Thoughts for the Future

Several exciting lines of research have emerged from the study of animal models of mental disorders. This chapter presents seven opportunities for enhancing the diagnosis and treatment of mental disorders. They include improvements to the system for diagnosis of mental disorders, use of induced pluripotent stem cells from patients to generate neuronal cultures for in vitro determination of effective drug therapies for those individuals, use of data-mining techniques for understanding patient variability, a commitment to a greater focus on the prevention of mental disorders, innovative uses of smartphones to track patients and individuals at high risk of developing a mental disorder, and developing next-generation therapies and delivery systems that target a specific area of the brain rather than the entire brain. A common theme in these seven thoughts for the future is a commitment to bringing precision medicine tools to the treatment of patients with mental disorders.

Post-Traumatic Stress Disorder

Two especially valuable animal models of post-traumatic stress disorder (PTSD) have been developed, including brief exposure of laboratory rats to a predator (a cat) or its odor, and the single prolonged stress paradigm. In each of these models, laboratory animals are evaluated for behavioral changes several days to several weeks following the stressful experience and are compared to unstressed controls. In both of these models, stressed animals display behavioral changes consistent with a PTSD-like phenotype. Using these models, investigators have explored central and peripheral neural and endocrine changes associated with the onset of PTSD-like symptoms and approaches to prevent or block the effects of the traumatic stressor on behavioral changes. Two particularly effective treatments that have been described include administration of a protein synthesis inhibitor and intra-nasal administration of neuropeptide Y. Animal models also provide an opportunity to study transgenerational transmission of PTSD risk.

Stress and Bipolar Disorder

Animal models of bipolar disorder (BD) should capture the switching of mood states from mania to depression and vice versa. Dopamine signaling pathways in brain, including variations in the dopamine transporter protein, have been a focus of many animal models of BD. Another aspect of BD in humans is reflected in circadian and seasonal changes in onset of symptoms. Other animal models of BD include the Myshkin and Madison mouse strains, both of which display mania-like behavior that is reversed by treatment with lithium or valproic acid. Another experimental approach has been to manipulate circadian clock genes and examine effects on dopamine signaling and behavior. Finally, manipulations of risk genes for BD in laboratory mice have advanced our understanding of the molecular mechanisms involved in extreme alterations in mood state.

Making the Case

Genome-wide association studies (GWAS) have revolutionized the field of psychiatric genetics by examining genetic variation at millions of single-nucleotide polymorphisms (SNPs) in many thousands of individual genome using microarrays. The sample sizes for these studies range from tens of thousands on up. Results to date from GWAS have called into question the validity of current diagnostic categories in psychiatry. For example, there may be some level of genetic risk that is shared across many psychiatric disorders, with the final symptom clusters of a given disorder being shaped by other genetic, epigenetic, and environmental variables. Research findings on three mental disorders are evaluated to make the case that stressful life events play a crucial role in the etiology of mental disorders. The mental disorders discussed include schizophrenia, bipolar disorder, and depression. These findings set the stage for the remainder of the book.

Evolution of the Stress Concept

Modern conceptions of health and disease can be traced back to early Chinese, Indian, Egyptian, and Greek civilizations. Galen of Pergamon, a Greek physician who practiced medicine for most of his career in Rome, had an enduring impact on the medical sciences for almost 15 centuries with his writings on the balance among the four humors: black bile, yellow bile, blood, and phlegm. At the end of the 19th century, Claude Bernard in Paris wrote about the importance of the constancy of the internal environment. In the early 20th century, Walter Cannon introduced the concept of homeostasis and studied the emergency function of the adrenal medulla. Hans Selye is credited with popularizing the concept of stress, and he introduced the concept of the general adaptation syndrome. More recent additions to the nomenclature on stress include allostasis, or stability through change, and allostatic load, which relates to a failure to adapt to chronic stressors.

