perspectives on thyroid hormone action in adult...

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

AbstractThyroid hormone exhibits profound effects on neural progen-itor turnover, survival, maturation, and differentiation duringperinatal development. Studies over the past decade haverevealed that thyroid hormone continues to retain an importantinfluence on progenitors within the neurogenic niches of theadult mammalian brain. The focus of the current review is tocritically examine and summarize the current state of under-standing of the role of thyroid hormone in regulating adultneurogenesis within the major neurogenic niches of thesubgranular zone in the hippocampus and the subventricularzone lining the lateral ventricles. We review in depth thestudies that highlight a role for thyroid hormone, in particularthe TRa1 receptor isoform, in regulating progenitor survivaland commitment to a neuronal fate. We also discuss putativemodels for the mechanism of action of thyroid hormone/TRa1

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

Thyroid hormone exerts pleiotropic effects during organis-mal development and in adulthood. Thyroid hormone actiontargets diverse cellular processes such as progenitor turnover,cell survival and differentiation, cellular homeostasis, andmetabolic regulation within multiple tissue types and organs(Yen 2001; Brent 2012; Pascual and Aranda 2013; Sirakovet al. 2013). The brain is highly sensitive to thyroid hormoneaction and extensive literature has addressed the criticalinfluence of thyroid hormone during neurodevelopment(Koibuchi and Chin 2000; Bernal 2007; Horn and Heuer2010; Grimaldi et al. 2013; Preau et al. 2014). Perturbationsof thyroid hormone status during embryonic and earlypostnatal development are associated with severe neurolog-ical consequences (Dugbartey 1998; Zoeller and Crofton2005; de Escobar et al. 2007; Williams 2008). In contrast,the adult brain was traditionally perceived to successfullybuffer fluctuations in thyroid hormone levels, in part becauseof the relatively subtle structural and functional changesevoked in the adult brain by altered thyroid hormonefunction (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 toembryonic and postnatal neurodevelopment (Bernal andNunez 1995; Zoeller and Rovet 2004; Gilbert and Sui 2006;Axelstad et al. 2008). This view has been modified based onreports that highlight the effects of thyroid hormone on themature brain (Schroeder and Privalsky 2014), with severalstudies (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; Zhanget 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 FundamentalResearch, Homi Bhabha Road, Mumbai 400005, India. E-mail:[email protected] used: DCX, doublecortin; DG, dentate gyrus; GFAP,

glial fibrillary acidic protein; PSA-NCAM, polysialylated neural celladhesion molecule; QNP, quiescent neural progenitor; RMS, rostralmigratory stream; RXRs, retinoid-X-receptors; SGZ, subgranular zone;SVZ, subventricular zone.

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

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et al. 2012; Shiraki et al. 2012; Preau et al. 2014; Remaudet al. 2014) indicating that thyroid hormone retains apowerful influence on ongoing new neuron generation withinadult neurogenic niches. Furthermore, behavioral changes incognitive performance and mood have been strongly asso-ciated with adult-onset disruption of thyroid hormone status(Bauer et al. 2008; Fernandez-Lamo et al. 2009; Cookeet al. 2014; Willoughby et al. 2014). Given the link betweenadult neurogenesis and the regulation of learning, memory,and mood (Zhao et al. 2008; Ming and Song 2011; Eisch andPetrik 2012; Miller and Hen 2014), this has raised importantquestions about whether the cognitive and emotional conse-quences of thyroid hormone dysfunction in adulthoodinvolve a role for the neurogenic effects of thyroid hormone.The focus of the present review was to summarize andcritically discuss the current status of literature addressing theeffects of thyroid hormone on adult neurogenesis, and tohighlight potential leads for future research.

Thyroid hormone action in the adult brain

Thyroid hormone action within the mature mammalian brainis regulated at several levels encompassing thyroid hormonetransport, local ligand availability through modulation viadeiodinases, non-genomic, and genomic actions of thyroidhormone, cell-specific thyroid hormone receptor (TR)expression levels, crosstalk of liganded/unliganded TRs withcoactivators and corepressors at thyroid hormone responseelements (TREs), and the interaction of TRs with othersignaling 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 thehypothalamus drives the secretion of thyroid-stimulatinghormone (TSH) from the pituitary, and evokes TSH-medi-ated thyroid hormone synthesis and secretion from thethyroid gland (Chiamolera and Wondisford 2009; Schroederand Privalsky 2014) (Fig. 1). Thyroid hormone is releasedinto blood, largely as the precursor thyroxine (3,30,5,50-tetraiodothyronine; T4), as well as lower amounts of theactive form of thyroid hormone (3,30,5-triiodothyronine; T3),and is transported in plasma bound to carriers such asthyroxine-binding globulin, albumin, and transthyretin(TTR) (Palha 2002; Williams 2008). Active transport ofthyroid hormone into the brain is mediated by the transport-ers monocarboxylate transporter-8 (MCT8) and organicanion transporter proteins, as well as TTR in the choroidplexus (Palha et al. 2000; Tohyama et al. 2004; Heuer et al.2005; Jansen et al. 2005; Schweizer and Kohrle 2013; Wirthet al. 2014). Local thyroid hormone levels within the brainare under the dynamic regulation of the selenoenzymes,iodothyronine deiodinases types I, II, and III (D1, D2, andD3), 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 T4to the active T3 form of thyroid hormone and D3, whichinactivates T3 and T4 by conversion to 3,30-diiodothyronine(T2) and 3,30,50-triiodothyronine (rT3), respectively, plays acrucial role in regulating local thyroid hormone bioavailabil-ity within the brain (Bernal 2007; St Germain et al. 2009;Hernandez et al. 2012; Arrojo e Drigo et al. 2013; Denticeet al. 2013). D2 activity within astrocytes results in localrelease of T3 into the brain milieu, which is then taken up byneighboring neurons through the MCT8 transporter (Morteand Bernal 2014).Thyroid hormone action at the genomic level is mediated

