Photoperiod, but not progesterone, has a strong impact upon the transcriptome of the medio-basal hypothalamus in female goats and ewes.

Photoperiod is the main environmental driver of seasonal responses in organisms living at temperate and polar latitudes. Other external cues such as food and temperature, and internal cues including hormones, intervene to fine-tune phasing of physiological functions to the solar year. In mammals, the medio-basal hypothalamus (MBH) is the key integrator of these cues, which orchestrates a wide array of seasonal functions, including breeding. Here, using RNAseq and RT-qPCR, we demonstrate that molecular components of the photoperiodic response previously identified in ewes are broadly conserved in does (female goats, Capra hircus), with a common core of ∼50 genes. This core group can be defined as the "MBH seasonal trancriptome", which includes key players of the pars tuberalis-tanycytes neuroendocrine retrograde pathway that governs intra-MBH photoperiodic switches of triiodothyronine (T3) production (Tshb, Eya3, Dio2 and SlcO1c1), the two histone methyltransferases Suv39H2 and Ezh2 and the secreted protein Vmo1. Prior data in ewes revealed that T3 and estradiol (E2), both key hormones for the proper timing of seasonal breeding, differentially impact the MBH seasonal transcriptome, and identified cellular and molecular targets through which these hormones might act. In contrast, information regarding the potential impact of progesterone (P4) upon the MBH transcriptome was nonexistent. Here, we demonstrate that P4 has no discernible transcriptional impact in either does or ewes. Taken together, our data show that does and ewes possess a common core set of photoperiod-responsive genes in the MBH and conclusively demonstrate that P4 is not a key regulator of the MBH transcriptome.

Highly-Sensitive In Vitro Bioassays for FSH, TSH, PTH, Kp, and OT in Addition to LH in Mouse Leydig Tumor Cell.

We demonstrate here that highly sensitive in vitro bioassays for FSH, TSH, and PTH can be set up in mouse Leydig Tumor Cells (mLTC), in addition to the normal LH/CG bioassay, after they were transfected with expression vectors encoding the corresponding Gs Protein-Coupled Receptors (GsPCR), such as FSHR, TSHR, or PTHR. Although the ß2 adrenergic receptor is also a GsPCR, its expression in mLTC led to a significant but very low cAMP response compared to those observed with FSH, TSH, or PTH. Similarly, after transfection of the GiPCR MT1 melatonin receptor, we did not observe any inhibitory effect by melatonin of the LH or hCG stimulation. Interestingly, after transfection of mLTC with the human kisspeptin receptor (hKpR), which is a GqPCR, we observed a dose-dependent synergy of 10-12-10-7 M kisspeptin variants with a fixed concentration of 0.3 nM LH or hCG. Without any exogenous receptor transfection, a 2 h preincubation with OT or AVP led to a dose-dependent cAMP response to a fixed dose of LH or hCG. Therefore, highly sensitive in vitro bioassays for various hormones and other GPCR ligands can be set up in mLTC to measure circulating concentrations in only 3-10 µL of blood or other body fluids. Nevertheless, the development of an LHRKO mLTC cell line will be mandatory to obtain strict specificity for these bioassays to eliminate potential cross-reaction with LH or CG.

Interactions between ß-endorphin and kisspeptin neurons of the ewe arcuate nucleus are modulated by photoperiod.

Opioid peptides are well-known modulators of the central control of reproduction. Among them, dynorphin coexpressed in kisspeptin (KP) neurons of the arcuate nucleus (ARC) has been thoroughly studied for its autocrine effect on KP release through κ opioid receptors. Other studies have suggested a role for ß-endorphin (BEND), a peptide cleaved from the pro-opiomelanocortin precursor, on food intake and central control of reproduction. Similar to KP, BEND content in the ARC of sheep is modulated by day length and BEND modulates food intake in a dose-dependent manner. Because KP levels in the ARC vary with photoperiodic and metabolic status, a photoperiod-driven influence of BEND neurons on neighboring KP neurons is plausible. The present study aimed to investigate a possible modulatory action of BEND on KP neurons located in the ovine ARC. Using confocal microscopy, numerous KP appositions on BEND neurons were found but there was no photoperiodic variation of the number of these interactions in ovariectomized, estradiol-replaced ewes. By contrast, BEND terminals on KP neurons were twice as numerous under short days, in ewes having an activated gonadotropic axis, compared to anestrus ewes under long days. Injection of 5 µg BEND into the third ventricle of short-day ewes induced a significant and specific increase of activated KP neurons (16% vs. 9% in controls), whereas the percentage of overall activated (c-Fos positive) neurons, was similar between both groups. These data suggest a photoperiod-dependent influence of BEND on KP neurons of the ARC, which may influence gonadotropin-releasing hormone pulsatile secretion and inform KP neurons about metabolic status.

