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1.
Horm Behav ; 164: 105579, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38905820

RESUMO

Oxytocin is a neuropeptide positively associated with prosociality in adults. Here, we studied whether infants' salivary oxytocin can be reliably measured, is developmentally stable, and is linked to social behavior. We longitudinally collected saliva from 62 U.S. infants (44 % female, 56 % Hispanic/Latino, 24 % Black, 18 % non-Hispanic White, 11 % multiracial) at 4, 8, and 14 months of age and offline-video-coded the valence of their facial affect in response to a video of a smiling woman. We also captured infants' affective reactions in terms of excitement/joyfulness during a live, structured interaction with a singing woman in the Early Social Communication Scales at 14 months. We detected stable individual differences in infants' oxytocin levels over time (over minutes and months) and in infants' positive affect over months and across contexts (video-based and in live interactions). We detected no statistically significant changes in oxytocin levels between 4 and 8 months but found an increase from 8 to 14 months. Infants with higher oxytocin levels showed more positive facial affect to a smiling person video at 4 months; however, this association disappeared at 8 months, and reversed at 14 months (i.e., higher oxytocin was associated with less positive facial affect). Infant salivary oxytocin may be a reliable physiological measure of individual differences related to socio-emotional development.

2.
Behav Res Methods ; 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38273072

RESUMO

Facial expressions are among the earliest behaviors infants use to express emotional states, and are crucial to preverbal social interaction. Manual coding of infant facial expressions, however, is laborious and poses limitations to replicability. Recent developments in computer vision have advanced automated facial expression analyses in adults, providing reproducible results at lower time investment. Baby FaceReader 9 is commercially available software for automated measurement of infant facial expressions, but has received little validation. We compared Baby FaceReader 9 output to manual micro-coding of positive, negative, or neutral facial expressions in a longitudinal dataset of 58 infants at 4 and 8 months of age during naturalistic face-to-face interactions with the mother, father, and an unfamiliar adult. Baby FaceReader 9's global emotional valence formula yielded reasonable classification accuracy (AUC = .81) for discriminating manually coded positive from negative/neutral facial expressions; however, the discrimination of negative from neutral facial expressions was not reliable (AUC = .58). Automatically detected a priori action unit (AU) configurations for distinguishing positive from negative facial expressions based on existing literature were also not reliable. A parsimonious approach using only automatically detected smiling (AU12) yielded good performance for discriminating positive from negative/neutral facial expressions (AUC = .86). Likewise, automatically detected brow lowering (AU3+AU4) reliably distinguished neutral from negative facial expressions (AUC = .79). These results provide initial support for the use of selected automatically detected individual facial actions to index positive and negative affect in young infants, but shed doubt on the accuracy of complex a priori formulas.

3.
Infancy ; 28(5): 910-929, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37466002

RESUMO

Although still-face effects are well-studied, little is known about the degree to which the Face-to-Face/Still-Face (FFSF) is associated with the production of intense affective displays. Duchenne smiling expresses more intense positive affect than non-Duchenne smiling, while Duchenne cry-faces express more intense negative affect than non-Duchenne cry-faces. Forty 4-month-old infants and their mothers completed the FFSF, and key affect-indexing facial Action Units (AUs) were coded by expert Facial Action Coding System coders for the first 30 s of each FFSF episode. Computer vision software, automated facial affect recognition (AFAR), identified AUs for the entire 2-min episodes. Expert coding and AFAR produced similar infant and mother Duchenne and non-Duchenne FFSF effects, highlighting the convergent validity of automated measurement. Substantive AFAR analyses indicated that both infant Duchenne and non-Duchenne smiling declined from the FF to the SF, but only Duchenne smiling increased from the SF to the RE. In similar fashion, the magnitude of mother Duchenne smiling changes over the FFSF were 2-4 times greater than non-Duchenne smiling changes. Duchenne expressions appear to be a sensitive index of intense infant and mother affective valence that are accessible to automated measurement and may be a target for future FFSF research.


