseases associate with metabolic disorders. For example, most malignant tumors progress with mal-nutrition and high consumption, that is, cachexia. Many components of the energy metabolism system, such as lactate dehydroge-nase (LDH), are now widely applied in clinical examina-tions as special markers for tumors and some other diseases. Opioid dependence and addiction are neurobiological diseases associated with malregulation of the metabolic system. However, how chronic drug administration induces metabolic abnormality is not understood. In a recent issue of

What’s in a Word? Addiction Versus Dependence in DSM-V

Back to table of contents Previous article Next article Letters to the EditorFull AccessWhat’s in a Word? Addiction Versus Dependence in DSM-VROBIN L. FAINSINGER M.D.VINCENT THAI M.B.B.S., M.Med., M.R.C.P., C.C.F.P., A.B.P.H.M.GARY FRANK B.A., B.Ed., R.N.JEAN FERGUSSON B.Sc., R.N.,ROBIN L. FAINSINGER M.D.Search for more papers by this authorVINCENT THAI M.B.B.S., M.Med., M.R.C.P., C.C.F.P., A.B.P.H.M.Search for more papers by this authorGARY FRANK B.A., B.Ed., R.N.Search for more papers by this authorJEAN FERGUSSON B.Sc., R.N.Search for more papers by this author,Published Online:1 Nov 2006https://doi.org/10.1176/ajp.2006.163.11.2014aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We agree with the call made by Charles O’Brien, M.D., Ph.D., et al. for a clarification of terminology in discussions of opioid use (1) . We also agree that the DSM Committees’ choice of terminology to date is problematic. The use of the term “dependence” as a euphemism for addiction originated as a well-intentioned attempt to counter negative effects of the social stigmatization of addicted patients. Unfortunately, it has resulted in creating significant confusion in discussions of pain management by clouding the important distinction between physical dependence and uncontrolled psychological craving (addiction). Examples of this confusion are replete in the literature (2 – 4) . One of the most important requirements for successful pain management is a rigorous, multidimensional assessment of the patient, including a clear description and classification of the pain syndrome. Recognition of addiction, and distinguishing addiction from physical dependence, is an important part of such an assessment. The experience of cancer pain specialists around the world has confirmed this time and again. The Edmonton Classification System for Cancer Pain (5 , 6) has shown that, among other factors, clear recognition and management of addiction is required for effective pain control in a subset of cancer patients. At the same time, clear distinction between physical dependence and addiction is an important tool in the prevention of “opioid-phobia” and the unwarranted fear of addiction that can impede effective pain management in any patient population. Unfortunately, the DSM Committee has not provided such clarity to date. Fortunately, other groups have done so. The American Pain Society, The American Academy of Pain Medicine, and the American Society of Addiction Medicine, for example, have developed a consensus document with clear and useful definitions of opioid-related phenomena:Addiction is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Physical dependence is a state of adaptation that is manifested by a drug-class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist (7) . In the interest of patients—addicted or not—we urge that the DSM-V Committee should pursue the same degree of clarity.Edmonton, Alberta, Canada