Psychiatric research: psychoproteomics,degradomics and systems biology

While proteomics has excelled in several disciplines in biology (cancer, injury and aging), neuroscience and psychiatryproteomic studies are still in their infancy. Several proteomic studies have been conducted in different areas of psychiatric disorders, including drug abuse (morphine, alcohol and methamphetamine) and other psychiatric disorders (depression, schizophrenia and psychosis). However, the exact cellular and molecular mechanisms underlying these conditions have not been fully investigated. Thus, one of the primary objectives of this review is to discuss psychoproteomic application in the area of psychiatric disorders, with special focus on substance- and drug-abuse research. In addition, we illustrate the potential role of degradomic utility in the area of psychiatric research and its application in establishing and identifying biomarkers relevant to neurotoxicity as a consequence of drug abuse. Finally, we will discuss the emerging role of systems biology and its current use in the field of neuroscience and its integral role in establishing a comprehensive understanding of specific brain disorders and brain function in general.     

CNS proteomes in alcohol and drug abuse and dependence

Drugs of abuse, including alcohol, can induce dependency formation and/or brain damage in brain regions important for cognition. 'High-throughput' approaches, such as cDNA microarray and proteomics, allow the analysis of global expression profiles of genes and proteins. These technologies have recently been applied to human brain tissue from patients with psychiatric illnesses, including substance abuse/dependence and appropriate animal models to help understand the causes and secondary effects of these complex disorders. Although these types of studies have been limited in number and by proteomics techniques that are still in their infancy, several interesting hypotheses have been proposed. Focusing on CNS proteomics, we aim to review and update current knowledge in this rapidly advancing area.     

CNS proteomes in alcohol and drug abuse and dependence

Drugs of abuse, including alcohol, can induce dependency formation and/or brain damage in brain regions important for cognition. ‘High-throughput’ approaches, such as cDNA microarray and proteomics, allow the analysis of global expression profiles of genes and proteins. These technologies have recently been applied to human brain tissue from patients with psychiatric illnesses, including substance abuse/dependence and appropriate animal models to help understand the causes and secondary effects of these complex disorders. Although these types of studies have been limited in number and by proteomics techniques that are still in their infancy, several interesting hypotheses have been proposed. Focusing on CNS proteomics, we aim to review and update current knowledge in this rapidly advancing area.     

Post-translational histone modifications and their interaction with sex influence normal brain development and elaboration of neuropsychiatric disorders

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex.     

Neural stem cells, adult neurogenesis, and galectin-1: from bench to bedside

Neural stem cells (NSCs) in the adult brain have been a consistent focus of biomedical research largely because of their potential clinical application. To fully exploit this potential, the molecular mechanisms that regulate NSCs must be clarified. Several lines of evidence show that a multifunctional protein, Galectin-1, is expressed and has a functional role in a subset of adult NSCs. Researchers, including our group, have explored the physiological role of Galectin-1 in NSCs and its application in the treatment of animal models of neurological disorders such as brain ischemia and spinal cord injury. Here, we summarize what is currently known regarding the role of Galectin-1 in adult NSCs. Furthermore, we discuss current issues in researching the role of Galectin-1 in adult NSCs under both physiological and pathological conditions.     

Genetics of craniofacial development and malformation

The head is anatomically the most sophisticated part of the body and its evolution was fundamental to the origin of vertebrates; understanding its development is a formidable problem in biology. A synthesis of embryology, evolution and mouse genetics is shaping our understanding of head development and in this review we discuss its application to studies of human craniofacial malformations. Many of these disorders have their origins in specific embryological processes, including abnormalities of brain patterning, of the migration and fusion of tissues in the face, and of bone differentiation in the skull vault.     

Deciphering the role of docosahexaenoic acid in brain maturation and pathology with magnetic resonance imaging

Animal studies have found that deficits in brain docosahexaenoic acid (DHA, 22:6n-3) accrual during perinatal development leads to transient and enduring abnormalities in brain development and function. Determining the relevance of this evidence to brain disorders in humans has been hampered by an inability to determine antimortem brain DHA levels and limitations associated with a postmortem approach. Accordingly, there is a need for alternate or complementary approaches to better understand the role of DHA in cortical function and pathology, and conventional magnetic resonance imaging (MRI) techniques may be ideally suited for this application. A major advantage of neuroimaging is that it permits prospective evaluation of the effects of manipulating DHA status on both clinical and neuroimaging variables. Emerging evidence from MRI studies suggest that greater DHA status is associated with cortical structural and functional integrity, and suggest that reduced DHA status and abnormalities in cortical function observed in psychiatric disorders may be interrelated phenomenon. Preliminary evidence from animal MRI studies support a critical role of DHA in normal brain development. Neuroimaging research in both human and animals therefore holds tremendous promise for developing a better understanding of the role of DHA status in cortical function, as well as for elucidating the impact of DHA deficiency on neuropathological processes implicated in the etiology and progression of neurodevelopmental and psychiatric disorders.     

Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders

Psychiatric disorders affect approximately 10% of adults in North-America. The complex nature of these illnesses makes the search for their pathophysiology a challenge. However, studies have consistently shown that mitochondrial dysfunction and oxidative stress are common features across major psychiatric disorders, including bipolar disorder and schizophrenia. Nevertheless, little is known about specific targets of oxidation in the brain. The search for redox sensors (protein targets for oxidation) will offer information about which pathways are regulated by oxidation in psychiatric disorders. Additionally, DNA is also a target for oxidative damage and recently, studies have suggested that oxidation of cytosine and guanosine can serve as an epigenetic modulator by decreasing or preventing further DNA methylation. Therefore, this review aims to discuss how we can use redox-proteomics and epigenomics to help explain the role of oxidative damage in major psychiatric disorders, which may ultimately lead to the identification of targets for development of new medications.     

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

The Hypocretin/Orexin System: Implications for Drug Reward and Relapse

Hypocretins (also known as orexins) are hypothalamic neuropeptides involved in the regulation of sleep/wake states and feeding behavior. Recent studies have also demonstrated an important role for the hypocretin/orexin system in the addictive properties of drugs of abuse, consistent with the reciprocal innervations between hypocretin neurons and brain areas involved in reward processing. This system participates in the primary reinforcing effects of opioids, nicotine, and alcohol. Hypocretins are also involved in the neurobiological mechanisms underlying relapse to drug-seeking behavior induced by drug-related environmental stimuli and stress, as mainly described in the case of psychostimulants. Based on these preclinical studies, the use of selective ligands targeting hypocretin receptors could represent a new therapeutical strategy for the treatment of substance abuse disorders. In this review, we discuss and update the current knowledge about the participation of the hypocretin system in drug addiction and the possible neurobiological mechanisms involved in these processes regulated by hypocretin transmission.     

Translocator protein (TSPO) and neurosteroids: implications in psychiatric disorders

The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.     

Molecular epigenetics,chromatin, and NeuroAIDS/HIV: Translational implications

We describe current research that applies epigenetics to a novel understanding of the immuno-neuropathogenesis of HIV-1 viral infection and NeuroAIDS. We propose the hypothesis that HIV-1 alters the structure-function relationship of chromatin, coding DNA and non-coding DNA, including RNA transcribed from these regions resulting in pathogenesis in AIDS, drug abuse, and NeuroAIDS. We discuss the general implications of molecular epigenetics with special emphasis on drug abuse, bar-codes, pyknons, and miRNAs for translational and clinical research. We discuss the application of the recent recursive algorithm of biology to this field and propose to synthesize the Genomic and Epigenomic views into a holistic approach of HoloGenomics.     

Glutamate and Brain Glutaminases in Drug Addiction

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.     

Neurologic effects of alcoholism.

Alcoholism, a worldwide disorder, is the cause of a variety of neurologic disorders. In this article we discuss the cellular pathophysiology of ethanol addition and abuse as well as evidence supporting and refuting the role of inheritance in alcoholism. A genetic marker for alcoholism has not been identified, but neurophysiologic studies may be promising. Some neurologic disorders related to longterm alcoholism are due predominantly to inadequate nutrition (the thiamine deficiency that causes Wernicke''s encephalopathy), but others appear to involve the neurotoxicity of ethanol on brain (alcohol withdrawal syndrome and dementia) and peripheral nerves (alcoholic neuropathy and myopathy).     

Potential biomarkers in psychiatry: focus on the cholesterol system

Measuring biomarkers to identify and assess illness is a strategy growing in popularity and relevance. Although already in clinical use for treating and predicting cancer, no biological measurement is used clinically for any psychiatric disorder. Biomarkers could predict the course of a medical problem, and aid in determining how and when to treat. Several studies have indicated that of candidate psychiatric biomarkers detected using proteomic techniques, cholesterol and associated proteins, specifically apolipoproteins (Apos), may be of interest. Cholesterol is necessary for brain development and its synthesis continues at a lower rate in the adult brain. Apos are the protein component of lipoproteins responsible for lipid transport. There is extensive evidence that the levels of cholesterol and Apos may be disturbed in psychiatric disorders, including autistic spectrum disorders (ASD). Here, we describe putative serum biomarkers for psychiatric disorders, and the role of cholesterol and Apos in central nervous system (CNS) disorders.     