via TRs which function as ligand-modulated transcriptionfactors that activate or repress target gene expression (Harveyand Williams 2002; Laurberg 2009; Cheng et al. 2010). TRalpha and beta genes generate several distinct TR isoforms,amongst which TRa1, TRa2, TRb1, and TRb2 are expressedwithin the mammalian brain (Mellstrom et al. 1991; Bradleyet al. 1992; Forrest and Vennstrom 2000). Both TRa1 andTRa2 are widely expressed in the adult brain (Cook andKoenig 1990; Wallis et al. 2010). TRa2, however, does notbind thyroid hormone and is suggested to play a dominant-negative role at TREs within promoter regions of thyroidhormone target genes (Koenig et al. 1989; Guissouma et al.2014). TRb isoforms exhibit increasing expression levelsacross postnatal development, with TRb1 showing a moreubiquitous expression pattern in the brain (Murata 1998;Forrest and Vennstrom 2000; Zhang and Lazar 2000),relative to the restricted expression within the hypothalamusand pituitary for the TRb2 receptor isoform (Cook et al.1992; Lechan et al. 1994; Abel et al. 2001). Transcriptionalregulation of TRE-containing thyroid hormone target genesis observed both in the presence of ligand-bound TRisoforms, as well as in response to the unliganded aporecep-tors (Zhang and Lazar 2000; Chassande 2003; Bernal andMorte 2013). TR aporeceptors are suggested to predomi-nantly repress thyroid hormone target genes by recruitingcorepressors, which exhibit histone deacetylase activity (Huand Lazar 2000; Jepsen and Rosenfeld 2002; Privalsky 2004;Astapova and Hollenberg 2013). The transcription of targetgenes is thought to shift toward transcriptional activationfollowing ligand-binding of T3 to the aporeceptor, accom-panied by recruitment of coactivators that mediate histoneacetylation and facilitate recruitment of RNA Polymerase IIand transcription initiation machinery (Harvey and Williams2002; Cheng et al. 2010; Liu and Brent 2010). Beyond theclassical genomic mode of action, non-genomic actions aremediated by membrane receptors for thyroid hormone, withevidence supporting a binding site for T3 within integrinaVb3, a putative membrane receptor for rapid actions ofthyroid hormone (Davis et al. 2009). The non-genomiceffects of thyroid hormone include, but are not restricted tochanges in a5/b3 integrin-mediated signaling (Bergh et al.

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

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2005; Davis et al. 2008) as well as PI3-kinase (Furuya et al.2009), MAPK (Davis et al. 2000; Alisi et al. 2004; D’Are-zzo 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). Thyroidhormone action in the adult brain is thus influenced byseveral factors including the modulation of local thyroidhormone concentration through regulation of thyroid metab-olism or uptake within the brain, the nature of TR isoformspresent in specific cell types, the combinatorial action of TRsalong with coactivators and corepressor complexes, as wellas ligand-dependent and aporeceptor-mediated effects on TRtarget gene expression (Fig. 1).

Adult neurogenesis

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

stages, each characterized by the expression of stage-specificmarkers, migration of the neuroblasts to their site ofintegration, and functional recruitment into existing neuro-circuitry (Ming and Song 2005, 2011). At each of thesestages of neurogenesis, progenitor development is regulatedby both cell-intrinsic and niche-mediated factors. Adultneurogenesis is highly sensitive to the hormonal, neurotrans-mitter, 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 theanimal (Zhao et al. 2008; Lieberwirth and Wang 2012). Theprimary neurogenic niches in the adult mammalian braininclude the subgranular zone (SGZ) in the dentate gyrus(DG) subfield of the hippocampus and the subventricularzone (SVZ) lining the lateral ventricles (Ming and Song2011; Vadodaria and Gage 2014). Several studies over thelast decade have reported a powerful effect of thyroidhormone on progenitor development within both of theseneurogenic niches, with overlapping as well as distinctive

(a)

(b)

Fig. 1 Thyroid hormone action in the adult rodent brain. (a) Theschematic illustrates the hypothalamic–pituitary–thyroid (HPT) axisregulation of thyroid hormone. Thyrotropin releasing hormone (TRH)

secreted by the hypothalamus in turn regulates thyroid-stimulatinghormone (TSH) from the pituitary, and evokes TSH-mediated thyroidhormone 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 theHPT axis besides their effects on diverse target organs including thebrain. 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 andreverse T3 (rT3), respectively. (b) Shown are molecular mechanisms

for the genomic actions of thyroid hormone. Thyroid hormone recep-tors (TRs) heterodimerize with the retinoid-X-receptor (RXR) andrecruit either corepressors or coactivators to regulate gene transcrip-

tion. The unliganded TR is predominantly thought to repress genetranscription through the recruitment of corepressors and the deacet-ylation of histones at promoters of thyroid hormone target genes thatcontain thyroid hormone response elements (TREs). The liganded TR

is thought to complex with coactivators and enhances gene transcrip-tion through increased histone acetylation at TRE-containing thyroidhormone target gene promoters.


Thyroid hormone and adult neurogenesis 601

actions of thyroid hormone on SGZ and SVZ progenitors(Ambrogini et al. 2005; Desouza et al. 2005, 2011; Lemkineet 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 hormonestatus, analysis of TR isoform-specific mutants, as well as anevaluation of direct effects of thyroid hormone on progen-itors in vitro to gain a mechanistic understanding of the roleof thyroid hormone in adult neurogenesis. While progresshas been made in understanding the stage-specific effects ofthyroid hormone on adult neurogenesis, the underlyingmolecular mechanisms and specific thyroid hormone targetgenes within progenitors and neighboring cells within theneurogenic milieu are yet to be clearly delineated. Further-more, the implications of neurogenic changes evoked bythyroid hormone in contributing to the behavioral andcognitive consequences of perturbed thyroid status (Fernan-dez-Lamo et al. 2009; Berent et al. 2014; Willoughby et al.2014) remain to be fully understood. In this review, wesummarize the current understanding of the effects of thyroidhormone on adult neurogenesis in both the SGZ and SVZneurogenic niches, comparing and contrasting the nature ofthese effects as well as highlighting open questions for futureresearch. We restrict our review to the neurogenic effects ofthyroid hormone as several previous reviews have high-lighted the critical influence of thyroid hormone on astro-cytes and oligodendrocytes, including effects on glialprogenitor turnover, survival, and maturation, as well as onmyelination (Rodriguez-Pena 1999; Calza et al. 2005, 2010;Mohacsik et al. 2011; Morte and Bernal 2014).

Thyroid hormone regulation of adult hippocampalneurogenesis

Stages of hippocampal progenitor development

Hippocampal progenitors within the SGZ of the DG subfieldpredominantly give rise to neuroblasts, that differentiate intogranule cell neurons which undergo maturation whilemigrating short distances into the granule cell layer of theDG and functionally integrate into the hippocampal network(Ming and Song 2011). While estimates suggest that about9000 progenitor cells are born daily within the SGZneurogenic niche of rodents, only about half of these survivebeyond 2–3 weeks. Among the surviving pool of progenitorsapproximately 85% migrate into the granule cell layer (GCL)to form granule cell neurons, with the remaining pool ofsurviving progenitors thought to acquire an astrocyticidentity (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 theType 1 cell, is a radial glial-like cell that expresses glialfibrillary acidic protein (GFAP), the intermediate filament