Assuntos
Expressão Facial , Mães , Feminino , Humanos , Lactente , Mães/psicologia , Sorriso/psicologia , Software
4.
Infancy ; 28(4): 836-860, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37194939

RESUMO

Infants vary in their ability to follow others' gazes, but it is unclear how these individual differences emerge. We tested whether social motivation levels in early infancy predict later gaze following skills. We longitudinally tracked infants' (N = 82) gazes and pupil dilation while they observed videos of a woman looking into the camera simulating eye contact (i.e., mutual gaze) and then gazing toward one of two objects, at 2, 4, 6, 8, and 14 months of age. To improve measurement validity, we used confirmatory factor analysis to combine multiple observed measures to index the underlying constructs of social motivation and gaze following. Infants' social motivation-indexed by their speed of social orienting, duration of mutual gaze, and degree of pupil dilation during mutual gaze-was developmentally stable and positively predicted the development of gaze following-indexed by their proportion of time looking to the target object, first object look difference scores, and first face-to-object saccade difference scores-from 6 to 14 months of age. These findings suggest that infants' social motivation likely plays a role in the development of gaze following and highlight the use of a multi-measure approach to improve measurement sensitivity and validity in infancy research.


Assuntos
Fixação Ocular , Motivação , Feminino , Humanos , Lactente
5.
Behav Res Methods ; 55(3): 1024-1035, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35538295

RESUMO

Automated detection of facial action units in infants is challenging. Infant faces have different proportions, less texture, fewer wrinkles and furrows, and unique facial actions relative to adults. For these and related reasons, action unit (AU) detectors that are trained on adult faces may generalize poorly to infant faces. To train and test AU detectors for infant faces, we trained convolutional neural networks (CNN) in adult video databases and fine-tuned these networks in two large, manually annotated, infant video databases that differ in context, head pose, illumination, video resolution, and infant age. AUs were those central to expression of positive and negative emotion. AU detectors trained in infants greatly outperformed ones trained previously in adults. Training AU detectors across infant databases afforded greater robustness to between-database differences than did training database specific AU detectors and outperformed previous state-of-the-art in infant AU detection. The resulting AU detection system, which we refer to as Infant AFAR (Automated Facial Action Recognition), is available to the research community for further testing and applications in infant emotion, social interaction, and related topics.


Assuntos
Expressão Facial , Reconhecimento Facial , Humanos , Lactente , Redes Neurais de Computação , Emoções , Interação Social , Bases de Dados Factuais
6.
Am J Epidemiol ; 191(8): 1407-1419, 2022 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-35362025

RESUMO

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (ß = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (ß = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Doenças Cardiovasculares , Diabetes Gestacional , Nascimento Prematuro , Transtorno do Espectro Autista/epidemiologia , Doenças Cardiovasculares/complicações , Criança , Feminino , Humanos , Recém-Nascido , Gravidez
7.
Dev Sci ; 25(2): e13177, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34592032

RESUMO

Over half of US children are enrolled in preschools, where the quantity and quality of language input from teachers are likely to affect children's language development. Leveraging repeated objective measurements, we examined the rate per minute and phonemic diversity of child and teacher speech-related vocalizations in preschool classrooms and their association with children's end-of-year receptive and expressive language abilities measured with the Preschool Language Scales (PLS-5). Phonemic diversity was computed as the number of unique consonants and vowels in a speech-related vocalization. We observed three successive cohorts of 2.5-3.5-year-old children enrolled in an oral language classroom that included children with and without hearing loss (N = 29, 16 girls, 14 Hispanic). Vocalization data were collected using child-worn audio recorders over 34 observations spanning three successive school years, yielding 21.53 mean hours of audio recording per child. The rate of teacher vocalizations positively predicted the rate of children's speech-related vocalizations while the phonemic diversity of teacher vocalizations positively predicted the phonemic diversity of children's speech-related vocalizations. The phonemic diversity of children's speech-related vocalizations was a stronger predictor of end-of-year language abilities than the rate of children's speech-related vocalizations. Mediation analyses indicated that the phonemic diversity of teacher vocalizations was associated with children's receptive and expressive language abilities to the extent that it influenced the phonemic diversity of children's own speech-related vocalizations. The results suggest that qualitatively richer language input expands the phonemic diversity of children's speech, which in turn is associated with language abilities.


