Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease.
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2020-06
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The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms-synaptic dysfunction, immune alterations, and gut-brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.
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Hollander, Jonathan A, Deborah A Cory-Slechta, Felice N Jacka, Steven T Szabo, Tomás R Guilarte, Staci D Bilbo, Carolyn J Mattingly, Sheryl S Moy, et al. (2020). Beyond the looking glass: recent advances in understanding the impact of environmental exposures on neuropsychiatric disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45(7). pp. 1086–1096. 10.1038/s41386-020-0648-5 Retrieved from https://hdl.handle.net/10161/28270.
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Scholars@Duke
Staci D. Bilbo
The brain, endocrine, and immune systems are inextricably linked. Immunocompetent cells are located throughout virtually every organ of the body, including the brain and other endocrine tissues, and sophisticated interactions occur among these cells, via hormones, neurotransmitters, and soluble protein messengers called cytokines and chemokines (small chemotactic cytokines). These immune molecules have a powerful impact on neuroendocrine function, including behavior, during health as well as sickness. Similarly, alterations in hormones, such as during stress, can powerfully impact immune function or reactivity. These functional shifts are evolved, adaptive responses that organize changes in behavior and mobilize immune resources but can also lead to pathology or exacerbate disease if prolonged or exaggerated. However, the mechanisms by which such pathology develops, in particular the precipitation of mental health disorders, remain largely misunderstood. The developing brain is exquisitely sensitive to both endogenous and exogenous signals, and increasing evidence suggests the immune system has a critical role in brain development and associated behavioral outcomes for the life of the individual. There is now ample evidence that immune activation during prenatal or early postnatal development can have profound and long-lasting effects on the brain, and I believe the early-life immune history of an individual may indeed be critical to understanding the later-life risk or resilience of developing certain neuropsychiatric disorders.
A particular focus of my research is on microglia, the primary immunocompetent cells of the CNS, which are involved in multiple aspects of brain development and function, including activity-dependent synaptic pruning and stripping, phagocytosis of apoptotic cells, and angiogenesis. Cytokines such as tumor necrosis factor [TNF]a, interleukin [IL]-1b, and IL-6 are produced primarily by glia within the CNS and are implicated in the developing and adult brain in synaptic scaling, long-term potentiation, and neurogenesis. Microglia originate early in the life of the fetus and are very long-lived, meaning they may have the capacity to reside in the brain for most of the life of the animal. Taken together, I have hypothesized that the developing brain is particularly sensitive to early-life immune activation and the associated risk of later-life neuropsychiatric disorders because (1)microglia are long-lived such that previously activated/functionally altered microglia (i.e. microglia exposed to an early-life immune challenge) may remain within the brain into adulthood, (2) immature microglia within the developing brain are functionally and/or immunologically different than microglia within the adult brain such that early-life immune activation can have greater consequences for neuroimmune function when compared to the adult brain, and (3) microglia and their inflammatory products are critical for normal cognitive function and behavior such that neuroimmune dysfunction results in mental health dysfunction.
The simple goal of my research is thus to understand the important role of the immune system during brain development, and thereby the ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, mood and cognition. In concert with this, I am interested in modeling current social and environmental issues (e.g. poverty, pollution, addiction) that impact the developing brain, and thereby how these factors may eventually be mitigated via careful scholarship, education, and engagement with trainees, collaborators, and members of society.
Edward Daniel Levin
Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.
The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learning memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenia, Alzheimer's Disease and Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.
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