Short photoperiod modulates behavior, cognition and hippocampal neurogenesis in male Japanese quail.

The mechanisms underlying the photoperiodic control of reproduction in mammals and birds have been recently clarified. In contrast, the potential impact of photoperiod on more complex, integrative processes, such as cognitive behaviors, remains poorly characterized. Here, we investigated the impact of contrasted long and short photoperiods (LP, 16 h light/day and SP, 8 h light/day, respectively) on learning, spatial orientation abilities, and emotional reactivity in male Japanese quail. In addition, we quantified cell proliferation and young cell maturation/migration within the hippocampus, a brain region involved in spatial orientation. Our study reveals that, in male quail, SP increases emotional responses and spatial orientation abilities, compared to LP. Behaviorally, SP birds were found to be more fearful than LP birds, exhibiting more freezing in the open field and taking longer to exit the dark compartment in the emergence test. Furthermore, SP birds were significantly less aggressive than LP birds in a mirror test. Cognitively, SP birds were slower to habituate and learn a spatial orientation task compared to LP birds. However, during a recall test, SP birds performed better than LP birds. From a neuroanatomical standpoint, SP birds had a significantly lower density of young neurons, and also tended to have a lower density of mature neurons within the hippocampus, compared to LP birds. In conclusion, our data reveal that, beyond breeding control, photoperiod also exerts a profound influence on behavior, cognition, and brain plasticity, which comprise the seasonal program of this species.

Impact of food restriction on the medio-basal hypothalamus of intact ewes as revealed by a large-scale transcriptomics study.

In mammals, the medio-basal hypothalamus (MBH) integrates photoperiodic and food-related cues to ensure timely phasing of physiological functions, including seasonal reproduction. The current human epidemics of obesity and associated reproductive disorders exemplifies the tight link between metabolism and reproduction. Yet, how food-related cues impact breeding at the level of the MBH remains unclear. In this respect, the sheep, which is a large diurnal mammal with a marked dual photoperiodic/metabolic control of seasonal breeding, is a relevant model. Here, we present a large-scale study in ewes (n = 120), which investigated the impact of food restriction (FRes) on the MBH transcriptome using unbiased RNAseq, followed by RT-qPCR. Few genes (~100) were impacted by FRes and the transcriptional impact was very modest (<2-fold increase or < 50% decrease for most genes). As anticipated, FRes increased expression of Npy/AgRP/LepR and decreased expression of Pomc/Cartpt, while Kiss1 expression was not impacted. Of particular interest, Eya3, Nmu and Dio2, genes involved in photoperiodic decoding within the MBH, were also affected by FRes. Finally, we also identified a handful of genes not known to be regulated by food-related cues (e.g., RNase6, HspA6, Arrdc2). In conclusion, our transcriptomics study provides insights into the impact of metabolism on the MBH in sheep, which may be relevant to human, and identifies possible molecular links between metabolism and (seasonal) reproduction.

How does apelin affect LH levels? An investigation at the level of GnRH and KNDy neurons.

Hypothalamic control of reproduction relies on GnRH and kisspeptin (KP) secretions. KP neurons are sensitive to sex steroids and metabolic status and their distribution overlaps with neurons producing apelin, a metabolic hormone known to decrease LH secretion in rats. Here, we observed neuroanatomical contacts between apelin fibers and both KP and GnRH neurons in the hypothalamus of male rodents. Intracerebroventricular apelin infusion for 2 weeks in male mice did not decrease LH levels nor did it affect gene expression for KP, neurokinin B and dynorphin. Finally, increasing apelin concentrations did not modulate Ca2+ levels of cultured GnRH neurons, while 10 µM apelin infusion on forskolin pretreated GnRH neurons revoked a rhythmic activity in 18% of GnRH neurons. These results suggest that acute apelin effect on LH secretion does not involve modulation of gene expression in KP neurons but may affect the secretory activity of GnRH neurons.

GnRH and the photoperiodic control of seasonal reproduction: Delegating the task to kisspeptin and RFRP-3.

