Modeling flexible behavior in childhood to adulthood shows age-dependent learning mechanisms and less optimal learning in autism in each age group

Crawley, Daisy; Zhang, Lei; Jones, Emily J. H.; Ahmad, Jumana; Oakley, Bethany; Cáceres, Antonia San José; Charman, Tony; Buitelaar, Jan K.; Murphy, Declan; Chatham, Christopher H.; Ouden, H.E.M. den; Loth, Eva

doi:10.1371/journal.pbio.3000908

Cited by 58 publications

(47 citation statements)

References 91 publications

(116 reference statements)

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“…Our finding of both decreasing preference uncertainty and increasing model fit with age reflect that behaviour is less variable in older subjects within our sample. Varying goodness-offit of a specific model is a challenge for developmental modelling studies 61,62 and may be indicative of either varying stochasticity or different cognitive processes underlying task behaviour at different ages. Potential solutions are now emerging in the literature, including novel data analysis strategies (e.g.…”

Section: Discussionmentioning

confidence: 99%

Preference uncertainty accounts for developmental effects on susceptibility to peer influence in adolescence

et al. 2021

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Adolescents are prone to social influence from peers, with implications for development, both adaptive and maladaptive. Here, using a computer-based paradigm, we replicate a cross-sectional effect of more susceptibility to peer influence in a large dataset of adolescents 14 to 24 years old. Crucially, we extend this finding by adopting a longitudinal perspective, showing that a within-person susceptibility to social influence decreases over a 1.5 year follow-up time period. Exploiting this longitudinal design, we show that susceptibility to social influences at baseline predicts an improvement in peer relations over the follow-up period. Using a Bayesian computational model, we demonstrate that in younger adolescents a greater tendency to adopt others’ preferences arises out of a higher uncertainty about their own preferences in the paradigmatic case of delay discounting (a phenomenon called ‘preference uncertainty’). This preference uncertainty decreases over time and, in turn, leads to a reduced susceptibility of one’s own behaviour to an influence from others. Neuro-developmentally, we show that a measure of myelination within medial prefrontal cortex, estimated at baseline, predicts a developmental decrease in preference uncertainty at follow-up. Thus, using computational and neural evidence, we reveal adaptive mechanisms underpinning susceptibility to social influence during adolescence.

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Section: Discussionmentioning

confidence: 99%

Preference uncertainty accounts for developmental effects on susceptibility to peer influence in adolescence

et al. 2021

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“…In another associative learning study where adults had to learn an association between a tone and a rotation direction in a very uncertain context, autistic adults managed to learn a prior, but failed to update it after an unexpected change in contingency [ 26 ]. Another study relying on a large cohort of children and adults performing a probabilistic reversal learning task also showed poorer performance in ASD and reduced flexible behaviours [ 27 ]. Finally, another probabilistic reward learning task in a volatile environment showed that having more autistic traits was associated with worse performance [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Prediction learning in adults with autism and its molecular correlates

et al. 2021

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Background According to Bayesian hypotheses, individuals with Autism Spectrum Disorder (ASD) have difficulties making accurate predictions about their environment. In particular, the mechanisms by which they assign precision to predictions or sensory inputs would be suboptimal in ASD. These mechanisms are thought to be mostly mediated by glutamate and GABA. Here, we aimed to shed light on prediction learning in ASD and on its neurobiological correlates. Methods Twenty-six neurotypical and 26 autistic adults participated in an associative learning task where they had to learn a probabilistic association between a tone and the rotation direction of two dots, in a volatile context. They also took part in magnetic resonance spectroscopy (MRS) measurements to quantify Glx (glutamate and glutamine), GABA + and glutathione in a low-level perceptual region (occipital cortex) and in a higher-level region involved in prediction learning (inferior frontal gyrus). Results Neurotypical and autistic adults had their percepts biased by their expectations, and this bias was smaller for individuals with a more atypical sensory sensitivity. Both groups were able to learn the association and to update their beliefs after a change in contingency. Interestingly, the percentage of correct predictions was correlated with the Glx/GABA + ratio in the occipital cortex (positive correlation) and in the right inferior frontal gyrus (negative correlation). In this region, MRS results also showed an increased concentration of Glx in the ASD group compared to the neurotypical group. Limitations We used a quite restrictive approach to select the MR spectra showing a good fit, which led to the exclusion of some MRS datasets and therefore to the reduction of the sample size for certain metabolites/regions. Conclusions Autistic adults appeared to have intact abilities to make predictions in this task, in contrast with the Bayesian hypotheses of ASD. Yet, higher ratios of Glx/GABA + in a frontal region were associated with decreased predictive abilities, and ASD individuals tended to have more Glx in this region. This neurobiological difference might contribute to suboptimal predictive mechanisms in ASD in certain contexts.

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“…In contrast to the enhanced novel discrimination learning, reversal learning was impaired in Nrxn1α +/− mice. This has translational relevance to the reversal learning deficit seen in neurodevelopmental disorders associated with 2p16.3 deletion, including that in ASD (Crawley et al, 2020), ScZ (Reddy et al, 2016; Schlagenhauf et al, 2014), and TS (Shephard et al, 2016). However, while these studies generally indicate perseveration and/or a lack of sensitivity to feedback as key mechanisms in the reversal learning deficit seen in these disorders (Crawley et al, 2020; Reddy et al, 2016), we found that sensitivity to punishment/feedback was not impaired in Nrxn1α +/− mice.…”

Section: Discussionmentioning

confidence: 98%

“…Despite these observations in relatively simple tests, the potential impact of Nrxn1α heterozygosity on discrimination/associative learning and cognitive flexibility has not been assessed. This is surprising given the altered discrimination learning (Plaisted et al, 1998), associative learning (Brambilla et al, 2011; Eordegh et al, 2020) and cognitive flexibility, including impaired reversal learning (Crawley et al, 2020; Lange et al, 2017; Schlagenhauf et al, 2014), reported in neurodevelopmental disorders associated with 2p16.3 deletion.…”

Section: Introductionmentioning

confidence: 99%

Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism‐associated 2p16.3 deletion

et al. 2022

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2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1α heterozygosity on cerebral metabolism, in mice, using 14 C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1α genotype. Our data show that Nrxn1α heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1α +/À mice. Behaviorally, Nrxn1α +/À mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1α +/À mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1α +/À mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1α heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1α +/À mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. Lay SummaryDeletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1α expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism.

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Modeling flexible behavior in childhood to adulthood shows age-dependent learning mechanisms and less optimal learning in autism in each age group

Cited by 58 publications

References 91 publications

Preference uncertainty accounts for developmental effects on susceptibility to peer influence in adolescence

Preference uncertainty accounts for developmental effects on susceptibility to peer influence in adolescence

Prediction learning in adults with autism and its molecular correlates

Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism‐associated 2p16.3 deletion

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