Perspectives on thyroid hormone action in adult neurogenesis.

JOURNAL OF NEUROCHEMISTRY

| 2015 | 133 | 599–616

doi: 10.1111/jnc.13093

Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India

Abstract Thyroid hormone exhibits profound effects on neural progenitor turnover, survival, maturation, and differentiation during perinatal development. Studies over the past decade have revealed that thyroid hormone continues to retain an important influence on progenitors within the neurogenic niches of the adult mammalian brain. The focus of the current review is to critically examine and summarize the current state of understanding of the role of thyroid hormone in regulating adult neurogenesis within the major neurogenic niches of the subgranular zone in the hippocampus and the subventricular zone lining the lateral ventricles. We review in depth the studies that highlight a role for thyroid hormone, in particular the TRa1 receptor isoform, in regulating progenitor survival and commitment to a neuronal fate. We also discuss putative models for the mechanism of action of thyroid hormone/TRa1

on specific stages of subgranular zone and subventricular zone progenitor development, and highlight potential thyroid hormone responsive target genes that may contribute to the neurogenic effects of thyroid hormone. The effects of thyroid hormone on adult neurogenesis are discussed in the context of a potential role of these effects in the cognitive- and moodrelated consequences of thyroid hormone dysfunction. Finally, we detail hitherto unexplored aspects of the effects of thyroid hormone on adult neurogenesis that provide impetus for future studies to gain a deeper mechanistic insight into the neurogenic effects of thyroid hormone. Keywords: hippocampus, neural stem cell, progenitor, subgranular zone, subventricular zone, thyroid hormone receptor. J. Neurochem. (2015) 133, 599–616.

Thyroid hormone exerts pleiotropic effects during organismal development and in adulthood. Thyroid hormone action targets diverse cellular processes such as progenitor turnover, cell survival and differentiation, cellular homeostasis, and metabolic regulation within multiple tissue types and organs (Yen 2001; Brent 2012; Pascual and Aranda 2013; Sirakov et al. 2013). The brain is highly sensitive to thyroid hormone action and extensive literature has addressed the critical influence of thyroid hormone during neurodevelopment (Koibuchi and Chin 2000; Bernal 2007; Horn and Heuer 2010; Grimaldi et al. 2013; Preau et al. 2014). Perturbations of thyroid hormone status during embryonic and early postnatal development are associated with severe neurological consequences (Dugbartey 1998; Zoeller and Crofton 2005; de Escobar et al. 2007; Williams 2008). In contrast, the adult brain was traditionally perceived to successfully buffer fluctuations in thyroid hormone levels, in part because of the relatively subtle structural and functional changes evoked in the adult brain by altered thyroid hormone function (Calza et al. 1997; Sarkar 2002; Koromilas et al. 2010). This led to the prevalent notion that the critical period

for thyroid hormone action was predominantly restricted to embryonic and postnatal neurodevelopment (Bernal and Nunez 1995; Zoeller and Rovet 2004; Gilbert and Sui 2006; Axelstad et al. 2008). This view has been modified based on reports that highlight the effects of thyroid hormone on the mature brain (Schroeder and Privalsky 2014), with several studies (Mackay-Sim and Beard 1987; Fernandez et al. 2004; Ambrogini et al. 2005; Desouza et al. 2005, 2011; Lemkine et al. 2005; Montero-Pedrazuela et al. 2006; Zhang et al. 2009; Kapoor et al. 2010, 2011, 2012; Lopez-Juarez

Received November 13, 2014; revised manuscript received February 18, 2015; accepted February 24, 2015. Address correspondence and reprint requests to Vidita A. Vaidya, Department of Biological Sciences, Tata Institute of Fundamental Research, Homi Bhabha Road, Mumbai 400005, India. E-mail: [email protected] Abbreviations used: DCX, doublecortin; DG, dentate gyrus; GFAP, glial fibrillary acidic protein; PSA-NCAM, polysialylated neural cell adhesion molecule; QNP, quiescent neural progenitor; RMS, rostral migratory stream; RXRs, retinoid-X-receptors; SGZ, subgranular zone; SVZ, subventricular zone.

© 2015 International Society for Neurochemistry, J. Neurochem. (2015) 133, 599--616

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et al. 2012; Shiraki et al. 2012; Preau et al. 2014; Remaud et al. 2014) indicating that thyroid hormone retains a powerful influence on ongoing new neuron generation within adult neurogenic niches. Furthermore, behavioral changes in cognitive performance and mood have been strongly associated with adult-onset disruption of thyroid hormone status (Bauer et al. 2008; Fernandez-Lamo et al. 2009; Cooke et al. 2014; Willoughby et al. 2014). Given the link between adult neurogenesis and the regulation of learning, memory, and mood (Zhao et al. 2008; Ming and Song 2011; Eisch and Petrik 2012; Miller and Hen 2014), this has raised important questions about whether the cognitive and emotional consequences of thyroid hormone dysfunction in adulthood involve a role for the neurogenic effects of thyroid hormone. The focus of the present review was to summarize and critically discuss the current status of literature addressing the effects of thyroid hormone on adult neurogenesis, and to highlight potential leads for future research.

Thyroid hormone action in the adult brain Thyroid hormone action within the mature mammalian brain is regulated at several levels encompassing thyroid hormone transport, local ligand availability through modulation via deiodinases, non-genomic, and genomic actions of thyroid hormone, cell-specific thyroid hormone receptor (TR) expression levels, crosstalk of liganded/unliganded TRs with coactivators and corepressors at thyroid hormone response elements (TREs), and the interaction of TRs with other signaling pathways (Bianco and Kim 2006; Bianco 2011; Bernal and Morte 2013; Schroeder and Privalsky 2014). Thyroid hormone synthesis by follicular cells of the thyroid gland is activated by the hypothalamic–pituitary– thyroid axis. Thyrotropin releasing hormone from the hypothalamus drives the secretion of thyroid-stimulating hormone (TSH) from the pituitary, and evokes TSH-mediated thyroid hormone synthesis and secretion from the thyroid gland (Chiamolera and Wondisford 2009; Schroeder and Privalsky 2014) (Fig. 1). Thyroid hormone is released into blood, largely as the precursor thyroxine (3,30 ,5,50 tetraiodothyronine; T4), as well as lower amounts of the active form of thyroid hormone (3,30 ,5-triiodothyronine; T3), and is transported in plasma bound to carriers such as thyroxine-binding globulin, albumin, and transthyretin (TTR) (Palha 2002; Williams 2008). Active transport of thyroid hormone into the brain is mediated by the transporters monocarboxylate transporter-8 (MCT8) and organic anion transporter proteins, as well as TTR in the choroid plexus (Palha et al. 2000; Tohyama et al. 2004; Heuer et al. 2005; Jansen et al. 2005; Schweizer and Kohrle 2013; Wirth et al. 2014). Local thyroid hormone levels within the brain are under the dynamic regulation of the selenoenzymes, iodothyronine deiodinases types I, II, and III (D1, D2, and D3), thus changing the amount of active thyroid hormone

