Thomas R. Insel

Grand challenges in global mental health

A consortium of researchers, advocates and clinicians announces here research priorities for improving the lives of people with mental illness around the world, and calls for urgent action and investment.

Toward the future of psychiatric diagnosis: the seven pillars of RDoC

BackgroundCurrent diagnostic systems for mental disorders rely upon presenting signs and symptoms, with the result that current definitions do not adequately reflect relevant neurobiological and behavioral systems - impeding not only research on etiology and pathophysiology but also the development of new treatments.DiscussionThe National Institute of Mental Health began the Research Domain Criteria (RDoC) project in 2009 to develop a research classification system for mental disorders based upon dimensions of neurobiology and observable behavior. RDoC supports research to explicate fundamental biobehavioral dimensions that cut across current heterogeneous disorder categories. We summarize the rationale, status and long-term goals of RDoC, outline challenges in developing a research classification system (such as construct validity and a suitable process for updating the framework) and discuss seven distinct differences in conception and emphasis from current psychiatric nosologies.SummaryFuture diagnostic systems cannot reflect ongoing advances in genetics, neuroscience and cognitive science until a literature organized around these disciplines is available to inform the revision efforts. The goal of the RDoC project is to provide a framework for research to transform the approach to the nosology of mental disorders.

Social amnesia in mice lacking the oxytocin gene.

The development of social familiarity in rodents depends predominantly on olfactory cues and can critically influence reproductive success. Researchers have operationally defined this memory by a reliable decrease in olfactory investigation in repeated or prolonged encounters with a conspecific. Brain oxytocin (OT) and vasopressin (AVP) seem to modulate a range of social behaviour from parental care to mate guarding. Pharmacological studies indicate that AVP administration may enhance social memory, whereas OT administration may either inhibit or facilitate social memory depending on dose, route or paradigm. We found that male mice mutant for the oxytocin gene (Oxt−/−) failed to develop social memory, whereas wild-type (Oxt+/+) mice showed intact social memory. Measurement of both olfactory foraging and olfactory habituation tasks indicated that olfactory detection of non-social stimuli is intact in Oxt−/− mice. Spatial memory and behavioural inhibition measured in a Morris water-maze, Y-maze, or habituation of an acoustic startle also seemed intact. Treatment with OT but not AVP rescued social memory in Oxt−/− mice, and treatment with an OT antagonist produced a social amnesia-like effect in Oxt+/+ mice. Our data indicate that OT is necessary for the normal development of social memory in mice and support the hypothesis that social memory has a neural basis distinct from other forms of memory.

The neurobiology of attachment

It is difficult to think of any behavioural process that is more intrinsically important to us than attachment. Feeding, sleeping and locomotion are all necessary for survival, but humans are, as Baruch Spinoza famously noted, “a social animal” and it is our social attachments that we live for. Over the past decade, studies in a range of vertebrates, including humans, have begun to address the neural basis of attachment at a molecular, cellular and systems level. This review describes some of the important insights from this work.

The Knockout Mouse Project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.

Early Life Programming and Neurodevelopmental Disorders

For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009.

The ontogeny of excitatory amino acid receptors in rat forebrain—I.N-methyl-d-aspartate and quisqualate receptors

The ontogeny of radioligand binding to N-methyl-D-aspartate and quisqualate receptors in rat forebrain was studied quantitatively using in vitro receptor autoradiography. Specific binding to both receptors could be detected by postnatal day 1 in hippocampus and striatum. The adult pattern of binding to N-methyl-D-aspartate receptors emerged by postnatal day 14 with high densities of binding in CA1 (stratum oriens and stratum radiatum), dentate gyrus (molecular layer) and striatum (caudate-putamen). Binding to the outer laminae of frontal cortex was as much as 45% above adult levels during development. Binding of [3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid to quisqualate receptors showed a similar overshoot during development, but also manifested a unique distribution with CA3 and medial aspects of the amygdala exhibiting transient, intense labeling. Homogenate binding studies with [3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid demonstrated a 73% increase in quisqualate receptors in whole brain at postnatal day 21 compared with adult levels. The selectivity of excitatory amino acid binding to the quisqualate site in development was similar to the selectivity in adult brain. These data taken with other recent reports, suggest that quisqualate receptors may have a role in development distinct from their function in the adult brain.

Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it

Patients with mental disorders show many biological abnormalities which distinguish them from normal volunteers; however, few of these have led to tests with clinical utility. Several reasons contribute to this delay: lack of a biological ‘gold standard’ definition of psychiatric illnesses; a profusion of statistically significant, but minimally differentiating, biological findings; ‘approximate replications’ of these findings in a way that neither confirms nor refutes them; and a focus on comparing prototypical patients to healthy controls which generates differentiations with limited clinical applicability. Overcoming these hurdles will require a new approach. Rather than seek biomedical tests that can ‘diagnose’ DSM-defined disorders, the field should focus on identifying biologically homogenous subtypes that cut across phenotypic diagnosis—thereby sidestepping the issue of a gold standard. To ensure clinical relevance and applicability, the field needs to focus on clinically meaningful differences between relevant clinical populations, rather than hypothesis-rejection versus normal controls. Validating these new biomarker-defined subtypes will require longitudinal studies with standardized measures which can be shared and compared across studies—thereby overcoming the problem of significance chasing and approximate replications. Such biological tests, and the subtypes they define, will provide a natural basis for a ‘stratified psychiatry’ that will improve clinical outcomes across conventional diagnostic boundaries.

Increased affiliative response to vasopressin in mice expressing the V1a receptor from a monogamous vole.

Arginine vasopressin influences male reproductive and social behaviours in several vertebrate taxa through its actions at the V1a receptor in the brain. The neuroanatomical distribution of vasopressin V1a receptors varies greatly between species with different forms of social organization,. Here we show that centrally administered arginine vasopressin increases affiliative behaviour in the highly social, monogamous prairie vole, but not in the relatively asocial, promiscuous montane vole. Molecular analyses indicate that gene duplication and/or changes in promoter structure of the prairie vole receptor gene may contribute to the species differences in vasopressin-receptor expression. We further show that mice that are transgenic for the prairie vole receptor gene have a neuroanatomical pattern of receptor binding that is similar to that of the prairie vole, and exhibit increased affiliative behaviour after injection with arginine vasopressin. These data indicate that the pattern of V1a-receptor gene expression in the brain may be functionally associated with species-typical social behaviours in male vertebrates.

The Neuroendocrine Basis of Social Recognition

Studies conducted in the past two years have yielded several new insights about neuroendocrine regulation of social recognition. The social recognition deficits seen in oxytocin knockout mice have now been demonstrated in both males and females, as well as in female estrogen receptor knockout mice. The male vasopressin V1A receptor knockout mouse (but not V1B) has a profound social recognition deficit. Preliminary evidence suggests that female V1B receptor knockout mice could also have social memory deficits. Several lines of evidence have emerged that indicate that neuropeptide regulation is significantly modulated by gonadal and corticosteroid activation.