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BioRxiv : the Preprint Server For... Feb 2024Animals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones....
Animals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones. Behavioral responses are elicited when certain properties of a stimulus such as its intensity or size reach a critical value, and such behavioral thresholds can be a simple and effective mechanism to filter sensory information. For example, the acoustic startle response is a conserved and stereotyped defensive behavior induced by sudden loud sounds, but dysregulation of the threshold to initiate this behavior can result in startle hypersensitivity that is associated with sensory processing disorders including schizophrenia and autism. Through a previous forward genetic screen for regulators of the startle threshold a nonsense mutation in () was found that causes startle hypersensitivity in zebrafish larvae, but the molecular mechanisms by which Cyfip2 establishes the acoustic startle threshold are unknown. Here we used conditional transgenic rescue and CRISPR/Cas9 to determine that Cyfip2 acts though both Rac1 and FMRP pathways, but not the closely related FXR1 or FXR2, to establish the acoustic startle threshold during early neurodevelopment. To identify proteins and pathways that may be downstream effectors of Rac1 and FMRP, we performed a candidate-based drug screen that indicated that Cyfip2 can also act acutely to maintain the startle threshold branched actin polymerization and N-methyl D-aspartate receptors (NMDARs). To complement this approach, we used unbiased discovery proteomics to determine that loss of Cyfip2 alters cytoskeletal and extracellular matrix components while also disrupting oxidative phosphorylation and GABA receptor signaling. Finally, we functionally validated our proteomics findings by showing that activating GABA receptors, which like NMDARs are also FMRP targets, restores normal startle sensitivity in mutants. Together, these data reveal multiple mechanisms by which Cyfip2 regulates excitatory/inhibitory balance in the startle circuit to control the processing of acoustic information.
PubMed: 38187577
DOI: 10.1101/2023.12.22.573054 -
Science Advances Jan 2024The ability to predict the future based on past experience lies at the core of the brain's ability to adapt behavior. However, the neural mechanisms that participate in...
The ability to predict the future based on past experience lies at the core of the brain's ability to adapt behavior. However, the neural mechanisms that participate in generating and updating predictions are not clearly understood. Further, the evolutionary antecedents and the prevalence of predictive processing among vertebrates are even less explored. Here, we show evidence of predictive processing via the involvement of cerebellar circuits in larval zebrafish. We presented stereotyped optic flow stimuli to larval zebrafish to evoke swims and discovered that lesioning the cerebellum abolished prediction-dependent modulation of swim latency. When expectations of optic flow direction did not match with reality, error signals arrive at Purkinje cells via the olivary climbing fibers, whereas granule cells and Purkinje cells encode signals of expectation. Strong neural representations of expectation correlate with faster swim responses and vice versa. In sum, our results show evidence for predictive processing in nonmammalian vertebrates with the involvement of cerebellum, an evolutionarily conserved brain structure.
Topics: Animals; Zebrafish; Larva; Cerebellum; Purkinje Cells; Neurons
PubMed: 38170763
DOI: 10.1126/sciadv.adi6470 -
MSystems Jan 2024Probiotics can effectively improve a variety of neurological diseases, but there is little research on autism, and the specific mechanism is unclear. In this study,...
Probiotics can effectively improve a variety of neurological diseases, but there is little research on autism, and the specific mechanism is unclear. In this study, shotgun metagenomics analysis was used to investigate the preventive and therapeutic effects of subsp. Probio-M8 on autism. The results showed that Probio-M8 treatment significantly alleviated valproate (VPA)-induced autism in mice, with autistic symptoms characterized by increased stereotyped behaviors such as grooming, reduced learning ability, and decreased desire to socialize. Further studies have found that Probio-M8 can alleviate autism by optimizing gut microbiota diversity and regulating metabolic levels. Probio-M8 regulates gut microbiota structure by increasing the abundance of beneficial bacteria such as and . In addition, Probio-M8 regulates metabolic activity by increasing levels of choline, which corrects CAZy disorders. In conclusion, Probio-M8 is therapeutic in the VPA-induced autism mouse model by regulating the gut microbiome and metabolic levels.IMPORTANCEIndividuals with autism often exhibit symptoms of social invariance, obsessive-compulsive tendencies, and repetitive behaviors. However, early intervention and treatment can be effective in improving social skills and mitigating autism symptoms, including behaviors related to irritability. Although taking medication for autism may lead to side effects such as weight gain, probiotics can be an ideal intervention for alleviating these symptoms. In this study, we investigated the effects of Probio-M8 intervention on the behavior of autistic mice using an open-field test, a three-chamber sociability test, and a novel object recognition test. Metagenomic analysis revealed differences in gut microbiota diversity among groups, predicted changes in metabolite levels, and functionally annotated CAZy. Additionally, we analyzed serum neurotransmitter levels and found that probiotics were beneficial in mitigating neurotransmitter imbalances in mice with autism.