available within the brain milieu (Bianco and Kim 2006; Bianco 2011). The balance between D2, which converts T4 to the active T3 form of thyroid hormone and D3, which inactivates T3 and T4 by conversion to 3,30 -diiodothyronine (T2) and 3,30 ,50 -triiodothyronine (rT3), respectively, plays a crucial role in regulating local thyroid hormone bioavailability within the brain (Bernal 2007; St Germain et al. 2009; Hernandez et al. 2012; Arrojo e Drigo et al. 2013; Dentice et al. 2013). D2 activity within astrocytes results in local release of T3 into the brain milieu, which is then taken up by neighboring neurons through the MCT8 transporter (Morte and Bernal 2014). Thyroid hormone action at the genomic level is mediated via TRs which function as ligand-modulated transcription factors that activate or repress target gene expression (Harvey and Williams 2002; Laurberg 2009; Cheng et al. 2010). TR alpha and beta genes generate several distinct TR isoforms, amongst which TRa1, TRa2, TRb1, and TRb2 are expressed within the mammalian brain (Mellstrom et al. 1991; Bradley et al. 1992; Forrest and Vennstrom 2000). Both TRa1 and TRa2 are widely expressed in the adult brain (Cook and Koenig 1990; Wallis et al. 2010). TRa2, however, does not bind thyroid hormone and is suggested to play a dominantnegative role at TREs within promoter regions of thyroid hormone target genes (Koenig et al. 1989; Guissouma et al. 2014). TRb isoforms exhibit increasing expression levels across postnatal development, with TRb1 showing a more ubiquitous expression pattern in the brain (Murata 1998; Forrest and Vennstrom 2000; Zhang and Lazar 2000), relative to the restricted expression within the hypothalamus and pituitary for the TRb2 receptor isoform (Cook et al. 1992; Lechan et al. 1994; Abel et al. 2001). Transcriptional regulation of TRE-containing thyroid hormone target genes is observed both in the presence of ligand-bound TR isoforms, as well as in response to the unliganded aporeceptors (Zhang and Lazar 2000; Chassande 2003; Bernal and Morte 2013). TR aporeceptors are suggested to predominantly repress thyroid hormone target genes by recruiting corepressors, which exhibit histone deacetylase activity (Hu and Lazar 2000; Jepsen and Rosenfeld 2002; Privalsky 2004; Astapova and Hollenberg 2013). The transcription of target genes is thought to shift toward transcriptional activation following ligand-binding of T3 to the aporeceptor, accompanied by recruitment of coactivators that mediate histone acetylation and facilitate recruitment of RNA Polymerase II and transcription initiation machinery (Harvey and Williams 2002; Cheng et al. 2010; Liu and Brent 2010). Beyond the classical genomic mode of action, non-genomic actions are mediated by membrane receptors for thyroid hormone, with evidence supporting a binding site for T3 within integrin aVb3, a putative membrane receptor for rapid actions of thyroid hormone (Davis et al. 2009). The non-genomic effects of thyroid hormone include, but are not restricted to changes in a5/b3 integrin-mediated signaling (Bergh et al.


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Fig. 1 Thyroid hormone action in the adult rodent brain. (a) The schematic illustrates the hypothalamic–pituitary–thyroid (HPT) axis regulation of thyroid hormone. Thyrotropin releasing hormone (TRH) secreted by the hypothalamus in turn regulates thyroid-stimulating hormone (TSH) from the pituitary, and evokes TSH-mediated thyroid hormone synthesis and secretion from the thyroid gland. Thyroxine (T4) and the active form of the thyroid hormone, tri-iodothyronine (T3) are released into circulation and exert a feedback regulation of the HPT axis besides their effects on diverse target organs including the brain. The transfer of T4 and T3 across the blood–brain barrier (BBB) is mediated by thyroid hormone transporters monocarboxylate 8 (MCT8) and organic anion transporter protein 1 (OATP1). Deiodinase 2 (D2) activity in astrocytes converts T4 to the active T3 form, which influences local thyroid hormone bioavailability within the brain.

Neuronal uptake of T3 is mediated by MCT8. Deiodinase 3 (D3) within the neuronal cell body converts T3 and T4 to inactive T2 and reverse T3 (rT3), respectively. (b) Shown are molecular mechanisms for the genomic actions of thyroid hormone. Thyroid hormone receptors (TRs) heterodimerize with the retinoid-X-receptor (RXR) and recruit either corepressors or coactivators to regulate gene transcription. The unliganded TR is predominantly thought to repress gene transcription through the recruitment of corepressors and the deacetylation of histones at promoters of thyroid hormone target genes that contain thyroid hormone response elements (TREs). The liganded TR is thought to complex with coactivators and enhances gene transcription through increased histone acetylation at TRE-containing thyroid hormone target gene promoters.

2005; Davis et al. 2008) as well as PI3-kinase (Furuya et al. 2009), MAPK (Davis et al. 2000; Alisi et al. 2004; D’Arezzo et al. 2004) and mTOR-p70S6K (Cao et al. 2005) signaling pathways, alterations of Na+/H+ antiporter activity (Incerpi et al. 1999), and effects on actin polymerization (Leonard and Farwell 1997; Silva et al. 2006). Thyroid hormone action in the adult brain is thus influenced by several factors including the modulation of local thyroid hormone concentration through regulation of thyroid metabolism or uptake within the brain, the nature of TR isoforms present in specific cell types, the combinatorial action of TRs along with coactivators and corepressor complexes, as well as ligand-dependent and aporeceptor-mediated effects on TR target gene expression (Fig. 1).

stages, each characterized by the expression of stage-specific markers, migration of the neuroblasts to their site of integration, and functional recruitment into existing neurocircuitry (Ming and Song 2005, 2011). At each of these stages of neurogenesis, progenitor development is regulated by both cell-intrinsic and niche-mediated factors. Adult neurogenesis is highly sensitive to the hormonal, neurotransmitter, and growth factor milieu within the neurogenic niche (Vaidya et al. 2007; Galea et al. 2013; Perez-Domper et al. 2013) as well as the external environment experienced by the animal (Zhao et al. 2008; Lieberwirth and Wang 2012). The primary neurogenic niches in the adult mammalian brain include the subgranular zone (SGZ) in the dentate gyrus (DG) subfield of the hippocampus and the subventricular zone (SVZ) lining the lateral ventricles (Ming and Song 2011; Vadodaria and Gage 2014). Several studies over the last decade have reported a powerful effect of thyroid hormone on progenitor development within both of these neurogenic niches, with overlapping as well as distinctive

Adult neurogenesis The process of adult neurogenesis involves the proliferation of progenitors, survival, and maturation through specific


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actions of thyroid hormone on SGZ and SVZ progenitors (Ambrogini et al. 2005; Desouza et al. 2005, 2011; Lemkine et al. 2005; Montero-Pedrazuela et al. 2006; Kapoor et al. 2010, 2011, 2012; Preau et al. 2014; Remaud et al. 2014). These studies have used perturbations of thyroid hormone status, analysis of TR isoform-specific mutants, as well as an evaluation of direct effects of thyroid hormone on progenitors in vitro to gain a mechanistic understanding of the role of thyroid hormone in adult neurogenesis. While progress has been made in understanding the stage-specific effects of thyroid hormone on adult neurogenesis, the underlying molecular mechanisms and specific thyroid hormone target genes within progenitors and neighboring cells within the neurogenic milieu are yet to be clearly delineated. Furthermore, the implications of neurogenic changes evoked by thyroid hormone in contributing to the behavioral and cognitive consequences of perturbed thyroid status (Fernandez-Lamo et al. 2009; Berent et al. 2014; Willoughby et al. 2014) remain to be fully understood. In this review, we summarize the current understanding of the effects of thyroid hormone on adult neurogenesis in both the SGZ and SVZ neurogenic niches, comparing and contrasting the nature of these effects as well as highlighting open questions for future research. We restrict our review to the neurogenic effects of thyroid hormone as several previous reviews have highlighted the critical influence of thyroid hormone on astrocytes and oligodendrocytes, including effects on glial progenitor turnover, survival, and maturation, as well as on myelination (Rodriguez-Pena 1999; Calza et al. 2005, 2010; Mohacsik et al. 2011; Morte and Bernal 2014).

