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Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day.

The structures of two rat brain-specific 1B236 mRNAs, alternative splice products from a single gene regulated differently during postnatal brain development, were deduced from full-length cDNA clones. The 626-and 582-amino acid-long encoded proteins are indistinguishable from two forms of myelin-associated glycoprotein, a cell adhesion molecule involved in axonal-glial and glial-glial interactions in postnatal brain development, particularly in myelination. The two proteins share a single membrane-spanning domain and a glycosylated N terminus but differ in the structures of their C termini. The N terminus consists of five domains related in sequence to each other and to immunoglobulin-like molecules, especially the neural cell adhesion molecule N-CAM, suggesting a common structure for cell adhesion molecules. Rat brain protein 1B236 was originally defined by nucleotide sequence analysis of randomly selected cDNA clones of mRNAs expressed in adult rat brain but not detectable in liver or kidney (1,2). Antisera to synthetic peptides corresponding to nonoverlapping regions of the partial 1B236 sequence detected a postnatally expressed 100-kDa rat brain protein containing "30% N-linked carbohydrate and proteolytic fragments derived from its C-terminal regions (2-5). During early postnatal development, 1B236 is expressed predominantly by oligodendrocytes in myelinating fiber tracts. Subsequently, there is gradual elaboration of the adult pattern in which 1B236 mRNA is detected predominantly in subsets of neurons in grey matter regions and the 1B236 protein is restricted to specific neuronal cell bodies and fibers (refs. 2, 4, and 6; G. A. Higgins, H. Schmale, F.E.B., M. C. Wilson, R.J.M., unpublished data).We have now analyzed 1B236 expression more completely and report here the structures of two differently regulated, alternatively spliced 1B236 mRNAs that encode proteins with alternative C-terminal tails. The shared N-terminal region consists of five domains that are related in sequence to each other and to proteins of the immunoglobulin super family (8), especially the neural cell adhesion molecule N-CAM (9). We show that the 1B236 protein is indistinguishable from myelin-associated glycoprotein (MAG), a nervous system-specific glycoprotein of 100 kDa that contains -30% carbohydrate (10). MAG has been implicated in the interactions between myelinating cells and axons (10) and the formation and maintenance of the periaxonal space (11). In the peripheral nervous system, MAG appears to take over Schwann cell-axon and Schwann cell-Schwann cell interactions initiated by N-CAM and L1/neuron-glia cell adhesion molecule (12). Thus two cell adhesion molecules that act at successive stages of neural development also share significant structural properties. EXPERIMENTSPrimary Structure of the 1B236 mRNA: Alternative Splicing Produces Two Forms. We described a 1500-nucleotide (nt) partial cDNA clone of the 2500-nt 1B236 mRNA (2). Two additional clones (p1B236-18 and plB236-20) with apparently full-length inserts were...

More than 76 million people worldwide are estimated to have diagnosable Alcohol Use Disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The U.S. Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism’s (NIAAA’s) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: 1) to make the drug development process more efficient; 2) to identify more efficacious medications, personalize treatment approaches, or both, and 3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options, and ultimately lessen the impact of this devastating disorder.