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Genomic and proteomic studies of neurodegenerative disorders require complementary approaches to integrate the massive amount of data generated in high throughput experimental procedures. We propose a Bioinformatics pipeline in which expression studies guide the selection of candidate genes that should be screened for potential new genetic variations from a public expressed site tags (ESTs) database. Motivated by the former interest of our group in genetic polymorphisms involved with the immune system, we selected five genes from a previous expression microarrays study of hippocampal cornu ammonis (CA1) area of Alzheimer's Disease subjects (AD). The CLCbio Workbench Combined version 3.6.2. was initially used to build ESTs and mRNA files retrieved respectively from the Goldenpath of University of California Santa Cruz (UCSC) and National Center for Biotechnology Information (NCBI) databases and latter to perform multiple batches of Smith-Waterman alignments. A total of 116 ESTs sequences were selected after proper stringent parameters were applied to the first set of mismatches. The annotation revealed various classes of variations, most of them deletions (176). Amongst this specific group, some were frameshift deletions (35) and the virtual translation of a few others (5) were predicted to induce no change other than a single aminoacid removal, with no subsequent repercussions at the protein sequence. In addition, the analysis identified transitions (three), transversions (52), synonymous (41), non-synonymous (12), and deletions in 36 ESTs located in Untranslated Regions -UTRs (Supplementary data). Deletions are often associated to major genetics syndromes with dysmorphic features. However, various recent studies show that common microdeletions might be highly associated with common neuropsychiatric disorders such as schizophrenia, autism, mental retardation, or even in various ethnicities, detected in whole genome sequencing experiments. A virtual validation confirmed that some of the variations identified were previously reported and confirmed in DNA samples, showing that this method is a feasible way to detect genetic variations that merit further exploration in AD genetic risk factor association studies.
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PMID:In silico identification of new genetic variations as potential risk factors for Alzheimer's disease in a microarray-oriented simulation. 1929 Apr 94

Psychiatry includes the assessment, treatment, and prevention of complex brain disorders, such as depression, bipolar disorder, anxiety disorders, schizophrenia, developmental disorders (e.g., autism), and neurodegenerative disorders (e.g., Alzheimer dementia). Its core mission is to prevent and alleviate the distress and impairment caused by these disorders, which account for a substantial part of the global burden of illness-related disability. Psychiatry is grounded in clinical neuroscience. Its core mission, now and in the future, is best served within this context because advances in assessment, treatment, and prevention of brain disorders are likely to originate from studies of etiology and pathophysiology based in clinical and translational neuroscience. To ensure its broad public health relevance in the future, psychiatry must also bridge science and service, ensuring that those who need the benefits of its science are also its beneficiaries. To do so effectively, psychiatry as clinical neuroscience must strengthen its partnerships with the disciplines of public health (including epidemiology), community and behavioral health science, and health economics.The authors present a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis of psychiatry and identify strategies for strengthening its future and increasing its relevance to public health and the rest of medicine. These strategies encompass new approaches to strengthening the relationship between psychiatry and neurology, financing psychiatry's mission, emphasizing early and sustained multidisciplinary training (research and clinical), bolstering the academic infrastructure, and reorganizing and refinancing mental health services both for preventive intervention and cost-effective chronic disease management.
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PMID:The future of psychiatry as clinical neuroscience. 1988 7

The rise in Infantile Autism, learning problems, cognitive decline with age, Alzheimer's, Parkinson's Diseases and the SIDS epidemic, has a common cause in the rising dietary deficit in Omega-3 brain-food. This paper suggests that aside from the wider concept of Autism Spectrum Disorders (ASD) and Pervasive Developmental Disorders (PDD), the rise in Infantile Autism (IA) in the last decade is the effect of deficient brain-food (Omega-3). The consequent delay of development prolongs the 2nd regressive event in infancy to pruning of the centre in the Medial Frontal Lobe System that connects Hippocampus and Cingulum. With a consequently defective Supplementary Motor Area (SMA), the Delayed Response Function is affected leading to persistent psychosis. Post-Pubertal Episodic Psychoses are associated with acute reduction of excitation, a risk of breakdown of circuitry, insufficient fill-in mechanisms, and silent spots. An acute psychosis occurs if the silent spots comprise of SMA. Only two brain areas have continuous neurogenesis, indicating their important functions: the Hippocampus and Olfactory Bulb that belongs to the Lateral Frontal Lobe System essential to survival. Concerned with necessity of action in response to the environment, it relies upon short-term memory and Acute Feedback Mechanisms influenced by emotion and motivation from the external world. In contrast, the Medial Frontal Lobe network is controlled by Feed-Forward Predictive Mechanisms related to storage of information. The Delayed Response Function is mastered at 7 months, when 2nd event occurs with pruning of axons and dendrites. An abolished or defective Delayed Response Function seriously incapacitates an individual: A defective "Social Brain" with an inability for conscious action and to communicate, predominates in IA. There is a near lack of speech, despite normal vision and hearing in the minority without marked adversity in pregnancy, at delivery or in infancy. I propose that the recent rise in IA despite no rise in adversity signifies a rising deficiency in brain-food. That this is so is suggested by a changing clinical picture: no Mental Retardation in an IA majority. Deficit in Olfaction is pathognomonic in schizophrenia since 30 yrs and distinguishes the Asperger Syndrome. If brain-food deficiency alone sufficiently prolongs pruning to cause absent activity in SMA in infancy, less mentally retarded IA from other causes might be observed. Deficit in brain-food was evident in the Sudden Infant Death Syndrome: birthweight averaged 200-300 g lower than sibs, Omega-3 levels in brainstem were lower than controls. Only 20 % SIDS died in first hypoxic episode, suggesting such episodes are more frequent than we imagined. Children with learning-behaviour problems have similarly depressed birthweight. A general deficiency in Omega-3 contributes to the lacking reduction in Schizophrenia, despite early puberty predominates. Olfactory Bulb is first affected in the Alzheimer's and Parkinson's Disease. Cognitive decline with age, Hippocampal dysfunctions rise markedly irrespective of disease, but the major mental illnesses and Infantile Autism in particular, benefit from "brain-food" that might also prevent a development of these disorders. To secure optimal brain function in the coming generations, there is a need to change the diet now from its emphasis on protein for body growth to food for the brain. This means there is a need to increase fish and sea food consumption.
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PMID:Infantile autism: a chronic psychosis since infancy due to synaptic pruning of the supplementary motor area. 1932 37

