Repeated Prenatal Exposure to Valproic Acid Results in Auditory Brainstem Hypoplasia and Reduced Calcium Binding Protein Immunolabeling

Zimmerman, Ryan; Patel, Raina; Smith, Amanda D.; Pasos, Julio; Kulesza, Randy J.

doi:10.1016/j.neuroscience.2018.02.030

Cited by 26 publications

(45 citation statements)

References 99 publications

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“…In fact, in both human cases of ASD and VPA-exposed animals, we found significantly fewer neurons in the medial superior olive (MSO), LSO, MNTB, LNTB, and superior paraolivary nucleus (SPON; Kulesza et al, 2011 ; Lukose et al, 2015 ). However, morphology of VNTB neurons was not significantly different in our study of over 56 human subjects with ASD and in our study of VPA-exposed animals ( Kulesza and Mangunay, 2008 ; Kulesza et al, 2011 ; Lukose et al, 2015 ; Zimmerman et al, 2018 ). Specifically, we found no differences in the total number of neurons and no differences in the size or shape of VNTB neurons, even when split by cell type ( Kulesza et al, 2011 ; Lukose et al, 2015 ; Zimmerman et al, 2018 ).…”

Section: Introductioncontrasting

confidence: 70%

“…However, morphology of VNTB neurons was not significantly different in our study of over 56 human subjects with ASD and in our study of VPA-exposed animals ( Kulesza and Mangunay, 2008 ; Kulesza et al, 2011 ; Lukose et al, 2015 ; Zimmerman et al, 2018 ). Specifically, we found no differences in the total number of neurons and no differences in the size or shape of VNTB neurons, even when split by cell type ( Kulesza et al, 2011 ; Lukose et al, 2015 ; Zimmerman et al, 2018 ). These observations led us to consider that despite the drastic changes in the surrounding SOC nuclei, the VNTB is spared in ASD and animal models of this condition.…”

Section: Introductioncontrasting

confidence: 70%

“…On postnatal day (P) 21, litters were weaned and only male pups were included in the study since gender-specific effects of VPA exposure are established ( Schneider et al, 2008 ). We conducted this study under the assumption that all male pups in a given litter were equally affected by VPA exposure; our previous studies provide data consistent with this strategy ( Main and Kulesza, 2017 ; Zimmerman et al, 2018 , 2020 ; Mansour et al, 2019 , 2021 ). We additionally utilized archival collections of Giemsa-stained tissue sections (i.e., every 3rd tissue section at a thickness of 40 μm) from previous investigations as reference for morphological features of the VNTB ( Zimmerman et al, 2018 ; Mansour et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

“…We conducted this study under the assumption that all male pups in a given litter were equally affected by VPA exposure; our previous studies provide data consistent with this strategy ( Main and Kulesza, 2017 ; Zimmerman et al, 2018 , 2020 ; Mansour et al, 2019 , 2021 ). We additionally utilized archival collections of Giemsa-stained tissue sections (i.e., every 3rd tissue section at a thickness of 40 μm) from previous investigations as reference for morphological features of the VNTB ( Zimmerman et al, 2018 ; Mansour et al, 2019 ). While our previous work provides evidence for abnormal tonotopic maps and/or hyperactivation of brainstem centers in VPA-exposed animals ( Dubiel and Kulesza, 2016 ) and abnormal ascending projections to the midbrain and thalamus ( Zimmerman et al, 2020 ; Mansour et al, 2021 ), we did not perform any hearing tests or audiometric screening on the animals used in this study.…”

Section: Methodsmentioning

confidence: 99%

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The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder

Mansour

Kulesza

2021

Front. Integr. Neurosci.