Topics: Mice; Animals; Bifidobacterium animalis; Autistic Disorder; Gastrointestinal Microbiome; Weight Gain; Neurotransmitter Agents
PubMed: 38108654
DOI: 10.1128/msystems.01013-23 -
Molecular Psychiatry Jan 2024Autism spectrum disorder (ASD) comprises a large group of neurodevelopmental conditions featuring, over a wide range of severity and combinations, a core set of...
Curation of causal interactions mediated by genes associated with autism accelerates the understanding of gene-phenotype relationships underlying neurodevelopmental disorders.
Autism spectrum disorder (ASD) comprises a large group of neurodevelopmental conditions featuring, over a wide range of severity and combinations, a core set of manifestations (restricted sociality, stereotyped behavior and language impairment) alongside various comorbidities. Common and rare variants in several hundreds of genes and regulatory regions have been implicated in the molecular pathogenesis of ASD along a range of causation evidence strength. Despite significant progress in elucidating the impact of few paradigmatic individual loci, such sheer complexity in the genetic architecture underlying ASD as a whole has hampered the identification of convergent actionable hubs hypothesized to relay between the vastness of risk alleles and the core phenotypes. In turn this has limited the development of strategies that can revert or ameliorate this condition, calling for a systems-level approach to probe the cross-talk of cooperating genes in terms of causal interaction networks in order to make convergences experimentally tractable and reveal their clinical actionability. As a first step in this direction, we have captured from the scientific literature information on the causal links between the genes whose variants have been associated with ASD and the whole human proteome. This information has been annotated in a computer readable format in the SIGNOR database and is made freely available in the resource website. To link this information to cell functions and phenotypes, we have developed graph algorithms that estimate the functional distance of any protein in the SIGNOR causal interactome to phenotypes and pathways. The main novelty of our approach resides in the possibility to explore the mechanistic links connecting the suggested gene-phenotype relations.
Topics: Humans; Phenotype; Autism Spectrum Disorder; Genetic Predisposition to Disease; Neurodevelopmental Disorders; Gene Regulatory Networks; Autistic Disorder; Genetic Association Studies; Proteome
PubMed: 38102483
DOI: 10.1038/s41380-023-02317-3 -
Cognition Mar 2024Humans and some other animals can autonomously generate action choices that contribute to solving complex problems. However, experimental investigations of the cognitive...
Humans and some other animals can autonomously generate action choices that contribute to solving complex problems. However, experimental investigations of the cognitive bases of human autonomy are challenging, because experimental paradigms typically constrain behaviour using controlled contexts, and elicit behaviour by external triggers. In contrast, autonomy and freedom imply unconstrained behaviour initiated by endogenous triggers. Here we propose a new theoretical construct of adaptive autonomy, meaning the capacity to make behavioural choices that are free from constraints of both immediate external triggers and of routine response patterns, but nevertheless show appropriate coordination with the environment. Participants (N = 152) played a competitive game in which they had to choose the right time to act, in the face of an opponent who punished (in separate blocks) either choice biases (such as always responding early), sequential patterns of action timing across trials (such as early, late, early, late…), or predictable action-outcome dependence (such as win-stay, lose-shift). Adaptive autonomy was quantified as the ability to maintain performance when each of these influences on action selection was punished. We found that participants could become free from habitual choices regarding when to act and could also become free from sequential action patterns. However, they were not able to free themselves from influences of action-outcome dependence, even when these resulted in poor performance. These results point to a new concept of autonomous behaviour as flexible adaptation of voluntary action choices in a way that avoids stereotypy. In a sequential analysis, we also demonstrated that participants increased their reliance on belief learning in which they attempt to understand the competitor's beliefs and intentions, when transition bias and reinforcement bias were punished. Taken together, our study points to a cognitive mechanism of adaptive autonomy in which competitive interactions with other agents could promote both social cognition and volition in the form of non-stereotyped action choices.
