Avian Endocrinology Eds A Dawson & C M Chaturvedi Copyright @ 2000 Narosa Publishing House, New Delhi, India Downstream from corticosterone: seasonality of binding globulins, receptors and behavior in the Avian stress response C W Breuner and M Orchinik Department of Biology, Box 871501, Arizona State University, Tempe,AZ 85287-1501, USA Introduction Seasonal animalsface different challenges depending on the time of year. During the breeding season, birds must find enough food to supportthemselves and their nestlings while defending their nests and territories against predators and conspecifics. During. migration, energetic demandsand nutrient intake change dramatically between migratory flights and stopovers. During winter, birds are often subjectto harshweatherand spatially unpredictable food resources. As the seasons change, metabolic needs and behavioral strategies also change. Because glucocorticoids affect both metabolism and behavior, it is not surprising that the adrenocortical response to stress is also modulated seasonally. Recent studies have worked towards an understanding of the functional significance of seasonal changes in the hypothalamic-pituitary-adrenal (HPA) axis. For example, baseline and stress-induced corticosterone (CaRT) levels during molt are low compared to levels throughout the rest of the year in manypasserines (1, 3, 7, 11, 37-39, 51). One hypothesis is that lower CaRT levels during molt protect energy reserves and protein stores for feather growth (1, 3, 38). Another example is found among species that breedin extremeenvironments. Someof these speciesshowreduced adrenocortical responses to stressduring the breeding season; this may promote higher toleranceof environmental perturbations, so that theseanimals successfully raiseyoung despite extreme environmental change (36, 50, 53, 55). The majority of hypothesesregarding seasonalvariation in the stress response arebased on changes in plasma concentrations of corticosterone (CaRT). However, multiple physiological components besides circulating levels of CaRT per se are involved in the organismal stress response. In this review, we focus on events downstream of the HP A-axis, in particular the interaction of CaRT with corticosteroid binding globulins (CBG), corticosteroidreceptors, and behavior. Corticosteroid-binding globulins are importantbecause they can alter the amount of free CaRT available to the tissues. Thus, seasonal changes in CBG may accentuate or diminishthe seasonal changes in free CaRT, relative to total CaRT. Corticosteroid receptors are important because they determine tissue and organismal sensitivityto particular levels of free CaRT. In some species, free or total CaRT may be higher during nesting than molt, but the cellular or organismal responses to elevated hormone during cannot be predicted a priori, without information about the tissue levels of corticosteroid receptors. Studies on behavioraleffectsof CaRT can help to elucidate the mechanism of CaRT action.
Transcript
Avian Endocrinology
Eds A Dawson & C M Chaturvedi
Copyright @ 2000 Narosa Publishing House, New Delhi, India
Downstream from corticosterone: seasonality of bindingglobulins, receptors and behavior in the Avian stressresponse
C W Breuner and M Orchinik
Department of Biology, Box 871501, Arizona State University, Tempe, AZ85287-1501, USA
IntroductionSeasonal animals face different challenges depending on the time of year. Duringthe breeding season, birds must find enough food to support themselves and theirnestlings while defending their nests and territories against predators andconspecifics. During. migration, energetic demands and nutrient intake changedramatically between migratory flights and stopovers. During winter, birds areoften subject to harsh weather and spatially unpredictable food resources. As theseasons change, metabolic needs and behavioral strategies also change. Becauseglucocorticoids affect both metabolism and behavior, it is not surprising that theadrenocortical response to stress is also modulated seasonally. Recent studies haveworked towards an understanding of the functional significance of seasonalchanges in the hypothalamic-pituitary-adrenal (HPA) axis. For example, baselineand stress-induced corticosterone (CaRT) levels during molt are low compared tolevels throughout the rest of the year in many passerines (1, 3, 7, 11, 37-39, 51).One hypothesis is that lower CaRT levels during molt protect energy reserves andprotein stores for feather growth (1, 3, 38). Another example is found amongspecies that breed in extreme environments. Some of these species show reducedadrenocortical responses to stress during the breeding season; this may promotehigher tolerance of environmental perturbations, so that these animals successfullyraise young despite extreme environmental change (36, 50, 53, 55).
