Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism

Walker, Benjimen R.; Diefenbach, Katia S; Parikh, Tanvi

doi:10.1016/j.bbr.2006.08.008

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Following the protocol established by (Walker et al, 2007) one day prior to testing, rats were brought into the testing room and placed in the testing apparatus for a 15-min habituation period. Social interaction was measured in each animal on postnatal 25, 30, 35, 45, and 55 using a three-chambered apparatus (Habitest, Coulbourn Instruments, Whitehall, PA) in which preference for home cage territory or an unknown stimulus rat of the same sex was examined over the course of a 15-min testing session.…”

Section: Methodsmentioning

confidence: 99%

“…The total numbers of movements and nose-hole pokes and the total times of movement, non-locomotor behavior, and ambulation (total movement time - non-locomotor time/60) were measured by the TruScan software. Exploration was operationally defined as the number of nose-hole pokes per minute of ambulation during a 10-min observation period (Walker et al, 2007). This allows for the separation of spontaneous movements from motivated exploration.…”

Section: Methodsmentioning

confidence: 99%

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Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Oskvig

Elkahloun

Johnson

et al. 2012

Brain, Behavior, and Immunity

221

149

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Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother’s immune system and alter the fetal environment, with consequential effects on CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on gestational day 15. LPS significantly elevated pro-inflammatory cytokine levels in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-treated dams exhibited reduced social preference and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate the possible molecular mechanisms by which MIA affects the fetal brain. We observed dysregulation of 3,285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons, including the Distal-less (Dlx) family of transcription factors required for tangential migration from progenitor pools within the ganglionic eminences into the cerebral cortex. Our results provide a novel mechanism by which MIA induces the widespread down-regulation of critical neurodevelopmental genes, including those previously associated with autism.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Oskvig

Elkahloun

Johnson

et al. 2012

Brain, Behavior, and Immunity

221

149

View full text Add to dashboard Cite

show abstract

“…nAChR abnormalities were correlated with ASD also in the genetic level, as CHRNA7, the gene encoding the a7 nAChR subunit, was found mutated in one ASD patient (Mikhail et al, 2011) and duplicated in 13 others (Leblond et al, 2012). Furthermore, deletion of the gene Chrnb2 encoding the b2-subunit of nAChR (Granon et al, 2003), M1 type mAChR inhibition (McCool et al, 2008), and lesion of cholinergic cells (Walker et al, 2007) leads to autism-related behaviors in rodents.…”

Section: Introductionmentioning

confidence: 99%

Acetylcholine Elevation Relieves Cognitive Rigidity and Social Deficiency in a Mouse Model of Autism

Karvat

Kimchi

2013

Neuropsychopharmacol

164

136

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Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T þ tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

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“…The cholinergic basal forebrain is connected with the cerebellum 29 and the cholinergic cerebellar neurons contribute to mental functions related to cognition, behavior and emotions. In autism, there are numerous reports of volume changes in the cerebellar vermis.…”

Section: Figmentioning

confidence: 99%

Basal Forebrain Involvement in Low-Functioning Autistic Children: A Voxel-Based Morphometry Study

Riva¹,

Bulgheroni²,

Aquino³

et al. 2011

AJNR Am J Neuroradiol

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Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism

Cited by 7 publications

References 53 publications

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response

Acetylcholine Elevation Relieves Cognitive Rigidity and Social Deficiency in a Mouse Model of Autism

Basal Forebrain Involvement in Low-Functioning Autistic Children: A Voxel-Based Morphometry Study

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