Synchronization of mammalian breeding activity to the annual change of photoperiod and environmental conditions is of the utmost importance for individual survival and species perpetuation. Subsequent to the early 1960s, when the central role of melatonin in this adaptive process was demonstrated, our comprehension of the mechanisms through which light regulates gonadal activity has increased considerably. The current model for the photoperiodic neuroendocrine system points to pivotal roles for the melatonin-sensitive pars tuberalis (PT) and its seasonally-regulated production of thyroid-stimulating hormone (TSH), as well as for TSH-sensitive hypothalamic tanycytes, radial glia-like cells located in the basal part of the third ventricle. Tanycytes respond to TSH through increased expression of thyroid hormone (TH) deiodinase 2 (Dio2), which leads to heightened production of intrahypothalamic triiodothyronine (T3) during longer days of spring and summer. There is strong evidence that this local, long-day driven, increase in T3 links melatonin input at the PT to gonadotropin-releasing hormone (GnRH) output, to align breeding with the seasons. The mechanism(s) through which T3 impinges upon GnRH remain(s) unclear. However, two distinct neuronal populations of the medio-basal hypothalamus, which express the (Arg)(Phe)-amide peptides kisspeptin and RFamide-related peptide-3, appear to be well-positioned to relay this seasonal T3 message towards GnRH neurons. Here, we summarize our current understanding of the cellular, molecular and neuroendocrine players, which keep track of photoperiod and ultimately govern GnRH output and seasonal breeding.

Microbiota and stress: a loop that impacts memory.

Chronic stress and the gut microbiota appear to comprise a feed-forward loop, which contributes to the development of depressive disorders. Evidence suggests that memory can also be impaired by either chronic stress or microbiota imbalance. However, it remains to be established whether these could be a part of an integrated loop model and be responsible for memory impairments. To shed light on this, we used a two-pronged approach in Japanese quail: first stress-induced alterations in gut microbiota were characterized, then we tested whether this altered microbiota could affect brain and memory function when transferred to a germ-free host. The cecal microbiota of chronically stressed quails was found to be significantly different from that of unstressed individuals with lower α and ß diversities and increased Bacteroidetes abundance largely represented by the Alistipes genus, a well-known stress target in rodents and humans. The transfer of this altered microbiota into germ-free quails decreased their spatial and cue-based memory abilities as previously demonstrated in the stressed donors. The recipients also displayed increased anxiety-like behavior, reduced basal plasma corticosterone levels and differential gene expression in the brain. Furthermore, cecal microbiota transfer from a chronically stressed individual was sufficient to mimic the adverse impact of chronic stress on memory in recipient hosts and this action may be related to the Alistipes genus. Our results provide evidence of a feed-forward loop system linking the microbiota-gut-brain axis to stress and memory function and suggest that maintaining a healthy microbiota could help alleviate memory impairments linked to chronic stress.

Photoperiod is involved in the regulation of seasonal breeding in male water voles (Arvicola terrestris).

Mammals living at temperate latitudes typically display annual cyclicity in their reproductive activity: births are synchronized when environmental conditions are most favorable. In a majority of these species, day length is the main proximate factor used to anticipate seasonal changes and to adapt physiology. The brain integrates this photoperiodic signal through key hypothalamic structures, which regulate the reproductive axis. In this context, our study aimed to characterize regulations that occur along the hypothalamo-pituitary-gonadal (HPG) axis in male fossorial water voles (Arvicola terrestris, also known as Arvicola amphibius) throughout the year and to further probe the implication of photoperiod in these seasonal regulations. Our monthly field monitoring showed dramatic seasonal changes in the morphology and activity of reproductive organs, as well as in the androgen-dependent lateral scent glands. Moreover, our data uncovered seasonal variations at the hypothalamic level. During the breeding season, kisspeptin expression in the arcuate nucleus (ARC) decreases, while RFRP3 expression in the dorsomedial hypothalamic nucleus (DMH) increases. Our follow-up laboratory study revealed activation of the reproductive axis and confirmed a decrease in kisspeptin expression in males exposed to a long photoperiod (summer condition) compared with those maintained under a short photoperiod (winter condition) that retain all features reminiscent of sexual inhibition. Altogether, our study characterizes neuroendocrine and anatomical markers of seasonal reproductive rhythmicity in male water voles and further suggests that these seasonal changes are strongly impacted by photoperiod.

