Download Seasonality_and_T3_manuscript_revision

Banks et al
1
2
3
Running title: Light and thyroid regulation of reproduction and immune function.
4
5
6
Title: Photoperiod- and triiodothyronine-dependent regulation of reproductive neuropeptides, pro-
7
inflammatory cytokines and peripheral physiology in Siberian hamsters (Phodopus sungorus).
8
9
Authors: Ruth Banks1, 2, Mirela Delibegovic2, Tyler J Stevenson1
10
11
Affiliation: 1Institute for Biological and Environmental Sciences, 2Institute for Medical Sciences,
12
University of Aberdeen, Aberdeen, United Kingdom
13
14
15
16
17
18
19
20
21
22
Contact:
23
Disclosure statement: The authors have nothing to declare.
Tyler Stevenson
Institute for Biological and Environmental Sciences
University of Aberdeen
Aberdeen, United Kingdom
[email protected]
24
1
Banks et al
25
Abstract
26
Seasonal trade-offs in reproduction and immunity are ubiquitous in nature. The mechanisms that
27
govern transitions across seasonal physiological states appear to involve reciprocal switches in the
28
local synthesis of thyroid hormone. In long day (LD) summer-like conditions, increased
29
hypothalamic triiodothyronine (T3) stimulates gonadal development. Alternatively, short day (SD)
30
winter-like conditions, increase peripheral leukocytes and enhance multiple aspects of immune
31
function. These data indicate that the localized effects of T3 in the hypothalamus and leukocytes are
32
photoperiod-dependent. We tested the hypothesis that increased peripheral T3 in SD conditions
33
would increase aspects of reproductive physiology and inhibit immune function, whereas T3
34
injections in LD conditions would facilitate aspects of immune function (i.e. leukocytes).
35
Additionally, we also examined whether T3 regulates hypothalamic neuropeptide expression as well
36
as hypothalamic and splenic pro-inflammatory cytokine expression. Adult male Siberian hamsters
37
were maintained in LD (15L: 9D) or transferred to SD (9L:15D) for 8 weeks. A subset of LD and
38
SD hamsters were treated daily with 5 µg T3 for 2 weeks. LD and SD controls were injected with
39
saline. Daily T3 administration in SD hamsters (SD+T3) resulted in a rapid and substantial decrease
40
in peripheral leukocyte concentrations and stimulated gonadal development. T3 treatment in LD
41
(LD+T3) had no effect on testicular volumes, but significantly increased leukocyte concentrations.
42
Molecular analyses revealed that T3 stimulated interleukin 1β mRNA expression in the spleen and
43
inhibited RFamide Related Peptide-3 mRNA expression in the hypothalamus. Moreover, there was
44
a photoperiod-dependent decrease in splenic tumour necrosis factor-α mRNA expression. These
45
findings reveal that T3 has tissue-specific and photoperiod-dependent regulation of seasonal
46
rhythms in reproduction and immune function.
47
48
Key words: Circannual, thyroid, immune, rodent, photoperiod
49
2
Banks et al
50
Introduction
51
Seasonal rhythms in reproduction and immunity are common in temperate species (Nelson,
52
2004; Stevenson & Prendergast, 2015). Seasonal temporal strategies are important as they
53
coordinate energetic activities across the year; winter is generally associated with reduced energy
54
availability but requires the highest energy demands (Nelson et al., 1998; Sheldon & Verhulst,
55
1996). Seasonal rhythms in hormones involved in energy balance, such as leptin, have been
56
implicated as mediators of yearly trade-offs according to energetic demands (Drazen et al., 2001;
57
Demas, 2004). Thyroid hormones are also key regulators of energy balance and form an integral
58
part of the neuroendocrine regulation of seasonal rhythms (Ebling, 2014). Thyroid hormones are
59
similarly potent immunomodulators (Dorshkind and Horseman, 2000). Thus, thyroid hormones are
60
poised to mediate seasonal trade-offs in energetic demands involved in timing reproduction and
61
immune function.
