Gregg D. Stanwood

Environmental exposures produce heritable traits that can linger in the population for one or two generations. Millions of individuals consume substances such as artificial sweeteners daily that are declared safe by regulatory agencies without evaluation of their potential heritable effects. We show that consumption of aspartame, an FDA-approved artificial sweetener, daily for up to 16-weeks at doses equivalent to only 7-15% of the FDA recommended maximum daily intake value (equivalent to 2-4 small, 8 oz diet soda drinks per day) produces significant spatial learning and memory deficits in mice. Moreover, the cognitive deficits are transmitted to male and female descendants along the paternal lineage suggesting that aspartame’s adverse cognitive effects are heritable, and that they are more pervasive than current estimates, which consider effects in the directly exposed individuals only. Traditionally, deleterious environmental exposures of pregnant and nursing women are viewed as risk factors for the health of future generations. Environmental exposures of men are not considered to pose similar risks. Our findings suggest that environmental exposures of men can produce adverse impact on mental health of future generations and demonstrate the need for considering heritable effects via the paternal lineage as part of the regulatory evaluations of artificial sweeteners.

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2^fl/fl, Nkx2.1-Cre⁺ (referred to as GABA-D2R-cKO mice) or Drd2^fl/fl, Emx1-Cre⁺ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

Major depressive disorder (MDD or depression) is a debilitating neuropsychiatric syndrome with genetic, epigenetic, and environmental contributions. Depression is one of the largest contributors to chronic disease burden; it affects more than one in six individuals in the United States. A wide array of cellular and molecular modifications distributed across a variety of neuronal processes and circuits underlie the pathophysiology of depression—no established mechanism can explain all aspects of the disease. MDD suffers from a vast treatment gap worldwide, and large numbers of individuals who require treatment do not receive adequate care. This mini-review focuses on dysregulation of brain dopamine (DA) systems in the pathophysiology of MDD and describing new cellular targets for potential medication development focused on DA-modulated micro-circuits. We also explore how neurodevelopmental factors may modify risk for later emergence of MDD, possibly through dopaminergic substrates in the brain.

Mindfulness-based art therapy (MBAT) combines mindfulness practices with art therapy to promote health, wellness, and adaptive responses to stress. Mindfulness-based stress reduction programs have been demonstrated to reduce anxiety symptoms in people with generalized anxiety disorder and serious medical conditions such as cancer. However, the benefits of MBAT specifically—not just in clinical anxiety disorders, but also for routine day-to-day anxiousness—have received little attention until recently. In this mini-review, we summarize how several established mindfulness-based interventions affect mental health with a specific focus on MBAT. We also describe and evaluate data indicating involvement of specific neural circuits and neuroendocrine markers of stress and/or anxiety. Lastly, we suggest areas of focus for future rigorous research on MBAT interventions and propose multiple biobehavioral and physiological mechanisms through which therapeutic benefits may be achieved.Impact statement: Recent studies demonstrate the therapeutic potential of intensive MBAT and other mindfulness-based interventions for severe health conditions including cancer, heart disease, and anxiety, with effectiveness that rivals and sometimes even exceeds cognitive behavior therapy. MBAT-based approaches appear to be poised to mature into large-scale, cost-effective therapies for mental health disorders and symptoms comorbid with other serious health issues. However, the field currently suffers from inconsistent deployment protocols and needs additional validation data—at the behavioral, neuroendocrine, and neural levels—in order to establish best practices.

The devastating impact of opioid abuse and dependence on the individual, family, and society are well known but extremely difficult to combat. During pregnancy, opioid drugs and withdrawal also affect fetal brain development and newborn neural functions, in addition to maternal effects. Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome (NAS/NOWS) rates have drastically increased in the US in the past decade. Solutions to this complex problem must be multi-faceted, which would be greatly enhanced by a translational, multidisciplinary understanding. Therefore, this mini-review incorporates biomedical, clinical, and policy aspects of opioid use during pregnancy. We review the known roles for endogenous opioids in mediating circuit formation and function in the developing brain, discuss how exogenous opioid drug use and addiction impact these processes in animal models and humans, and discuss the implications of these data on public policy. We suggest that some current policy initiatives produce unintended harm on both mothers and their children and delineate recommendations for how legislation could better contribute to addiction recovery and increase neural resilience in affected children. Impact statement: Opioid abuse is a critical epidemic affecting individuals, families, and communities. This mini-review summarizes current literature on the impact of opioid drugs—including prescription pain relievers and illicit opioids—on neurobiological and neurobehavioral development. Using concepts related to the medical model of addiction as a brain disease, we review the public policy implications of these data and identify needs for future investigations.

The K‐Cl cotransporter KCC2 is essential in the development of the “GABA switch” that produces a change in neuronal responses to GABA signaling from excitatory to inhibitory early in brain development, and alterations in this progression have previously been hypothesized to play a causal role in autism spectrum disorder (ASD). We investigated the KCC2b (Slc12a5) heterozygous knockout mouse using a battery of rodent behavioral tests relevant to core and comorbid ASD symptoms. Compared to wild‐type littermates, KCC2^+/− mice were normal in standard measures of locomotor activity, grooming and digging behaviors, and social, vocalization, and anxiety‐like behaviors. However, KCC2^+/− mice exhibited increased social dominance behaviors and increased amplitude of spontaneous postsynaptic currents in the medial prefrontal cortex (PFC) that were previously implicated in governing social hierarchy and dominance behaviors. Treatment of wild‐type mouse brain slices with the KCC2 inhibitor VU0240511 increased the amplitude and frequency of excitatory postsynaptic currents, partially recapitulating the phenotype of KCC2^+/− mice. These findings indicate that the activity of KCC2 plays a role in social dominance, in parallel with effects on PFC signaling, further suggesting that KCC2 function has some relevance to social behavior but without the breadth of impact on autism‐like behavior suggested by previous studies. Further testing could assess whether KCC2 alters other circuits and whether additional factors such as environmental insults may precipitate autism‐related behavioral phenotypes. Autism Research 2019, 12: 732–743. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.Lay Summary: A mouse model of altered chloride transporter expression was used to look for a role in behaviors and brain function relevant to autism. There was an imbalance in signaling in the prefrontal cortex, and increased social dominance behavior, although other autism‐related behaviors were not changed. These findings indicate that altered chloride transporter function affects prefrontal cortex function and social dominance without a broader impact on autism‐like behaviors.