Assuntos
Desenvolvimento da Linguagem , Fala , Aptidão , Linguagem Infantil , Pré-Escolar , Feminino , Humanos , Idioma , Masculino , Instituições Acadêmicas
8.
Dev Sci ; 25(3): e13185, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34743364

RESUMO

Infant attachment is a key predictor of later socioemotional functioning, but it is not clear how parental responsivity to infant expressive behavior is associated with attachment outcomes. A mid-range model of responsivity holds that both unresponsive and highly reactive parental behaviors lead to insecure and disorganized attachment. We examined the relationship between maternal (and infant) contingent responsivity and attachment in a high-risk sample. Participants were 625 infant-mother pairs from a longitudinal study of children with and without prenatal drug exposure and variable levels of associated social risks. Infant-mother pairs participated in the Face-to-Face/Still-Face paradigm (FFSF) at 4-months and in the Strange Situation Procedure (SSP) at 18-months. A model incorporating both linear and quadratic responsivity effects indicated that mothers who were either very high (reactive) or very low (unresponsive) in responsivity were more likely to have infants with disorganized attachment outcomes. While maternal responsivity was associated with attachment disorganization, no associations between maternal responsivity, and attachment security/insecurity were detected. Infant responsivity to mother was not associated with attachment outcomes. The findings suggest the importance of mid-range levels of maternal responsivity in the development of organized attachment among infants facing high levels of prenatal and social risk.


Assuntos
Comportamento do Lactente , Apego ao Objeto , Criança , Feminino , Humanos , Lactente , Comportamento do Lactente/psicologia , Estudos Longitudinais , Comportamento Materno/psicologia , Gravidez
9.
Dev Psychobiol ; 64(7): e22324, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36282740

RESUMO

In childhood, higher levels of temperamental fear-an early-emerging proclivity to distress in the face of novelty-are associated with lower social responsivity and greater social anxiety. While the early emergence of temperamental fear in infancy is poorly understood, it is theorized to be driven by individual differences in reactivity and self-regulation to novel stimuli. The current study used eye tracking to capture infants' (N = 124) reactions to a video of a smiling stranger-a common social encounter-including infant gaze aversions from the stranger's face (indexing arousal regulation) and pupil dilation (indexing physiological reactivity), longitudinally at 2, 4, 6, and 8 months of age. Multilevel mixed-effects models indicated that more fearful infants took more time to look away from a smiling stranger's face than less fearful infants, suggesting that high-fear infants may have slower arousal regulation. At 2 and 4 months, more fearful infants also exhibited greater and faster pupil dilation before gaze aversions, consistent with greater physiological reactivity. Together, these findings suggest that individual differences in infants' gaze aversions and pupil dilation can index the development of fearful temperament in early infancy, facilitating the identification of, and interventions for, risk factors to social disruptions.


Assuntos
Pupila , Sorriso , Lactente , Humanos , Pupila/fisiologia , Medo , Temperamento/fisiologia , Afeto
10.
Infancy ; 27(4): 836-862, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35403337

RESUMO

Interaction with unfamiliar partners is a component of social life from infancy onward. Yet little is known about preverbal communication with strangers. This study compared the development of infant communication with strangers to communication with mothers and fathers and examined the contribution of temperament to partner-specific communication patterns. A sample of 58 infants was observed at four and eight months during separate home-based face-to-face interactions with three partners (mother, father, and stranger). Infant visual, facial, and vocal communication behaviors were coded microanalytically. Each parent reported on infant temperament at both ages. Multilevel regression analyses indicated that infants gazed longer at strangers than at fathers, exhibited less smiling to strangers than to mothers, and produced fewer vocalizations with strangers than with either parent. Both age and temperament moderated these differences. Vocal communication with fathers became more frequent at eight months; smiling to mothers was accentuated among infants with higher levels of temperamental surgency. Importantly, levels of communication behaviors with strangers were concurrently and longitudinally associated with those with mothers and fathers. Overall, findings suggest that infant emotional communication patterns are modulated by individual temperamental differences and are reproduced in and over time, though at different levels, when interacting with novel partners.