62
Several neuropeptides located in the hypothalamus are involved in regulating the
63
neuroendocrine timing of seasonal reproduction, such as gonadotropin-releasing hormone (gnrh;
64
Stevenson et al., 2012), kisspeptin (kiss; Greives et al., 2007) and RFamide-related peptide 3 (rfrp3;
65
Tsutsui et al., 2013). The annual change in day length is a predictive proximate cue that drives
66
seasonal variation in the timing of reproduction (Stevenson & Ball, 2011). Increased summer day
67
length (LD) triggers the local synthesis of triiodothyronine (T3) in the mediobasal hypothalamus
68
leading to gonadotropin secretion and subsequent gonadal development (Yoshimura, 2015; Rani &
69
Kumar, 2014). Moreover, increased hypothalamic T3 is proposed to regulate the expression of
70
several neuropeptides involved in the control of seasonal reproduction; such as RFRP3 and KiSS1
71
(Henson et al., 2013). Hypothalamic RFRP3 expression in both Siberian and Syrian hamsters is
72
greater in LD compared to short day conditions (SD; Ubuka et al., 2012; Mason et al., 2010,
73
respectively). T3 implants or exogenous T3 injection in SD hamsters has been shown to induce
74
growth of the gonads (Freeman et al., 2007; Barrett et al., 2007; Klosen et al., 2013). Daily T3
75
administration also acts in the hypothalamus to trigger increased anteroventral periventricular
3
Banks et al
76
nucleus KiSS1, decreased arcuate nucleus KiSS1 and increased RFRP3 expression (Henson et al.,
77
2013). It is clear that thyroid hormones are an integral component of the neuroendocrine circuitry
78
that regulates seasonal reproduction; however, the local role of triiodothyronine in the timing of
79
annual rhythms in immune function is in its infancy.
80
Unlike seasonal rhythms in reproduction, immune function does not exhibit an overall
81
potentiation or involution during any phase of the yearly cycle (Nelson, 2004; Sheldon & Verhulst,
82
1996). Instead, the immune system displays a collection of trait-specific enhancements at specific
83
times across the year. Short winter-like photoperiods (SD) lead to enhanced immunosurveillance
84
capacity (e.g. leukocyte proliferation; Bilbo et al., 2002; Stevenson et al., 2014). However, in some
85
rodent species, humoral immune function is suppressed following adaptation to SD conditions
86
(Drazen et al., 2000; Drazen et al., 2001). Thyroid hormones have been implicated in the regulation
87
of multiple aspects of immune function, including T3 enhanced T-cell dependent (Type IV)
88
delayed-type hypersensitivity reactions (DTH) skin responses (Chandel & Chatterjee, 1989),
89
mitogen-induced splenocyte proliferation and blood leukocyte concentrations (Chatterjee &
90
Chandel, 1983). In Siberian hamsters, SD leukocytes have increased intracellular T3 concentrations;
91
the local synthesis is likely involved in the timing of SD enhanced immune function, such as
92
memory T-cell dependent adaptive immune responses (DTH; Stevenson et al., 2014). Furthermore,
93
exogenous T3 in LD conditions induced an increase in peripheral leukocyte concentrations to values
94
similar to SD hamsters (Stevenson et al., 2014). These data indicate that in addition to regulating
95
the neuroendocrine control of seasonal reproduction, T3 has a powerful effect on enhancing trait-
96
specific aspects of immunity.
97
These patterns indicate a dual role of thyroid hormones for the seasonal control of
98
reproduction and immune function: LD hypothalamic T3 stimulates neuroendocrine mechanisms
99
that trigger gonadal development and SD enhances leukocyte-T3 mediated components of immune
100
function. The goal of this paper was to examine the sufficiency of T 3 to drive photoperiodic
101
dependent switches in immune and reproductive function in LD and SD conditions, respectively. To
4
Banks et al
102
examine this goal, we sought to establish whether daily peripheral administration of T3 for 2 weeks
103
in LD and SD conditions would induce inverse effects on reproduction and immunosurveillance.
104
We hypothesised that T3 would facilitate measures of immune function in LD and stimulate
105
reproductive development in SD animals. Siberian hamsters (Phodopus sungorus) are a common
106
laboratory animal used to investigate seasonal biology. A simple switch in day length from LD (15
107
hrs light) to SD (9 hrs light) triggers a range of genetic and physiological changes leading to
108
gonadal involution and immune plasticity (Heldmaier et al., 1981; Bartness & Wade, 1985; Bilbo et
109
al., 2002; Prendergast et al., 2013; Stevenson et al., 2014). In order to assess the sufficiency of
110
triiodothyronine on regulating neuroendocrine control of seasonal reproduction and immune
111
function we examined photoperiodic and daily injections of T3 on hypothalamic expression of two
112
neuropeptides, gnrh and rfrp3, and downstream effects on body mass and testicular volume. We
113
also surveyed the number of circulating leukocytes and proinflammantory cytokine expression in
114
the hypothalamus and spleen, well-established measures of immune function (Dhabhar et al., 1995,
115
Yellon et al., 1999, Bilbo et al., 2002). Finally, we investigated whether daily T3 injections, would
116
in part, regulate the expression of two pro-inflammatory cytokines: interleukin-1β (il1β) and tumor-
117
necrosis factor-α (tnfα).