protein nestin, as well as the transcription factor and stem cellmarker Sox2 (Kempermann et al. 2004; Ming and Song2011). QNPs are slowly dividing cells that undergo asym-metric divisions to generate the transiently amplifying neuralprogenitors/Type 2a cells that are immunopositive for nestin,but no longer express GFAP or Sox2. Amplifying neuralprogenitors divide relatively rapidly to generate the Type 2bcells, which are neuroblasts expressing Nestin as well as themicrotubule-associated protein doublecortin (DCX). Type 2bcells have been reported to retain the ability to undergolimited cell division (Kempermann et al. 2004; Ming andSong 2011). At this stage neuroblasts also express the pro-neurogenic basic helix-loop-helix transcription factor Neu-roD that is involved in neuronal cell fate acquisition. TheType 2b cells migrate into the GCL, and form DCX-positiveType 3 cells that lose their immunopositivity for nestin. Inaddition to DCX, Type 3 cells express polysialylated neuralcell adhesion molecule (PSA-NCAM), as well as markerssuch as Stathmin and TUC-4 (Kempermann et al. 2004;Zhao et al. 2008; Ming and Song 2011). DCX-positiveimmature neurons transiently express calretinin as theyundergo morphological maturation to form mature granulecell neurons that are immunopositive for Tuj1 (beta IIItubulin), Neuronal nuclei (NeuN) and calbindin (Brandtet al. 2003). The process of maturation of a hippocampalprogenitor into a mature granule cell neuron that isfunctionally integrated into DG neurocircuitry can take upto 4–6 weeks (Ming and Song 2011).

Thyroid hormone status and adult hippocampalneurogenesis

The first reports of the effects of thyroid hormone on thehippocampal neurogenic niche came from studies of per-turbed thyroid hormone status in rat models, with hypothy-roidism evoked by thyroidectomy/goitrogen treatment(Ambrogini et al. 2005; Desouza et al. 2005; Montero-Pedrazuela et al. 2006) or via thyroid hormone administra-tion to generate hyperthyroidism (Desouza et al. 2005).Goitrogen-induced adult-onset hypothyroidism in rats selec-tively decreased progenitor survival and neuronal differen-tiation, with no change observed in hippocampal progenitorcell division (Desouza et al. 2005). The decline in progenitorsurvival and neuronal differentiation was restored by the re-establishment of euthyroid status. The decrease in progenitorsurvival was accompanied by an increase in the number ofapoptotic cells in the hippocampal neurogenic niche of adulthypothyroid rats. This decline in progenitor survival was alsoreflected by a reduction in DCX, PSA-NCAM, and NeuroD-immunopositive cell numbers within the hippocampal neu-rogenic niche. In contrast, hyperthyroidism in adult rats didnot evoke any change in hippocampal progenitor prolifera-tion, survival, or differentiation (Desouza et al. 2005).Ambrogini et al. (2005) demonstrated that goitrogen-induced hypothyroidism in adult rats evoked decreased



progenitor survival and a delay in neuronal differentiation.This study reported a prolonged expression of TUC-4, animmature neuronal marker, accompanied by decreasedmorphological maturation of newborn neurons, with noeffects noted on hippocampal progenitor cell turnover. Incontrast, thyroidectomy in adult rats resulted in decreasedhippocampal progenitor proliferation (Montero-Pedrazuelaet al. 2006), accompanied by a decline in DCX-positiveimmature neurons with reduced dendritic complexity. Thiswas correlated with a depressive phenotype as evidenced byincreased immobility in the forced swim test in hypothyroidrats, 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-onsethypothyroidism, they differ in the interpretation of specificprogenitor stages influenced by perturbed thyroid hormonestatus. While one report indicates effects of adult-onsethypothyroidism on hippocampal progenitor turnover (Mon-tero-Pedrazuela et al. 2006), the other two studies (Ambroginiet al. 2005; Desouza et al. 2005) demonstrate the targeting ofpost-mitotic stages of progenitor survival and neuronaldifferentiation. It is important to resolve the discrepancies

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(b) (d)

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Fig. 2 Thyroid hormone regulation of adult hippocampal neurogene-

sis. Shown is a (a) sagittal and (b, upper panel) coronal section of therodent brain illustrating the location of hippocampal progenitors withinthe 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 progres-sion to form mature granule cell neurons. The stages of progenitordevelopment commence from the QNP/Type 1 cell that divides

asymmetrically to self-renew and produce transit amplifying progeni-tors/Type 2a cells. Type 2b cells, are neuroblasts that express bothNestin and the microtubule-associated protein doublecortin (DCX), as

well as the proneural gene, NeuroD. Type 2b cells migrate into theGCL, and form DCX-positive Type 3 cells that lose their immunopo-sitivity 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 asthey mature to form Tuj1, NeuN, and calbindin-positive mature GCneurons. 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 andthe TRa1 receptor isoform. In the presence of T3, TRa1 holoreceptorsenhance gene transcription enhancing proneural gene expression and

promoting cell survival. Potential thyroid hormone responsive targetgenes 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 asresulting in decreased cell survival.



that may have arisen owing to the different methods used togenerate hypothyroid status, and the treatment regimesemployed with the mitotic marker bromodeoxyuridine toassess effects on neurogenesis. Bromodeoxyuridine treatmentparadigms based on the time-point of sacrifice can capturemultiple stages of progenitor development, yielding results inwhich it is difficult to distinguish effects on proliferationversus short-term survival (Taupin 2007).Transgenic mousemodels havemade it possible to study the

stage-specific effects of thyroid hormone on adult hippocam-pal progenitor development. Studies in transgenic Nestin-Green Fluorescent Protein (GFP) reporter mice (Yu et al.2005) have aided analysis of the effects of perturbed thyroidhormone status on Type 1, 2a, and 2b hippocampal progen-itors that can be distinguished using triple immunofluores-cence approaches along with Nestin-GFP reporter expression.Adult-onset hypothyroidism did not alter the total pool ofNestin-GFP-positive progenitors, which encompasses theproliferative stages (Type1, 2a, and 2b) of hippocampalprogenitor development (Kapoor et al. 2012). However,hypothyroid mice showed a robust decline in the number ofDCX- and NeuroD-positive progenitors indicating reducedpost-mitotic survival of hippocampal progenitors. While thetotal pool of Nestin-GFP cells was unchanged in thehippocampal neurogenic niche, triple immunofluorescencefor Nestin-GFP, GFAP, and DCX revealed a significantdecline in the percentage of predominantly post-mitotic Type2b (GFP+ DCX+) neuroblasts within the total pool of Nestin-GFP-positive hippocampal progenitors. These findings indi-cate that adult-onset hypothyroidism targets Type 2b and Type3 hippocampal progenitors, suggesting that post-mitotic stagesof hippocampal progenitor development may be the mostsensitive 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 revealedsignificant increases in the number of DCX and NeuroD-positive hippocampal progenitors (Kapoor et al. 2012).Studies with transgenic Nestin-GFP reporter mice revealedaccelerated hippocampal progenitor maturation, withincreases noted in DCX-positive Type 3 immature neuronsin hyperthyroid mice, and a hastening of mature neuronalmarker acquisition in hippocampal progenitors. The differ-ences noted in the effects of adult-onset hyperthyroidism onhippocampal progenitor development suggest potential spe-cies-specific distinctions in the degree of saturation of TRsunder 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 clarifywhether the effects of thyroid hormone are directly mediatedon adult hippocampal progenitors or are effects evoked via

