Thyroid Hormone Accelerates the Differentiation of Adult Hippocampal Progenitors

Abstract

Disrupted thyroid hormone function evokes severe physiological consequences in the immature brain. In adulthood, although clinical reports document an effect of thyroid hormone status on mood and cognition, the molecular and cellular changes underlying these behavioural effects are poorly understood. More recently, the subtle effects of thyroid hormone on structural plasticity in the mature brain, in particular on adult hippocampal neurogenesis, have come to be appreciated. However, the specific stages of adult hippocampal progenitor development that are sensitive to thyroid hormone are not defined. Using nestin-green fluorescent protein reporter mice, we demonstrate that thyroid hormone mediates its effects on hippocampal neurogenesis by influencing Type 2b and Type 3 progenitors, although it does not alter proliferation of either the Type 1 quiescent progenitor or the Type 2a amplifying neural progenitor. Thyroid hormone increases the number of doublecortin (DCX)-positive Type 3 progenitors, and accelerates neuronal differentiation into both DCX-positive immature neurones and neuronal nuclei-positive granule cell neurones. Furthermore, we show that this increase in neuronal differentiation is accompanied by a significant induction of specific transcription factors involved in hippocampal progenitor differentiation. In vitro studies using the neurosphere assay support a direct effect of thyroid hormone on progenitor development because neurospheres treated with thyroid hormone are shifted to a more differentiated state. Taken together, our results indicate that thyroid hormone mediates its neurogenic effects via targeting Type 2b and Type 3 hippocampal progenitors, and suggests a role for proneural transcription factors in contributing to the effects of thyroid hormone on neuronal differentiation of adult hippocampal progenitors.

Thyroid Hormone Signaling and Adult Neurogenesis in Mammals

“…These niches produce newborn neurons from neural stem cells (NSC) throughout life and so, contribute to brain plasticity during learning, memory, and recovery from brain damage (9). Many extrinsic and intrinsic signaling factors regulate different stages of adult neurogenesis (10), with TH signaling being well known to control NSC homeostasis [see below and (11–16)]. Understanding the mechanisms underlying T 3 regulation of adult neurogenesis is crucial to develop treatments for neurocognitive disorders.…”

“…Recently, T 3 was demonstrated to exert critical roles in cell proliferation and NSC commitment toward neuroblasts in both the rodent SVZ and SGZ in vivo (15, 16). T 3 acts on transcription through nuclear receptors, Thyroid Hormone Receptors (TRs).…”

“…In vertebrates, different isoforms derive from the Thra (TRα2 and TRα2) and Thrb (TRβ1 and TRβ2) genes. The adult hippocampus expresses TRα1, TRβ1, and β2 isoforms (16, 34), whereas only TRα1 is expressed in the adult mouse SVZ (13, 15). …”

“…In the SGZ, TRα1 has different effects on proliferation and differentiation (16, 35). First, progenitor proliferation is unaffected by TRα1 loss (TRα1 −/− mutant) or overexpression (TRα2 −/− mutant) (35).…”

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“…114 Recent attention has focused on the permissive role of THs in regulating physiological processes in adults, including neurological plasticity, mood, cognition, and reproduction. 90,115 In fish, THs are important mediators of many physiological, developmental, and behavioral processes, including growth and metamorphic transitioning, 116,117 osmoregulation, 118 olfactory imprinting, 119 interrenal regulation, 120 otolith formation, 121 and reproduction, 90,122 often acting in concert with other hormones.…”