Thyroid hormone regulation of adult hippocampal neurogenesis Stages of hippocampal progenitor development Hippocampal progenitors within the SGZ of the DG subfield predominantly give rise to neuroblasts, that differentiate into granule cell neurons which undergo maturation while migrating short distances into the granule cell layer of the DG and functionally integrate into the hippocampal network (Ming and Song 2011). While estimates suggest that about 9000 progenitor cells are born daily within the SGZ neurogenic niche of rodents, only about half of these survive beyond 2–3 weeks. Among the surviving pool of progenitors approximately 85% migrate into the granule cell layer (GCL) to form granule cell neurons, with the remaining pool of surviving progenitors thought to acquire an astrocytic identity (Cameron and McKay 2001; Ming and Song 2005). Hippocampal progenitor development is characterized by stage-specific marker expression (Kempermann et al. 2004; Vadodaria and Gage 2014) (Fig. 2). The putative stem cell/ quiescent neural progenitor (QNP), also referred to as the Type 1 cell, is a radial glial-like cell that expresses glial fibrillary acidic protein (GFAP), the intermediate filament

protein nestin, as well as the transcription factor and stem cell marker Sox2 (Kempermann et al. 2004; Ming and Song 2011). QNPs are slowly dividing cells that undergo asymmetric divisions to generate the transiently amplifying neural progenitors/Type 2a cells that are immunopositive for nestin, but no longer express GFAP or Sox2. Amplifying neural progenitors divide relatively rapidly to generate the Type 2b cells, which are neuroblasts expressing Nestin as well as the microtubule-associated protein doublecortin (DCX). Type 2b cells have been reported to retain the ability to undergo limited cell division (Kempermann et al. 2004; Ming and Song 2011). At this stage neuroblasts also express the proneurogenic basic helix-loop-helix transcription factor NeuroD that is involved in neuronal cell fate acquisition. The Type 2b cells migrate into the GCL, and form DCX-positive Type 3 cells that lose their immunopositivity for nestin. In addition to DCX, Type 3 cells express polysialylated neural cell adhesion molecule (PSA-NCAM), as well as markers such as Stathmin and TUC-4 (Kempermann et al. 2004; Zhao et al. 2008; Ming and Song 2011). DCX-positive immature neurons transiently express calretinin as they undergo morphological maturation to form mature granule cell neurons that are immunopositive for Tuj1 (beta III tubulin), Neuronal nuclei (NeuN) and calbindin (Brandt et al. 2003). The process of maturation of a hippocampal progenitor into a mature granule cell neuron that is functionally integrated into DG neurocircuitry can take up to 4–6 weeks (Ming and Song 2011). Thyroid hormone status and adult hippocampal neurogenesis The first reports of the effects of thyroid hormone on the hippocampal neurogenic niche came from studies of perturbed thyroid hormone status in rat models, with hypothyroidism evoked by thyroidectomy/goitrogen treatment (Ambrogini et al. 2005; Desouza et al. 2005; MonteroPedrazuela et al. 2006) or via thyroid hormone administration to generate hyperthyroidism (Desouza et al. 2005). Goitrogen-induced adult-onset hypothyroidism in rats selectively decreased progenitor survival and neuronal differentiation, with no change observed in hippocampal progenitor cell division (Desouza et al. 2005). The decline in progenitor survival and neuronal differentiation was restored by the reestablishment of euthyroid status. The decrease in progenitor survival was accompanied by an increase in the number of apoptotic cells in the hippocampal neurogenic niche of adult hypothyroid rats. This decline in progenitor survival was also reflected by a reduction in DCX, PSA-NCAM, and NeuroDimmunopositive cell numbers within the hippocampal neurogenic niche. In contrast, hyperthyroidism in adult rats did not evoke any change in hippocampal progenitor proliferation, survival, or differentiation (Desouza et al. 2005). Ambrogini et al. (2005) demonstrated that goitrogeninduced hypothyroidism in adult rats evoked decreased



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Fig. 2 Thyroid hormone regulation of adult hippocampal neurogenesis. Shown is a (a) sagittal and (b, upper panel) coronal section of the rodent brain illustrating the location of hippocampal progenitors within the subgranular zone (SGZ) of the dentate gyrus (DG) subfield (b, lower panel), within the adult hippocampus. (c) Adult SGZ progenitors progress through specific developmental milestones on their progression to form mature granule cell neurons. The stages of progenitor development commence from the QNP/Type 1 cell that divides asymmetrically to self-renew and produce transit amplifying progenitors/Type 2a cells. Type 2b cells, are neuroblasts that express both Nestin and the microtubule-associated protein doublecortin (DCX), as well as the proneural gene, NeuroD. Type 2b cells migrate into the GCL, and form DCX-positive Type 3 cells that lose their immunopositivity for nestin, but coexpress polysialylated neural cell adhesion

molecule (PSA-NCAM), as well as Stathmin and TUC-4. DCX-positive immature granule cell (GC) neurons transiently express calretinin as they mature to form Tuj1, NeuN, and calbindin-positive mature GC neurons. The putative thyroid hormone sensitive window (blue box, c) is thought to encompass the Type 2b and Type 3 cells. (d) Shown is the putative model for the neurogenic effects of thyroid hormone and the TRa1 receptor isoform. In the presence of T3, TRa1 holoreceptors enhance gene transcription enhancing proneural gene expression and promoting cell survival. Potential thyroid hormone responsive target genes include the proneural genes NeuroD, Ngn1, Ngn2, Math1, Tlx, Tis21, Dlx2, and Klf9. In contrast, TRa1 aporeceptors repress gene transcription and reduce proneural gene expression as well as resulting in decreased cell survival.

progenitor survival and a delay in neuronal differentiation. This study reported a prolonged expression of TUC-4, an immature neuronal marker, accompanied by decreased morphological maturation of newborn neurons, with no effects noted on hippocampal progenitor cell turnover. In contrast, thyroidectomy in adult rats resulted in decreased hippocampal progenitor proliferation (Montero-Pedrazuela et al. 2006), accompanied by a decline in DCX-positive immature neurons with reduced dendritic complexity. This was correlated with a depressive phenotype as evidenced by increased immobility in the forced swim test in hypothyroid rats, whereas cognitive performance in the novel object

recognition test was unaffected (Montero-Pedrazuela et al. 2006). While all the above studies draw the same conclusion of a decline in hippocampal neurogenesis following adult-onset hypothyroidism, they differ in the interpretation of specific progenitor stages influenced by perturbed thyroid hormone status. While one report indicates effects of adult-onset hypothyroidism on hippocampal progenitor turnover (Montero-Pedrazuela et al. 2006), the other two studies (Ambrogini et al. 2005; Desouza et al. 2005) demonstrate the targeting of post-mitotic stages of progenitor survival and neuronal differentiation. It is important to resolve the discrepancies


