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Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease's progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant ( Dsg2 mut/mut ) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2 mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2 mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2 mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.

Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within 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-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.

Arrhythmogenic Cardiomyopathy (ACM) is a familial heart disease, characterized by contractile dysfunction, ventricular arrhythmias (VAs), and the risk of sudden cardiac death. Currently, implantable cardioverter defibrillators and antiarrhythmics are the mainstays in ACM therapeutics. Angiotensin receptor blockers (ARBs) have been highlighted in the treatment of heart diseases, including ACM. Yet, recent research has additionally implicated ARBs in the genesis of VAs and myocardial lipolysis via the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. The latter is of particular interest, as fibrofatty infiltration is a pathological hallmark in ACM. Here, we tested two ARBs, Valsartan and Telmisartan, and the PPAR agonist, Rosiglitazone, in an animal model of ACM, homozygous Desmoglein-2 mutant mice ( Dsg2 mut/mut ). Cardiac function, premature ventricular contractions (PVCs), fibrofatty scars, PPARα/γ protein levels, and PPAR-mediated mRNA transcripts were assessed. Of note, not a single mouse treated with Rosiglitazone made it to the study endpoint (i.e., 100% mortality: n = 5/5). Telmisartan-treated Dsg2 mut/mut mice displayed the preservation of contractile function (percent ejection fraction [%EF]; 74.8 ± 6.8%EF) compared to Vehicle- (42.5 ± 5.6%EF) and Valsartan-treated (63.1 ± 4.4%EF) mice. However, Telmisartan-treated Dsg2 mut/mut mice showed increased cardiac wall motion abnormalities, augmented %PVCs, electrocardiographic repolarization/depolarization abnormalities, larger fibrotic lesions, and increased expression of PPARy-regulated gene transcripts compared to their Dsg2 mut/mut counterparts. Alternatively, Valsartan-treated Dsg2 mut/mut mice harbored fewer myocardial scars, reduced %PVC, and increased Wnt-mediated transcripts. Considering our findings, caution should be taken by physicians when prescribing medications that may increase PPARy signaling in patients with ACM.

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.

Infant emotion regulation has long-term implications for human development, highlighting the need for preventive interventions that support emotion regulation early in life. Such interventions may be especially important for infants higher in emotional reactivity who need to regulate their emotions more frequently and intensely than infants lower in emotional reactivity. The current randomized trial examined main and moderated effects of an attachment-based intervention on (a) infants' use of mother-oriented and self-soothing emotion regulation strategies and (b) infant emotion dysregulation in 186 low-income, predominantly Latino infants. We tested the brief (10-session) Attachment and Biobehavioral Catch-up (ABC) intervention in the context of home-based federal Early Head Start (EHS) services. Control participants received home-based EHS plus 10 weekly books. Intent-to-treat analyses with covariates revealed main effects of the intervention on infants' use of mother-oriented emotion regulation strategies during a brief (40-s) novel and potentially fear-inducing procedure (d = 0.31). Infant emotional reactivity moderated intervention impacts on mother-oriented emotion regulation strategies and on infant emotion dysregulation: We found stronger effects of the intervention for infants relatively higher in emotional reactivity. Findings are discussed in terms of the preventive value of attachment-based interventions for supporting early emotion regulation.

Many psychological theories posit foundational links between two fundamental constructs: (1) our ability to produce, perceive, and represent action; and (2) our ability to understand the meaning and motivation behind the action (i.e. Theory of Mind; ToM). This position is contentious, however, and long-standing competing theories of social-cognitive development debate roles for basic action-processing in ToM. Developmental research is key to investigating these hypotheses, but whether individual differences in neural and behavioral measures of motor action relate to social-cognitive development is unknown. We examined 3- to 5-year-old children's (N = 26) EEG mu-desynchronization during production of object-directed action, and explored associations between mu-desynchronization and children's behavioral motor skills, behavioral action-representation abilities, and behavioral ToM. For children with high (but not low) mu-desynchronization, motor skill related to action-representation abilities, and action-representation mediated relations between motor skill and ToM. Results demonstrate novel foundational links between action-processing and ToM, suggesting that basic motor action may be a key mechanism for social-cognitive development, thus shedding light on the origins and emergence of higher social cognition., (© 2016 John Wiley & Sons Ltd.)

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., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

The current study harnessed the variability in infants' neural and behavioral responses as a novel method for evaluating the potential relations between motor system activation and social behavior. We used electroencephalography (EEG) to record neural activity as 7-month-old infants observed and responded to the actions of an experimenter. To determine whether motor system activation predicted subsequent imitation behavior, we assessed event-related desynchronization (ERD) at central sites during action observation as a function of subsequent behavior. Greater mu desynchronization over central sites was observed when infants subsequently reproduced the experimenter's goal than when they did not reproduce the goal and instead selected the nongoal object. We also found that mu desynchronization during action execution predicted the infants' later propensity to reproduce the experimenter's goal-directed behavior. These results provide the first evidence that motor system activation predicts the imitation of other individuals' goals during infancy., (© The Author(s) 2016.)