modulation of the neurogenic niche. Given the powerfuleffects of thyroid hormone on astrocytes (Martinez andGomes 2002; Mohacsik et al. 2011; Dezonne et al. 2013;Morte and Bernal 2014), and the role of astrocytes withinneurogenic niches (Seri et al. 2001; Ma et al. 2005; Ashtonet al. 2012) in providing key extrinsic cues for hippocampalprogenitor development, defining the direct versus indirecteffects of thyroid hormone on progenitor development iscritical to gain an understanding of underlying molecularmechanisms. Thus far, specific in vitro evidence suggeststhat thyroid hormone does exert direct effects on hippocam-pal progenitor development (Desouza et al. 2005; Kapooret al. 2012). Adult hippocampal progenitors maintainedin vitro as dispersed progenitor cultures or as neurosphereshave been shown to express multiple TR isoforms. However,thus far it remains unclear whether thyroid hormonetransporters or deiodinases are expressed by hippocampalprogenitors and the stoichiometry of TR isoforms asprogenitors proceed through their developmental progressionis also unknown. Studies with dispersed adult hippocampalprogenitor cultures indicate effects on proliferation, survival,and glial differentiation following thyroid hormone treatment(Desouza et al. 2005). In vitro evidence from neurosphereassays indicates no change in neurosphere number but a shiftin pattern from large-sized neurospheres to predominantlysmaller neurospheres (Kapoor et al. 2012). This reduction insize is suggestive of a shift from proliferation toward adifferentiated state, which is confirmed by increased Tuj-1-positive neurons in thyroid hormone treated neurospheres.While these in vitro results (Desouza et al. 2005; Kapooret al. 2012) do not recapitulate in entirety the nature of effectsobserved in vivo in response to thyroid hormone administra-tion (Ambrogini et al. 2005; Desouza et al. 2005; Montero-Pedrazuela et al. 2006), they do exhibit a component ofoverlap. Given this, one cannot preclude the possibility thatthe in vivo effects of thyroid hormone on adult hippocampalneurogenesis involve both direct effects on progenitors, aswell 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 roleof astrocytes in the effects of thyroid hormone on adultneurogenesis are relatively unexplored. Astrocytes in vitrohave been reported to express TR receptor isoforms (Carlsonet al. 1996), whereas in vivo studies fail to provideimmunohistochemical evidence of TR isoform expressionin GFAP-positive cells (Carlson et al. 1994). More recentstudies indicate TRa1 expression in astrocytes and support arole for TRa1 in astrocyte maturation (Trentin et al. 1995;Lima et al. 1997; Gomes et al. 1999; Martinez and Gomes2002, 2005; Morte et al. 2004; Manzano et al. 2007). It isinteresting to note that astrocytes from distinct regions of thebrain respond differently to thyroid hormone treatment, bothmorphologically and in protein expression (Lima et al. 1997,



1998). Recent reviews have extensively dealt with astrocyte-neuronal communication in the context of modulation oflocal thyroid hormone signaling (Mohacsik et al. 2011;Morte and Bernal 2014). Future studies are required to assessthe effects of thyroid hormone on astrocytes within thehippocampal neurogenic niche, to assess whether astrocyteswithin close proximity of hippocampal progenitors serve assources of local thyroid hormone to neural stem cells via D2-mediated regulation of local T3 bioavailability, and throughthyroid hormone-mediated modulation of the release ofastrocytic factors that influence hippocampal progenitordevelopment.

Thyroid hormone receptors and adult hippocampalneurogenesis

Mounting evidence suggests that the neurogenic effects ofthyroid hormone in the hippocampus are predominantly onpost-mitotic neuronally committed Type 2b and Type 3progenitors, and this period of adult hippocampal progenitordevelopment represents a critical window of thyroid hor-mone sensitivity (Kapoor et al. 2012). This notion is inkeeping with the effects of thyroid hormone previouslyreported on other progenitors (for example: oligodendrocyticprogenitors, embryonic stem cells, and myogenic progeni-tors), namely to serve as a timing switch for the initiation ofcellular 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 mechanismsthat mediate the effects of thyroid hormone on adulthippocampal progenitors as yet remain largely uncharacter-ized. While a couple of studies have reported the role ofspecific TR isoforms in the regulation of adult hippocampalneurogenesis (Kapoor et al. 2010, 2011), these studies havebeen performed capitalizing on currently available whole-body TR knockout mouse lines without the advantage oftemporal and spatial control that would be provided byconditional knockout mouse lines.The role of TRa1, the predominant TR isoform that

constitutes about 70% of TR isoform expression in themammalian brain (Schwartz et al. 1992; Wallis et al. 2010),has been studied in the regulation of adult hippocampalneurogenesis using four different mutant mouse lines,namely TRa1�/�, TRa2�/� mice which exhibit TRa1over-expression, TRa1+/m heterozygous mice carrying apoint mutation (TRa1R384C) that lowers thyroid hormoneaffinity 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 ofhippocampal progenitors, whereas mice with an unligandedTRa1 aporeceptor, either through over-expression of TRa1as observed in the TRa2�/� mice or in the dominant-negative TRa1+/m mouse line with reduced ligand affinity,showed a significant decline in hippocampal progenitor

survival and neuronal differentiation (Kapoor et al. 2010).These effects are reminiscent of the decreased hippocampalprogenitor survival and neuronal differentiation observed inadult-onset hypothyroidism (Ambrogini et al. 2005; Desouzaet al. 2005; Montero-Pedrazuela et al. 2006), and the effectsin the TRa2�/� and TRa1+/m mouse lines were rescued byliganding the mutant TRa1 aporeceptor through exogenousthyroid hormone administration (Kapoor et al. 2010). Unli-ganded TRa1 could be a crucial contributing factor to thedetrimental effects of adult-onset hypothyroidism on hippo-campal neurogenesis, and has been speculated to thuscontribute to the cognitive and emotional dysfunctionobserved with hypothyroidism.Examination of GFP reporter expression in TRa1-GFP