118
119
Materials and methods
120
Subjects
121
Adult male hamsters (N=31; 3-6 month old) were randomly selected from a colony maintained at
122
the University of Aberdeen. Hamsters were housed in polypropylene cages illuminated for 15h/day
123
(15L: 9D). Food and water were provided ad libitum; cotton-nesting material was available in the
124
cage. All procedures were approved by the Animal Welfare and Ethics Review Board at the
125
University of Aberdeen and conducted under the Home Office licence (70/7917).
126
127
Study design
5
Banks et al
128
Hamsters were group housed in LD (n=15) or transferred to SD (9L: 15D; n=16) cabinets for 8
129
weeks (Arrowmight, Hereford UK). LD and SD hamsters were then divided into two treatment
130
groups that received daily saline controls (LD+S and SD+S) or T3 injections (LD+ T3 and SD+ T3).
131
The final treatment group sample sizes were LD+S (n=9), LD+ T3 (n=6), SD+S (n=8) and SD+ T3
132
(n=8). Body mass and estimated testes volume (ETV see below) were measured to confirm SD
133
induced weight loss and gonadal involution (PRE). Body mass was determined using aeADAM
134
scales (Adam Equipment PGL2002) and measured to ±0.1g. In order to evaluate the effect of
135
exogenous T3 on peripheral physiology as well as hypothalamic and splenic mRNA expression,
136
hamsters were given daily subcutaneous (s.c.) injections of 5 µg T3/ 100g (T2877, Sigma-Aldrich)
137
for 2 weeks. This dose and injection regimen was selected based on previous work that revealed a
138
significant increase in circulating leukocytes in LD male hamsters (Stevenson et al., 2014).
139
Peripheral T3 readily crosses the blood brain barrier, mediated in part by transporters such as
140
Monocarboxylate transporter 8 (Heuer, 2007). Hypothalamic MCT8 exhibits photoperiodic
141
variation and is proposed to facilitate the local concentration of T3 in brain regions implicated in the
142
neuroendocrine control of seasonal rhythms (Herwig et al., 2013). SD and LD control hamsters
143
received s.c. saline (0.1 ml) for the same 2 week period. Body weight measurements and ETVs
144
were collected after 2 weeks of daily injections (POST).
145
146
Estimated Testes Volume (ETV)
147
ETVs were used to determine the response to photoperiod and T3, in brief; ETV is calculated by
148
testis width squared multiplied by length. Hamsters were lightly anaesthetized with
149
isofluorane:oxygen vapours (4% induction; 1% maintenance) and testes were measured using
150
analogue callipers. This approach to assess reproductive state is widely used as it is strongly
151
correlated with actual testicular volume (Gorman and Zucker, 1995). Testicular volumes of
152
hamsters indicated reproductive competence (LD) or gonadal involution (SD).
153
6
Banks et al
154
Leukocyte analyses
155
At the termination of the study, hamsters were anesthetized with isoflurane gas (4%) and 500 µl
156
whole blood was collected via the right retroorbital sinus using Natelson tubes coated with sodium
157
heparin. A 30 µl aliquot of blood was mixed with 3% acetic acid at a 1:20 dilution. Leukocyte were
158
counted under light microscope (Zeiss Axioskop) and values were obtained according to methods
159
reported previously (Stevenson et al., 2014, Prendergast et al., 2003).