Topics: Animals; Humans; Volition; Choice Behavior; Reinforcement, Psychology; Intention
PubMed: 38101173
DOI: 10.1016/j.cognition.2023.105684 -
Scientific Reports Dec 2023Acoustic sequences have been described in a range of species and in varying complexity. Cetaceans are known to produce complex song displays but these are generally...
Acoustic sequences have been described in a range of species and in varying complexity. Cetaceans are known to produce complex song displays but these are generally limited to mysticetes; little is known about call combinations in odontocetes. Here we investigate call combinations produced by killer whales (Orcinus orca), a highly social and vocal species. Using acoustic recordings from 22 multisensor tags, we use a first order Markov model to show that transitions between call types or subtypes were significantly different from random, with repetitions and specific call combinations occurring more often than expected by chance. The mixed call combinations were composed of two or three calls and were part of three call combination clusters. Call combinations were recorded over several years, from different individuals, and several social clusters. The most common call combination cluster consisted of six call (sub-)types. Although different combinations were generated, there were clear rules regarding which were the first and last call types produced, and combinations were highly stereotyped. Two of the three call combination clusters were produced outside of feeding contexts, but their function remains unclear and further research is required to determine possible functions and whether these combinations could be behaviour- or group-specific.
Topics: Humans; Animals; Whale, Killer; Vocalization, Animal; Social Behavior; Iceland; Sound Spectrography
PubMed: 38065973
DOI: 10.1038/s41598-023-48349-1 -
PloS One 2023In this paper, we examine whether patient narratives alter the impact of stereotyping on choice of primary care clinicians: in this case, the common presumption that...
In this paper, we examine whether patient narratives alter the impact of stereotyping on choice of primary care clinicians: in this case, the common presumption that female doctors will be more attentive to empathic relationships with patients. 1052 individuals were selected from a nationally representative Internet panel to participate in a survey experiment. Participants were given performance data about 12 fictitious primary care physicians, including a randomized set of narrative feedback from patients. We compared the choice of clinician made by participants who value bedside manner and were exposed to narratives in the experiment, compared to those valuing bedside manner who had not had this exposure. We estimated multivariate logistic regressions to assess whether exposure to patient comments that "disrupt" stereotypes influenced choice of physicians. Participants who saw patient comments and had previously reported caring about bedside manner had a 67% higher odds of choosing a female physician than those participants that did not see a patient comments, controlling for the content of the narratives themselves. When participants were exposed to patient comments that disrupt gendered stereotypes, they had a 40% lower odds of choosing a female physician. Simple exposure to patient narratives that do not clearly disrupt gendered stereotypes increased the likelihood of choosing a female clinician by priming attention to relational aspects of care. However, when the content of a sufficient proportion of patient comments runs counter stereotypes, even a minority of narratives is sufficient to disrupt gendered-expectations and alter choices.
Topics: Female; Humans; Physicians; Primary Health Care; Stereotyped Behavior; Stereotyping; Surveys and Questionnaires
PubMed: 38060553
DOI: 10.1371/journal.pone.0295243 -
Scientific Reports Dec 2023Objective magnitude representations may be prone to subjective percepts when judging human beings. An elderly man is clearly "large" in terms of age. But, is he truly...