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Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by repetitive behaviors, poor social skills, and difficulties with communication and hearing. The hearing deficits in ASD range from deafness to extreme sensitivity to routine environmental sounds. Previous research from our lab has shown drastic hypoplasia in the superior olivary complex (SOC) in both human cases of ASD and in an animal model of autism. However, in our study of the human SOC, we failed to find any changes in the total number of neurons in the ventral nucleus of the trapezoid body (VNTB) or any changes in cell body size or shape. Similarly, in animals prenatally exposed to the antiepileptic valproic acid (VPA), we failed to find any changes in the total number, size or shape of VNTB neurons. Based on these findings, we hypothesized that the neurotransmitter profiles, ascending and descending axonal projections of the VNTB are also preserved in these neurodevelopmental conditions. We investigated this hypothesis using a combination of immunohistochemistry and retrograde tract tracing. We found no difference between control and VPA-exposed animals in the number of VNTB neurons immunoreactive for choline acetyltransferase (ChAT). Additionally, we investigated the ascending projections from the VNTB to both the central nucleus of the inferior colliculus (CNIC) and medial geniculate (MG) and descending projections to the cochlea. Our results indicate no significant differences in the ascending and descending projections from the VNTB between control and VPA-exposed animals despite drastic changes in these projections from surrounding nuclei. These findings provide evidence that certain neuronal populations and circuits may be protected against the effects of neurodevelopmental disorders.

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Section: Introductioncontrasting

confidence: 70%

Section: Introductioncontrasting

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder

Mansour

Kulesza

2021

Front. Integr. Neurosci.

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“…For example, ASD-like behaviors and brain overgrowth in rodents were accompanied by aberrant cytoarchitecture and altered neurotransmission in the monoaminergic centers in the brainstem ( Ali and Elgoly, 2013 ; Miller et al, 2013 ; Le Belle et al, 2014 ). Further, in utero VPA exposure was found to significantly alter neuronal number ( Lukose et al, 2011 ), as well as morphology and monoaminergic innervation of the auditory brainstem in rats ( Zimmerman et al, 2018 ). Notably, similar histological abnormalities within the auditory brainstem were found in postmortem brains of individuals with ASD (see section “Postmortem Histology Data Supporting Brainstem Implication in ASD”; Bailey et al, 1998 ).…”

Section: Animal Models Of Autism In the Brainstem-based Asd Pathogenementioning

confidence: 99%

Evidence for Brainstem Contributions to Autism Spectrum Disorders

Dadalko

Travers

2018

Front. Integr. Neurosci.

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Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects one in 59 children in the United States. Although there is a mounting body of knowledge of cortical and cerebellar contributions to ASD, our knowledge about the early developing brainstem in ASD is only beginning to accumulate. Understanding how brainstem neurotransmission is implicated in ASD is important because many of this condition’s sensory and motor symptoms are consistent with brainstem pathology. Therefore, the purpose of this review was to integrate epidemiological, behavioral, histological, neuroimaging, and animal evidence of brainstem contributions to ASD. Because ASD is a neurodevelopmental condition, we examined the available data through a lens of hierarchical brain development. The review of the literature suggests that developmental alterations of the brainstem could have potential cascading effects on cortical and cerebellar formation, ultimately leading to ASD symptoms. This view is supported by human epidemiology findings and data from animal models of ASD, showing that perturbed development of the brainstem substructures, particularly during the peak formation of the brainstem’s monoaminergic centers, may relate to ASD or ASD-like behaviors. Furthermore, we review evidence from human histology, psychophysiology, and neuroimaging suggesting that brainstem development and maturation may be atypical in ASD and may be related to key ASD symptoms, such as atypical sensorimotor features and social responsiveness. From this review there emerges the need of future research to validate early detection of the brainstem-based somatosensory and psychophysiological behaviors that emerge in infancy, and to examine the brainstem across the life span, while accounting for age. In all, there is preliminary evidence for brainstem involvement in ASD, but a better understanding of the brainstem’s role would likely pave the way for earlier diagnosis and treatment of ASD.

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In utero exposure to valproic acid disrupts ascending projections to the central nucleus of the inferior colliculus from the auditory brainstem

et al. 2020

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Repeated Prenatal Exposure to Valproic Acid Results in Auditory Brainstem Hypoplasia and Reduced Calcium Binding Protein Immunolabeling

Cited by 26 publications

References 99 publications

The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder

The Untouchable Ventral Nucleus of the Trapezoid Body: Preservation of a Nucleus in an Animal Model of Autism Spectrum Disorder

Evidence for Brainstem Contributions to Autism Spectrum Disorders

In utero exposure to valproic acid disrupts ascending projections to the central nucleus of the inferior colliculus from the auditory brainstem

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