New Frontiers in Animal Research of Psychiatric Illness

Abstract

Alterations in neurodevelopment are thought to modify risk of numerous psychiatric disorders, including schizophrenia, autism, ADHD, mood and anxiety disorders, and substance abuse. However, little is known about the cellular and molecular changes that guide these neurodevelopmental changes and how they contribute to mental illness. In this review, we suggest that elucidating this process in humans requires the use of model organisms. Furthermore, we advocate that such translational work should focus on the role that genes and/or environmental factors play in the development of circuits that regulate specific physiological and behavioral outcomes in adulthood. This emphasis on circuit development, as a fundamental unit for understanding behavior, is distinct from current approaches of modeling psychiatric illnesses in animals in two important ways. First, it proposes to replace the diagnostic and statistical manual of mental disorders (DSM) diagnostic system with measurable endophenotypes as the basis for modeling human psychopathology in animals. We argue that a major difficulty in establishing valid animal models lies in their reliance on the DSM/International Classification of Diseases conceptual framework, and suggest that the Research Domain Criteria project, recently proposed by the NIMH, provides a more suitable system to model human psychopathology in animals. Second, this proposal emphasizes the developmental origin of many (though clearly not all) psychiatric illnesses, an issue that is often glossed over in current animal models of mental illness. We suggest that animal models are essential to elucidate the mechanisms by which neurodevelopmental changes program complex behavior in adulthood. A better understanding of this issue, in animals, is the key for defining human psychopathology, and the development of earlier and more effective interventions for mental illness.

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety

“…These effects are accompanied by gene expression changes in the amygdala that emerge in early postnatal life (when the cross-fostering experience is ongoing) and persist through adulthood. There is a growing appreciation that emotional disorders involve a developmental component, and that changes in the developing brain can set the stage for later emotional health [32]. The present study illustrates how an early-life manipulation such as cross-fostering changes the brain’s developmental trajectory, ultimately impacting adult behavior.…”

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

“…families of probands with one or the other diagnosis (7) and, although not a part of the diagnostic criteria for ASD, many of the latter subjects meet clinical criteria for ADHD (78). These epidemiological findings suggest that the detection of the DAT Val559 variant in ADHD, BPD, and ASD subjects may relate to the differing trajectories of complex neuropsychiatric disorders that emerge from common biological substrates, supportive of a move away from categorical definitions in the development of animal models of psychiatric disorders (79). The availability of the Val559 mouse model also allows us to explore other, sometimes unexpected, phenotypic consequences that upon further analysis may connect to the existing biological underpinnings of neuropsychiatric disorders.…”

Ontogeny of contextual fear memory formation, specificity, and persistence in mice

“…Pinpointing the precise age when animals begin to form memories of aversive events can be valuable for understanding the onset of anxiety and mood disorders stemming from maladaptive early life experience (Pine 2009;Bale et al 2010;Marco et al 2011) and for detecting early cognitive impairment in models of autism, attention deficit/hyperactivity disorder, and fetal alcohol syndrome (Schneider et al 2011;Kaffman and Krystal 2012). During infancy and adolescence, the progressive growth and refinement of neural circuitry supporting sensation and perception (Bourne 2010;Froemke and Jones 2011), cognition (Benes et al 2000;Dumas 2005), and emotion (Braun 2011) gradually enables young rodents to begin learning about their surroundings.…”