Objective magnitude representations may be prone to subjective percepts when judging human beings. An elderly man is clearly "large" in terms of age. But, is he truly perceived as "big" in our minds? We investigated whether "objective" representation of age interacts with subjective stereotypical percepts of aging, using a numeral classification task preceded by prime images containing human figures. First, prime images of children and young adults demonstrated a positive correlation between perceived age and numerical size. Second, negatively and positively valenced prime images were associated with small and big numerical values, respectively. Third, joint effects of age and valence on numerical value perception revealed a linkage between old adults and small numerical values. It seems that magnitude perception is vulnerable to implicit subjective biases and stereotypical judgments dominate objective magnitude representation.
Topics: Male; Child; Female; Young Adult; Pregnancy; Humans; Aged; Judgment; Ageism; Reaction Time; Aging; Stereotyped Behavior
PubMed: 38040733
DOI: 10.1038/s41598-023-40876-1 -
Journal of Neuroscience Methods Mar 2024Self-grooming behavior in rodents serves as a valuable behavioral index for investigating stereotyped and perseverative responses. Most current grooming analyses rely on...
BACKGROUND
Self-grooming behavior in rodents serves as a valuable behavioral index for investigating stereotyped and perseverative responses. Most current grooming analyses rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer.
NEW METHOD
Grooming behavior is quantified by calculating ratios of relevant movement power spectral bands. These ratios are input into a naïve Bayes classifier, trained with manual video observations. The effectiveness of this method was tested using CIN-d mice, an animal model developed through early-life depletion of striatal cholinergic interneurons (CIN-d) and featuring prolonged grooming responses to acute stressors. Behavioral monitoring was simultaneously conducted on the force-place actometer and by video recording.
RESULTS
The naïve Bayes approach achieved 93.7% accurate classification and an area under the receiver operating characteristic curve of 0.894. We confirmed that male CIN-d mice displayed significantly longer grooming durations than controls. However, this elevation was not correlated with increases in grooming force. Notably, the dopaminergic antagonist haloperidol reduced grooming force and duration.
COMPARISON WITH EXISTING METHODS
In contrast to observation-based approaches, our method affords rapid, unbiased, and automated assessment of grooming duration, frequency, and force.
CONCLUSIONS
Our novel approach enables fast and accurate automated detection of grooming behaviors. This method holds promise for high-throughput assessments of grooming stereotypies in animal models of neuropsychiatric disorders.
Topics: Mice; Male; Animals; Behavior, Animal; Grooming; Bayes Theorem; Movement; Haloperidol; Rodentia
PubMed: 38029972
DOI: 10.1016/j.jneumeth.2023.110026 -
Frontiers in Cellular Neuroscience 2023Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing prevalence. Over 1,000 risk genes have now been implicated in ASD, suggesting... (Review)
Review
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing prevalence. Over 1,000 risk genes have now been implicated in ASD, suggesting diverse etiology. However, the diagnostic criteria for the disorder still comprise two major behavioral domains - deficits in social communication and interaction, and the presence of restricted and repetitive patterns of behavior (RRBs). The RRBs associated with ASD include both stereotyped repetitive movements and other motor manifestations including changes in gait, balance, coordination, and motor skill learning. In recent years, the striatum, the primary input center of the basal ganglia, has been implicated in these ASD-associated motor behaviors, due to the striatum's role in action selection, motor learning, and habit formation. Numerous mouse models with mutations in ASD risk genes have been developed and shown to have alterations in ASD-relevant behaviors. One commonly used assay, the accelerating rotarod, allows for assessment of both basic motor coordination and motor skill learning. In this corticostriatal-dependent task, mice walk on a rotating rod that gradually increases in speed. In the extended version of this task, mice engage striatal-dependent learning mechanisms to optimize their motor routine and stay on the rod for longer periods. This review summarizes the findings of studies examining rotarod performance across a range of ASD mouse models, and the resulting implications for the involvement of striatal circuits in ASD-related motor behaviors. While performance in this task is not uniform across mouse models, there is a cohort of models that show increased rotarod performance. A growing number of studies suggest that this increased propensity to learn a fixed motor routine may reflect a common enhancement of corticostriatal drive across a subset of mice with mutations in ASD-risk genes.
PubMed: 38026686
DOI: 10.3389/fncel.2023.1270489