The current study examined age-related differences in electroencephalogram (EEG) activity during perception of means-end actions and production of grasps, and how EEG activity may relate to infants' motor competence. We collected data from 9- and 12-month-old infants during perception of means-end actions made with a tool and during execution of their own grasps. We computed event-related desynchronization (ERD) during perception and production events and assessed infants' reach-grasp competence by looking at their latency to complete grasps. Although we found greater ERD during perception of means-end actions in 9-month-olds compared with 12-month-olds, we found the relation between ERD during perception and emerging reach-grasp competence to be specific for 12-month-olds and not for 9-month-olds. These results provide evidence for an emerging neural system that supports the coupling of action and perception with infants' emerging motor competence in the first year of life., (© 2015 The British Psychological Society.)

A fundamental issue in cognitive neuroscience is how the brain encodes others' actions and intentions. In recent years, a potential advance in our knowledge on this issue is the discovery of mirror neurons in the motor cortex of the nonhuman primate. These neurons fire to both execution and observation of specific types of actions. Researchers use this evidence to fuel investigations of a human mirror system, suggesting a common neural code for perceptual and motor processes. Among the methods used for inferring mirror system activity in humans are changes in a particular frequency band in the electroencephalogram (EEG) called the mu rhythm. Mu frequency appears to decrease in amplitude (reflecting cortical activity) during both action execution and action observation. The current meta-analysis reviewed 85 studies (1,707 participants) of mu that infer human mirror system activity. Results demonstrated significant effect sizes for mu during execution (Cohen's d = 0.46, N = 701) as well as observation of action (Cohen's d = 0.31, N = 1,508), confirming a mirroring property in the EEG. A number of moderators were examined to determine the specificity of these effects. We frame these meta-analytic findings within the current discussion about the development and functions of a human mirror system, and conclude that changes in EEG mu activity provide a valid means for the study of human neural mirroring. Suggestions for improving the experimental and methodological approaches in using mu to study the human mirror system are offered., ((c) 2016 APA, all rights reserved).)

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., (© 2016 S. Karger AG, Basel.)

Objective: To assess the developmental trajectory of spectral, topographic, and source structural properties of functional mu desynchronization (characterized during voluntary reaching/grasping movement), and investigate its spectral/topographic relation to spontaneous EEG in the developing alpha band., Methods: Event related desynchronization (ERD) and power spectral density spectra/topography are analyzed in 12 month-old infants, 4 year-old children, and adults. Age-matched head models derived from structural MRI are used to obtain current density reconstructions of mu desynchronization across the cortical surface., Results: Infant/child EEG contains spectral peaks evident in both the upper and lower developing alpha band, and spectral/topographic properties of functionally identified mu rhythm strongly reflect those of upper alpha in all subject groups. Source reconstructions show distributed frontoparietal patterns of cortical mu desynchronization concentrated in specific central and parietal regions which are consistent across age groups., Conclusions: Peak frequencies of mu desynchronization and spontaneous alpha band EEG increase with age, and characteristic mu topography/source-structure is evident in development at least as early as 12 months., Significance: Results provide evidence for a cortically distributed functional mu network, with spontaneous activity measurable in the upper alpha band throughout development., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Recent reports of similar patterns of brain electrical activity (electroencephalogram: EEG) during action execution and observation, recorded from scalp locations over motor-related regions in infants and adults, have raised the possibility that two foundational abilities--controlling one's own intentional actions and perceiving others' actions--may be integrally related during ontogeny. However, to our knowledge, there are no published reports of the relations between developments in motor skill (i.e. recording actual motor skill performance) and EEG during both action execution and action observation. In the present study we collected EEG from 21 9-month-olds who were given opportunities to reach for toys and who also observed an experimenter reach for toys. Event-related desynchronization (ERD) was computed from the EEG during the reaching events. We assessed infants' reaching-grasping competence, including reach latency, errors, preshaping of the hand, and bimanual reaches, and found that desynchronization recorded in scalp electrodes over motor-related regions during action observation was associated with action competence during execution. Infants who were more competent reachers, compared to less competent reachers, exhibited greater ERD while observing reaching-grasping. These results provide initial evidence for an early emerging neural system integrating one's own actions with the perception of others' actions., (© 2015 John Wiley & Sons Ltd.)

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., (© 2017 S. Karger AG, Basel.)