knockin mouse models (Wallis et al. 2010) illustrates thatTRa1 is primarily expressed by post-mitotic hippocampalprogenitors committed to the acquisition of a neuronal fate,and does not seem to be expressed by proliferating progen-itors (Kapoor et al. 2010). This differs from in vitro studieswherein TRa1 gene expression is noted in proliferative cellswithin neurosphere cultures as well as dispersed hippocam-pal progenitors (Kapoor et al. 2012). It will be veryinteresting to ascertain the expression pattern of TR isoformsat the distinct stages of hippocampal progenitor developmentand to examine whether shifts in the stoichiometry of TRisoform expression are noted as progenitors undergo devel-opmental progression. Our results suggest the speculativepossibility that TRa1 aporeceptor activity arrests hippocam-pal progenitors at the early post-mitotic stage prior to theacquisition of NeuroD-positive identity and the commitmentto a neuronal fate, with enhanced targeting toward cell deathin the absence of the ligand thyroid hormone. Thyroidhormone may then serve as a switch to facilitate progressiontoward neuronal differentiation. Enhanced TRa1 expressionin post-mitotic hippocampal progenitors along with thebinding of the ligand thyroid hormone may serve as a timerswitch to initiate neuronal differentiation, in keeping withsuch functions demonstrated for TR isoforms in oligodendr-ocytic 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 regulateadult hippocampal progenitor turnover (Kapoor et al. 2011).Both TRb1 and TRb2 isoforms are expressed in thehippocampal neurogenic niche (Desouza et al. 2005; Kapooret al. 2012). TRb�/� mice exhibit increased hippocampalprogenitor proliferation as well as enhanced NeuroD-positivecell number, but no commensurate increase in DCX-positiveimmature neurons. TRb isoforms may exert an inhibitoryeffect on SGZ progenitor turnover, either as a consequence ofthe loss of T3-mediated inhibitory effects via TRb or throughthe absence of unliganded TRb evoked repression of celldivision. However, previous evidence of an adult hypothy-roidism evoked decline in progenitor turnover reported by



Montero-Pedrazuela et al. (2006) which can be rescued bythyroid hormone replacement, supports the notion thatenhanced proliferation in TRb�/� mice is likely throughthe loss of TRb aporeceptor-mediated repressive control ofprogenitor turnover. TRb isoforms are reported to attenuatethe mitogenic effects of growth factors such as epidermalgrowth factor and insulin-like growth factor 1 (IGF-1) intumor cell lines (Martinez-Iglesias et al. 2009). One canspeculate that the loss of TRb could also alter growth factordriven proliferation of hippocampal progenitors. However, itis also important to note that TRb�/� mice exhibit elevatedcirculating 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, forexample, TRa1 and the presence of enhanced circulatinglevels of thyroid hormone.While currently available TR mutant mice have provided a

degree of insight into the nature of TR-mediated effects onadult hippocampal neurogenesis, TR mutant mice come withthe caveat of a whole-body loss of function resulting inpotential alterations of circulating T3, T4, and TSH levels, aswell as the possibility of specific effects during embryonic andpostnatal neurodevelopment that may hamper interpretationof effects on adult neurogenesis (O’Shea and Williams 2002;Flamant and Gauthier 2013). Insights from other mutantmouse lines that perturb deiodinase expression as well asdisruption of thyroid hormone transporters (Darras et al.2013) would also further aid in providing a completeunderstanding of the effects of thyroid hormone on adulthippocampal neurogenesis. However, the key experimentsthat are required to gain deeper mechanistic insight necessitatethe generation of conditional TR isoform knockout mice thatexhibit selective perturbation of specific TR isoform expres-sion, as well as double mutants that perturb TR stoichiometricbalance, at specific stages of hippocampal progenitor devel-opment. These studies are required to critically analyze thecurrently prevalent hypothesis that Type 2b and Type 3 adulthippocampal progenitors are the key stages of hippocampalprogenitor development that exhibit thyroid hormone sensi-tivity, with an emerging role for thyroid hormone as animportant regulator of post-mitotic progenitor survival andneuronal cell fate specification. To further gain insights on theeffects of thyroid hormone in the neurogenic niche, studies arealso required in TR mutant mice that permit a temporal andspatial regulation of TR isoforms within specific componentsof the hippocampal neurogenic niche, such as the maturegranule cell neurons, astrocytes, and vasculature.

Thyroid hormone regulation of adult SVZneurogenesis

Stages of SVZ progenitor development

The SVZ lining the lateral ventricles contains the highestnumbers of dividing progenitors within the adult mammalian

brain. An estimated number of 30 000 progenitors aregenerated in the adult SVZ daily (Cameron and McKay2001; Ming and Song 2005). The SVZ is composed of theependymal layer facing the lumen of the lateral ventricle andthe adjoining proliferative zone with resident progenitor cellsof three types: ‘type B’ cells that are the predominantlyquiescent, multi-potent neural stem cells, the rapidly prolif-erating, transit amplifying cells or ‘type C’ cells; and themigrating neuroblasts or the ‘type A’ cells (Ming and Song2011) (Fig. 3). The radial glia-like type B cells expressGFAP, Nestin, and Sox2, and divide asymmetrically to self-renew and produce transiently amplifying type C daughtercells that are positive for the homeobox transcription factorDlx2 (Braun and Jessberger 2014; Vadodaria and Gage2014). Type A progenitors that are DCX and PSA-NCAMimmunopositive are migrating neuroblasts that follow atangential trajectory along the rostral migratory stream(RMS) to the olfactory bulb (OB), where they integrate intoexisting OB neurocircuitry differentiating into OB interneu-rons (granule cells and periglomerular neurons) (Sakamotoet al. 2014). The type of newborn OB interneuron generateddepends upon the rostrocaudal positioning of the progenitorsfrom which they arise (Ming and Song 2011; Sakamoto et al.2014). Most newborn progenitors within the SVZ are slatedfor death with a relatively small fraction migrating along theRMS to acquire OB interneuron identity (Zhao et al. 2008;Ming and Song 2011). Regulation of SVZ progenitorsurvival is observed at the neuroblast stage, as well as atthe timepoint of immature neuron integration. While thereare many similarities between neurogenesis in the SGZ andSVZ, amongst the most obvious differences is that SGZneurogenesis occurs entirely within the DG subfield withrelatively short distances for migration, whereas SVZprogenitors are born at relatively large distances from theirfinal destination and undergo tangential and then radialmigration to eventually become OB interneurons. SVZneurogenesis is tightly regulated through the orchestrationof both cell autonomous cues and non-cell autonomousfactors that respond to changes in the SVZ microenviron-ment, as well as altered environmental experiences of theanimal (Alvarez-Buylla and Garcia-Verdugo 2002). Severalreports indicate that newborn OB neurons are highlyresponsive to novel odorant cues, supporting the theory thatthe process of OB neurogenesis may actively participate inthe structural or physiological plasticity required for adap-tations 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 SVZneurogenesis, influencing multiple stages of SVZ progenitordevelopment (Fig. 3) (Lemkine et al. 2005; Lopez-Juarezet al. 2012). The TRa1 isoform is thus far thought to be the



only TR expressed within the SVZ, differing in this mannerfrom the SGZ where hippocampal progenitors expressmultiple TR isoforms (Lemkine et al. 2005; Lopez-Juarezet al. 2012). Within the adult SVZ, adult-onset hypothyroid-ism decreases progenitor proliferation, with evidence of afailure in progenitor cell cycle entry, an effect rescued by

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

(a)

(b)

(d)

(c)

Fig. 3 Thyroid hormone regulation of subventricular zone (SVZ)neurogenesis. Shown is a (a) sagittal and (b, upper panel) coronalsection of the brain depicting the SVZ lining the lateral ventricles (LV).