The majority of hypotheses regarding seasonal variation in the stressresponse are based on changes in plasma concentrations of corticosterone (CaRT).However, multiple physiological components besides circulating levels of CaRTper se are involved in the organismal stress response. In this review, we focus onevents downstream of the HP A-axis, in particular the interaction of CaRT withcorticosteroid binding globulins (CBG), corticosteroid receptors, and behavior.Corticosteroid-binding globulins are important because they can alter the amountof free CaRT available to the tissues. Thus, seasonal changes in CBG mayaccentuate or diminish the seasonal changes in free CaRT, relative to total CaRT.Corticosteroid receptors are important because they determine tissue andorganismal sensitivity to particular levels of free CaRT. In some species, free ortotal CaRT may be higher during nesting than molt, but the cellular or organismalresponses to elevated hormone during cannot be predicted a priori, withoutinformation about the tissue levels of corticosteroid receptors. Studies onbehavioral effects of CaRT can help to elucidate the mechanism of CaRT action.
2 SeasonalitY of corticosterone binding. Breuner and Orchinik
For example, evaluating the rapidity of the behavioral response to CaRT canindicate which corticosteroid recep,tor mediates the response. We believe that afuller understanding of the behavioral and physiological significance of the stressresponse in seasonal animals requires that we understand the regulation of"downstream" components, such as plasma binding globulins and corticosteroidreceptors. Our goal here is to review information on the seasonal regulation ofthese "downstream" components, towards the end of understanding themechanisms behind the seasonality of the behavioral response to CaRT in birds.For a review of seasonality of the adrenocortical response to stress, see Romero'sreview in this book, and Wingfield et al. from the previous ISAE proceedings (50).
Corticosteroid binding globulinCorticosteroid binding globulin (CBG), a protein that binds corticosterone 'withhigh affinity (-2nM (7,10,16,52)), has been found in every avian species that hasbeen studied (e.g. 10, 16,37,38,46,52). CBG is known to regulate bioavailabilityand metabolic clearance of CaRT (19). Determination of CBG binding capacityusing equilibrium saturation binding experiments is relatively straightforward.Once CBG capacity and total CaRT titers are known, free CaRT titers can beestimated using the mass action-based equation of Barsano and Baumann (4):
HiraI! = 0.5 X [H;olal -Bmax -1/ Ka ::!:~(Bmax -Hlolal + 1/ Ka)2 -4(H;alal / KaQ
in which Hfree = free hormone, Htotal = total hormone, Bmax = total binding capacity
ofCBG, and Ka =1/Kd
Seasonality in CBGSeasonal regulation of CBG has been examined in a number of passerine species.In White-crowned sparrows (Zonotrichia leucophrys gambelii), CBG capacity ishigher during breeding than during winter or migration (40). In House sparrows(Passer domesticus) and Lapland longspurs (Calcarius lapponicus), CBG levelsare higher during breeding than during molt (7,38). And studies in both Dark-eyedjuncos (Junco hyemalis) and Pied flycatchers (Ficedula hypoleuca) show that CBGlevels are higher at the beginning of the breeding season than at the end (10, 46).These studies provide evidence for a common conclusion; CBG levels are highestwhen testosterone levels are elevated. A study by Klukowski et aI, (26)demonstrated that ,experimentally elevated testosterone in juncos can double theCBG capacity. However, testosterone'implants in Klukowski's study also elevatedcorticosterone titers, and in each study mentioned above, baseline COR T titers arehigher when CBG levels are elevated. Hence, it is difficult to determine if CBGcapacity is regulated by testosterone or corticosterone.