Assuntos
Emoções , Mães , Comunicação , Pai/psicologia , Feminino , Humanos , Lactente , Masculino , Mães/psicologia , Temperamento
11.
Early Child Res Q ; 60(3): 201-213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35273424

RESUMO

Children with hearing loss often attend inclusive preschool classrooms aimed at improving their spoken language skills. Although preschool classrooms are fertile environments for vocal interaction with peers, little is known about the dyadic processes that influence children's speech to one another and foster their language abilities and how these processes may vary in children with hearing loss. We used new objective measurement approaches to identify and quantify children's vocalizations during social contact, as determined by children's proximity and mutual orientation. The contributions of peer vocalizations to children's future vocalizations and language abilities were examined in oral language inclusion classrooms containing children with hearing loss who use hearing aids or cochlear implants and their typically hearing peers. Across over 600 hours of recorded vocal interactions of twenty-nine 2.5-3.5 year olds (16 girls) in three cohorts of children in a classroom, we found that vocalizations from each peer on a given observation predicted a child's vocalizations to that same peer on the subsequent observation. Children who produced more vocalizations to their peers had higher receptive and expressive language abilities, as measured by a standardized end-of-year language assessment. In fact, vocalizations from peers had an indirect association with end-of-year language abilities as mediated by children's vocalizations to peers. These findings did not vary as a function of hearing status. Overall, then, the results demonstrate the importance of dyadic peer vocal interactions for children's language use and abilities.

12.
Multivariate Behav Res ; 56(5): 739-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32530313

RESUMO

Head movement is an important but often overlooked component of emotion and social interaction. Examination of regularity and differences in head movements of infant-mother dyads over time and across dyads can shed light on whether and how mothers and infants alter their dynamics over the course of an interaction to adapt to each others. One way to study these emergent differences in dynamics is to allow parameters that govern the patterns of interactions to change over time, and according to person- and dyad-specific characteristics. Using two estimation approaches to implement variations of a vector-autoregressive model with time-varying coefficients, we investigated the dynamics of automatically-tracked head movements in mothers and infants during the Face-Face/Still-Face Procedure (SFP) with 24 infant-mother dyads. The first approach requires specification of a confirmatory model for the time-varying parameters as part of a state-space model, whereas the second approach handles the time-varying parameters in a semi-parametric ("mostly" model-free) fashion within a generalized additive modeling framework. Results suggested that infant-mother head movement dynamics varied in time both within and across episodes of the SFP, and varied based on infants' subsequently-assessed attachment security. Code for implementing the time-varying vector-autoregressive model using two R packages, dynr and mgcv, is provided.


Assuntos
Movimentos da Cabeça , Mães , Emoções , Face , Feminino , Humanos , Lactente , Relações Mãe-Filho
13.
Dev Sci ; 23(5): e12953, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32078210

RESUMO

Although difficulties with social relationships are key to autism spectrum disorder (ASD), no previous study has examined infant attachment security prior to ASD diagnosis. We prospectively assessed attachment security at 15 months in high-risk infants with later ASD (high-risk/ASD, n = 16), high-risk infants without later ASD (high-risk/no-ASD, n = 40), and low-risk infants without later ASD (low-risk/no-ASD, n = 39) using the Strange Situation Procedure. High-risk/ASD infants were disproportionately more likely to be classified as insecure (versus secure) and more likely to be classified as insecure-resistant (versus secure or avoidant) than high-risk/no-ASD and low-risk/no-ASD infants. High-risk infants with insecure-resistant attachments were over nine times more likely to receive an ASD diagnosis than high-risk infants with secure attachments. Insecure-resistant attachment in high-risk infants suggests a propensity toward negative affect with the parent in conditions of stress. Insecure-resistant attachment may prove useful as a potential early index of propensity toward ASD diagnosis in high-risk siblings, while insecure-resistant attachment in the context of emergent autism may contribute to difficulties experienced by children with ASD and their families.