Different pathologies of the central and peripheral nervous system show sex differences in their incidence, symptomatology and/or neurodegenerative outcome. These include Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, traumatic brain injury, stroke, autism, schizophrenia, depression, anxiety disorders, eating disorders and peripheral neuropathy. These sex differences reveal the need for sex-specific neuroprotective strategies. This review article and other manuscripts published in this issue of Hormones and Behavior analyze possible sex-specific therapeutic strategies based on neuroactive steroids. In particular in our introductory article, the possibility that sex differences in the levels or in the action of neuroactive steroids may represent causative factors for sex differences in the incidence or manifestation of pathologies of the nervous system is considered.
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PMID:Sex-specific therapeutic strategies based on neuroactive steroids: In search for innovative tools for neuroprotection. 1952 84

Deficits in social behaviour is a characteristic of numerous mental disorders including autism, schizophrenia, depression and Alzheimer's disease. For the assessment of pharmacological and genetic experimental disease models, conventional social interaction tasks bear the uncertainty that any drug-induced abnormality of the investigator may feed back to the drug-free companion modifying its reactions. A considerable technical improvement was recently reported by Moy et al. [Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson T, et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behaviours in mice. Genes Brain Behav 2004;3:287-302] in which the drug free partner is confined to a small cage and social contacts of the investigator are recorded uncontaminated of any social reactions of the stranger. Using this novel behavioural paradigm, we here show in C57Bl/6 female mice that sociability (social interaction with a stranger mouse) is not impaired after administration of the anxiolytic diazepam (0.1-1 mg/kg) or the muscarinic antagonist scopolamine hydrobromide (0.1-1 mg/kg). However, social memory tested after a short time interval was impaired by both drugs in a dose-dependent manner (diazepam: > or = 0.5mg/kg; scopolamine: > or = 0.3mg/kg). The scopolamine-induced short-term memory deficit was reversed to normal by the choline esterase inhibitor donepezil (1 mg/kg). Given this dependence of social recognition on the cholinergic system, combined with the clinical observation of reduced social contacts in dementia patients, sociability may offer a novel endpoint biomarker with translational value in experimental models of cognitive dysfunction.
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PMID:Scopolamine-induced deficits in social memory in mice: reversal by donepezil. 1952 54

Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.
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PMID:Genetic aspects of behavioral neurotoxicology. 1964 18

Would you entrust your brain to a bank? Well, many people do after they die, and such brain banks-often funded by government agencies or disease charities-are essential for neuroscience research. They collect and store the healthy and diseased brain specimens that neuroscientists need to explore neurological disorders such as Alzheimer's disease, schizophrenia and autism. Each brain bank typically has a limited supply of samples and tends to operate fairly independently. This means that researchers often have to trawl through numerous brain banks to find their desired specimens. Furthermore, there is a general shortage of brain samples. To help resolve these issues in the UK, James Ironside, professor of clinical neuropathology at the University of Edinburgh, was appointed in June as the director of the new UK Brain Banks Network. An expert in human prion diseases, particularly Creutzfeldt-Jakob disease (CJD), Ironside knows all about brain banks. He established the Brain and Tissue Bank at the UK's National CJD Surveillance Unit and is involved in the Sudden Death Brain and Tissue Bank at the University of Edinburgh. Jon Evans recently caught up with Ironside to discuss his new leadership position and how the brain network will benefit neuroscience research.
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PMID:Straight talk with...James Ironside. [Interviewed by Jon Evans]. 1966 81

BACKGROUND: Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype-based genetic and small molecule compound screening. OBJECTIVE/METHOD: The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by more than six hundred disorders in humans. I discuss the past, present, and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer's, Parkinson's, and Hungtington's disease, and neural system dysfunctions such as anxiety/depression and addiction. CONCLUSION: These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders.
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PMID:Using zebrafish to assess the impact of drugs on neural development and function. 1977 94

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders, such as Alzheimer's disease, manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a 'Latent Early-life Associated Regulation' (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders.
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PMID:The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. 1985 Dec 80

Historically, our understanding of synapse formation has been shaped by studies focusing on neurons. However, with advancements in live imaging techniques and molecular and genetic tools we are rapidly uncovering new roles for glia in synapse formation and function. Contact-mediated signals from glia instruct dendrites to become receptive to synaptic partners. Glia-secreted factors coordinate the assembly and apposition of pre-synaptic and post-synaptic specializations. Glial cells also provide cues that are required for synaptic maturation and remodeling of spines both during development and in the adult. As we continue to learn about glial contributions to synapse formation and maintenance, it is likely that glia-derived signals will emerge as potential therapeutic targets for diseases that involve aberrant circuit function such as autism, epilepsy and Alzheimer's Disease.
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PMID:Look who is weaving the neural web: glial control of synapse formation. 1987 29


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