How do seasonal changes in CBG affect free CaRT levels? In three studiesshowing seasonal or testosterone-induced changes in corticosterone and CBG, wecan estimate the amount of free CaRT (Fig. 1). In male House sparrows, baselineand stress-induced total CaRT levels are higher in breeding than in molting orwintering birds (Fig. 1, top panel (7». In male juncos, baseline total CaRT levelsare higher at the beginning of the breeding season than at the end (Fig. 1, middlepanel (10)), and are higher in testosterone-implanted males than controls (Fig. 1,lower panel (26)). CBG capacity changes in a similar manner in each case,
Fig.! Estimations of free CaRT levels in House spalTows and juncos. A) Insparrows, baseline and stress-induced total CaRT and CBG titers changedseasonally, but there was no significant difference in estimated baseline or stress-induced free CaRT (ANOV A, p = 0.85). Free CaRT titers were estimated for eachindividual, means:!:: SE calculated from that data. B) In free-living juncos, totalCaRT and CBG titers are higher at the beginning of the breeding season than at theend. C) In captive juncos, baseline total CaRT and CBG titers are higher intestosterone implanted males ~'T"\ than in control males. In both studies (B and C),differences in total CaRT are not reflected in free CaRT titers. In juncos, means for
4 Seasonality of corticosterone binding. Breuner and Orchinik
total CaRT levels and CBG capacity were used to estimate a mean for free CaRT.Error bars for free CaRT were estimated by putting total caRT mean:!: SE andCBG mean:!: SE into the Barsano and Baumann equation. Differences in CBOcapacity between studies in the junco (B and C) may be due to differences in assayprotocol. Deviche et ai., (B) used rapid vacuum filtration to separate bound fromfree steroid at the end of the assay, whereas Klukowski et ai., (C) used charcoalseparation. (Data were redrawn from A) (7), B) (10, 11), and C) (26).
so that free CaRT levels are similar between season or treatment. Ifprotein-boundsteroids are not biologically active (the 'free hormone hypothesis' (14, 31)) thenlarge seasonal changes in total caRT may not be physiologically relevant. '
Studies in mammalian systems, however, suggest a more complex role forCBG, in which CBG binds to specific binding sites in the plasma membranes of ratand human tissues (23, 24, 41, 47). In addition, the CBG-CORT complex canincrease adenylate cyclase activity, resulting in the accumulation of intracellularcAMP (41). CBG can also effect the local concentration of free CaRT. Forexample, the CBG-CORT complex may be internalized upon binding to themembrane receptor on MCF:-7 culture cells (32, 41), potentially increasingintracellular concentrations of free CaRT. Alternatively, the CBG molecule maybe proteolytically cleaved as specific sites, such as sites of inflammation,increasing the local concentration of free CaRT in the plasma (20, 21, 35). Tak~ntogether, CBG potentially regulates steroid action at several levels. The role ofCBG as an active component of the stress response is poorly understood andwarrants further study.
Furthermore, CBG appears to be a physiologically relevant binding globulinfor testosterone in both juncos and White-crowned sparrows (10,52). In the Dark-eyed junco, testosterone binds to CBG with approximately ,20 nM affInity (10), sothat under baseline CaRT conditions, up to 90% of total testosterone will be boundto CBG in the spring. So while there may not be a typical sex-steroid bindingglobulin in avian plasma (52), there is a physiologically relevant binding proteinfor T in some species, and CEG levels may change seasonally not to buffercorticosterone, but testosterone.
Two recent changes in experimental protocol have improved the sensitivityand precision of the CBG assay. The first is a switch from charcoal incubation torapid vacuum filtration to separate bound from free tritiated steroids at the end ofthe assay. Charcoal separation lasts ~10 min, and CBG's rapid off-rate (k-u makesit vulnerable to excessive stripping by charcoal. As the charcoal adsorbs freehormone, the equilibrium shifts and ligand dissociates from CBG. Rapid (-30 sec)vacuum filtration over polyethylenimine (a polycationic solution)-soaked filtersdecreases this problem. The second change is the method of analysis. Previously,CBG affinity and capacity were estimated by Scatchard linearization ofcompetition data. Recently, preference has switched to nonlinear analysis ofequilibrium saturation data to estimate affinity and capacity, only using theScatchard analysis to help with visual interpretation of the data. This method ispreferred because linear transformation distorts experimental error, and theScatchard transformation specifically violates one of the assumptions of linearregression, with experimental error of the bound estimations appearing in both theX and Y axes. For further discussion, see Graph-pad prism website:
11tm:/ /curvefit.coln/avoid_lineanLing.htm.