160
161
Quantification of hypothalamic and splenic RNA expression
162
Hypothalamic and spleen tissue was rapidly dissected as previously described (Stevenson &
163
Prendergast, 2013) and frozen in powder dry ice. RNA was extracted from tissues using Trizol
164
(ThermoFisher Scientific). Nucleic acid concentration and quality were determined by
165
spectrophotometer (Nanodrop, Thermo Scientific). cDNA was synthesized using Superscript III
166
(Invitrogen) and cDNA was stored at -20ºC until quantitative PCR was performed. All cDNA tissue
167
samples were run in triplicate. qPCRs for mRNA expression in hypothalamic tissue were performed
168
using BIORAD CFX96, splenic mRNA were assayed using Roche LightCycler 480. qPCR
169
parameters were as follows: i) an initial denature at 95°C for 30 secs, then 39 cycles of ii) 95°C for
170
10 sec, iii) annealing dependent on target mRNA (See Table 1) for 30 secs and then iv) an extension
171
at 72°C for 30 sec. A melting curve analysis was added to determine the quality and specificity of
172
each reaction. Quantification of mRNA expression levels was accomplished with iQ Sybr Green
173
Supermix (BIORAD, UK). We used PCR Miner (Zhao & Fernald 2005) to calculate reaction
174
efficiencies (E) and cycle thresholds (CTs). According to the MIQE guidelines, samples that had
175
efficiency values below 0.8 or above 1.2 were excluded from analyses (Bustin et al., 2009). The
176
expression levels of hypothalamic transcript were determined using glyceraldehyde 3-phosphate
177
dehydrogenase (gapdh) as the reference. For splenic transcripts, we used the average of 18s and
178
hrpt cycling time. Fold change in expression for all target transcripts was calculated using 2-(delta-
179
deltaCt).
7
Banks et al
180
181
Statistical analyses
182
Repeated Two-way ANOVA was conducted to examine the effects of T3 on body mass and ETVs.
183
Leukocyte counts, hypothalamic and splenic mRNA expression were analysed using Two-way
184
ANOVAs. Post-hoc analyses were performed using Fisher’s LSD method. Log-transformation was
185
performed on mRNA values when violations of normality were observed. Statistical analyses were
186
performed using SigmaStat 12.0 and difference considered significant when P<0.05.
187
188
Results
189
Photoperiod- and T3- regulation of peripheral physiology.
190
Repeated Two-way ANOVA revealed a significant interaction of photoperiod and T3
191
treatment on hamster body mass (F=20.72; P<0.001; Fig1A). Post-hoc analyses confirmed that
192
saline injected controls did not exhibit a significant change in body mass after 2 weeks of daily
193
injections (P>0.08 for LD+S and SD+S). Daily T3 injections were found to significantly reduce
194
body weight in LD+T3 (P<0.001) and SD+T3 (P<0.001).
195
Daily T3 injections lead to a significant increase in ETV only in SD housed hamsters
196
(F=5.34; P<0.005; Fig1B). Post-hoc analyses indicated that both LD and SD hamsters injected with
197
daily saline maintained constant ETV levels (P>0.85). Similarly, daily T3 injections did not
198
significantly augment ETV in LD hamsters (P<0.05). In SD, T3 injections resulted in a significant
199
increase in ETV (P<0.001). These data suggest that T3 has photoperiod-dependent effects on
200
testicular volumes; there was a stimulatory effect only after gonadal involution had occurred.
201
Two-way ANOVA also revealed a significant interaction on leukocyte concentrations
202
(F=54.61; P<0.001; Fig1C). Consistent with previous publications, post-hoc analyses confirmed
203
that SD hamsters had significantly greater peripheral leukocyte numbers compared to LD controls
204
(P<0.001). Daily T3 injections had significant photoperiod-dependent effects; LD hamsters had
205
significantly greater leukocyte counts (P<0.001), whereas under SD, there was a reduction
8
Banks et al
206
(P<0.001). These robust findings indicate that exogenous T3 can have opposing effects on leukocyte
207
numbers that is, in part, regulated by photoperiodic history.
208
Hypothalamic mRNA expression is regulated by photoperiodic condition.
209
Next, we examined the impact of photoperiodic condition and exogenous T3 on the
210
expression of reproductive neuropeptides gnrh and rfrp3 as well as pro-inflammatory cytokines il1β
211
and tnfα expression. We did not detect significant variation in gnrh expression across photoperiodic
212
(F=0.36; P=0.55; Fig2A), T3 treatment (F=0.22; P=0.64) or interaction (F=0.61; P=0.44). We
213
observed a significant photoperiodic effect on rfrp3 expression with reduced levels in SD hamsters
214
(F=54.87; P<0.001; Fig2B). Furthermore, daily T3 injections also reduced rfrp3 expression (F=5.20;
215
P<0.05). There was no significant interaction for rfrp3 expression (F=0.33; P=0.57).
216
Analyses of hypothalamic il1β and tnfα indicate that these cytokines are constitutively
217
expressed across photoperiodic and are not regulated by T3. There was no significant photoperiod
218
(F=2.05; P=0.16; Fig2C), T3 dependent (F=0.01; P=0.98) or interaction (F=1.64; P=0.21) for il1β
219
expression. Similarly, tnfα expression was not driven by photoperiod (F=0.08; P=0.78; Fig2D),
220
daily T3 (F=0.34; P=0.56) or driven by an interaction of the two factors (F=2.81; P=0.10). Overall,
221
these data suggest that T3 does not appear to regulate pro-inflammatory cytokine expression in the
222
hamster hypothalamus.