Individuals who are high in rejection sensitivity are vigilant toward social cues that signal rejection, and they exhibit attention biases towards information that confirms expectations of rejection. Little is known, however, about the neural correlates of rejection sensitivity. The present study examined whether rejection sensitivity is associated with individuals' neural responses to rejection-relevant information. Female participants, classified as high or average in rejection sensitivity, completed a modified dot-probe task in which a neutral face was paired with either another neutral face or a gaze-averted ("rejecting") face while EEG was collected and ERP components were computed. Behavioral results indicated that average rejection sensitive participants showed an attention bias away from rejecting faces, while high rejection sensitive participants were equally vigilant to neutral and rejecting faces. High rejection sensitivity was associated with ERP components signaling elevated attention and arousal to faces. These findings suggest that rejection sensitivity shapes behavioral and neurocognitive responses to faces.

Since the discovery of mirror neurons in premotor and parietal areas of the macaque monkey, the idea that action and perception may share the same neural code has been of central interest in social, developmental, and cognitive neurosciences. A fundamental question concerns how a putative human mirror neuron system may be tuned to the motor experiences of the individual. The current study tested the hypothesis that prior motor experience modulated the sensorimotor mu and beta rhythms. Specifically, we hypothesized that these sensorimotor rhythms would be more desynchronized after active motor experience compared to passive observation experience. To test our hypothesis, we collected EEG from adult participants during the observation of a relatively novel action: an experimenter used a claw-like tool to pick up a toy. Prior to EEG collection, we trained one group of adults to perform this action with the tool (performers). A second group comprised trained video coders, who only had experience observing the action (observers). Both the performers and the observers had no prior motor and visual experience with the action. A third group of novices was also tested. Performers exhibited the greatest mu rhythm desynchronization in the 8-13 Hz band, particularly in the right hemisphere compared to observers and novices. This study is the first to contrast active tool-use experience and observation experience in the mu rhythm and to show modulation with relatively shorter amounts of experience than prior mirror neuron expertise studies. These findings are discussed with respect to its broader implication as a neural signature for a mechanism of early social learning.

The EEG mu rhythm, recorded from scalp regions overlying the sensorimotor cortex, appears to exhibit mirroring properties: It is reactive when performing an action and when observing another perform the same action. Recently, there has been an exponential increase in developmental mu rhythm research, partially due to the mu rhythm's potential role in our understanding of others' actions as well as a variety of other social and cognitive processes (e.g., imitation, theory of mind, language). Unfortunately, various methodological issues impede integrating these findings into a comprehensive theory of mu rhythm development. The present manuscript provides a review of the infant mu rhythm literature while focusing on current methodological problems that impede between study comparisons. By highlighting these issues and providing an in depth description and analysis we aim to heighten awareness and propose guidelines (when possible) that will promote rigorous infant mu rhythm research and facilitate between study comparisons. This paper is intended as a resource for developmental scientists, regardless of EEG expertise.

Predicting the actions of others is critical to smooth social interactions. Prior work suggests that both understanding and anticipation of goal-directed actions appears early in development. In this study, on-line goal prediction was tested explicitly using an adaptation of Woodward's (1998) paradigm for an eye-tracking task. Twenty 11-month-olds were familiarized to movie clips of a hand reaching to grasp one of two objects. Then object locations were swapped, and the hand made an incomplete reach between the objects. Here, infants reliably made their first look from the hand to the familiarized goal object, now in a new location. A separate control condition of 20 infants familiarized to the same movements of an unfamiliar claw revealed the opposite pattern: reliable prediction to the familiarized location, rather than the familiarized object. This study suggests that by 11 months infants actively use goal analysis to generate on-line predictions of an agent's next action., (© 2011 Blackwell Publishing Ltd.)

Recent work implicates a link between action control systems and action understanding. In this study, we investigated the role of the motor system in the development of visual anticipation of others' actions. Twelve-month-olds engaged in behavioral and observation tasks. Containment activity, infants' spontaneous engagement in producing containment actions; and gaze latency, how quickly they shifted gaze to the goal object of another's containment actions, were measured. Findings revealed a positive relationship: infants who received the behavior task first evidenced a strong correlation between their own actions and their subsequent gaze latency of another's actions. Learning over the course of trials was not evident. These findings demonstrate a direct influence of the motor system on online visual attention to others' actions early in development., (© 2011 Blackwell Publishing Ltd.)

In the current study we investigate the proposal that one aspect of social perception, action anticipation , involves the recruitment of representations for self-produced action. An eye tracking paradigm was implemented to measure prospective gaze to a goal while performing either a motor or working memory task. Results indicate an effect of the motor task, suggesting the interference of a shared motor and action perception representation.