Title: Sensing echoes: temporal misalignment in auditory brainstem responses as the earliest marker of neurodevelopmental derailment
Abstract Neurodevelopmental disorders are on the rise worldwide, with diagnoses that detect derailment from typical milestones by 3 to 4.5 years of age. By then, the circuitry in the brain has already reached some level of maturation that inevitably takes neurodevelopment through a different course. There is a critical need then to develop analytical methods that detect problems much earlier and identify targets for treatment. We integrate data from multiple sources, including neonatal auditory brainstem responses (ABR), clinical criteria detecting autism years later in those neonates, and similar ABR information for young infants and children who also received a diagnosis of autism spectrum disorders, to produce the earliest known digital screening biomarker to flag neurodevelopmental derailment in neonates. This work also defines concrete targets for treatment and offers a new statistical approach to aid in guiding a personalized course of maturation in line with the highly nonlinear, accelerated neurodevelopmental rates of change in early infancy. more »« less
Kasdan, Anna; Gordon, Reyna L.; Lense, Miriam D.
(, Behavioral and Brain Sciences)
null
(Ed.)
Abstract Our commentary addresses how two neurodevelopmental disorders, Williams syndrome and autism spectrum disorder, provide novel insights into the credible signaling and music and social bonding hypotheses presented in the two target articles. We suggest that these neurodevelopmental disorders, characterized by atypical social communication, allow us to test hypotheses about music, social bonding, and their underlying neurobiology.
Abstract Olfaction supports a multitude of behaviors vital for social communication and interactions between conspecifics. Intact sensory processing is contingent upon proper circuit wiring. Disturbances in genetic factors controlling circuit assembly and synaptic wiring can lead to neurodevelopmental disorders, such as autism spectrum disorder (ASD), where impaired social interactions and communication are core symptoms. The variability in behavioral phenotype expression is also contingent upon the role environmental factors play in defining genetic expression. Considering the prevailing clinical diagnosis of ASD, research on therapeutic targets for autism is essential. Behavioral impairments may be identified along a range of increasingly complex social tasks. Hence, the assessment of social behavior and communication is progressing towards more ethologically relevant tasks. Garnering a more accurate understanding of social processing deficits in the sensory domain may greatly contribute to the development of therapeutic targets. With that framework, studies have found a viable link between social behaviors, circuit wiring, and altered neuronal coding related to the processing of salient social stimuli. Here, the relationship between social odor processing in rodents and humans is examined in the context of health and ASD, with special consideration for how genetic expression and neuronal connectivity may regulate behavioral phenotypes.
Abstract Prenatal brain development is particularly sensitive to chemicals that can disrupt synapse formation and cause neurodevelopmental disorders. In most cases, such chemicals increase cellular oxidative stress. For example, prenatal exposure to the anti-epileptic drug valproic acid (VPA), induces oxidative stress and synaptic alterations, promoting autism spectrum disorders (ASD) in humans and autism-like behaviors in rodents. Using VPA to model chemically induced ASD, we tested whether activation of cellular mechanisms that increase antioxidant gene expression would be sufficient to prevent VPA-induced synaptic alterations. As a master regulator of cellular defense pathways, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) promotes expression of detoxification enzymes and antioxidant gene products. To increase NRF2 activity, we used the phytochemical and potent NRF2 activator, sulforaphane (SFN). In our models of human neurodevelopment, SFN activated NRF2, increasing expression of antioxidant genes and preventing oxidative stress. SFN also enhanced expression of genes associated with synapse formation. Consistent with these gene expression profiles, SFN protected developing neural networks from VPA-induced reductions in synapse formation. Furthermore, in mouse cortical neurons, SFN rescued VPA-induced reductions in neural activity. These results demonstrate the ability of SFN to protect developing neural networks during the vulnerable period of synapse formation, while also identifying molecular signatures of SFN-mediated neuroprotection that could be relevant for combatting other environmental toxicants.
Tuberous Sclerosis (TS) is a rare genetic disorder manifesting with multiple benign tumors impacting the function of vital organs. In TS patients, dominant negative mutations in TSC1 or TSC2 increase mTORC1 activity. Increased mTORC1 activity drives tumor formation, but also severely impacts central nervous system function, resulting in infantile seizures, intractable epilepsy, and TS-associated neuropsychiatric disorders, including autism, attention deficits, intellectual disability, and mood disorders. More recently, TS has also been linked with frontotemporal dementia. In addition to TS, accumulating evidence implicates increased mTORC1 activity in the pathology of other neurodevelopmental and neurodegenerative disorders. Thus, TS provides a unique disease model to address whether developmental neural circuit abnormalities promote age-related neurodegeneration, while also providing insight into the therapeutic potential of mTORC1 inhibitors for both developing and degenerating neural circuits. In the following review, we explore the ability of both mouse and human brain organoid models to capture TS pathology, elucidate disease mechanisms, and shed light on how neurodevelopmental alterations may later contribute to age-related neurodegeneration.
