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Altered dynamic functional and effective connectivity in drug-naive children with Tourette syndrome.Translational Psychiatry Jan 2024Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by repetitive, stereotyped, involuntary tics, the neurological basis of which remains...
Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by repetitive, stereotyped, involuntary tics, the neurological basis of which remains unclear. Although traditional resting-state MRI (rfMRI) studies have identified abnormal static functional connectivity (FC) in patients with TS, dynamic FC (dFC) remains relatively unexplored. The rfMRI data of 54 children with TS and 46 typically developing children (TDC) were analyzed using group independent component analysis to obtain independent components (ICs), and a sliding-window approach to generate dFC matrices. All dFC matrices were clustered into two reoccurring states, the state transition metrics were obtained. We conducted Granger causality and nodal topological analyses to further investigate the brain regions that may play the most important roles in driving whole-brain switching between different states. We found that children with TS spent more time in state 2 (P < 0.001), a state characterized by strong connectivity between ICs, and switched more quickly between states (P = 0.025) than TDC. The default mode network (DMN) may play an important role in abnormal state transitions because the FC that changed the most between the two states was between the DMN and other networks. Additionally, the DMN had increased degree centrality, efficiency and altered causal influence on other networks. Certain alterations related to executive function (r = -0.309, P < 0.05) and tic symptom ratings (r = 0.282; 0.413, P < 0.05) may represent important aspects of the pathophysiology of TS. These findings facilitate our understanding of the neural basis for the clinical presentation of TS.
Topics: Child; Humans; Tourette Syndrome; Brain; Executive Function; Stereotyped Behavior
PubMed: 38253543
DOI: 10.1038/s41398-024-02779-1 -
Audiology Research Jan 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by stereotyped and repetitive behavior patterns. In addition to neurological and behavioral... (Review)
Review
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by stereotyped and repetitive behavior patterns. In addition to neurological and behavioral problems, individuals with ASD commonly experience otolaryngological comorbidities. Individuals with ASD often have auditory disorders including hearing loss and auditory processing disorders such as central auditory processing disorder (CAPD), as well as both chronic and recurrent otitis media. These challenges negatively impact a person's ability to effectively communicate and may further impact their neurological functioning, particularly when not appropriately treated. Individuals diagnosed with ASD also have difficulty sleeping which contributes to increased irritability and may further aggravate the core behavioral symptoms of autism. The individuals with ASD also have a higher rate of sinusitis which contributes to the worsening of the autism behavior phenotype. The high prevalence of otolaryngological comorbidities in individuals with ASD warrants a better collaboration between their various healthcare providers and otolaryngologists with expertise in auditory, sleep, and sinus disorders in pursuit of improving the quality of life of affected individuals and their families/caregivers.
PubMed: 38247561
DOI: 10.3390/audiolres14010005 -
Progress in Neuro-psychopharmacology &... Apr 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and...
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and interests with a male to female bias of 4.2/1. Social behavior in ASD animal models is commonly analyzed in males, and seldomly in females, using the widely implemented three-chambers test procedure. Here, we implemented a novel procedure, the Live Mouse Tracker (LMT), combining artificial intelligence, machine learning procedures and behavioral measures. We used it on mice that were prenatally exposed to valproic acid (VPA) (450 mg/kg) at embryonic day 12.5, a widely recognized and potent ASD model that we had previously extensively characterized. We focused on female mice offspring, in which social deficits have been rarely documented when using the 3-CT procedure. We recorded several parameters related to social behavior in these mice, continuously for three days in groups of four female mice. Comparisons were made on groups of 4 female mice with the same treatment (4 saline or 4 VPA) or with different treatments (3 saline and 1 VPA). We report that VPA females show several types of social deficits, which are different in nature and magnitude in relation with time. When VPA mice were placed in the LMT alongside saline mice, their social deficits showed significant improvement as early as 1 h from the start of the experiment, lasting up to 3 days throughout the duration of the experiment. Our findings suggest that ASD may be underdiagnosed in females. They also imply that ASD-related social deficits can be ameliorated by the presence of typical individuals.
Topics: Female; Male; Animals; Mice; Humans; Valproic Acid; Artificial Intelligence; Autism Spectrum Disorder; Social Behavior; Stereotyping; Prenatal Exposure Delayed Effects; Disease Models, Animal; Behavior, Animal
PubMed: 38244714
DOI: 10.1016/j.pnpbp.2024.110948 -
Current Biology : CB Feb 2024Diverse animal species exhibit highly stereotyped behavioral actions and locomotor sequences as they explore their natural environments. In many such cases, the neural...