Shown are adult progenitors within the SVZ (b, lower panel) (c) SVZprogenitors traverse-specific developmental stages which are charac-terized by stage-specific marker expression. Type B cells are quies-

cent, multi-potent radial glia-like stem cells which divide asymmetricallyto self-renew and generate rapidly proliferating, transit amplifying typeC 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 andType 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 indicatesthe 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, TRa1holoreceptors are thought to repress gene transcription likely throughputative-negative TREs within the stem cell gene Sox2 and the cell

cycle genes Cyclin D1 and c-myc expression, thus hastening cell cycleexit and promoting stem cell progression toward the neuroblast stageand 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 anundifferentiated, proliferative state.



with reduced cell death observed in TTR null mice. TTR nullmice exhibit lowered thyroid hormone levels in the brain andsimilar to the effects of hypothyroidism appear to reduceapoptotic cell loss within the SVZ neurogenic niche (Rich-ardson et al. 2007). Nestin-positive progenitors in the SVZexhibit TRa expression, and TRa0/0 loss of function micephenocopy the effects of hypothyroidism with a hamperingof progenitor cell cycle progression (Lemkine et al. 2005).TRa1 is expressed by both transit amplifying type Cprogenitors and type A migratory neuroblasts in the SVZ(Lopez-Juarez et al. 2012). The absence of TRa1 in the typeB quiescent neural stem cells, and the appearance of TRa1 intransit amplifying progenitors and migratory neuroblastshave led to the hypothesis that TRa1 may predispose SVZprogenitors toward neuronal cell fate specification. In supportof this notion, TRa1 over-expression results in enhancednumbers of migratory neuroblasts (Lopez-Juarez et al.2012). The pro-neurogenic effects of TRa1 isoforms aresuggested to be mediated via repressive effects on theexpression of the neural stem cell gene Sox2 (Lopez-Juarezet al. 2012), and also through thyroid hormone-mediatedrepression of the cell cycle genes cyclinD1 and c-myc(Lemkine et al. 2005; Lopez-Juarez et al. 2012). Interest-ingly, TRa1 siRNA knockdown increases the number of typeB neural stem cells likely through the removal of thyroidhormone-mediated repressive effects on the stem cell geneSox2 (Lopez-Juarez et al. 2012). These results implicateligand-mediated TRa1 effects that promote progressiontoward neuronal differentiation via repression of the stemcell factor Sox2, and through a curtailing of cell cycleprogression by the repression of cell cycle genes. However,thus far reports do not indicate transcriptional activatoryeffects of T3/TRa1 on neurogenic gene expression of factorslike NeuroD, Ngn1/Ngn2 raising the question whetherthyroid hormone in the SVZ milieu plays a permissive roleversus an active switching on of proneural gene expression.In vitro studies with SVZ-derived progenitors indicate thatneural stem cells show a shift toward a more mature statewhen derived from hyperthyroid animals, with a shift towardoligodendrogenesis (Fernandez et al. 2004). Interestingly, arecent report indicates that thyroid hormone receptor inter-acting protein 6 (TRIP6), a zyxin family gene member, isrequired for SVZ-derived neural stem cell proliferation andinhibits differentiation, likely through effects on Notchsignaling (Lai et al. 2014). Thus far, no studies haveexamined the local expression of deiodinases and thyroidhormone transporters within the SVZ neurogenic niche. Thiswould add a further layer through which thyroid hormoneaction within the SVZ neurogenic milieu may be dynami-cally regulated.Thyroid hormone appears to influence SVZ and SGZ

progenitors through the TRa1 isoform, with critical sensi-tivity to thyroid hormone observed in type C and type Aprogenitor cells within the SVZ, and Type 2b and Type 3

progenitor cells in the SGZ (Lemkine et al. 2005; Kapooret al. 2012; Lopez-Juarez et al. 2012). The effects of thyroidhormone on cell survival within the SVZ and SGZ appear todiffer, with hypothyroidism associated with decreased celldeath in SVZ progenitors and enhanced cell death of SGZprogenitors, indicating that thyroid hormone effects on adultprogenitors may exhibit niche-specific effects. While thus farother TR isoforms have not been reported to be expressedwithin the SVZ neurogenic niche, it is important to carry outa systematic profiling to confirm that this is indeed the case.Furthermore, spatio-temporal control that facilitates stage-specific perturbation of TRa1 within the type B, A, and Ccells of the SVZ niche would help to clearly delineate thedistinct effects on these progenitor cell types, and also toidentify the specific target genes within these stages of SVZprogenitor development.

Putative molecular mechanisms for the neurogeniceffects of thyroid hormone

The action of thyroid hormone in modulating gene tran-scription is mediated by the TRa and TRb isoforms, that aremembers of the nuclear receptor superfamily and bind to thepromoters of target genes as homo- or hetero-dimers withretinoid-X-receptors (RXRs), to form TR-RXR-coregulatorcomplexes, at TREs in regulatory regions of thyroid hormonetarget genes (Wu et al. 2001; Lee and Privalsky 2005;Williams 2008; Tagami et al. 2009; Brent 2012). TRs canbind chromatin as liganded receptors or as unligandedaporeceptors (Chassande 2003; Bernal and Morte 2013) andeither enhance or repress transcription depending on thenature of the TRE. Most TREs are positive TREs, in whichTR aporeceptors repress gene transcription, whereas ligandedTRs function as transcriptional activators (Harvey andWilliams 2002; Liu and Brent 2010; Astapova and Hollen-berg 2013). Conversely, negative TREs are those whereintranscription is activated by unliganded TRs and repressed byligand binding to the TRs (Wu and Koenig 2000). Ligandedand unliganded TRs mediate their transcriptional effects viathe recruitment of coactivator/corepressor complexes thatserve as transcriptional mediators which communicate withtranscriptional machinery. Furthermore, these corepressors(Hu and Lazar 2000; Privalsky 2004; Astapova and Hollen-berg 2013) and coactivators (Goodman and Smolik 2000; Itoand Roeder 2001) are part of multi-subunit enzyme com-plexes, which in addition to histone acetylation/deacetylationfunctions, also have enzymes such as methylases, kinases,phosphatases, which interact in a combinatorial way with TRisoforms, to provide flexibility and yet specificity in mod-ulating gene expression (Cheng et al. 2010; Bernal andMorte 2013).Thus far, a detailed molecular analysis of the TR-