Avian Endocrinology 5
Corticosteroid receptorsWe have found that avian tissues contain three distinct corticosteroid receptors, twocytosolic, and one membrane-bound. The intracellular receptors have beencharacterized through both radio ligand binding experiments andimmunocytochemistry. In the domestic duck Anas platyrhynchos (13) and theHouse sparrow (7), radio ligand binding experiments have identified twointracellular receptors which are similar to mammalian high-affInitymineralocorticoid receptor (MR), and the lower-affmity glucocorticoid receptor(GR). Estimates of Kd range from 0.1 -0.7 I)M for the high-affinity receptor, and3.0-11.0 nM for the low-affinity receptor. Radioligand binding studies in chickenkidney and bursa of fabricus describe a cytosolic receptor similar to the lowaffmityreceptor (5, 17). Immunocytochemical studies, using a monoclonal antibody to ratliver GR, identify a GR-like protein in the quail (Coturni.x co turn ix japQnica) brain(28), and preliminary western blot experiments using a polyclonal antibody tohuman GR have identified a 94 kD protein (similar to mammalian OR) in theHouse sparrow brain (C. Breuner, A. Weiss, and M. Orchinik, unpublished data).
':g'100 ,~A
..§-j'-'00~ 5"0 6
] ~C)~ 3C)Q)
~ 0
10 15 20
[3H-CORT] (nM)
Fig. 2 Equilibrium saturation analysis of house sparrow neuronal membranes. Dataare best fit by a one site model with ~ = 19.0 :I: 2.2 nM, Bmax = 174.6 :f 11.7pmol/mg proto Permission from (7).
The membrane corticosteroid receptor is not well characterized in birds. Specificbinding of [3H]CORT to cell membranes has been characterized in rat, newt andsalamander tissues (e.g. 33, 34, 48, 49). In the brain of the newt (Tarichagranulosa), membrane corticosteroid receptors were localized to the neuropil of theamygdala, preoptic area, and hypothalamus (34). In the House sparrow, nonlinearregression analysis of equilitJ.J.uffi saturation binding data demonstrates a single
6 Seasonality of corticosterone binding. Breuner and Orchinik
binding site for CaRT in neuronal membranes, with relatively low affInitycompared to the intracellular receptors (Kd = 19.0:l: 2.2 nM, Bmax = 174.6:l: 11.7
pmol/mg protein; Figure 2; (7)). Because the affInity is low, few receptors will besignificantly activated until circulating CaRT reaches stress-induced levels. Toensure that We were not simply measuring a binding site for CBG in the membrane,we compared specific binding of [3H]CORT to neuronal membranes in perfusedand non-perfused tissue (perfusion should remove the majority of CBG in thetissue). Perfusion did not affect specific binding.
Seasonality in receptorsAll three corticosteroid receptors in the house sparrow brain are seasonallyregulated. While there is no seasonal change in affinity, both high- and low.:affinitycytosqlic receptors have higher levels during nesting and molt than during winter(7). In contrast, levels of the membrane receptor are lowest during nesting (Fig. 3).Receptor number was measured in individual brains, and a mean and standard errorfigured for each season.
A) high-affinity B) low-affinity C) membrane receptorintracellular receptor intracellular receptor
100 100 1000...~ 80 80 80S *,
:::::i~ 60 60 60t.+:;;'--'~ 40 40 40-.a~:E 20 20 20Q~.-Q 0 0 08-Ci) nesting molt winter nesting molt winter nesting molt winter
Fig. 3 Seasonal changes in corticosteroid receptor number in the avian brain. A) andB) High- and low-affinity corticosteroid receptor number is lower during winter thanduring nesting or molt (*p < 0.0015, **p < 0.0015). C) Membrane corticosteroidreceptor number is lowest during nesting (***p < 0.015). Receptor number estimateswere made using subsatttrating concentrations of [3H]CORT (10 nM for A and B,and 20 nM for C). Based on affinity estimates derived from equilibrium saturationanalysis, this ligand concentration should occupy approximately >95% (A), 63%(B), and 40% (C) of receptors. Redrawn with pennission from (7).