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that may have arisen owing to the different methods used to generate hypothyroid status, and the treatment regimes employed with the mitotic marker bromodeoxyuridine to assess effects on neurogenesis. Bromodeoxyuridine treatment paradigms based on the time-point of sacrifice can capture multiple stages of progenitor development, yielding results in which it is difficult to distinguish effects on proliferation versus short-term survival (Taupin 2007). Transgenic mouse models have made it possible to study the stage-specific effects of thyroid hormone on adult hippocampal progenitor development. Studies in transgenic NestinGreen Fluorescent Protein (GFP) reporter mice (Yu et al. 2005) have aided analysis of the effects of perturbed thyroid hormone status on Type 1, 2a, and 2b hippocampal progenitors that can be distinguished using triple immunofluorescence approaches along with Nestin-GFP reporter expression. Adult-onset hypothyroidism did not alter the total pool of Nestin-GFP-positive progenitors, which encompasses the proliferative stages (Type1, 2a, and 2b) of hippocampal progenitor development (Kapoor et al. 2012). However, hypothyroid mice showed a robust decline in the number of DCX- and NeuroD-positive progenitors indicating reduced post-mitotic survival of hippocampal progenitors. While the total pool of Nestin-GFP cells was unchanged in the hippocampal neurogenic niche, triple immunofluorescence for Nestin-GFP, GFAP, and DCX revealed a significant decline in the percentage of predominantly post-mitotic Type 2b (GFP+ DCX+) neuroblasts within the total pool of NestinGFP-positive hippocampal progenitors. These findings indicate that adult-onset hypothyroidism targets Type 2b and Type 3 hippocampal progenitors, suggesting that post-mitotic stages of hippocampal progenitor development may be the most sensitive to perturbed thyroid hormone status (Kapoor et al. 2012). Intriguingly, while adult-onset hyperthyroidism had no effect on adult hippocampal neurogenesis in rat models (Desouza et al. 2005), studies in hyperthyroid mice revealed significant increases in the number of DCX and NeuroDpositive hippocampal progenitors (Kapoor et al. 2012). Studies with transgenic Nestin-GFP reporter mice revealed accelerated hippocampal progenitor maturation, with increases noted in DCX-positive Type 3 immature neurons in hyperthyroid mice, and a hastening of mature neuronal marker acquisition in hippocampal progenitors. The differences noted in the effects of adult-onset hyperthyroidism on hippocampal progenitor development suggest potential species-specific distinctions in the degree of saturation of TRs under euthyroid conditions in mice versus rats.

In vitro effects of thyroid hormone on hippocampal progenitors The in vivo studies in rat and mouse models do not clarify whether the effects of thyroid hormone are directly mediated on adult hippocampal progenitors or are effects evoked via

modulation of the neurogenic niche. Given the powerful effects of thyroid hormone on astrocytes (Martinez and Gomes 2002; Mohacsik et al. 2011; Dezonne et al. 2013; Morte and Bernal 2014), and the role of astrocytes within neurogenic niches (Seri et al. 2001; Ma et al. 2005; Ashton et al. 2012) in providing key extrinsic cues for hippocampal progenitor development, defining the direct versus indirect effects of thyroid hormone on progenitor development is critical to gain an understanding of underlying molecular mechanisms. Thus far, specific in vitro evidence suggests that thyroid hormone does exert direct effects on hippocampal progenitor development (Desouza et al. 2005; Kapoor et al. 2012). Adult hippocampal progenitors maintained in vitro as dispersed progenitor cultures or as neurospheres have been shown to express multiple TR isoforms. However, thus far it remains unclear whether thyroid hormone transporters or deiodinases are expressed by hippocampal progenitors and the stoichiometry of TR isoforms as progenitors proceed through their developmental progression is also unknown. Studies with dispersed adult hippocampal progenitor cultures indicate effects on proliferation, survival, and glial differentiation following thyroid hormone treatment (Desouza et al. 2005). In vitro evidence from neurosphere assays indicates no change in neurosphere number but a shift in pattern from large-sized neurospheres to predominantly smaller neurospheres (Kapoor et al. 2012). This reduction in size is suggestive of a shift from proliferation toward a differentiated state, which is confirmed by increased Tuj-1positive neurons in thyroid hormone treated neurospheres. While these in vitro results (Desouza et al. 2005; Kapoor et al. 2012) do not recapitulate in entirety the nature of effects observed in vivo in response to thyroid hormone administration (Ambrogini et al. 2005; Desouza et al. 2005; MonteroPedrazuela et al. 2006), they do exhibit a component of overlap. Given this, one cannot preclude the possibility that the in vivo effects of thyroid hormone on adult hippocampal neurogenesis involve both direct effects on progenitors, as well as indirect influences mediated via the neurogenic niche. Astrocytes serve as a local source of thyroid hormone through the conversion of T4 to T3 via astrocytic D2 activity (Mohacsik et al. 2011; Morte and Bernal 2014), and the role of astrocytes in the effects of thyroid hormone on adult neurogenesis are relatively unexplored. Astrocytes in vitro have been reported to express TR receptor isoforms (Carlson et al. 1996), whereas in vivo studies fail to provide immunohistochemical evidence of TR isoform expression in GFAP-positive cells (Carlson et al. 1994). More recent studies indicate TRa1 expression in astrocytes and support a role for TRa1 in astrocyte maturation (Trentin et al. 1995; Lima et al. 1997; Gomes et al. 1999; Martinez and Gomes 2002, 2005; Morte et al. 2004; Manzano et al. 2007). It is interesting to note that astrocytes from distinct regions of the brain respond differently to thyroid hormone treatment, both morphologically and in protein expression (Lima et al. 1997,



1998). Recent reviews have extensively dealt with astrocyteneuronal communication in the context of modulation of local thyroid hormone signaling (Mohacsik et al. 2011; Morte and Bernal 2014). Future studies are required to assess the effects of thyroid hormone on astrocytes within the hippocampal neurogenic niche, to assess whether astrocytes within close proximity of hippocampal progenitors serve as sources of local thyroid hormone to neural stem cells via D2mediated regulation of local T3 bioavailability, and through thyroid hormone-mediated modulation of the release of astrocytic factors that influence hippocampal progenitor development. Thyroid hormone receptors and adult hippocampal neurogenesis Mounting evidence suggests that the neurogenic effects of thyroid hormone in the hippocampus are predominantly on post-mitotic neuronally committed Type 2b and Type 3 progenitors, and this period of adult hippocampal progenitor development represents a critical window of thyroid hormone sensitivity (Kapoor et al. 2012). This notion is in keeping with the effects of thyroid hormone previously reported on other progenitors (for example: oligodendrocytic progenitors, embryonic stem cells, and myogenic progenitors), namely to serve as a timing switch for the initiation of cellular differentiation (Baas et al. 1997; Billon et al. 2001, 2002; Daury et al. 2001; Fernandez et al. 2004; Chen et al. 2012; Pascual and Aranda 2013). The molecular mechanisms that mediate the effects of thyroid hormone on adult hippocampal progenitors as yet remain largely uncharacterized. While a couple of studies have reported the role of specific TR isoforms in the regulation of adult hippocampal neurogenesis (Kapoor et al. 2010, 2011), these studies have been performed capitalizing on currently available wholebody TR knockout mouse lines without the advantage of temporal and spatial control that would be provided by conditional knockout mouse lines. The role of TRa1, the predominant TR isoform that constitutes about 70% of TR isoform expression in the mammalian brain (Schwartz et al. 1992; Wallis et al. 2010), has been studied in the regulation of adult hippocampal neurogenesis using four different mutant mouse lines, namely TRa1/, TRa2/ mice which exhibit TRa1 over-expression, TRa1+/m heterozygous mice carrying a point mutation (TRa1R384C) that lowers thyroid hormone affinity 10-fold, as well as a TRa1-GFP knock-in mouse line (Wikstrom et al. 1998; Salto et al. 2001; Tinnikov et al. 2002; Kapoor et al. 2010; Wallis et al. 2010). TRa1/ mice exhibited an increase in post-mitotic survival of hippocampal progenitors, whereas mice with an unliganded TRa1 aporeceptor, either through over-expression of TRa1 as observed in the TRa2/ mice or in the dominantnegative TRa1+/m mouse line with reduced ligand affinity, showed a significant decline in hippocampal progenitor