223
T3 regulation of proinflammatory cytokines in the hamster spleen
224
We found that il1β expression was significantly upregulated in the hamster spleen after two
225
weeks of daily T3 injection (F=28.12; P<0.001; Fig3A). However, there was no significant
226
photoperiod effect (F=2.34; P=0.14) or a significant interaction (F=0.18; P=0.67).
227
Two-way ANOVA revealed a significant main effect of daily T3 on spleen tnfα expression
228
(F=5.63; P<0.05). There was no significant main effect of photoperiod (F=0.58; P=0.45) or
229
significant interaction (F=1.85; P=0.19). Post-hoc analyses indicated that T3 induced reductions in
230
tnfα expression was primarily due to lower levels in SD+T3 hamster compared to SD+S (P=0.01).
231
There was no significant difference between LD+S and LD+T3 (P=0.55).
9
Banks et al
232
233
234
Discussion
In this study, we show that exposure to SD reduced body weight, testicular volume and
235
enhanced circulating leukocyte concentrations in adult male Siberian hamsters.
236
corroborates that hamsters maintained in LD photoperiods have greater hypothalamic RFRP3
237
expression compared to SD-photo-regressed animals (Ubuka et al., 2012; Mason et al., 2010). We
238
identified that T3 injections led to a significant inhibition in peripheral leukocyte concentrations in
239
SD hamster (i.e. SD+T3), a modest increase in ETV and reduced body mass. Furthermore, daily T3
240
significantly reduced spleen tnfα expression only in SD hamsters. We reveal that T3 categorically
241
decreased hypothalamic rfrp3 expression and increased spleen il1β expression, regardless of
242
photoperiodic condition. These data indicate that exogenous T3 treatment exerts distinct
243
photoperiod- as well as cell- and tissue-specific control over measures of immune and reproduction
244
function.
Our work
245
This study permitted the dissection of timescale effects of T3 induced changes in multiple
246
aspects of organismal physiology. Circulating concentrations of T4 and T3 do not exhibit
247
photoperiodic variation and instead maintain constitutive levels in the periphery (O’Jile and
248
Bartness, 1992). Cell-specific expression of thyroid hormone enzymes, referred to as deiodinases
249
(DIO) are critical for regulating intracellular levels of T4 and T3 (St Germain et al., 2009). Thus,
250
photoperiodic regulation of hypothalamic and leukocytes DIO expression provides the ability to
251
enhance the effects of T3 on localized genomic and physiological function (Prendergast et al., 2013;
252
Stevenson et al., 2014; Stevenson & Prendergast, 2015). T3 injections in SD hamsters induced a
253
51% inhibition in peripheral leukocytes, 40% increase in ETV and a negligible effect on body mass
254
(3% inhibition; within margin of error). Our findings also illustrate that T3 effects on peripheral
255
physiology and immune function are photoperiod-dependent. In LD hamsters, body mass was
256
significantly reduced, there was no change in testicular volume and leukocytes increased to levels
10
Banks et al
257
comparable to SD controls. These data suggest that the diverse tissues/cells of the peripheral
258
nervous system exhibit photoperiodic- and T3- dependent regulation.
259
Previous work has illustrated that both central and peripheral exogenous T3 stimulates
260
reproductive development in the SD phenotype (Freeman et al., 2007; Klosen et al., 2013; Barrett et
261
al., 2007). Here, we confirm that daily T3 in SD hamsters (SD+T3) significantly increased ETV.
262
However, we observed that T3 reduced hypothalamic rfrp3 expression; regardless of photoperiodic
263
condition. Henson and colleagues (2013) demonstrated that the numbers of RFRP3 cells determined
264
by immunocytochemistry are greater after daily T3 in SD hamsters. Since we observed a reduction
265
in rfrp3 expression in LD+T3; it is likely that T3 has an inhibitory effect on RFRP3 function in the
266
hamster hypothalamus. We propose that T3 inhibits rfrp3 expression and the greater RFRP3 cell
267
numbers observed by Henson and colleagues (2013) likely reflects an accumulation of protein
268
content due to reduced transport/release from nerve terminals. Our findings also provide evidence
269
that chronic exposure to photoperiod and T3 does not regulate gnrh expression. Indeed
270
hypothalamic GnRH content exhibits slight variation during rapid transitions from LD to SD
271
conditions (Bernard et al., 1999). It remains possible that acute changes in local T3 could augment
272
hypothalamic GnRH expression. These data indicate that T3 mediated effects on neuroendocrine-
273
gonadal axis is likely due to the reduction in rfrp3 expression leading to gonadal development in
274
SD hamsters. The absence of any effect on testicular volumes in LD is presumably the result of a
275
‘ceiling-effect’ in which the testes are already at, or near, maximum volume.
