Abstract:Thyroid hormones (THs) are essential for brain development, but few rodent models exist that link TH inefficiency to apical neurodevelopmental endpoints. We have previously described a structural anomaly, a heterotopia, in the brains of rats treated in utero with propylthiouracil (PTU). However, how the timing of an exposure relates to this birth defect is unknown. This study seeks to understand how various temporal treatments of the mother relates to TH insufficiency and adverse neurodevelopment of the offspr… Show more
“…In rats, propylthiouracil (PTU)‐induced hypothyroidism during gestation and perinatal development reduced cell proliferation and survival in the adult hippocampus, a well‐established neurogenic niche (see part 3, Thyroid hormones regulate NSC cell fate in the adult mammalian brain ), leading to smaller brains . Furthermore, prenatal PTU exposure led to the occurrence of heterotopias, resulting in abnormal brain function in later life . These data indicate that embryonic NSCs are sensitive to altered TH signalling from early stages onwards with potentially adverse long‐term effects in the adult brain, even if the period of TH perturbation was only transient …”
Section: Evidence For Thyroid Hormone Regulating Embryonic Nsc Physiomentioning
In the vertebrate brain, neural stem cells (NSCs) generate both neuronal and glial cells throughout life. However, their neuro-and gliogenic capacity changes as a function of the developmental context. Despite the growing body of evidence on the variety of intrinsic and extrinsic factors regulating NSC physiology, their precise cellular and molecular actions are not fully determined. Our review focuses on thyroid hormone (TH), a vital component for both development and adult brain function that regulates NSC biology at all stages. First, we review comparative data to analyse how TH modulates neuro-and gliogenesis during vertebrate brain development. Second, as the mammalian brain is the most studied, we highlight the molecular mechanisms underlying TH action in this context. Lastly, we explore how the interplay between TH signalling and cell metabolism governs both neurodevelopmental and adult neurogenesis. We conclude that, together, TH and cellular metabolism regulate optimal brain formation, maturation and function from early foetal life to adult in vertebrate species. cell fate, development, evo-devo, metabolism, mitochondria, neural stem cell, thyroid hormone This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
K E Y W O R D S
“…In rats, propylthiouracil (PTU)‐induced hypothyroidism during gestation and perinatal development reduced cell proliferation and survival in the adult hippocampus, a well‐established neurogenic niche (see part 3, Thyroid hormones regulate NSC cell fate in the adult mammalian brain ), leading to smaller brains . Furthermore, prenatal PTU exposure led to the occurrence of heterotopias, resulting in abnormal brain function in later life . These data indicate that embryonic NSCs are sensitive to altered TH signalling from early stages onwards with potentially adverse long‐term effects in the adult brain, even if the period of TH perturbation was only transient …”
Section: Evidence For Thyroid Hormone Regulating Embryonic Nsc Physiomentioning
In the vertebrate brain, neural stem cells (NSCs) generate both neuronal and glial cells throughout life. However, their neuro-and gliogenic capacity changes as a function of the developmental context. Despite the growing body of evidence on the variety of intrinsic and extrinsic factors regulating NSC physiology, their precise cellular and molecular actions are not fully determined. Our review focuses on thyroid hormone (TH), a vital component for both development and adult brain function that regulates NSC biology at all stages. First, we review comparative data to analyse how TH modulates neuro-and gliogenesis during vertebrate brain development. Second, as the mammalian brain is the most studied, we highlight the molecular mechanisms underlying TH action in this context. Lastly, we explore how the interplay between TH signalling and cell metabolism governs both neurodevelopmental and adult neurogenesis. We conclude that, together, TH and cellular metabolism regulate optimal brain formation, maturation and function from early foetal life to adult in vertebrate species. cell fate, development, evo-devo, metabolism, mitochondria, neural stem cell, thyroid hormone This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
K E Y W O R D S
“…Interestingly, this phenotype is present in offspring even when maternal thyroid stimulating hormone (TSH) is not significantly increased 13 , an intriguing observation given that TSH is the benchmark measure for estimating TH dysfunction during human pregnancy. While we currently understand that the heterotopia is ameliorated by maternal T4 infusion 12 , and that primarily prenatal TH insufficiency is required for its formation 14 , we do not know what cellular processes underlie its development.Figure 1Perinatal exposure to an anti-thyroid agent is sufficient for cortical heterotopia formation. ( a ) The heterotopia is a permanent malformation.…”
Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.
“…As such, serum concentrations of the dam and fetus at mid-gestation, rather than the postnatal assessments reported here, may be more appropriate indicators of potential contrast gain deficits in response to TH insufficiency. Expressing maternal serum T4 decrements as a function of gestational-age matched controls reveals PTU-induced decrements of 30-50% on GD10-GD15 in pregnant rats at a dose of 3 ppm PTU (Hassan et al, 2017, O'Shaughnessy et al, 2018. Together, these findings suggest that a 30% drop in maternal T4 in mid-gestation, the critical time for thalamocortical connectivity, may be sufficient to impair visual contrast encoding in the adult offspring.…”
Section: Timing and Magnitude Of Thyroid Hormone Insufficiencymentioning
Thyroid hormone (TH) is critical for many aspects of neurodevelopment and can be disrupted by a variety of environmental contaminants. Sensory systems, including audition and vision are vulnerable to TH insufficiencies, but little data are available on visual system development at less than severe levels of TH deprivation. The goal of the current experiments was to explore dose-response relations between graded levels of TH insufficiency during development and the visual function of adult offspring. Pregnant Long Evans rats received 0 or 3 ppm (Experiment 1), or 0, 1, 2, or 3 ppm (Experiment 2) of propylthiouracil (PTU), an inhibitor of thyroid hormone synthesis, in drinking water from gestation day (GD) 6 to postnatal day (PN) 21. Treatment with PTU caused dose-related reductions of serum T4, with recovery on termination of exposure, and euthyroidism by the time of visual function testing. Tests of retinal (electroretinograms; ERGs) and visual cortex (visual evoked potentials; VEPs) function were assessed in adult offspring. Dark-adapted ERG a-waves, reflecting rod photoreceptors, were increased in amplitude by PTU. Light-adapted green flicker ERGs, reflecting M-cone photoreceptors, were reduced by PTU exposure. UV-flicker ERGs, reflecting S-cones, were not altered. Pattern-elicited VEPs were significantly reduced by 2 and 3 ppm PTU across a range of stimulus contrast values. The slope of VEP amplitude-log contrast functions was reduced by PTU, suggesting impaired visual contrast gain. Visual contrast gain primarily reflects function of visual cortex, and is responsible for adjusting sensitivity of perceptual mechanisms in response to changing visual scenes. The results indicate that moderate levels of pre-and post-natal TH insufficiency led to alterations in visual function of adult rats, including both retinal and visual cortex sites of dysfunction.
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