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survival and neuronal differentiation (Kapoor et al. 2010). These effects are reminiscent of the decreased hippocampal progenitor survival and neuronal differentiation observed in adult-onset hypothyroidism (Ambrogini et al. 2005; Desouza et al. 2005; Montero-Pedrazuela et al. 2006), and the effects in the TRa2/ and TRa1+/m mouse lines were rescued by liganding the mutant TRa1 aporeceptor through exogenous thyroid hormone administration (Kapoor et al. 2010). Unliganded TRa1 could be a crucial contributing factor to the detrimental effects of adult-onset hypothyroidism on hippocampal neurogenesis, and has been speculated to thus contribute to the cognitive and emotional dysfunction observed with hypothyroidism. Examination of GFP reporter expression in TRa1-GFP knockin mouse models (Wallis et al. 2010) illustrates that TRa1 is primarily expressed by post-mitotic hippocampal progenitors committed to the acquisition of a neuronal fate, and does not seem to be expressed by proliferating progenitors (Kapoor et al. 2010). This differs from in vitro studies wherein TRa1 gene expression is noted in proliferative cells within neurosphere cultures as well as dispersed hippocampal progenitors (Kapoor et al. 2012). It will be very interesting to ascertain the expression pattern of TR isoforms at the distinct stages of hippocampal progenitor development and to examine whether shifts in the stoichiometry of TR isoform expression are noted as progenitors undergo developmental progression. Our results suggest the speculative possibility that TRa1 aporeceptor activity arrests hippocampal progenitors at the early post-mitotic stage prior to the acquisition of NeuroD-positive identity and the commitment to a neuronal fate, with enhanced targeting toward cell death in the absence of the ligand thyroid hormone. Thyroid hormone may then serve as a switch to facilitate progression toward neuronal differentiation. Enhanced TRa1 expression in post-mitotic hippocampal progenitors along with the binding of the ligand thyroid hormone may serve as a timer switch to initiate neuronal differentiation, in keeping with such functions demonstrated for TR isoforms in oligodendrocytic progenitor development (Gao et al. 1998; Billon et al. 2002; Fernandez et al. 2004). In addition to a role for TRa1 in adult hippocampal neurogenesis, TRb isoforms have been shown to regulate adult hippocampal progenitor turnover (Kapoor et al. 2011). Both TRb1 and TRb2 isoforms are expressed in the hippocampal neurogenic niche (Desouza et al. 2005; Kapoor et al. 2012). TRb/ mice exhibit increased hippocampal progenitor proliferation as well as enhanced NeuroD-positive cell number, but no commensurate increase in DCX-positive immature neurons. TRb isoforms may exert an inhibitory effect on SGZ progenitor turnover, either as a consequence of the loss of T3-mediated inhibitory effects via TRb or through the absence of unliganded TRb evoked repression of cell division. However, previous evidence of an adult hypothyroidism evoked decline in progenitor turnover reported by


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Montero-Pedrazuela et al. (2006) which can be rescued by thyroid hormone replacement, supports the notion that enhanced proliferation in TRb/ mice is likely through the loss of TRb aporeceptor-mediated repressive control of progenitor turnover. TRb isoforms are reported to attenuate the mitogenic effects of growth factors such as epidermal growth factor and insulin-like growth factor 1 (IGF-1) in tumor cell lines (Martinez-Iglesias et al. 2009). One can speculate that the loss of TRb could also alter growth factor driven proliferation of hippocampal progenitors. However, it is also important to note that TRb/ mice exhibit elevated circulating levels of thyroid hormone (Forrest et al. 1996) and the effects noted within the neurogenic niche of TRb/ mice may involve a role for the intact TR isoforms, for example, TRa1 and the presence of enhanced circulating levels of thyroid hormone. While currently available TR mutant mice have provided a degree of insight into the nature of TR-mediated effects on adult hippocampal neurogenesis, TR mutant mice come with the caveat of a whole-body loss of function resulting in potential alterations of circulating T3, T4, and TSH levels, as well as the possibility of specific effects during embryonic and postnatal neurodevelopment that may hamper interpretation of effects on adult neurogenesis (O’Shea and Williams 2002; Flamant and Gauthier 2013). Insights from other mutant mouse lines that perturb deiodinase expression as well as disruption of thyroid hormone transporters (Darras et al. 2013) would also further aid in providing a complete understanding of the effects of thyroid hormone on adult hippocampal neurogenesis. However, the key experiments that are required to gain deeper mechanistic insight necessitate the generation of conditional TR isoform knockout mice that exhibit selective perturbation of specific TR isoform expression, as well as double mutants that perturb TR stoichiometric balance, at specific stages of hippocampal progenitor development. These studies are required to critically analyze the currently prevalent hypothesis that Type 2b and Type 3 adult hippocampal progenitors are the key stages of hippocampal progenitor development that exhibit thyroid hormone sensitivity, with an emerging role for thyroid hormone as an important regulator of post-mitotic progenitor survival and neuronal cell fate specification. To further gain insights on the effects of thyroid hormone in the neurogenic niche, studies are also required in TR mutant mice that permit a temporal and spatial regulation of TR isoforms within specific components of the hippocampal neurogenic niche, such as the mature granule cell neurons, astrocytes, and vasculature.

Thyroid hormone regulation of adult SVZ neurogenesis Stages of SVZ progenitor development The SVZ lining the lateral ventricles contains the highest numbers of dividing progenitors within the adult mammalian

brain. An estimated number of 30 000 progenitors are generated in the adult SVZ daily (Cameron and McKay 2001; Ming and Song 2005). The SVZ is composed of the ependymal layer facing the lumen of the lateral ventricle and the adjoining proliferative zone with resident progenitor cells of three types: ‘type B’ cells that are the predominantly quiescent, multi-potent neural stem cells, the rapidly proliferating, transit amplifying cells or ‘type C’ cells; and the migrating neuroblasts or the ‘type A’ cells (Ming and Song 2011) (Fig. 3). The radial glia-like type B cells express GFAP, Nestin, and Sox2, and divide asymmetrically to selfrenew and produce transiently amplifying type C daughter cells that are positive for the homeobox transcription factor Dlx2 (Braun and Jessberger 2014; Vadodaria and Gage 2014). Type A progenitors that are DCX and PSA-NCAM immunopositive are migrating neuroblasts that follow a tangential trajectory along the rostral migratory stream (RMS) to the olfactory bulb (OB), where they integrate into existing OB neurocircuitry differentiating into OB interneurons (granule cells and periglomerular neurons) (Sakamoto et al. 2014). The type of newborn OB interneuron generated depends upon the rostrocaudal positioning of the progenitors from which they arise (Ming and Song 2011; Sakamoto et al. 2014). Most newborn progenitors within the SVZ are slated for death with a relatively small fraction migrating along the RMS to acquire OB interneuron identity (Zhao et al. 2008; Ming and Song 2011). Regulation of SVZ progenitor survival is observed at the neuroblast stage, as well as at the timepoint of immature neuron integration. While there are many similarities between neurogenesis in the SGZ and SVZ, amongst the most obvious differences is that SGZ neurogenesis occurs entirely within the DG subfield with relatively short distances for migration, whereas SVZ progenitors are born at relatively large distances from their final destination and undergo tangential and then radial migration to eventually become OB interneurons. SVZ neurogenesis is tightly regulated through the orchestration of both cell autonomous cues and non-cell autonomous factors that respond to changes in the SVZ microenvironment, as well as altered environmental experiences of the animal (Alvarez-Buylla and Garcia-Verdugo 2002). Several reports indicate that newborn OB neurons are highly responsive to novel odorant cues, supporting the theory that the process of OB neurogenesis may actively participate in the structural or physiological plasticity required for adaptations in olfactory perception in the adult mammalian brain (Alvarez-Buylla and Garcia-Verdugo 2002; Zhao et al. 2008). Thyroid hormone status, TR isoforms, and SVZ neurogenesis Thyroid hormone has been demonstrated to regulate SVZ neurogenesis, influencing multiple stages of SVZ progenitor development (Fig. 3) (Lemkine et al. 2005; Lopez-Juarez et al. 2012). The TRa1 isoform is thus far thought to be the