276
In this paper, we confirm that LD+T3 hamsters have greater blood leukocyte concentrations
277
compared to LD+S (Stevenson et al., 2014) and reveal that T3 effects are photoperiod-dependent as
278
SD+T3 exhibit significantly lower concentrations. We suggest that the reduced leukocytes in SD-T3
279
are not the result of direct inhibition on immune function by thyroid hormones. Instead, peripheral
280
T3 may be involved in diverting energy demands in SD hamsters to testicular growth and
281
subsequent steroidogenesis (e.g. testosterone). The increase energy demands for reproduction
282
and/or the increased production of testosterone reduces leukocyte counts and ultimately, immune
11
Banks et al
283
function (Prendergast et al., 2003; Trigunaite et al., 2015). At a molecular level, we demonstrate
284
that T3 significantly increased splenic il1β expression. T3 has been shown to stimulate il1β
285
expression in human bone marrow stromal cells (Kim et al., 1999) suggesting that T3 can potentiate
286
il1β expression across diverse tissues. Interestingly, we did not detect a significant difference in
287
hypothalamic il1β expression indicating a degree of tissue-specific regulation. A similar pattern was
288
observed for tnfα expression as T3 significantly reduced spleen levels in a photoperiod-dependent
289
manner and showed complete absence of an effect on hypothalamic expression. In addition to the
290
spleen, T3 increased tnfα expression in Kupffer (Valencia et al., 2004) and liver cells (Tapia et al.,
291
2003). Thus, T3 has a powerful effect on multiple aspects of immune function (i.e. leukocytes and
292
pro-inflammatory cytokine expression) that is driven by photoperiodic history and is tissue-specific.
293
In conclusion, our results indicate that localised signalling of T3 differentially regulates
294
seasonal timing in immune and reproduction function. T3 has direct effects on pro-inflammatory
295
cytokine expression in spleen tissue and hypothalamic rfrp3 expression. In both cases, T3 effects on
296
rfrp3 and il1β are regulated independent of photoperiod condition. However, T3 effects on
297
peripheral measures are photoperiod-dependent; enhanced leukocytes in LD and gonadal
298
development in SD. We propose that enhanced peripheral T3 concentration overrides the presiding
299
photoperiodic signal, directly stimulates reproductive development in SD and indirectly leads to the
300
inhibition in leukocyte cells.
301
302
Acknowledgements
303
The study hypotheses and design were conceived by TJS. RB and TJS conducted, collected and
304
analysed the data. RB, MD and TJS wrote the paper. This work was financed by the University of
305
Aberdeen College of Life Sciences and Medicine fund to TJS. We thank Elisabetta Tolla for her
306
technical assistance.
307
308
References
12
Banks et al
309
Barrett P Ebling FJ Schuhler S Wilson D Ross AW Warner A Jethwa P Boelen A Visser TJ Ozanne
310
DM Archer ZA Mercer JG Morgan PJ (2007) Hypothalamic thyroid hormone catabolism acts
311
as a gatekeeper for the seasonal control of body weight and reproduction. Endocrinol.
312
148:3608-3617.
313
314
Bartness TJ Wade GN (1985) Photoperiodic control of seasonal body weight cycles in hamsters.
Neurosci. Biobehav. Rev. 9:599-612.
315
Bernard DJ Avuav-Nussbaum R Horton TH Turek FW (1999) Photoperiodic effects on
316
gonadotropin-releasing hormone (GnRH) content and the GnRH-immunoreactive neuronal
317
system of male Siberian hamsters. Biol Reprod. 60:272-276.
318
Bilbo SD Dhabhar FS Viswanathan K Saul A Yellon SM Nelson RJ (2002) Short day lengths
319
augment stress-induced leukocyte trafficking and stress-induced enhancement of skin immune
320
function. Proc Natl Acad Sci. 99:4067-4072.