Field study reveals morphological and neuroendocrine correlates of seasonal breeding in female water voles, Arvicola terrestris.

Seasonally breeding mammals display timely physiological switches between reproductive activity and sexual rest, which ensure synchronisation of births at the most favourable time of the year. These switches correlate with seasonal changes along the hypothalamo-pituitary-gonadal axis, but they are primarily orchestrated at the hypothalamic level through environmental control of KISS1-dependent GnRH release. Our field study shows that births of fossorial water voles, Arvicola terrestris, are concentrated between March and October, which indicates the existence of an annual reproductive cycle in this species. Monthly field monitoring for over a year further reveals dramatic seasonal changes in the morphology of the ovary, uterus and lateral scent glands, which correlate with the reproductive status. Finally, we demonstrate seasonal variation in kisspeptin expression within the hypothalamic arcuate nucleus. Altogether, this study demonstrates a marked rhythm of seasonal breeding in the water vole and we speculate that this is governed by seasonal changes in photoperiod.

Thyroid hormone and hypothalamic stem cells in seasonal functions.

Seasonal rhythms are a pervasive feature of most living organisms, which underlie yearly timeliness in breeding, migration, hibernation or weight gain and loss. To achieve this, organisms have developed inner timing devices (circannual clocks) that endow them with the ability to predict then anticipate changes to come, usually using daylength as the proximate cue. In Vertebrates, daylength interpretation involves photoperiodic control of TSH production by the pars tuberalis (PT) of the pituitary, which governs a seasonal switch in thyroid hormone (TH) availability in the neighboring hypothalamus. Tanycytes, specialized glial cells lining the third ventricle (3V), are responsible for this TH output through the opposite, PT-TSH-driven, seasonal control of deiodinases 2/3 (Dio 2/3). Tanycytes comprise a photoperiod-sensitive stem cell niche and TH is known to play major roles in cell proliferation and differentiation, which suggests that seasonal control of tanycyte proliferation may be involved in the photoperiodic synchronization of seasonal rhythms. Here we review our current knowledge of the molecular and neuroendocrine pathway linking photoperiodic information to seasonal changes in physiological functions and discuss the potential implication of tanycytes, TH and cell proliferation in seasonal timing.

The piggyBac-derived protein 5 (PGBD5) transposes both the closely and the distantly related piggyBac-like elements Tcr-pble and Ifp2.

The vertebrate piggyBac derived transposase 5 (PGBD5) encodes a domesticated transposase, which is active and able to transpose its distantly related piggyBac-like element (pble), Ifp2. This raised the question whether PGBD5 would be more effective at mobilizing a phylogenetically closely related pble element. We aimed to identify the pble most closely related to the pgbd5 gene. We updated the landscape of vertebrate pgbd genes to develop efficient filters and identify the most closely related pble to each of these genes. We found that Tcr-pble is phylogenetically the closest pble to the pgbd5 gene. Furthermore, we evaluated the capacity of two murine and human PGBD5 isoforms, Mm523 and Hs524, to transpose both Tcr-pble and Ifp2 elements. We found that both pbles could be transposed by Mm523 with similar efficiency. However, integrations of both pbles occurred through both proper transposition and improper PGBD5-dependent recombination. This suggested that the ability of PGBD5 to bind both pbles may not be based on the primary sequence of element ends, but may involve recognition of inner DNA motifs, possibly related to palindromic repeats. In agreement with this hypothesis, we identified internal palindromic repeats near the end of 24 pble sequences, which display distinct sequences.

The C-terminal Domain of piggyBac Transposase Is Not Required for DNA Transposition.

PiggyBac(PB)-like elements (pble) are members of a eukaryotic DNA transposon family. This family is of interest to evolutionary genomics because pble transposases have been domesticated at least 9 times in vertebrates. The amino acid sequence of pble transposases can be split into three regions: an acidic N-terminal domain (~100 aa), a central domain (~400 aa) containing a DD[D/E] catalytic triad, and a cysteine-rich domain (CRD; ~90 aa). Two recent reports suggested that a functional CRD is required for pble transposase activity. Here we found that two CRD-deficient pble transposases, a PB variant and an isoform encoded by the domesticated PB-derived vertebrate transposase gene 5 (pgbd5) trigger transposition of the Ifp2 pble. When overexpressed in HeLa cells, these CRD-deficient transposases can insert Ifp2 elements with proper and improper transposon ends, associated with deleterious effects on cells. Finally, we found that mouse CRD-deficient transposase Pgbd5, as well as PB, do not insert pbles at random into chromosomes. Transposition events occurred more often in genic regions, in the neighbourhood of the transcription start sites and were often found in genes predominantly expressed in the human central nervous system.

