Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research.

Inhibition of nuclear factor kappa-B (NF kappa B) signaling prevents disease in Dsg2mut/mut mice, a model of arrhythmogenic cardiomyopathy (ACM). Moreover, NF kappa B is activated in ACM patient-derived iPSC-cardiac myocytes under basal conditions in vitro. Here, we used genetic approaches and sequencing studies to define the relative pathogenic roles of immune signaling in cardiac myocytes vs. inflammatory cells in Dsg2mut/mut mice. We found that NF kappa B signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. It does this by mobilizing cells expressing C-C motif chemokine receptor-2 (CCR2+ cells) to the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA sequencing and cellular indexing of transcriptomes and epitomes (CITE-seq) studies revealed marked pro-inflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts and CCR2+ cells. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were modulated by actions of CCR2+ cells. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.

Prenatal cocaine exposure remains a major public health concern because of its adverse effects on cognitive function. Although the molecular mechanisms underlying the cognitive impairment are not fully understood, brain-derived neurotrophic factor (BDNF) signaling via its receptor tyrosine kinase B (TrkB) is emerging as a potential candidate. We used a mouse model to examine the impact of ongoing cocaine exposure on BDNF expression in the dorsal forebrain on embryonic day 15 (E15) as well as the long-term effects of prenatal cocaine exposure on BDNF-TrkB signaling in the frontal cortex in early postnatal (postnatal day 16; P16) and adult (P60) male and female mice. We found that ongoing cocaine exposure decreased BDNF expression in the E15 dorsal forebrain, prenatal cocaine exposure did not alter BDNF or TrkB (total or phosphorylated) expression in the frontal cortex at P16, and that the prenatal cocaine exposure produced significant increases in BDNF, the activated (phosphorylated) form of TrkB, as well as Bdnf mRNA in the frontal cortex at P60. The increase in BDNF protein and mRNA expression at P60 was concurrent with hyperacetylation of histone H3 at the Bdnf promoter in the frontal cortex. The increase in frontal cortical BDNF and activated TrkB at P60 occurred in male but not female mice. Thus, our data demonstrate that ongoing cocaine exposure produces a decrease in BDNF expression in the embryonic brain, and that prenatal cocaine exposure produces a sex-specific increase in frontal cortical BDNF-TrkB signaling at P60 only in male mice. Lastly, hyperacetylation of histone H3 at the Bdnf promoter is one epigenetic mechanism mediating the effects of prenatal cocaine exposure on Bdnf expression at P60 in male mice.

the use of non-nutritive sweeteners such as saccharin is widely prevalent. Although saccharin is considered safe for human consumption, it produces behavioral changes in experimental animals. We report that saccharin's behavioral effects are much more pervasive than currently recognized. In a mouse model, saccharin exposure produced motor impulsivity not only in the saccharin-exposed males but also in their offspring. In addition, the offspring showed locomotor hyperactivity and working memory deficit not observed in fathers. Spermatazoal DNA was hypermethylated in the saccharin-exposed fathers, especially at dopamine receptor promoter regions, suggesting that epigenetic modification of germ cell DNA may mediate transgenerational transmission of behavioral phenotypes. Dopamine's role in hyperactivity was further highlighted by the finding that the stimulant drug methylphenidate mitigated the hyperactivity. nicotine is another substance that is widely used. its use via smokeless tobacco products, some of which contain saccharin, is on the rise contributing to concerns about adverse outcomes of co-exposure to saccharin and nicotine. We found that co-exposure of male mice to saccharin and nicotine produced significant behavioral impairment in their offspring. Thus, our data point to potential adverse neurobehavioral consequences of exposure to saccharin alone or saccharin and nicotine for the exposed individuals and their descendants. Nearly 40% of adults in the United States consume low-calorie sweeteners such as saccharin 1. Although saccharin is not metabolized in the body and although it is regarded as safe for human consumption, it activates brain's reward circuitry 2,3 , suggesting that saccharin may influence neurobehavioral phenotypes. Nicotine is another substance that is widely used and its use via traditional cigarettes, smokeless tobacco products, and electronic cigarettes is on the rise, especially among the youth and young adults 4-7. Given the wide prevalence of nicotine and saccharin use, the risk of co-exposure to saccharin and nicotine remains very high. In fact, some smokeless tobacco products contain saccharin at levels nearly 25-fold higher than its levels in food products 8 and expose the user to both saccharin and nicotine. Approximately 3% of adults were current users of smokeless tobacco products in 2016 9. Despite these noteworthy statistics, the mental health implications of exposure to saccharin alone or co-exposure to saccharin and nicotine have not received the attention they may deserve. Preclinical models of oral nicotine exposure employ saccharin as a sweetener to mask the bitter taste of nicotine 10-22. Thus, co-exposure to nicotine and saccharin occurs in a number of preclinical models. Many of the preclinical studies were focused on the effects of developmental exposure of the offspring to saccharin or nicotine 10-13,18-23. As a result, female animals were exposed to saccharin alone or nicotine and saccharin. These studies did not report significant effects of exposure to sacchari...

Prenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF) is a key regulator of cognitive functions, and because prenatal cocaine exposure increases the expression of BDNF and the phosphorylated form of its receptor, tyrosine kinase B (TrkB), we examined whether BDNF-TrkB signaling is involved in mediating the reversal learning deficit in prenatally cocaine-exposed mice. Systemic administration of a selective TrkB receptor antagonist restored normal reversal learning in prenatally cocaine-exposed mice, suggesting that increased BDNF-TrkB signaling may be an underlying mechanism of reversal learning deficits. Our findings provide novel mechanistic insights into the reversal learning phenomenon and may have significant translational implications because impaired cognitive flexibility is a key symptom in psychiatric conditions of developmental onset.