Assuntos
Transtorno do Espectro Autista/psicologia , Apego ao Objeto , Feminino , Humanos , Lactente , Masculino , Pais , Estudos Prospectivos , Fatores de Risco , Irmãos , Comportamento Social
14.
Neuroimage ; 165: 158-169, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29030103

RESUMO

Brain-behavior associations in fMRI studies are typically restricted to a single level of analysis: either a circumscribed brain region-of-interest (ROI) or a larger network of brain regions. However, this common practice may not always account for the interdependencies among ROIs of the same network or potentially unique information at the ROI-level, respectively. To account for both sources of information, we combined measurement and structural components of structural equation modeling (SEM) approaches to empirically derive networks from ROI activity, and to assess the association of both individual ROIs and their respective whole-brain activation networks with task performance using three large task-fMRI datasets and two separate brain parcellation schemes. The results for working memory and relational tasks revealed that well-known ROI-performance associations are either non-significant or reversed when accounting for the ROI's common association with its corresponding network, and that the network as a whole is instead robustly associated with task performance. The results for the arithmetic task revealed that in certain cases, an ROI can be robustly associated with task performance, even when accounting for its associated network. The SEM framework described in this study provides researchers additional flexibility in testing brain-behavior relationships, as well as a principled way to combine ROI- and network-levels of analysis.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Adulto , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Masculino , Análise e Desempenho de Tarefas , Adulto Jovem
15.
Dev Sci ; 21(4): e12609, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28952202

RESUMO

The meaning, mechanism, and function of imitation in early infancy have been actively discussed since Meltzoff and Moore's (1977) report of facial and manual imitation by human neonates. Oostenbroek et al. (2016) claim to challenge the existence of early imitation and to counter all interpretations so far offered. Such claims, if true, would have implications for theories of social-cognitive development. Here we identify 11 flaws in Oostenbroek et al.'s experimental design that biased the results toward null effects. We requested and obtained the authors' raw data. Contrary to the authors' conclusions, new analyses reveal significant tongue-protrusion imitation at all four ages tested (1, 3, 6, and 9 weeks old). We explain how the authors missed this pattern and offer five recommendations for designing future experiments. Infant imitation raises fundamental issues about action representation, social learning, and brain-behavior relations. The debate about the origins and development of imitation reflects its importance to theories of developmental science.


Assuntos
Encéfalo/fisiologia , Cognição , Comportamento Imitativo/fisiologia , Viés , Feminino , Humanos , Lactente , Recém-Nascido , Projetos de Pesquisa , Aprendizado Social
17.
Dev Sci ; 20(5)2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27774733

RESUMO

Using existing longitudinal data from 570 infants in the Maternal Lifestyle Study, we explored the predictive value of maternal and infant affect and maternal vocalizations during 2 minutes of face-to-face interactions at 4 months on IQ scores at 4.5 and 7 years. After controlling for demographic factors, maternal depression, and prenatal drug exposure, maternal positive affect and maternal positive vocalizations emerged as predictors of both verbal and performance IQ at 4.5 and 7 years. Although infant positive affect during the interaction with the mother was not predictive of these outcome measures, infant positive affect towards an examiner predicted verbal but not performance IQ at 4.5 years. These results suggest that maternal positive affect may index emotional engagement in interaction that facilitates both verbal and nonverbal cognitive development, while infant social positive affect is specifically related to the acquisition of verbal reasoning abilities. These findings are significant because they are based on a discrete snapshot of observable behavior in infancy (just 2 minutes of interaction), because they extend the range of maternal behaviors and characteristics known to support positive developmental outcomes, and because they are derived from high-risk infants where prevention efforts may be beneficial. Potential mechanisms for these associations are discussed, as are the clinical implications for identifying dyads most in need of targeted interventions.