321
Bustin SA Benes V Garson JA Hellemans J Huggett J Kubista M Mueller R Nolan T Pfaffl MW
322
Shipley GL Vandesompele J Wittwer CT (2009) The MIQE guidelines: minimum
323
information for publication of quantitative real-time PCR experiments. Clin Chem. 55:611-
324
622.
325
326
Chandel AS Chatterjee S (1989) Effect of thyroid hormones on delayed type hypersensitivity
reaction. Indian J Exp Biol 27:408-411.
327
Chatterjee S Chandel AS (1983) Immunomodulatory role of thyroid hormones: in vivo effect of
328
thyroid hormones on the blastogenic response of lymphoid tissues. Acta Endocrinol (Copenh)
329
103:95-100.
330
331
332
333
Demas GE (2004) The energetic of immunity: a neuroendocrine link between energy balance and
immune function. Horm Behav. 45:173-180.
Dhabhar FS Miller AH McEwen BS Spencer RL (1995) Effects of stress on immune cell
distribution, dynamics and hormonal mechanisms. J Immunol. 154:5511-5527.
13
Banks et al
334
Dorshking K Horseman ND (2000) The roles of prolactin, growth hormone, insulin-like growth
335
factor-I and thyroid hormone in leukocyte development and function: insights from genetic
336
models of hormone and hormone receptor deficiency. Endocr Rev. 21:292-312.
337
338
Drazen DL Klein SL Yellon SM Nelson RJ (2000) In vitro melatonin treatment enhances
splenocyte proliferation in prairie voles. J Pineal Res. 28:34-40.
339
Drazen DL Demas DL Nelson RJ (2001) Leptin effects on immune function and energy balance are
340
photoperiod dependent in Siberian hamsters (Phodopus sungorus). Endocrinol. 142:2768-
341
2775.
342
343
344
345
346
347
Ebling FJ (2014) On the value of seasonal mammals for identifying mechanisms underlying the
control of food intake and body weight. Horm Behav. 66:56-64.
Freeman DA, Teubner BJW Smith CD Prendergast BJ (2007) Exogenous T3 mimics long day
lengths in Siberian hamsters. Am. J. Physiol. 292:R2368-R2372.
Gorman MR Zucker I (1995) Seasonal adaptation of Siberian hamsters II. Pattern of change in day
length controls annual testicular and body weight rhythms. Biol. Reprod. 53:116–125.
348
Greives TJ Mason AO Scotti MA Levine J Ketterson ED Kriegsfeld LJ Demas GE (2007)
349
Environmental control of kisspeptin: implications for seasonal reproduction. Endocrinol.
350
148:1158-1166.
351
352
Heldmaier G Steinlechner S Rafael J Vsiansky P (1981) Photoperiodic control and effects of
melatonin on nonshivering thermogenesis and brown adipose tissue. Science 212:917-919.
353
Henson JR Carter SN Freeman DA (2013) Exogenous T3 elicits long day-like alterations in testis
354
size and the RFamides Kisspeptin and gonadotropin-inhibitory hormone in short-day Siberian
355
hamsters. J Biol Rhythms 28:193-200.
356
Herwig A de Vries EM Bolborea M Wilson D Mercer JG Ebling FJP Morgan PJ Barrett P (2013)
357
Hypothalamic ventricular ependymal thyroid hormone deiodinases are an important element
358
of circannual timing in the Siberian hamster. PLoS One 8(4):e62003
14
Banks et al
359
360
Heuer H (2007) The importance of thyroid hormone transporters for brain development and
function. Best Pract Res Clin Endocrinol Metab 21:265–267.
361
Kim CH Kim HK Shong YK Lee KU Kim GS (1999) Thyroid hormone stimulates basal and
362
interleukin (IL)-1 induced IL-6 production in human bone marrow stromal cells: a possible
363
mediator of thyroid hormone induced bone-loss. J Endocrinol. 160:97-102.
364
Klosen P Sebert ME Rasri K Laran-Chich PM Simonneaux V (2013). TSH restores a summer
365
phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin. FASEB J
366
27:1-10.
367
Mason AO Duffy S Zhao S Ubuka T Bentley GE Tsutsui K Silver R Kriegsfeld LJ (2010)
368
Photoperiod and reproductive condition are associated with changes in RFamide-related
369
peptide (RFRP) expression in Syrian hamsters (Mesocricetus auratus). J Biol Rhythms,
370
25:176-185.
371
Nelson RJ (2004) Seasonal immune function and sickness responses. Cell 25:187- 192.
