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Updated: Jun 27, 2026
Analysis of Gene Expression Changes in the Rat Hippocampus After Deep Brain Stimulation of the Anterior Thalamic Nucleus
Published on: March 8, 2015
A genomic analysis of subclinical hypothyroidism in hippocampus and neocortex of the developing rat brain
J E Royland1, J S Parker, M E Gilbert
1Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. royland.joyce@epa.gov
Insights
Thyroid hormone deficiency, even mild forms, significantly alters gene expression in developing rodent brains. These changes highlight the sensitivity of brain development to thyroid function, impacting crucial developmental processes.
Area of Science:
- Neuroscience
- Endocrinology
- Developmental Biology
Background:
- Maternal hypothyroidism during pregnancy and early postnatal periods can severely impact offspring neurological development.
- The effects of subclinical hypothyroidism and hypothyroxinemia on neurodevelopment are not well-established.
Purpose of the Study:
- To investigate the impact of graded levels of hypothyroidism, from subclinical to severe, on global gene expression in the developing rodent brain.
- To determine if mild thyroid perturbations affect gene expression critical for brain development.
Main Methods:
- Pregnant rats were administered varying doses of propylthiouracil (PTU) to induce hypothyroidism.
- Gene expression in the hippocampus and neocortex of pups was analyzed using specialized and genome-wide microarrays (Affymetrix Rat Neurobiology array RN_U34 and Rat 230A).
Main Results:
- Dose-dependent up- and down-regulation of gene transcripts crucial for brain development and function were observed.
- Alterations in gene expression were detected even at a PTU dose (1 ppm) causing mild hypothyroxinemia in dams and pups.
- Approximately 25 genes in each brain region showed altered expression levels with mild hypothyroidism.
Conclusions:
- Genes involved in critical developmental processes are sensitive to moderate disruptions in the thyroid axis.
- The degree of gene expression alteration correlates with the extent of thyroid hormone reduction.
- Subclinical thyroid conditions may lead to structural and functional abnormalities in the developing central nervous system, emphasizing a continuum of thyroid disease effects.
Abstract:
Hypothyroidism during pregnancy and the early postnatal period has severe neurological consequences for the developing offspring. The impact of milder degrees of perturbation of the thyroid axis as encompassed in conditions of subclinical hypothyroidism and hypothyroxinemia, however, has not been established. The present investigation examined the effects of graded levels of hypothyroidism, from subclinical to severe, on global gene expression in the developing rodent brain. Thyroid hormone insufficiency was induced by administration of propylthiouracil (PTU) to pregnant rats via drinking water from gestational day 6 until sacrifice of pups prior to weaning. In the first study a specialised microarray, the Affymetrix Rat Neurobiology array RN_U34, was used to contrast gene expression in the hippocampus of animals exposed to 0 or 10 ppm (10 mg/l) PTU, a treatment producing severe hypothyroidism. In the second study, a more complete genome array (Affymetrix Rat 230A) was used to compare gene expression in the neocortex and hippocampus of postnatal day (PN) 14 animals experiencing graded degrees of thyroid hormone insufficiency induced by delivery of 0, 1, 2 or 3 ppm PTU to the dam. Dose-dependent up- and down-regulation were observed for gene transcripts known to play critical roles in brain development and brain function. Expression levels of a subset of approximately 25 genes in each brain region were altered at a dose of PTU (1 ppm) that induced mild hypothyroxinemia in dams and pups. These data indicate that genes driving important developmental processes are sensitive to relatively modest perturbations of the thyroid axis, and that the level of gene expression is related to the degree of hormone reduction. Altered patterns of gene expression during critical windows of brain development indicate that thyroid disease must be viewed as a continuum and that conditions typically considered 'subclinical' may induce structural and functional abnormalities in the developing central nervous system.