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Fig. 3 Thyroid hormone regulation of subventricular zone (SVZ) neurogenesis. Shown is a (a) sagittal and (b, upper panel) coronal section of the brain depicting the SVZ lining the lateral ventricles (LV). Shown are adult progenitors within the SVZ (b, lower panel) (c) SVZ progenitors traverse-specific developmental stages which are characterized by stage-specific marker expression. Type B cells are quiescent, multi-potent radial glia-like stem cells which divide asymmetrically to self-renew and generate rapidly proliferating, transit amplifying type C cells which in turn generate the migrating neuroblasts or Type A cells. Type B cells express glial fibrillary acidic protein (GFAP), Nestin, and Sox2, Type C are positive Nestin but no longer express GFAP and Type A neuroblasts are doublecortin (DCX) immunopositive and travel along the rostral migratory stream (RMS) to the olfactory bulb (OB)

where they integrate into local neurocircuitry. The blue bar indicates the potential thyroid hormone responsive SVZ progenitor stages. (d) Shown is the putative model for the effects of thyroid hormone and the TRa1 receptor isoform in SVZ progenitors. In the presence of T3, TRa1 holoreceptors are thought to repress gene transcription likely through putative-negative TREs within the stem cell gene Sox2 and the cell cycle genes Cyclin D1 and c-myc expression, thus hastening cell cycle exit and promoting stem cell progression toward the neuroblast stage and toward acquisition of a neuronal identity. In contrast, TRa1 aporeceptors activate gene transcription at negative TREs within Sox2, Cyclin D1, and c-myc genes likely keeping SVZ progenitors in an undifferentiated, proliferative state.

only TR expressed within the SVZ, differing in this manner from the SGZ where hippocampal progenitors express multiple TR isoforms (Lemkine et al. 2005; Lopez-Juarez et al. 2012). Within the adult SVZ, adult-onset hypothyroidism decreases progenitor proliferation, with evidence of a failure in progenitor cell cycle entry, an effect rescued by

thyroid hormone administration. Hypothyroidism is also associated with a decline in apoptosis within the SVZ, and a reduction in RMS migratory neuroblasts (Lemkine et al. 2005). In this regard, the choroid plexus secreted protein, TTR which regulates thyroid hormone transport, is also shown to regulate progenitor cell survival within the SVZ


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with reduced cell death observed in TTR null mice. TTR null mice exhibit lowered thyroid hormone levels in the brain and similar to the effects of hypothyroidism appear to reduce apoptotic cell loss within the SVZ neurogenic niche (Richardson et al. 2007). Nestin-positive progenitors in the SVZ exhibit TRa expression, and TRa0/0 loss of function mice phenocopy the effects of hypothyroidism with a hampering of progenitor cell cycle progression (Lemkine et al. 2005). TRa1 is expressed by both transit amplifying type C progenitors and type A migratory neuroblasts in the SVZ (Lopez-Juarez et al. 2012). The absence of TRa1 in the type B quiescent neural stem cells, and the appearance of TRa1 in transit amplifying progenitors and migratory neuroblasts have led to the hypothesis that TRa1 may predispose SVZ progenitors toward neuronal cell fate specification. In support of this notion, TRa1 over-expression results in enhanced numbers of migratory neuroblasts (Lopez-Juarez et al. 2012). The pro-neurogenic effects of TRa1 isoforms are suggested to be mediated via repressive effects on the expression of the neural stem cell gene Sox2 (Lopez-Juarez et al. 2012), and also through thyroid hormone-mediated repression of the cell cycle genes cyclinD1 and c-myc (Lemkine et al. 2005; Lopez-Juarez et al. 2012). Interestingly, TRa1 siRNA knockdown increases the number of type B neural stem cells likely through the removal of thyroid hormone-mediated repressive effects on the stem cell gene Sox2 (Lopez-Juarez et al. 2012). These results implicate ligand-mediated TRa1 effects that promote progression toward neuronal differentiation via repression of the stem cell factor Sox2, and through a curtailing of cell cycle progression by the repression of cell cycle genes. However, thus far reports do not indicate transcriptional activatory effects of T3/TRa1 on neurogenic gene expression of factors like NeuroD, Ngn1/Ngn2 raising the question whether thyroid hormone in the SVZ milieu plays a permissive role versus an active switching on of proneural gene expression. In vitro studies with SVZ-derived progenitors indicate that neural stem cells show a shift toward a more mature state when derived from hyperthyroid animals, with a shift toward oligodendrogenesis (Fernandez et al. 2004). Interestingly, a recent report indicates that thyroid hormone receptor interacting protein 6 (TRIP6), a zyxin family gene member, is required for SVZ-derived neural stem cell proliferation and inhibits differentiation, likely through effects on Notch signaling (Lai et al. 2014). Thus far, no studies have examined the local expression of deiodinases and thyroid hormone transporters within the SVZ neurogenic niche. This would add a further layer through which thyroid hormone action within the SVZ neurogenic milieu may be dynamically regulated. Thyroid hormone appears to influence SVZ and SGZ progenitors through the TRa1 isoform, with critical sensitivity to thyroid hormone observed in type C and type A progenitor cells within the SVZ, and Type 2b and Type 3

progenitor cells in the SGZ (Lemkine et al. 2005; Kapoor et al. 2012; Lopez-Juarez et al. 2012). The effects of thyroid hormone on cell survival within the SVZ and SGZ appear to differ, with hypothyroidism associated with decreased cell death in SVZ progenitors and enhanced cell death of SGZ progenitors, indicating that thyroid hormone effects on adult progenitors may exhibit niche-specific effects. While thus far other TR isoforms have not been reported to be expressed within the SVZ neurogenic niche, it is important to carry out a systematic profiling to confirm that this is indeed the case. Furthermore, spatio-temporal control that facilitates stagespecific perturbation of TRa1 within the type B, A, and C cells of the SVZ niche would help to clearly delineate the distinct effects on these progenitor cell types, and also to identify the specific target genes within these stages of SVZ progenitor development.

Putative molecular mechanisms for the neurogenic effects of thyroid hormone The action of thyroid hormone in modulating gene transcription is mediated by the TRa and TRb isoforms, that are members of the nuclear receptor superfamily and bind to the promoters of target genes as homo- or hetero-dimers with retinoid-X-receptors (RXRs), to form TR-RXR-coregulator complexes, at TREs in regulatory regions of thyroid hormone target genes (Wu et al. 2001; Lee and Privalsky 2005; Williams 2008; Tagami et al. 2009; Brent 2012). TRs can bind chromatin as liganded receptors or as unliganded aporeceptors (Chassande 2003; Bernal and Morte 2013) and either enhance or repress transcription depending on the nature of the TRE. Most TREs are positive TREs, in which TR aporeceptors repress gene transcription, whereas liganded TRs function as transcriptional activators (Harvey and Williams 2002; Liu and Brent 2010; Astapova and Hollenberg 2013). Conversely, negative TREs are those wherein transcription is activated by unliganded TRs and repressed by ligand binding to the TRs (Wu and Koenig 2000). Liganded and unliganded TRs mediate their transcriptional effects via the recruitment of coactivator/corepressor complexes that serve as transcriptional mediators which communicate with transcriptional machinery. Furthermore, these corepressors (Hu and Lazar 2000; Privalsky 2004; Astapova and Hollenberg 2013) and coactivators (Goodman and Smolik 2000; Ito and Roeder 2001) are part of multi-subunit enzyme complexes, which in addition to histone acetylation/deacetylation functions, also have enzymes such as methylases, kinases, phosphatases, which interact in a combinatorial way with TR isoforms, to provide flexibility and yet specificity in modulating gene expression (Cheng et al. 2010; Bernal and Morte 2013). Thus far, a detailed molecular analysis of the TRresponsive transcriptional targets within the SVZ and SGZ progenitor pool is largely lacking. A global profiling of