Tabbaa, Manal; Knoll, Allison; Levitt, Pat
(, Neuron)
Preclinical models of neurodevelopmental disorders typically use single inbred mouse strains, which fail to capture the genetic diversity and symptom heterogeneity that is common clinically. We tested whether modeling genetic background diversity in mouse genetic reference panels would recapitulate population and individual differences in responses to a syndromic mutation in the high-confidence autism risk gene, CHD8. We measured clinically relevant phenotypes in >1,000 mice from 33 strains, including brain and body weights and cognition, activity, anxiety, and social behaviors, using 5 behavioral assays: cued fear conditioning, open field tests in dark and bright light, direct social interaction, and social dominance. Trait disruptions mimicked those seen clinically, with robust strain and sex differences. Some strains exhibited large effect-size trait disruptions, sometimes in opposite directions, and-remarkably-others expressed resilience. Therefore, systematically introducing genetic diversity into models of neurodevelopmental disorders provides a better framework for discovering individual differences in symptom etiologies.
Torres, Elizabeth B., Varkey, Hannah, Vero, Joe, London, Eric, Phan, Ha, Kittler, Phyllis, Gordon, Anne, Delgado, Rafael E., Delgado, Christine F., Simpson, Elizabeth A., and Fleming, ed., Stephen. Sensing echoes: temporal misalignment in auditory brainstem responses as the earliest marker of neurodevelopmental derailment. PNAS Nexus 2.2 Web. doi:10.1093/pnasnexus/pgac315.
Torres, Elizabeth B., Varkey, Hannah, Vero, Joe, London, Eric, Phan, Ha, Kittler, Phyllis, Gordon, Anne, Delgado, Rafael E., Delgado, Christine F., Simpson, Elizabeth A., & Fleming, ed., Stephen. Sensing echoes: temporal misalignment in auditory brainstem responses as the earliest marker of neurodevelopmental derailment. PNAS Nexus, 2 (2). https://doi.org/10.1093/pnasnexus/pgac315
Torres, Elizabeth B., Varkey, Hannah, Vero, Joe, London, Eric, Phan, Ha, Kittler, Phyllis, Gordon, Anne, Delgado, Rafael E., Delgado, Christine F., Simpson, Elizabeth A., and Fleming, ed., Stephen.
"Sensing echoes: temporal misalignment in auditory brainstem responses as the earliest marker of neurodevelopmental derailment". PNAS Nexus 2 (2). Country unknown/Code not available: Oxford University Press. https://doi.org/10.1093/pnasnexus/pgac315.https://par.nsf.gov/biblio/10396932.
@article{osti_10396932,
place = {Country unknown/Code not available},
title = {Sensing echoes: temporal misalignment in auditory brainstem responses as the earliest marker of neurodevelopmental derailment},
url = {https://par.nsf.gov/biblio/10396932},
DOI = {10.1093/pnasnexus/pgac315},
abstractNote = {Abstract Neurodevelopmental disorders are on the rise worldwide, with diagnoses that detect derailment from typical milestones by 3 to 4.5 years of age. By then, the circuitry in the brain has already reached some level of maturation that inevitably takes neurodevelopment through a different course. There is a critical need then to develop analytical methods that detect problems much earlier and identify targets for treatment. We integrate data from multiple sources, including neonatal auditory brainstem responses (ABR), clinical criteria detecting autism years later in those neonates, and similar ABR information for young infants and children who also received a diagnosis of autism spectrum disorders, to produce the earliest known digital screening biomarker to flag neurodevelopmental derailment in neonates. This work also defines concrete targets for treatment and offers a new statistical approach to aid in guiding a personalized course of maturation in line with the highly nonlinear, accelerated neurodevelopmental rates of change in early infancy.},
journal = {PNAS Nexus},
volume = {2},
number = {2},
publisher = {Oxford University Press},
author = {Torres, Elizabeth B. and Varkey, Hannah and Vero, Joe and London, Eric and Phan, Ha and Kittler, Phyllis and Gordon, Anne and Delgado, Rafael E. and Delgado, Christine F. and Simpson, Elizabeth A. and Fleming, ed., Stephen},
}
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