responsive transcriptional targets within the SVZ and SGZprogenitor pool is largely lacking. A global profiling of



putative thyroid hormone target genes in neural cells in vitrounveiled targets such as Sox2, Jun, Notch1, Notch4, Klf7,Ngf, Pax 9, and Slit2 (Chatonnet et al. 2013). Furthermore,studies during embryonic neurodevelopment have identifiedgenes such as reelin (Alvarez-Dolado et al. 1999), Stat3(Chen et al. 2012), Tag1 (Alvarez-Dolado et al. 2001), andDab (Alvarez-Dolado et al. 1999) as thyroid hormone targetgenes during embryonic neurodevelopment and may also beinfluenced within adult neurogenic niches by thyroidhormone, which remains to be experimentally tested. Thy-roid hormone could also influence the regulation of neuro-genesis promoting, niche-derived factors such as the growthfactor brain-derived neurotrophic factor (BDNF) (Giordanoet al. 1992; Koibuchi et al. 1999) and the developmentalmorphogen sonic hedgehog, whose expression in adulthoodis regulated by thyroid hormone (Desouza et al. 2011).However, a detailed characterization of thyroid hormoneresponsive target genes within either adult SVZ or SGZ adultprogenitors 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 thyroidhormone target genes in SVZ progenitors. A putative modelfor thyroid hormone action within the SVZ progenitors,suggests that TRa1 aporeceptors at negative TREs in theregulatory regions of Sox2, cyclinD1, and c-myc activate theexpression of these genes keeping SVZ progenitors in anundifferentiated, proliferative state (Lemkine et al. 2005;Lopez-Juarez et al. 2012). Ligand binding of thyroidhormone to TRa1 would then repress the expression ofSox2, cyclinD1, and c-myc and promote cell cycle exit andprogression to neuroblast formation (Fig. 3). It is importantto identify which specific SVZ progenitor stage exhibitsthese nature of thyroid hormone driven gene expressionresponses, and to test this model using genetic tools toperturb TRa1 and the selective target genes in a progenitor-stage-dependent fashion.While thyroid hormone responsive genes within the

hippocampal neurogenic niche have been studied usingin vivo gene expression analysis and through in vitroneurosphere experiments, future experiments with chromatinimmunoprecipitation and promoter analysis are required todetermine whether these are bona-fide thyroid hormonetarget genes. The mRNA expression of several proneuralgenes such as Tis21, Tlx, Dlx2, Math-1, and Ngn1 wasregulated by thyroid hormone in the hippocampal neurogenicniche following in vivo administration of thyroid hormone(Kapoor et al. 2012). T3 exposure in vivo resulted inenhanced expression of the pro-neurogenic transcriptionfactors Dlx2 and Tis21. Tis21 is expressed in Type 2 andType 3 progenitors, and Tis21 activation evokes an accel-erated differentiation of hippocampal progenitors similar tothe effects observed with thyroid hormone treatment (Farioli-Vecchioli et al. 2009; Attardo et al. 2010). Thyroid hormonealso enhanced the expression of the proneural genes Tlx,

Math-1, and Ngn1 (Kapoor et al. 2012), suggesting theactivation of a pro-neurogenic program in hippocampalprogenitors following thyroid hormone treatment. However,experiments that assess whether these are direct effects inhippocampal progenitors or mediated via the niche, andpromoter analysis to assess TRE-mediated effects on theexpression of these pro-neural genes are required to gain adeeper mechanistic insight. A current working model thatrequires experimental validation suggests that TRa1 apore-ceptors in Type 2b/3 hippocampal progenitors may evokerepressive effects on pro-survival factors and on proneuralgenes resulting in cell death. The TRa1 holoreceptor wouldserve to activate pro-survival genes and enhance pro-neuralgene expression, thus promoting neuroblast survival anddifferentiation into granule cell neurons within the hippo-campal neurogenic niche (Fig. 2).Future experiments to generate chromatin immunoprecip-

itation sequencing (ChIPseq) data with TR isoform-specificantibodies would immensely aid in the identification ofthyroid hormone target genes within SVZ and SGZprogenitors. This has been hampered to an extent throughthe lack of high-quality, TR isoform-specific ChIP gradeantibodies. However, studies that capitalize on the avail-ability of TR isoform-specific knockin mice with GFP(Dudazy-Gralla et al. 2013) or use ChAP experiments withGST-tagged TR isoforms or pan-RXR ChIPs (Chatonnetet al. 2013) have been used to yield insights into TR targetgenes in neural cells. A similar analysis with TR isoform-specific knockin mice or GST/FLAG/HA-tagged TR iso-forms could also be used to generate a genome wideidentification of TRE-binding sites using ChIP/ChAP assaysin SVZ and SGZ progenitors. It will also be important toexamine potential non-genomic effects of thyroid hormoneon adult progenitors within the SVZ and SGZ neurogenicniches, to address whether thyroid hormone alters growthhormone sensitivity through effects on signaling pathwayssuch as the MAPK kinase cascade or potentially withinastrocytes of the neurogenic niche influencing the secretionand release of neurogenesis modulating factors. The molec-ular mechanisms of the effects of TR isoforms and thyroidhormone on adult progenitors remains relatively poorlyunderstood and require in depth investigation to gain criticalmechanistic insights.

Behavioral implications of the neurogenic actionsof thyroid hormone

Thyroid hormone regulates hippocampal neurogenesis-dependent behaviors such as cognitive performance- andmood-related behavior (Ming and Song 2011; Miller andHen 2014), and also influences SVZ neurogenesis-relatedbehavioral outputs such as olfactory discrimination (Alvarez-Buylla and Garcia-Verdugo 2002). Adult-onset hypothyroid-ism is linked to an enhanced susceptibility for depression