putative thyroid hormone target genes in neural cells in vitro unveiled targets such as Sox2, Jun, Notch1, Notch4, Klf7, Ngf, Pax 9, and Slit2 (Chatonnet et al. 2013). Furthermore, studies during embryonic neurodevelopment have identified genes such as reelin (Alvarez-Dolado et al. 1999), Stat3 (Chen et al. 2012), Tag1 (Alvarez-Dolado et al. 2001), and Dab (Alvarez-Dolado et al. 1999) as thyroid hormone target genes during embryonic neurodevelopment and may also be influenced within adult neurogenic niches by thyroid hormone, which remains to be experimentally tested. Thyroid hormone could also influence the regulation of neurogenesis promoting, niche-derived factors such as the growth factor brain-derived neurotrophic factor (BDNF) (Giordano et al. 1992; Koibuchi et al. 1999) and the developmental morphogen sonic hedgehog, whose expression in adulthood is regulated by thyroid hormone (Desouza et al. 2011). However, a detailed characterization of thyroid hormone responsive target genes within either adult SVZ or SGZ adult progenitors or in the neurogenic milieu is currently lacking, with the sole exception of Sox2 and cell cycle genes (cyclinD1 and c-myc) that have been reported as thyroid hormone target genes in SVZ progenitors. A putative model for thyroid hormone action within the SVZ progenitors, suggests that TRa1 aporeceptors at negative TREs in the regulatory regions of Sox2, cyclinD1, and c-myc activate the expression of these genes keeping SVZ progenitors in an undifferentiated, proliferative state (Lemkine et al. 2005; Lopez-Juarez et al. 2012). Ligand binding of thyroid hormone to TRa1 would then repress the expression of Sox2, cyclinD1, and c-myc and promote cell cycle exit and progression to neuroblast formation (Fig. 3). It is important to identify which specific SVZ progenitor stage exhibits these nature of thyroid hormone driven gene expression responses, and to test this model using genetic tools to perturb TRa1 and the selective target genes in a progenitorstage-dependent fashion. While thyroid hormone responsive genes within the hippocampal neurogenic niche have been studied using in vivo gene expression analysis and through in vitro neurosphere experiments, future experiments with chromatin immunoprecipitation and promoter analysis are required to determine whether these are bona-fide thyroid hormone target genes. The mRNA expression of several proneural genes such as Tis21, Tlx, Dlx2, Math-1, and Ngn1 was regulated by thyroid hormone in the hippocampal neurogenic niche following in vivo administration of thyroid hormone (Kapoor et al. 2012). T3 exposure in vivo resulted in enhanced expression of the pro-neurogenic transcription factors Dlx2 and Tis21. Tis21 is expressed in Type 2 and Type 3 progenitors, and Tis21 activation evokes an accelerated differentiation of hippocampal progenitors similar to the effects observed with thyroid hormone treatment (FarioliVecchioli et al. 2009; Attardo et al. 2010). Thyroid hormone also enhanced the expression of the proneural genes Tlx,

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Math-1, and Ngn1 (Kapoor et al. 2012), suggesting the activation of a pro-neurogenic program in hippocampal progenitors following thyroid hormone treatment. However, experiments that assess whether these are direct effects in hippocampal progenitors or mediated via the niche, and promoter analysis to assess TRE-mediated effects on the expression of these pro-neural genes are required to gain a deeper mechanistic insight. A current working model that requires experimental validation suggests that TRa1 aporeceptors in Type 2b/3 hippocampal progenitors may evoke repressive effects on pro-survival factors and on proneural genes resulting in cell death. The TRa1 holoreceptor would serve to activate pro-survival genes and enhance pro-neural gene expression, thus promoting neuroblast survival and differentiation into granule cell neurons within the hippocampal neurogenic niche (Fig. 2). Future experiments to generate chromatin immunoprecipitation sequencing (ChIPseq) data with TR isoform-specific antibodies would immensely aid in the identification of thyroid hormone target genes within SVZ and SGZ progenitors. This has been hampered to an extent through the lack of high-quality, TR isoform-specific ChIP grade antibodies. However, studies that capitalize on the availability of TR isoform-specific knockin mice with GFP (Dudazy-Gralla et al. 2013) or use ChAP experiments with GST-tagged TR isoforms or pan-RXR ChIPs (Chatonnet et al. 2013) have been used to yield insights into TR target genes in neural cells. A similar analysis with TR isoformspecific knockin mice or GST/FLAG/HA-tagged TR isoforms could also be used to generate a genome wide identification of TRE-binding sites using ChIP/ChAP assays in SVZ and SGZ progenitors. It will also be important to examine potential non-genomic effects of thyroid hormone on adult progenitors within the SVZ and SGZ neurogenic niches, to address whether thyroid hormone alters growth hormone sensitivity through effects on signaling pathways such as the MAPK kinase cascade or potentially within astrocytes of the neurogenic niche influencing the secretion and release of neurogenesis modulating factors. The molecular mechanisms of the effects of TR isoforms and thyroid hormone on adult progenitors remains relatively poorly understood and require in depth investigation to gain critical mechanistic insights.

Behavioral implications of the neurogenic actions of thyroid hormone Thyroid hormone regulates hippocampal neurogenesisdependent behaviors such as cognitive performance- and mood-related behavior (Ming and Song 2011; Miller and Hen 2014), and also influences SVZ neurogenesis-related behavioral outputs such as olfactory discrimination (AlvarezBuylla and Garcia-Verdugo 2002). Adult-onset hypothyroidism is linked to an enhanced susceptibility for depression


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(Dugbartey 1998; Jackson 1998; Berent et al. 2014; Demartini et al. 2014), and thyroid hormone is used clinically as an effective adjunct to antidepressant therapy (Haggerty and Prange 1995; Henley and Koehnle 1997; Bauer and Whybrow 2001; Cooper-Kazaz et al. 2007; Uhl et al. 2014). Furthermore, adult-onset hypothyroid status has been linked in clinical studies to impairments in learning, verbal fluency, and spatial performance (Osterweil et al. 1992; Baldini et al. 1997; Capet et al. 2000; Smith et al. 2002). Studies in rodent models also indicate deficits in learning performance (Fundaro 1989) and enhanced immobility on the forced swim test following adult-onset hypothyroidism (Kulikov et al. 1997; Montero-Pedrazuela et al. 2006). These findings have led to the suggestion that disrupted thyroid status may evoke morphological changes within the hippocampus, a brain region strongly implicated in learning, memory, and mood. It is tempting to speculate that the process of adult hippocampal neurogenesis, which is impaired following adult-onset hypothyroidism, may contribute causally to the impaired cognition and deficits in mood behavior observed in hypothyroidism. The adult-onset hypothyroidism effects on adult hippocampal neurogenesis have been suggested to arise because of TRa1 aporeceptor activity, with support coming from evidence that thyroid hormone administration can rescue the neurogenic decline in both adult-onset hypothyroid animals (Desouza et al. 2005) and also in animals with excess TRa1 aporeceptor activity (Kapoor et al. 2010). Mice carrying a dominant-negative TRa1 (TRa1+/m) with a 10fold reduced affinity to thyroid hormone exhibit increased anxiety and impaired recognition memory, as well as displaying a steep decline in hippocampal neurogenesis, effects which are rescued upon exogenous thyroid hormone administration (Venero et al. 2005; Pilhatsch et al. 2010, 2011). Taken together, these studies suggest that at least a component of the behavioral and neurogenic deficits associated with hypothyroidism could be a result of TRa1 aporeceptor activity. In addition, to a putative role of a decline in hippocampal neurogenesis in the cognitive and emotional behavioral perturbations noted with adult-onset hypothyroidism, neurogenic effects of thyroid hormone may also bear relevance to the mood-elevating effects of thyroid hormone augmentation of antidepressant action. Chronic antidepressant treatments increase hippocampal neurogenesis (Malberg et al. 2000) and this effect is important for specific behavioral actions of antidepressants (Santarelli et al. 2003; David et al. 2010). Thyroid hormone has been used clinically as an adjunct to antidepressant treatment and preclinical studies indicate a potentiation of the neurogenic effects of antidepressants by simultaneous administration of thyroid hormone (Eitan et al. 2010). These results suggest a possible role for hippocampal neurogenesis in contributing to the therapeutic benefits that ensue from thyroid hormone augmentation strategies in the treatment of depression.