No evidence that Spexin impacts LH release and seasonal breeding in the ewe.

Spexin (SPX) is a recently identified peptide hormone of 14 amino acids. Interestingly, Spx and Kiss1 genes share a common ancestor gene. Considering that KISS1 peptides are key controllers of breeding in mammals and circumstantial evidence that SPX regulates gonadotropins in some fish species, we hypothesized that SPX may play a KISS1-related role in sheep. Here, we cloned the ovine Spx cDNA, performed in vivo injection and infusion of SPX (i.c.v. route, with or without concomittant KISS1 presence) and assessed a potential regulation of Spx expression by season, thyroid hormone and estradiol in the medio-basal hypothalamus of the ewe. Our data do not provide support for a role of SPX in the control of the gonadotropic axis in the ewe.

Photoperiodic induction without light-mediated circadian entrainment in a High Arctic resident bird.

Organisms use changes in photoperiod to anticipate and exploit favourable conditions in a seasonal environment. While species living at temperate latitudes receive day length information as a year-round input, species living in the Arctic may spend as much as two-thirds of the year without experiencing dawn or dusk. This suggests that specialised mechanisms may be required to maintain seasonal synchrony in polar regions. Svalbard ptarmigan (Lagopus muta hyperborea) are resident at 74-81°N latitude. They spend winter in constant darkness (DD) and summer in constant light (LL); extreme photoperiodic conditions under which they do not display overt circadian rhythms. Here, we explored how Arctic adaptation in circadian biology affects photoperiodic time measurement in captive Svalbard ptarmigan. For this purpose, DD-adapted birds, showing no circadian behaviour, either remained in prolonged DD, were transferred into a simulated natural photoperiod (SNP) or were transferred directly into LL. Birds transferred from DD to LL exhibited a strong photoperiodic response in terms of activation of the hypothalamic thyrotropin-mediated photoperiodic response pathway. This was assayed through expression of the Eya3, Tshß and deiodinase genes, as well as gonadal development. While transfer to SNP established synchronous diurnal activity patterns, activity in birds transferred from DD to LL showed no evidence of circadian rhythmicity. These data show that the Svalbard ptarmigan does not require circadian entrainment to develop a photoperiodic response involving conserved molecular elements found in temperate species. Further studies are required to define how exactly Arctic adaptation modifies seasonal timer mechanisms.

Debunking the Myth of the Endogenous Antiangiogenic Vegfaxxxb Transcripts.

In this opinion article we critically assess evidence for the existence of a family of antiangiogenic vascular endothelial growth factor (Vegfaxxxb) transcripts, arising from the use of a phylogenetically conserved alternative distal splice site within exon 8 of the VEGFA gene. We explain that prior evidence for Vegfaxxxb transcripts in tissues rests heavily upon flawed RT-PCR methodologies, with the extensive use of 5'-tailing in primer design being the main issue. Furthermore, our analysis of large RNA-seq data sets (human and ovine) fails to identify a single Vegfaxxxb transcript. Therefore, we challenge the very existence of Vegfaxxxb transcripts, which further questions the physiological relevance of studies based on the use of 'anti-VEGFAxxxb' antibodies. Our analysis has implications for the proposed therapeutic use of isoform-specific anti-VEGFA strategies for treating cancer and retinopathies.

Circuit-level analysis identifies target genes of sex steroids in ewe seasonal breeding.

