The developmental origins of complex behavior and neuropsychiatric disease

Development is a period marked by a profound, prolonged maturation of the brain and attendant changes in behavior. It has also long been recognized that the seeds of psychiatric disease are planted early in life in the form of influential ontogenic events and as major life events (e.g., exposure to stress or drugs) that resonate throughout the lifespan. This issue of G2B^REVIEWS brings the question of development into focus with a collection of reviews by researchers who are leading efforts to understand how brain and behavior are shaped during the formative years of early life, and decipher the mechanisms by which genes and early environmental experience impact risk for an array of mental illnesses.

Autism is a canonical developmental disorder that has become a major focus in psychiatric genetics. The resultant findings have informed the generation of mice with engineered mutations in autism candidate genes and in turn necessitated reliable readouts of autism-relevant behaviors. Here, Kazdoba et al. (2015) review the current genetic models and behavioral assays for autism, many of which this group has pioneered. Their article provides an excellent overview and template for researchers delving into this field. The need for better phenotypic modeling is echoed by Cope et al. (2015) in the context of modeling cognitive deficits associated with neurodevelopmental diseases. These authors contend that the failure to translate preclinical findings to new pro-cognitive treatments results from the artificial strictures of diagnostic boundaries separating disorders, and they herald the adoption of dimensional approaches to diagnosis typified by the Research Domain Criteria as a framework for advancing cross-species behavioral assays.

Schizophrenia is a mental illness with profound cognitive dysfunction that has been long thought to have its roots in development. Schoenrock and Tarantino (2015) consider the intriguing hypothesis, based on animal models as well as epidemiological data from clinical studies, that prenatal vitamin D deficiency may be a risk factor for schizophrenia and a potential explanation for the greater incidence of the disease in individuals born in seasons or environments with lower sunlight (and hence vitamin D production). A major neural system implicated in schizophrenia and other developmentally related disorders in is the midbrain dopaminergic system. Bissonette and Roesch (2015) review the significant advances that have been made in delineating the ontogeny of this neurotransmitter system. They also offer a valuable description of the myriad genetic and molecular factors that modulate the fate of dopamine neurons and their connectivity with forebrain regions mediating cognition, reward and emotion. Dopamine is of course also well known for its role in reward, drug abuse and addiction. Belin et al. (2015) discuss how the work they have helped lead has provided novel insight into how specific, genetically related traits, such as impulsivity, may represent predictive markers for addiction-like behaviors. They also argue that research aimed at interrogating the developmental trajectory of addiction, and the contribution of individual differences in dopamine function and other neural processes, would be greatly facilitated by the availability of sound phenotypic measures of addiction-like behavior in rodents (Belin et al., 2015).

These findings have implications for studying a variety of mechanisms known to be involved in addictions, such as nicotinic acetylcholine receptors – the focus of the article by Melroy-Greif et al. (2015). These authors discuss the interesting observation that there are adaptations, notably functional upregulation, in nicotinic receptors expressed in reward-related circuits that vary as a function of developmental age (Melroy-Greif et al., 2015). They point out how this idiosyncratic feature of nicotinic receptor function may be particularly relevant to risk for addictions in view of genetic associations between nicotinic receptors and drug abuse. Like nicotinic receptors, endocannabinoids are defined as targets for a commonly used and abused drug, but have broad neurobiological functions. For instance, there is now a substantial body of research demonstrating a key role for endocannabinoids in regulating stress, anxiety and various emotional behaviors across species. Lee et al. (2015) have made many important discoveries in this regard and, here, underscore the parallels that exist between alterations in brain endocannabinoid signaling and learned fear behaviors across development. They also discuss the topical issues of the possible long-term effects of recreational cannabis use in young people, and the therapeutic potential of pharmacologically augmenting endocannabinoids for anxiety disorders.

The amygdala, a key site of action for various behavioral effects of endocannabinoids, recruits certain plasticity-related signaling pathways to instantiate fearful and other motivationally significant memory engrams that overlap with those recruited during development. An incisive and thought-provoking review by Ehrlich and Josselyn (2015) contends that these parallels may be highly consequential for amygdala development – with learning-driven plasticity in this region actively shaping its ontogenic course and defining its role as substrate for learning in adulthood. The unique nature of fear learning in infant rodents is the focus of a piece by Tallot et al. (2015). On the basis of landmark findings by their group and others, they illustrate how the maturation of key nodes in the fear-mediating neural systems that include the amygdala, as well as the prefrontal cortex and hippocampus, converges with, and as such may well account for, the emergence of adult-like fear behavior (Tallot et al., 2015). A seminal series of findings, represented here by Cowan et al. (2015), demonstrates how fear learning, and the corticolimbic circuits subserving it, continues to change beyond infanthood and into late adolescence. As these authors lay out, stressful experiences early in life can significantly impact these same behavioral processes and neural functions, not only across the lifespan but, remarkably, that these experiences can be transmitted across generations.

Epigenetic modification of critical gene sets may be one way in which developmental events exert pervasive effects long-term. Additionally, as expertly reviewed by Bryant and Yazdani (2015), there is growing appreciation of how gene expression during development is dynamically regulated by factors such as RNA binding proteins (RBPs). These authors summarize the various routes by which RBPs can modify gene transcription and post-transcriptional events to influence the neurodevelopmental trajectories of systems implicated in addictions and other brain disease states. Another once-overlooked feature of the genome is non-coding DNA. Barr and Misener (2015) discuss progress in the study of non-coding genomic regions, which until recently had been forestalled by certain technical challenges, particularly in developing brains. Armed with technical advances they cite important findings from their own work and others that has begun to parse the contribution of gene-regulatory variants to risk for psychiatric diseases.

Together, this collection of 12 reviews provides a very timely perspective on the current state of developmental research across a range of fields and illuminates some of the exciting paths this work is bound for in the coming years.