Length impairments of the axon initial segment in rodent models of attention-deficit hyperactivity disorder and autism spectrum disorder

et al. 2022

Preprint

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Genetic factors play a critical role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD), but environmental factors may also be responsible for ADHD symptoms. In this study, Lister hooded rats (LHRs), which are outbred rats that exhibit more hyperactive, inattentive, and impulsive behaviors than Wistar rats, were used as ADHD model animals. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in a large, tall cage with an enriched environment [EE]) until 9 weeks of age. EE rearing decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. LHRs reared in a large flat cage did not exhibit any apparent change in motor activity. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. The rats reared in an EE for 3 weeks from 6 weeks of age also showed an improvement in their ADHD-like behaviors. RNA sequencing revealed that the expression of immediate-early genes in the medial prefrontal cortex (mPFC) of LHRs reared in a standard cage was higher than that in the mPFC of LHRs reared in an EE. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE from childhood or adolescence improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.

Section: Discussionmentioning

confidence: 95%

Section: Effects Of the Rearing Conditions On Gene Expression In The ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rearing in an enriched environment ameliorates the ADHD-like behaviors of Lister hooded rats while suppressing neuronal activities in the medial prefrontal cortex

Utsunomiya

Mikami

et al. 2022

Preprint

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“…Recently, we reported impairments in social behaviors and increased repetitive behaviors in Zbtb16 KO mice (Usui et al, 2021). Furthermore, histological abnormalities in cortical layer thickness, axon initial segment (AIS) length of neurons, and myelination in the cortex have been reported in Zbtb16 KO mice (Usui et al, 2021(Usui et al, , 2022b. SHANK3, NLGN4, and NRXN1 are involved in synaptogenesis.…”

Section: Animal Models For Understanding Asd Pathophysiologymentioning

confidence: 96%

Genomic Strategies for Understanding the Pathophysiology of Autism Spectrum Disorder

Usui

et al. 2022

Front. Mol. Neurosci.

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Recent breakthroughs in sequencing technology and technological developments have made it easier to analyze the entire human genome than ever before. In addition to disease-specific genetic mutations and chromosomal aberrations, epigenetic alterations in individuals can also be analyzed using genomics. Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) caused by genetic and/or environmental factors. More than a thousand genes associated with ASD have been identified which are known to be involved in brain development. However, it is difficult to decode the roles of ASD-associated genes without in vitro and in vivo validations, particularly in the process of brain development. In this review, we discuss genomic strategies for understanding the pathological mechanisms underlying ASD. For this purpose, we discuss ASD-associated genes and their functions, as well as analytical strategies and their strengths and weaknesses in cellular and animal models from a basic research perspective.

“…Moreover, LHRs have been observed to exhibit an altered expression of several genes associated with ADHD [ 5 , 10 , 11 ]. Furthermore, compared with Wistar rats, which are much calmer than LHRs in terms of behaviors, LHRs have been reported to have a shortened axon initial segment (AIS), which is relevant in neuronal excitability in the medial prefrontal cortex (mPFC) [ 12 ]. Shortened AIS was also observed in the PFC of 6-hydroxydopamine-induced ADHD model mice [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Rearing in an Enriched Environment Ameliorates the ADHD-like Behaviors of Lister Hooded Rats While Suppressing Neuronal Activities in the Medial Prefrontal Cortex

Utsunomiya

Mikami

et al. 2022

Cells

Self Cite

In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.