Thyroid hormone (TH) and estradiol (E2) direct seasonal switches in ovine reproductive physiology. In sheep, as in other mammals and birds, control of thyrotropin (TSH) production by the pars tuberalis (PT) links photoperiod responsiveness to seasonal breeding. PT-derived TSH governs opposite seasonal patterns of the TH deiodinases Dio2/Dio3 expression in tanycytes of the neighboring medio-basal hypothalamus (MBH), which explain the key role of TH. We recently used RNA-Seq to identify seasonal markers in the MBH and define the impact of TH. This impact was found to be quite limited, in terms of number of target genes, and very restricted with regards to neuroanatomical location, as TH specifically impacts genes expressed in tanycytes and hypothalamus, not in the PT. Here we address the impact of E2 on these seasonal markers, which are specifically expressed in either PT, tanycytes or hypothalamus. We also investigate if progesterone (P4) may be involved in timing the seasonal transition to anestrus. Our analysis provides circuit-level insights into the impact of sex steroids on the ewe seasonal breeding cycle. First, seasonal gene expression in the PT is independent of the sex steroid status. The fact that seasonal gene expression in the PT is also TH-independent strengthens the view that the PT is a circannual timer. Second, select tanycytic markers display some level of responsiveness to E2 and P4, which indicates another potential level of feedback control by sex steroids. Third, Kiss1 neurons of the arcuate nucleus are responsive to both TH and E2, which places them at the crossroads of photoperiodic transduction pathway and sex steroid feedback. This provides strong support to the concept that these Kiss1 neurons are pivotal to the long-recognized "seasonal switch in the ability of E2 to exert negative feedback", which drives seasonal breeding.

Discontinuity in the molecular neuroendocrine response to increasing daylengths in Ile-de-France ewes: Is transient Dio2 induction a key feature of circannual timing?

In mammals, melatonin is responsible for the synchronisation of seasonal cycles to the solar year. Melatonin is secreted by the pineal gland with a profile reflecting the duration of the night and acts via the pituitary pars tuberalis (PT), which in turn modulates hypothalamic thyroid hormone status via seasonal changes in the production of locally-acting thyrotrophin. Recently, we demonstrated that, in the Soay sheep, photoperiodic induction of Tshb expression and consequent downstream hypothalamic changes occur over a narrow range of photoperiods between 12 and 14 hours in duration. In the present study, we aimed to extend our molecular characterisation of this pathway, based on transcriptomic analysis of photoperiodic changes in the pituitary and hypothalamus of ovariectomised, oestradiol-implanted Ile-de-France ewes. We demonstrate that photoperiodic treatments applied before the winter solstice elicit two distinctive modes of accelerated reproductive switch off compared to ewes held on a simulated natural photoperiod, with shut-down occurring markedly faster on photoperiods of 13 hours or more than on photoperiods of 12 hours and less. This pattern of response was reflected in gene expression profiles of photoperiodically sensitive markers, both in the PT (Tshb, Fam150b, Vmo1, Ezh2 and Suv39H2) and in tanycytes (Tmem252 and Dct). Unexpectedly, the expression of Dio2 in tanycytes did not show any noticeable increase in expression with lengthening photoperiods. Finally, the expression of Kiss1, the key activator of gonadotrophin-releasing hormone release, was proportionately decreased by lengthening photoperiods, in a pattern that correlated strongly with gonadotrophin suppression. These data show that stepwise increases in photoperiod lead to graded molecular responses at the level of the PT, a progressive suppression of Kiss1 in the hypothalamic arcuate nucleus and luteinising hormone/follicle-stimulating hormone release by the pituitary, despite apparently unchanged Dio2 expression in tanycytes. We hypothesise that this apparent discontinuity in the seasonal neuroendocrine response illustrates the transient nature of the thyroid hormone-mediated response to long days in the control of circannual timing.

An integrative view of mammalian seasonal neuroendocrinology.

Seasonal neuroendocrine cycles that govern annual changes in reproductive activity, energy metabolism and hair growth are almost ubiquitous in mammals that have evolved at temperate and polar latitudes. Changes in nocturnal melatonin secretion regulating gene expression in the pars tuberalis (PT) of the pituitary stalk are a critical common feature in seasonal mammals. The PT sends signal(s) to the pars distalis of the pituitary to regulate prolactin secretion and thus the annual moult cycle. The PT also signals in a retrograde manner via thyroid-stimulating hormone to tanycytes, which line the ventral wall of the third ventricle in the hypothalamus. Tanycytes show seasonal plasticity in gene expression and play a pivotal role in regulating local thyroid hormone (TH) availability. Within the mediobasal hypothalamus, the cellular and molecular targets of TH remain elusive. However, two populations of hypothalamic neurones, which produce the RF-amide neuropeptides kisspeptin and RFRP3 (RF-amide related peptide 3), are plausible relays between TH and the gonadotrophin-releasing hormone-pituitary-gonadal axis. By contrast, the ways by which TH also impinges on hypothalamic systems regulating energy intake and expenditure remain unknown. Here, we review the neuroendocrine underpinnings of seasonality and identify several areas that warrant further research.