Assuntos
Desenvolvimento Infantil/fisiologia , Comportamento do Lactente/fisiologia , Inteligência , Comportamento Materno/fisiologia , Relações Mãe-Filho , Comportamento Verbal/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Testes de Inteligência , Masculino , Análise de Regressão
18.
Dev Psychopathol ; 29(1): 319-329, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27048735

RESUMO

This study used a prospective longitudinal design to examine the early developmental pathways that underlie language growth in infants at high risk (n = 50) and low risk (n = 34) for autism spectrum disorder in the first 18 months of life. While motor imitation and responding to joint attention (RJA) have both been found to predict expressive language in children with autism spectrum disorder and those with typical development, the longitudinal relation between these capacities has not yet been identified. As hypothesized, results revealed that 15-month RJA mediated the association between 12-month motor imitation and 18-month expressive vocabulary, even after controlling for earlier levels of RJA and vocabulary. These results provide new information about the developmental sequencing of skills relevant to language growth that may inform future intervention efforts for children at risk for language delay or other developmental challenges.


Assuntos
Transtorno do Espectro Autista/psicologia , Desenvolvimento da Linguagem , Idioma , Atenção , Feminino , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/psicologia , Masculino , Estudos Prospectivos , Vocabulário
19.
Int J Comput Vis ; 123(3): 372-391, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28943718

RESUMO

Event discovery aims to discover a temporal segment of interest, such as human behavior, actions or activities. Most approaches to event discovery within or between time series use supervised learning. This becomes problematic when some relevant event labels are unknown, are difficult to detect, or not all possible combinations of events have been anticipated. To overcome these problems, this paper explores Common Event Discovery (CED), a new problem that aims to discover common events of variable-length segments in an unsupervised manner. A potential solution to CED is searching over all possible pairs of segments, which would incur a prohibitive quartic cost. In this paper, we propose an efficient branch-and-bound (B&B) framework that avoids exhaustive search while guaranteeing a globally optimal solution. To this end, we derive novel bounding functions for various commonality measures and provide extensions to multiple commonality discovery and accelerated search. The B&B framework takes as input any multidimensional signal that can be quantified into histograms. A generalization of the framework can be readily applied to discover events at the same or different times (synchrony and event commonality, respectively). We consider extensions to video search and supervised event detection. The effectiveness of the B&B framework is evaluated in motion capture of deliberate behavior and in video of spontaneous facial behavior in diverse interpersonal contexts: interviews, small groups of young adults, and parent-infant face-to-face interaction.

20.
J Neurosci ; 35(37): 12917-31, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26377476

RESUMO

The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR(-/-) mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release. SIGNIFICANCE STATEMENT: Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects.


Assuntos
Aprendizagem da Esquiva/fisiologia , Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Receptores Opioides kappa/fisiologia , Área Tegmentar Ventral/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia , (trans)-Isômero de 3,4-dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclo-hexil)-benzenoacetamida/farmacologia , Potenciais de Ação/efeitos dos fármacos , Analgésicos não Narcóticos/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Dopamina/metabolismo , Ativação Enzimática , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Técnicas de Silenciamento de Genes , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/metabolismo , Fosforilação/efeitos dos fármacos , Potássio/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Opioides kappa/deficiência , Receptores Opioides kappa/genética , Proteínas Recombinantes de Fusão/farmacologia , Teste de Desempenho do Rota-Rod , Neurônios Serotoninérgicos/fisiologia , Área Tegmentar Ventral/citologia , Proteínas Quinases p38 Ativadas por Mitógeno/deficiência , Proteínas Quinases p38 Ativadas por Mitógeno/genética
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