(Dugbartey 1998; Jackson 1998; Berent et al. 2014; Demar-tini et al. 2014), and thyroid hormone is used clinically as aneffective adjunct to antidepressant therapy (Haggerty andPrange 1995; Henley and Koehnle 1997; Bauer andWhybrow 2001; Cooper-Kazaz et al. 2007; Uhl et al.2014). Furthermore, adult-onset hypothyroid status has beenlinked in clinical studies to impairments in learning, verbalfluency, 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 learningperformance (Fundaro 1989) and enhanced immobility onthe forced swim test following adult-onset hypothyroidism(Kulikov et al. 1997; Montero-Pedrazuela et al. 2006).These findings have led to the suggestion that disruptedthyroid status may evoke morphological changes within thehippocampus, a brain region strongly implicated in learning,memory, and mood. It is tempting to speculate that theprocess of adult hippocampal neurogenesis, which isimpaired following adult-onset hypothyroidism, may con-tribute causally to the impaired cognition and deficits inmood behavior observed in hypothyroidism.The adult-onset hypothyroidism effects on adult hippo-

campal neurogenesis have been suggested to arise because ofTRa1 aporeceptor activity, with support coming fromevidence that thyroid hormone administration can rescuethe neurogenic decline in both adult-onset hypothyroidanimals (Desouza et al. 2005) and also in animals withexcess TRa1 aporeceptor activity (Kapoor et al. 2010). Micecarrying a dominant-negative TRa1 (TRa1+/m) with a 10-fold reduced affinity to thyroid hormone exhibit increasedanxiety and impaired recognition memory, as well asdisplaying a steep decline in hippocampal neurogenesis,effects which are rescued upon exogenous thyroid hormoneadministration (Venero et al. 2005; Pilhatsch et al. 2010,2011). Taken together, these studies suggest that at least acomponent of the behavioral and neurogenic deficits asso-ciated with hypothyroidism could be a result of TRa1aporeceptor activity. In addition, to a putative role of adecline in hippocampal neurogenesis in the cognitive andemotional behavioral perturbations noted with adult-onsethypothyroidism, neurogenic effects of thyroid hormone mayalso bear relevance to the mood-elevating effects of thyroidhormone augmentation of antidepressant action. Chronicantidepressant treatments increase hippocampal neurogenesis(Malberg et al. 2000) and this effect is important for specificbehavioral actions of antidepressants (Santarelli et al. 2003;David et al. 2010). Thyroid hormone has been used clini-cally as an adjunct to antidepressant treatment and preclinicalstudies indicate a potentiation of the neurogenic effects ofantidepressants by simultaneous administration of thyroidhormone (Eitan et al. 2010). These results suggest a possiblerole for hippocampal neurogenesis in contributing to thetherapeutic benefits that ensue from thyroid hormoneaugmentation strategies in the treatment of depression.

The effects of thyroid hormone on SVZ neurogenesis maybear relevance to the modulation of olfactory discriminationby thyroid hormone. During postnatal life, thyroid hormoneappears to play an important role in olfactory pathwaydevelopment (Hoyk et al. 1996). In rodents, thyroid hor-mone deficiency results in a decrease in the total olfactoryepithelia surface area as well as the number of matureolfactory receptor neurons (Paternostro and Meisami 1991).The olfactory system appears to retain this sensitivity tothyroid hormone in the adult as well, with olfactory behaviorbeing altered in hypothyroid mice. Adult-onset hypothyroidanimals lose their sense of smell, an effect that can bereversed when euthyroid status is restored (Beard andMackay-Sim 1987). It is tempting to speculate that thedeficits in olfaction noted in hypothyroid patients mayinvolve a role for thyroid hormone in the SVZ neurogenicniche. It is also possible that lack of thyroid hormone mayhave a more direct effect on the neural cells of the peripheralnasal epithelium. This is supported by studies from rodentswhere hypothyroidism disrupted the development of neuronswithin the olfactory epithelium and thyroxine treatmentrestores neurogenesis within the olfactory epithelium(Mackay-Sim and Beard 1987; Paternostro and Meisami1993, 1996). Hyperthyroidism has been linked to bothaccelerated maturation of OB neurons and development ofolfactory responsiveness (Johanson 1980; Brunjes et al.1982), although it remains unclear if neurogenic changescontribute to these changes.Almost the entire gamut of animal model studies thus far

that have examined the neurogenic influence of perturbedthyroid hormone signaling have involved experimentalinduction of hypo- or hyperthyroidism, or the use of TRisoform-specific mutant mice. However, thyroid hormonesignaling-related pathologies also encompass ‘non-thyroidalillness syndrome’ through perturbations of local thyroidhormone metabolism despite normal circulating levels ofthyroid hormone. Perturbations of deiodinase activity, dys-function of thyrotropin releasing hormone and TSH release,changes in affinity of hormone and serum binding partners,alterations of thyroid hormone transporter expression andfunction, dysregulation of TR isoforms or in the stoichiom-etry and binding of components of the TR isoform-corepressor/coactivator complexes could all impinge onthyroid-hormone-related signaling (Farwell 2013). There isa paucity of animal model studies that address the impact ofdisrupted thyroid hormone signaling on adult neurogenesisthrough the nature of perturbations listed above, and thiscomponent is critical to gain a more nuanced understandingof the effects of thyroid hormone on adult neural stem cells.

Future directions

Thyroid hormone exerts a wide array of effects on the centralnervous system, both during development and in adulthood.



In the adult mammalian brain, thyroid hormone plays animportant role in the regulation of SGZ and SVZ neurogen-esis, promoting neuronal fate choice acquisition and regu-lating post-mitotic survival of progenitors. Within both ofthese neurogenic niches, the TRa1 receptor isoform has beenimplicated to play a crucial role in mediating the neurogenicinfluence of thyroid hormone. However, there are severalopen questions that require detailed future investigation.What is the nature of local thyroid hormone metabolismwithin the adult neurogenic niches? Do progenitors transportthyroid hormone through MCT8 transporters? Do astrocytesof the neurogenic milieu that are in close proximity to adultprogenitors contribute to the dynamic regulation of thyroidhormone bioavailability to progenitors? What are the stage-specific expression patterns of TR isoforms and how doestheir stoichiometry vary across progenitor developmentalprogression? The development of reporter mouse lines,including TR isoform-specific knockin mice TRa1-GFP(Wallis et al. 2010), as well as a transgenic thyroid reportermouse with a fusion protein of a yeast Gal4 DNA-bindingdomain and a TRa ligand-binding domain to drive reporterexpression (Quignodon et al. 2004), could serve as usefultools in defining the stage-specific expression of TR isoformsin adult neural progenitors. Experiments are required toaddress the TR isoform-specific apo- and holoreceptor genetargets in distinct stages of progenitor development. Further-more, do the specific TR isoform-recruited coactivator andcorepressor complexes vary across stages of progenitordevelopment? An understanding is also required of theepigenetic mechanisms that are recruited by thyroid hormoneand TR isoforms to promote progenitor exit from cell cycleand commitment to the acquisition of a neuronal fate.Finally, studies that address the importance of the neurogeniceffects of thyroid hormone on the cognitive, emotional, andsensory systems will identify potential targets for thetreatment of the neurological and psychiatric consequencesof adult-onset thyroid hormone dysfunction.

Acknowledgments and conflict of interestdisclosure

The support of the Tata Institute of Fundamental Research andDepartment of Science and Technology, Government of India, isgratefully acknowledged. The authors have no conflicts of interest todeclare.

All experiments were conducted in compliance with the ARRIVEguidelines.

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