372
Nelson RJ Demas GE Klein SL (1998) Photoperiodic mediation of seasonal breeding and immune
373
374
375
function in rodents: a multifactorial approach. Am Zool 38:226-237.
O’Jile JR Bartness TJ (1992) Effects of thyroxine on the photoperiodic control of energy balance
and reproductive status in Siberian hamsters. Physiol. Behav. 52:267-270.
376
Prendergast BJ Hotchkiss AK Nelson BJ (2003) Photoperiodic regulation of circulating leukocytes
377
in juvenile Siberian hamsters: mediation by melatonin and testosterone. J Biol Rhythms
378
18:473-480.
379
Prendergast BJ Pyter LM Kampf-Lassin A Patel PN Stevenson TJ (2013) Rapid induction of
380
hypothalamic iodothyronine deiodinase expression by photoperiod and melatonin in juvenile
381
Siberian hamsters (Phodopus sungorus). Endocrinol. 154:831-841.
382
383
Rani S Kumar V (2014) Photoperiodic regulation of seasonal reproduction in higher vertebrates.
Indian J Exp Biol. 52:413-419.
15
Banks et al
384
385
386
387
388
389
390
391
Sheldon BC Verhulst S (1996) Ecological immunology: costly parasite defences and trafe-offs in
evolutionary ecology. Trends Ecol Evol. 11:317-321.
Stevenson TJ Ball GF (2011) Information theory and the neuropeptidergic regulation of seasonal
reproduction in birds and mammals. Proc. Biol Sci 278:2477-2485.
Stevenson TJ Hahn TP MacDougall-Shackleton SA Ball GF (2012) Gonadotropin-releasing
hormone plasticity: a comparative perspective. Front Neuroendocrinol. 33:287-300.
Stevenson TJ Prendergast BJ (2013) Reversible DNA methylation regulates seasonal photoperiodic
time measurement. Proc Natl Acad Sci. 110:16651-16656.
392
Stevenson TJ Onishi KG Bradley SP Prendergast BJ (2014) Cell-autonomous iodothyronine
393
deiodinase expression mediates seasonal plasticity in immune function. Brain Behav. Immun.
394
36:61-70.
395
396
Stevenson TJ Prendergast BJ (2015) Photoperiodic time measurement and seasonal immunological
plasticity. Front Neuroendocrinol. 37:76-88.
397
St. Germain DL Galton VA Hernandez A (2009) Minireview: defining the roles of the
398
iodothyronine deiodinases: current concepts and challenges. Endocrinol. 150:1097-1107.
399
Tapia G Fernandez V Varela P Cornejo P Guerrero J Videla LA (2003) Thyroid hormone-induced
400
oxidative stress triggers nuclear factor-κβ activation and cytokine gene expression in rat liver.
401
Free Radic Biol Med. 35:257-265.
402
403
Trigunaite A Dimo J Jorgensen TN (2015) Suppressive effects of androgens on the immune system.
Cell Immunol. 294:87-94.
404
Tsutsui K Ubuka T Bentley GE Kriegsfeld KJ (2013) Review: regulatory mechanisms of
405
gonadotropin-inhibitory hormone (GnIH) synthesis and release in photoperiodic animals.
406
Front Neurosci. 7:60.
407
Ubuka T Inoue K Fukuda Y Mizuno T Ukena K Kriegsfeld LJ Tsutsui K (2012) Identification,
408
expression and physiological functions of Siberian hamster gonadotropin-inhibitory hormone.
409
Endocrinol. 153:373-385.
16
Banks et al
410
Valencia C Cornejo P Romanque P Tapia G Varala P Videla LA Fernandez V (2004) Effects of
411
acute lindane intoxication and thyroid hormone administration in relation to nuclear factor κβ
412
activation, tumor necrosis factor-α expression and Kupffer cell function in the rat. Toxicol
413
Lett 148:21-28.
414
415
Yellon SM Fagoaga OR Nehlsen-Cannarella SL (1999) Influence of photoperiod on immune cell
functions in the male Siberian hamster. Am. J. Physiol. 276:R97–R102.
416
Yoshimura T Yasuo S Watanabe M Iigo M Yamamura T Hirunagi K Ebihara S (2003) Light-
417
induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds.
418
Nature 426:178-181.
419
420
Zhao S Fernald RD 2005 Comprehensive algorithm for quantitative real-time polymerase chain
reaction. J Comput Bio. 12:1047-1064.
17