Animal Models in Psychiatry

Darwin made a compelling case that studies of animals could provide insights into the behavior of humans. Early studies by Pavlov and Harlow paved the way for further developments of animal models of psychiatric disorders. Seligman and Maier’s learned helplessness model continues to be employed in laboratory studies of stress and depression. It has become clear that no single animal model can possibly reproduce all of the critical facets of a mental disorder in humans. However, animal models do provide an essential element in attempts to understand the mechanisms that underlie mental disorders and to reveal molecular targets for the development of new drug therapies. Concerns have been raised about the reproducibility of laboratory experiments with inbred strains of laboratory mice and rats. Any animal model should be evaluated based upon a battery of behavioral tests and the parameters of stressful stimulation employed in experiments should be chosen with care.

Stress Effector Systems

Three interacting peripheral stress effector systems are activated during exposure of humans and other animals to acute as well as chronic stressors. They include the sympathetic-adrenal medullary (SAM) system, the hypothalamic-pituitary-adrenocortical (HPA) axis, and the innate immune system. The SAM system includes the release of norepinephrine from sympathetic nerve terminals and epinephrine from the adrenal medulla. Plasma levels of norepinephrine and epinephrine have been utilized as an index of SAM activity under basal conditions and following exposure to stress. The HPA axis involves release of corticotropin-releasing factor from neurons in the paraventricular nucleus of the hypothalamus, which stimulates adrenocorticotrophic hormone (ACTH) release from the anterior pituitary, followed by cortisol or corticosterone release from the adrenal cortex. The HPA axis is regulated in part by a system of negative feedback loops. The chemical messengers of the innate immune system include proinflammatory (IL-1β‎, IL-6, and TNF-α‎) and anti-inflammatory cytokines (IL-4 and IL-10).

Resilience

A consistent finding from research on animal models of depression and PTSD is that some animals are highly susceptible to the effects of stressful stimulation, while others show few obvious effects. A relatively new of line of research on resilience has emerged and has directed attention to those animals that are resistant to the effects of chronic or traumatic stressors. By tracking animals that are resistant to the behavioral effects of these stressful paradigms, one can then explore the molecular underpinnings of resilience in the brains of these same animals. Using chronic social defeat stress, some investigators have focused their attention on the ventral tegmental area, nucleus accumbens, and the prefrontal cortex. Other systems that have been studied include signaling molecules of the immune system and communication pathways between the immune system and the brain. A related line of research has addressed the possibility that prior exposure to stressors may inoculate animals to the deleterious effects of later stressor exposure.

Stress and Anxiety Disorders

Much of the research relating to animal models of anxiety has been devoted to developing more effective drugs for the treatment of the various anxiety disorders. Using selective breeding of laboratory mice and rats, investigators have developed high-anxiety and low-anxiety lines that have been especially valuable for basic research purposes. Other approaches to enhance the expression of an anxiety-like phenotype have included prenatal or early postnatal exposure to stressors, maternal immune activation, or selecting offspring based upon differences in the maternal behaviors of their mothers. In addition, risk genes for anxiety disorders have been studied in animal models, including genes related to serotonin, neuropeptide Y, neuropeptide S, and corticotropin-releasing factor signaling in the brain. Finally, some infant rhesus monkeys display an anxious temperament and extreme behavioral inhibition when separated from their mothers. This nonhuman primate model affords many opportunities to explore brain mechanisms and interventions that may be effective in preventing the further development of an anxious phenotype as these monkeys mature.

Psychiatric Illnesses

Current systems for diagnosis of mental disorders have their roots in 19th-century German psychiatry. DSM-5 and ICD-11 are categorical systems (well versus ill), while other systems take a dimensional approach. Dimensional approaches include the Research Domain Criteria (RDoC) development by the National Institute of Mental Health and the Hierarchical Taxonomy of Psychopathology (HiTOP). Currents efforts are focused on the identification of valid biomarkers for specific mental disorders and the development of precision medicine approaches in psychiatric practice. Associated with the incorporation of principles of precision medicine in psychiatry will be decision-support tools at the point of care that consider a patient’s genotype in decisions relating to optimal choices of a given treatment regimen. These challenges are especially critical to address given the significant contribution of mental disorders to the global burden of disease.