Brain Development and the Risk for Substance Abuse

Drug and alcohol dependence affects millions each year. Adolescence is a period of increased risk for substance use disorders. Understanding how the brain is changing during this developmental window relative to childhood and adulthood and how these changes vary across individuals is critical for predicting risk of later substance abuse and dependence. This chapter provides an overview of recent human imaging and animal studies of brain development focusing on changes in corticostriatal circuitry that has been implicated in addiction. Behavioral, clinical, and neurobiological evidence is provided to help elucidate who may be most at risk for developing a substance abuse problem and whenthey may be most vulnerable.

Neurobiology and Treatment of OCD

Obsessive Compulsive Disorder (OCD) is a chronic, disabling disorder with a lifetime prevalence of up to 2-3%, and is a leading cause of illness-related disability. OCD is characterized by recurrent intrusive thoughts, images, or impulses (obsessions) that cause anxiety or distress, and repetitive mental or behavioral acts (compulsions). Though the etiology of OCD is unclear, current evidence implicates both genetic and environmental factors in its development. Our understanding of the neurobiology underlying OCD is still evolving, with convergent evidence from clinical and preclinical studies highlighting the importance of abnormalities in cortico-striatal-thalamo-cortical (CSTC) circuits. Evidence-based treatments for OCD include both pharmacotherapy and cognitive-behavioral therapy. This chapter will review the etiology and neurobiology of OCD, and will provide an overview of treatment strategies.

Genetics of Anxiety Disorders

This chapter provides a broad overview of the state of current research in the genetics of the major anxiety disorders. In addition tosummarizing findings regarding the individual clinical syndromes, we present data supporting genetic hypotheses that explain their comorbidity with each other and with related phenotypessuch as anxious personality traits and depression. We conceptually divide the chapter into three main sections based upon methodology: (1) genetic epidemiology of adult and pediatric anxiety (twin and family studies), (2) human molecular genetics (linkage and association), and (3) animal genetic models. These approaches provide complimentary and concurring evidence supporting the genetic basis underlying anxiety disorders as well as preliminary insight into the genetic mechanisms involved in their expression.

Molecular and Cellular Pathogenesis of Depression and Mechanisms for Treatment Response

Early theories of depression were centered on the monoamines, but more recent work has focused on the amino acid neurotransmitters, glutamate and GABA. Imbalances of glutamate and GABA transmission in key cortical and limbic structures are thought to contribute to disruption of brain circuits that control emotion and mood. These imbalances, together with stress activated pathways that regulate neurotrophic factors and inflammatory cytokines could contribute to atrophy and loss of neurons observed in depressed patients and rodent stress models. The significance of synaptic connections in depression is highlighted by new studies demonstrating that a rapid acting, highly efficacious antidepressant agent increases synaptogenesis, paving the way for a new generation of medications for the treatment of depression.

Genetics of Depression

Categorical major depressive disorder has been the focus of most genetic studies, although some studies use continuous measures or consider both depression and anxiety. Lifetime risk of major depression is high (12-20%), heritability is below 40%, and the relative risk to first-degree relatives is approximately 3. These characteristics are challenging for current genetic methods. There have been several significant linkage findings which do not consistently replicate. Genomewide association studies have not produced significant findings, but analyses that cut across diagnostic boundaries seem promising. Candidate gene studies have been fraught with methodological problems, although the largest meta-analysis to date supported the hypothesis that 5-HTTLPR genotype and specific stressors interact to predict depressive episodes (but not lifetime risk of depression). Future steps include application of sequencing and stem cell technologies. Methods are need to build larger samples with more detailed clinical assessment. Outstanding genetic epidemiological issues should be addressed by new studies.

Neurodevelopment and Schizophrenia

A neurodevelopmental model of schizophrenia postulates that some of the key aspects of brain development that normally occur both pre- and post-natally are not occurring correctly, either in time or space. Complex neural circuitry needs to form and be modulated by experience. Classically, proliferation, migration, arborization and myelination occur prenatally. Elaboration and refining of dendritic trees and synapses as well as myelination of the nervous system continues through the first two-decade of life. There are opportunities for genetic and environmental abnormalities and variation to profoundly influence the trajectories of all of these critical functional processes.

Mouse Models of Schizophrenia and Bipolar Disorder

Despite the recent advances in research into schizophrenia and bipolar disorder, the neurobiology of these maladies remains poorly understood. Animal models can be instrumental in elucidating the underlying mechanisms of neuropsychiatric disorders. Early animal models of schizophrenia and bipolar disorder used lesion methods, pharmacologic challenges or environmental interventions to mimic pathogenic features of the diseases. The recent progress in genetics has stimulated the development of etiological models that have begun to provide insight into pathogenesis. In this review, we evaluate the strengths and weaknesses of the existing genetic mouse models of schizophrenia and discuss potential developments for the future.

Genomic Syndromes in Schizophrenia

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

Principles of Molecular Biology

This chapter provides an overview of the fundamental molecular processes by which information is encoded in the genome and how this information is expressed within an environmental context. We describe what genes are, how they function, and how their expression into RNA and protein is regulated by signals from outside the cell. Particular attention is given to a series of stimulus-regulated transcription factors, which play important roles in transducing information from the cell surface to the nucleus. Work in this area has shown that the control of gene expression by extracellular signals is a critical arena for gene–environment interactions that are highly relevant to psychiatry.

Principles of Signal Transduction

Chapter 4 covers postreceptor intracellular messenger cascades through which neurotransmitters and neurotrophic factors, and their receptors, produce their diverse physiological effects. A major advance over the past generation of research has been an appreciation of the complex webs of intracellular signaling pathways that control every aspect of a neuron’s functioning, from neurotransmitter signaling to cell shape and motility to gene expression. While only a small number of medications used in psychiatry today have as their initial target intracellular signaling proteins, it is likely that drug development efforts will look increasingly to such proteins for the discovery of novel medications with fundamentally new mechanisms of action.