Diverse animal species exhibit highly stereotyped behavioral actions and locomotor sequences as they explore their natural environments. In many such cases, the neural basis of behavior is well established, where dedicated neural circuitry contributes to the initiation and regulation of certain response sequences. At the microscopic scale, single-celled eukaryotes (protists) also exhibit remarkably complex behaviors and yet are completely devoid of nervous systems. Here, to address the question of how single cells control behavior, we study locomotor patterning in the exemplary hypotrich ciliate Euplotes, a highly polarized cell, which actuates a large number of leg-like appendages called cirri (each a bundle of ∼25-50 cilia) to swim in fluids or walk on surfaces. As it navigates its surroundings, a walking Euplotes cell is routinely observed to perform side-stepping reactions, one of the most sophisticated maneuvers ever observed in a single-celled organism. These are spontaneous and stereotyped reorientation events involving a transient and fast backward motion followed by a turn. Combining high-speed imaging with simultaneous time-resolved electrophysiological recordings, we show that this complex coordinated motion sequence is tightly regulated by rapid membrane depolarization events, which orchestrate the activity of different cirri on the cell. Using machine learning and computer vision methods, we map detailed measurements of cirri dynamics to the cell's membrane bioelectrical activity, revealing a differential response in the front and back cirri. We integrate these measurements with a minimal model to understand how Euplotes-a unicellular organism-manipulates its membrane potential to achieve real-time control over its motor apparatus.
Topics: Animals; Euplotes; Walking; Cilia; Gait
PubMed: 38237598
DOI: 10.1016/j.cub.2023.12.051 -
Heliyon Jan 2024Autism is a severe neurodevelopmental disorder characterized by social interaction deficits, impairments in communication, and restricted and repetitive stereotyped...
BACKGROUND
Autism is a severe neurodevelopmental disorder characterized by social interaction deficits, impairments in communication, and restricted and repetitive stereotyped behavior and activities. Family and twin studies suggested an essential role of genetic factors in the etiology of autism spectrum disorder (ASD). Also, other studies found and () might be involved in brain development and susceptible to ASD.
METHODS
In this study, 17 genome-wide significant SNPs reported in previous ASD genome-wide association studies (GWAS) and 7 SNPs in strong linkage disequilibrium with known ASD GWAS hits were selected to investigate the association between these SNPs and autism in the Han Chinese population. Then, 10 tagSNPs in and 11 tagSNPs in were selected to analyze the association between these SNPs and autism. The selected 24 SNPs and tagSNPs were genotyped using the Agena MassARRAY SNP genotyping assay in 757 Han Chinese autism trios.
RESULTS
Rs1484144 in was significantly associated with autism; significance remained after the Bonferroni correction ( < 0.0022). Also, rs79879286, rs12154597, and rs12540919 near as well as rs9787523 and rs3750261 in were nominally associated with autism.
CONCLUSION
Our study suggests that rs1484144 in is a significant SNP for autism in the Han Chinese population, while and might be the susceptibility genes for autism in this population.
PubMed: 38234914
DOI: 10.1016/j.heliyon.2023.e23677 -
Molecular Psychiatry May 2024The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1,...
The pathophysiology of autism spectrum disorders (ASDs) is causally linked to postsynaptic scaffolding proteins, as evidenced by numerous large-scale genomic studies [1, 2] and in vitro and in vivo neurobiological studies of mutations in animal models [3, 4]. However, due to the distinct phenotypic and genetic heterogeneity observed in ASD patients, individual mutation genes account for only a small proportion (<2%) of cases [1, 5]. Recently, a human genetic study revealed a correlation between de novo variants in FERM domain-containing-5 (FRMD5) and neurodevelopmental abnormalities [6]. In this study, we demonstrate that deficiency of the scaffolding protein FRMD5 leads to neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency results in morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice display learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics revealed that FRMD5 deletion affects the distribution of synaptic proteins involved in the pathological process of ASD. Collectively, our findings delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, suggesting potential therapeutic implications for the treatment of ASD.
Topics: Animals; Mice; Autism Spectrum Disorder; Disease Models, Animal; Neurodevelopmental Disorders; Membrane Proteins; Male; Neurons; Behavior, Animal; Cytoskeletal Proteins; Mice, Knockout; Autistic Disorder; Mice, Inbred C57BL; Social Behavior; Stereotyped Behavior; Synapses; Female
PubMed: 38228891
DOI: 10.1038/s41380-024-02407-w -
Behavioural Brain Research Mar 2024Abnormal repetitive stereotypic behaviours (SBs) (e.g. pacing, body-rocking) are common in animals with poor welfare (e.g. socially isolated/in barren housing). But how...