The effects of thyroid hormone on SVZ neurogenesis may bear relevance to the modulation of olfactory discrimination by thyroid hormone. During postnatal life, thyroid hormone appears to play an important role in olfactory pathway development (Hoyk et al. 1996). In rodents, thyroid hormone deficiency results in a decrease in the total olfactory epithelia surface area as well as the number of mature olfactory receptor neurons (Paternostro and Meisami 1991). The olfactory system appears to retain this sensitivity to thyroid hormone in the adult as well, with olfactory behavior being altered in hypothyroid mice. Adult-onset hypothyroid animals lose their sense of smell, an effect that can be reversed when euthyroid status is restored (Beard and Mackay-Sim 1987). It is tempting to speculate that the deficits in olfaction noted in hypothyroid patients may involve a role for thyroid hormone in the SVZ neurogenic niche. It is also possible that lack of thyroid hormone may have a more direct effect on the neural cells of the peripheral nasal epithelium. This is supported by studies from rodents where hypothyroidism disrupted the development of neurons within the olfactory epithelium and thyroxine treatment restores neurogenesis within the olfactory epithelium (Mackay-Sim and Beard 1987; Paternostro and Meisami 1993, 1996). Hyperthyroidism has been linked to both accelerated maturation of OB neurons and development of olfactory responsiveness (Johanson 1980; Brunjes et al. 1982), although it remains unclear if neurogenic changes contribute to these changes. Almost the entire gamut of animal model studies thus far that have examined the neurogenic influence of perturbed thyroid hormone signaling have involved experimental induction of hypo- or hyperthyroidism, or the use of TR isoform-specific mutant mice. However, thyroid hormone signaling-related pathologies also encompass ‘non-thyroidal illness syndrome’ through perturbations of local thyroid hormone metabolism despite normal circulating levels of thyroid hormone. Perturbations of deiodinase activity, dysfunction of thyrotropin releasing hormone and TSH release, changes in affinity of hormone and serum binding partners, alterations of thyroid hormone transporter expression and function, dysregulation of TR isoforms or in the stoichiometry and binding of components of the TR isoformcorepressor/coactivator complexes could all impinge on thyroid-hormone-related signaling (Farwell 2013). There is a paucity of animal model studies that address the impact of disrupted thyroid hormone signaling on adult neurogenesis through the nature of perturbations listed above, and this component is critical to gain a more nuanced understanding of the effects of thyroid hormone on adult neural stem cells.

Future directions Thyroid hormone exerts a wide array of effects on the central nervous system, both during development and in adulthood.



In the adult mammalian brain, thyroid hormone plays an important role in the regulation of SGZ and SVZ neurogenesis, promoting neuronal fate choice acquisition and regulating post-mitotic survival of progenitors. Within both of these neurogenic niches, the TRa1 receptor isoform has been implicated to play a crucial role in mediating the neurogenic influence of thyroid hormone. However, there are several open questions that require detailed future investigation. What is the nature of local thyroid hormone metabolism within the adult neurogenic niches? Do progenitors transport thyroid hormone through MCT8 transporters? Do astrocytes of the neurogenic milieu that are in close proximity to adult progenitors contribute to the dynamic regulation of thyroid hormone bioavailability to progenitors? What are the stagespecific expression patterns of TR isoforms and how does their stoichiometry vary across progenitor developmental progression? The development of reporter mouse lines, including TR isoform-specific knockin mice TRa1-GFP (Wallis et al. 2010), as well as a transgenic thyroid reporter mouse with a fusion protein of a yeast Gal4 DNA-binding domain and a TRa ligand-binding domain to drive reporter expression (Quignodon et al. 2004), could serve as useful tools in defining the stage-specific expression of TR isoforms in adult neural progenitors. Experiments are required to address the TR isoform-specific apo- and holoreceptor gene targets in distinct stages of progenitor development. Furthermore, do the specific TR isoform-recruited coactivator and corepressor complexes vary across stages of progenitor development? An understanding is also required of the epigenetic mechanisms that are recruited by thyroid hormone and TR isoforms to promote progenitor exit from cell cycle and commitment to the acquisition of a neuronal fate. Finally, studies that address the importance of the neurogenic effects of thyroid hormone on the cognitive, emotional, and sensory systems will identify potential targets for the treatment of the neurological and psychiatric consequences of adult-onset thyroid hormone dysfunction.

Acknowledgments and conflict of interest disclosure The support of the Tata Institute of Fundamental Research and Department of Science and Technology, Government of India, is gratefully acknowledged. The authors have no conflicts of interest to declare. All experiments were conducted in compliance with the ARRIVE guidelines.

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Thyroid hormone signaling and adult neurogenesis in mammals.

Thyroid hormone action in postnatal heart development.

Thyroid thermogenesis in adult rat hepatocytes in primary monolayer culture: direct action of thyroid hormone in vitro.

The mitochondrial route of thyroid hormone action.

Thyroid hormone action: astrocyte-neuron communication.

The noradrenergic component in tapentadol action counteracts μ-opioid receptor-mediated adverse effects on adult neurogenesis.

Interdependence of growth hormone and thyroid hormone action on thymulin synthesis: clinical evidence.

Effects of Gadolinium-Based Contrast Agents on Thyroid Hormone Receptor Action and Thyroid Hormone-Induced Cerebellar Purkinje Cell Morphogenesis.

Biochemical basis of thyroid hormone action in the heart.

Thyroid Hormone Availability and Action during Brain Development in Rodents.

Effect of Opioid on Adult Hippocampal Neurogenesis.

A Cold-Blooded View on Adult Neurogenesis.

Adult neurogenesis: Encouraging integration.

SnapShot: adult hippocampal neurogenesis.

Thyroid - hormone effects on steroid - hormone metabolism.

Neurogenesis in the Adult Hippocampus.

Adult neurogenesis in intellectual disabilities.

Tissue specificity of inhibitory action of excess thyroid hormone on creatine transport in the rat.

Thyroid hormone action on lipid metabolism in humans: a role for endogenous insulin.

Spatially regulated adult neurogenesis.

Current perspectives on the link between neuroinflammation and neurogenesis.

Perspectives of TRPV1 Function on the Neurogenesis and Neural Plasticity.

Effects of maternal nicotine exposure on thyroid hormone metabolism and function in adult rat progeny.

Estrogen action on growth hormone in pituitary cell cultures from adult and juvenile macaques.