Drug abuse,psychiatric disorders,and AIDS. Dual and triple diagnosis.

Substance abuse and psychiatric disorders commonly occur together. This form of dual diagnosis is notable because it complicates assessment and makes treatment more difficult for both psychiatric and drug abuse problems. Drugs can cause psychiatric disorders and can also be used as an attempt to "cure" them by self-medication. The spread of the human immunodeficiency virus (HIV) among drug users has added a third potential clinical problem, that of the acquired immunodeficiency syndrome, to the difficulties already presented by drug abuse and psychiatric disorders. Patients with this triple diagnosis pose challenges to primary care physicians as well as addiction medicine specialists or psychiatrists. Assessment should include a drug abuse history, preferably corroborated by others, evaluation of the mental state, and examination focusing on signs of drug abuse and HIV infection. Treatment should include the management of HIV disease, abstinence from drug abuse, and access to psychiatric care. New systems of health care service, including interdisciplinary case management, may be needed to manage patients with a triple diagnosis.     

Mixing pleasures: Review of the effects of drugs on sex behavior in humans and animal models

Drugs of abuse act on the brain circuits mediating motivation and reward associated with natural behaviors. There is ample evidence that drugs of abuse impact male and female sexual behavior. First, the current review discusses the effect of drugs of abuse on sexual motivation and performance in male and female humans. In particular, we discuss the effects of commonly abused drugs including psychostimulants, opiates, marijuana/THC, and alcohol. In general, drug use affects sexual motivation, arousal, and performance and is commonly associated with increased sexual risk behaviors. Second, studies on effects of systemic administration of drugs of abuse on sexual behavior in animals are reviewed. These studies analyze the effects on sexual performance and motivation but do not investigate the effects of drugs on risk-taking behavior, creating a disconnect between human and animal studies. For this reason, we discuss two studies that focus on the effects of alcohol and methamphetamine on inhibition of maladaptive sex-seeking behaviors in rodents. Third, this review discusses potential brain areas where drugs of abuse may be exerting their effect on sexual behavior with a focus on the mesolimbic system as the site of action. Finally, we discuss recent studies that have brought to light that sexual experience in turn can affect drug responsiveness, including a sensitized locomotor response to amphetamine in female and male rodents as well as enhanced drug reward in male rats.     

Modeling madness in mice: one piece at a time

Mouse models that recapitulate the full phenotypic spectrum of a psychiatric disorder, such as schizophrenia, are impossible. However, a more piecemeal recreation of phenotypic components is feasible and promises to harness the power of animal models using approaches that are either off limits or confounded by drug treatment in humans. In that context, animal models will have a central and indispensable role in the process of discovering the causes of psychiatric disorders and generating novel, mechanism-based treatments. Here, we discuss current approaches used to generate animal models of psychiatric disorders, address the different components of these disorders that can be modeled in animals, and describe currently available analytical tools. We also discuss accumulating empirical data and take an in-depth look at what we believe to be the future of animal models made possible by recent advances in psychiatric genetics.     

Advanced diffusion MRI fiber tracking in neurosurgical and neurodegenerative disorders and neuroanatomical studies: A review

Diffusion MRI enabled in vivo microstructural imaging of the fiber tracts in the brain resulting in its application in a wide range of settings, including in neurological and neurosurgical disorders. Conventional approaches such as diffusion tensor imaging (DTI) have been shown to have limited applications due to the crossing fiber problem and the susceptibility of their quantitative indices to partial volume effects. To overcome these limitations, the recent focus has shifted to the advanced acquisition methods and their related analytical approaches. Advanced white matter imaging techniques provide superior qualitative data in terms of demonstration of multiple crossing fibers in their spatial orientation in a three dimensional manner in the brain. In this review paper, we discuss the advancements in diffusion MRI and introduce their roles. Using examples, we demonstrate the role of advanced diffusion MRI-based fiber tracking in neuroanatomical studies. Results from its preliminary application in the evaluation of intracranial space occupying lesions, including with respect to future directions for prognostication, are also presented. Building upon the previous DTI studies assessing white matter disease in Huntington's disease and Amyotrophic lateral sclerosis; we also discuss approaches which have led to encouraging preliminary results towards developing an imaging biomarker for these conditions.     

Serotonin and Prefrontal Cortex Function: Neurons,Networks, and Circuits

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.