Abnormal repetitive stereotypic behaviours (SBs) (e.g. pacing, body-rocking) are common in animals with poor welfare (e.g. socially isolated/in barren housing). But how (or even whether) poor housing alters animals' brains to induce SBs remains uncertain. To date, there is little evidence for environmental effects on the brain that also correlate with individual SB performance. Using female mice from two strains (SB-prone DBA/2s; SB-resistant C57/BL/6s), displaying two forms of SB (route-tracing; bar-mouthing), we investigated how housing (conventional laboratory conditions vs. well-resourced 'enriched' cages) affects long-term neuronal activity as assessed via cytochrome oxidase histochemistry in 13 regions of interest (across cortex, striatum, basal ganglia and thalamus). Conventional housing reduced activity in the cortex and striatum. However, DBA mice had no cortical or striatal differences from C57 mice (just greater basal ganglia output activity, independent of housing). Neural correlates for individual levels of bar-mouthing (positive correlations in the substantia nigra and thalamus) were also independent of housing; while route-tracing levels had no clear neural correlates at all. Thus conventional laboratory housing can suppress cortico-striatal activity, but such changes are unrelated to SB (since not mirrored by congruent individual and strain differences). Furthermore, the neural correlates of SB at individual and strain levels seem to reflect underlying predispositions, not housing-mediated changes. To aid further work, hypothesis-generating model fit analyses highlighted this unexplained housing effect, and also suggested several regions of interest across cortex, striatum, thalamus and substantia nigra for future investigation (ideally with improved power to reduce risks of Type II error).
Topics: Female; Animals; Mice; Mice, Inbred DBA; Stereotyped Behavior; Basal Ganglia; Brain; Housing, Animal
PubMed: 38216059
DOI: 10.1016/j.bbr.2024.114862 -
Zoo Biology 2024In the wild, female polar bears (Ursus maritimus) with cubs may spend extended periods of time within the den following initial emergence. As a result, studying...
In the wild, female polar bears (Ursus maritimus) with cubs may spend extended periods of time within the den following initial emergence. As a result, studying behavioral development of cubs at the denning site has been difficult and unreliable. Although care staff at zoological institutions have easier access to animals, every effort is made to minimize intrusions to maternal groups, which presents research limitations. Detroit Zoological Society staff used audio-equipped cameras installed in behind-the-scenes spaces to conduct approximately 9 weeks of monitoring on two female polar bear cubs of the same litter, one of whom (Laerke) was hand-reared while the other (Astra) was mother-reared. Monitoring spanned ages 14-24 weeks and consisted of 12, 5-min focal observations per observation day timed to evenly cover the entire 24-h day. Using generalized linear mixed models, we examined relationships between behavior and time of day, hour, and age. We also conducted descriptive analyses and used these to draw comparisons between the two cubs where appropriate. Despite different rearing environments, both cubs had highly comparable patterns of inactive, locomotory, and independent play behaviors. Astra generally decreased time spent nursing and in proximity to Suka as she aged. Data presented here represent a continuation of previous neonatal observations conducted on Astra, adding to the minimal body of knowledge currently available on first year polar bear cub development. We also report successful mitigation of stereotypic behavior in Laerke. Further studies of captive maternal groups can provide insight into this critical developmental stage, supporting both captive-based breeding efforts and in situ conservation efforts.
Topics: Humans; Female; Animals; Ursidae; Animals, Zoo; Stereotyped Behavior
PubMed: 38214214
DOI: 10.1002/zoo.21814 -
Neurotoxicology Mar 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive/stereotyped behaviors. Prenatal exposure to valproic acid...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive/stereotyped behaviors. Prenatal exposure to valproic acid (VPA) has been reported to induce ASD-like symptoms in human and rodents. However, the etiology and pathogenesis of ASD have not been well elucidated. This study aimed to explore the mechanisms underlying VPA-induced ASD-like behaviors using zebrafish model and investigated whether vitamin A could prevent VPA-induced neurotoxicity. Here, zebrafish embryos were exposed to 0, 25 and 50 μM VPA from 4 to 96 h post fertilization (hpf) and the neurotoxicity was assessed. Our results showed that VPA affected the normal development of zebrafish larvae and induced ASD-like behaviors, including reduced locomotor activity, decreased distance near conspecifics, impaired social interaction and repetitive swimming behaviors. Exposure to VPA decreased the GFP signal in transgenic HuC:egfp zebrafish according to the negative effect of VPA on the expression of neurodevelopmental genes. In addition, VPA enhanced oxidative stress by promoting the production of reactive oxygen species (ROS) and hydrogen peroxide (HO) and inhibiting the activity of superoxide dismutase, then triggered apoptosis by upregulation of apoptotic genes. These adverse outcomes were mitigated by vitamin A, suggesting that vitamin A rescued VPA-induced ASD-like symptoms by inhibiting oxidative stress and apoptosis. Overall, this study identified vitamin A as a promising strategy for future therapeutic regulator of VPA-induced ASD-like behaviors.
Topics: Pregnancy; Animals; Female; Humans; Valproic Acid; Autistic Disorder; Zebrafish; Autism Spectrum Disorder; Vitamin A; Larva; Hydrogen Peroxide; Social Behavior; Behavior, Animal; Oxidative Stress; Disease Models, Animal; Prenatal Exposure Delayed Effects
PubMed: 38191030
DOI: 10.1016/j.neuro.2023.12.015 -
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