How does seasonal change in receptor number affect the responsivity of thestress-response pathway? Given the relative affinities of each receptor, the high-affinity receptor is probably only responsive to changes in baseline CaRT levels,whereas the low-affinity cytosolic and membrane receptors (with their 25- and 130-fold lower affInity for CaRT, respectively) may mediate the physiological andbehavioral responses to stre ,j-induced CaRT. Hence, while the slower-onset
Avian Endocrinology 7
changes in response to stress-induced CaRT, presumably mediated by the low-affinity intracellular receptor, may be more sensitive to stressors during nestingthan. winter, the rapid-onset changes in physiology and behavior, presumablymediated by. the membrane receptor, should be less sensitive to a stressor during
nesting.
Corticosteroids and behaviorInvestigations into the behavioral effects of CaRT can help to elucidate themechanism of CaRT action in the brain. Dose response studies can indicate therange of circulating CaRT necessary to significantly activate a receptor system,and that range of sensitivity can be compared to differences in affinity betweenreceptor types. Temporal studies can differentiate between intracellular andmembrane corticosteroid receptor action. Intracellular receptors' work astranscription factors and therefore effect changes in behavior only after asignificant time delay, usually> 30 min. Membrane receptors, however, typicallyact rapidly, causing changes in seconds to minutes.
Although pharmacological evidence for a membrane corticosteroid receptorin birds is sparse, there is substantial behavioral evidence for their existence. Rapid« 20 min) behavioral effects of corticosteroids, consistent with a non-genomicmechanism of action, have been demonstrated in White-crowned sparrows,Mountain chickadees and chickens. In captive White-crowned sparrows, CaRTincreases perch-hopping activity within 15 min (6, 8). Notably, activity levelsincrease only while CaRT levels are elevated; in contrast to the well-knowngenomic mechanism for CaRT action, CaRT elevation and behavioral change aretemporally synchronized in this system. .In captive Mountain chickadees (Par usgambeli), CaRT rapidly increases the recovery rate of previously cached seeds(42). Saldanha et at. (42) argue that these data support a rol.e for CaRT in memoryretrieval, not memory formation, because CaRT given at the time of caching doesnot elevate retrieval rate 24 h later. In contrast, Sandi et at. reported an effect ofCaRT on memory formation in day-old chicks learning a passive avoidance task(43). Chicks trained on a strong-aversion task showed an increase in circulatingCaRT, and retained the aversion 24 h later. In contrast, chicks trained on a weak-aversion task, showed no elevation of CaRT during the trial, and showed noaversion 24 h later. However, if 1 I-Lg CaRT was injected intracranially during theweak-aversion learning trial, aversion was retained 24 h later. In a similarexperiment, CaRT had to be injected before, or just after (? 15 min) the learningtrial to be effective. These data suggest that CaRT has a rapid effect on memoryformation.
A final point of interest is that in White-crowned sparrows and.day-oldchicks, only intermediate levels of CaRT affected behavior. In White-crownedsparrows, 4 and 8 I-Lg of CaRT (resulting in ~24 and 40 ng/ml circulating CaRT)increased perch-hopping activity, whereas 14 and 20 I-Lg (resulting in ~65 and 97ng/ml) had no effect (8). In day-old chicks subjected to a weak-aversion learningtrial, 1 I-Lg CaRT (injected intracranially) increased aversion to the beads 24 h later,whereas 0.1 and 5 I-Lg CaRT had no significant effect (43). This inverted U-shapeddose-response curve has been associated with corticosteroid action over the last 30years (12, 27), and has been thought to result from differential occupation of thetwo intracellular corticosterojr receptors as CaRT levels increase. Recently,
8 Seasonality of corticosterone binding. Brenner and Orchinik
evidence from avian and mammalian (25,44) species suggests that rapid actions ofCaRT also show the same inverted-U dose-response curve.
5~.9 c::=J 0 ~g caRT~.~ 4 -4 ~gCaRT
>..i 3
~"'tj.~ """,.-, *.~ c.S d) 2u"'tjbD~ d) S
~"t..g.~ d) 1~ t::: 0
0 ~d) u II
~'-.I~ 0
photo stimulated photosensitive
Fig. 4 CaRT increases perch hopping in long-day, photostimulated sparrows, butnot in short-day, photosensitive sparrows. Activity was recorded before and afterCaRT administration, and activity levels corrected for daily variation. 1 = nochange in activity from,before CaRT or vehicle administration. *p <0.05: CaRTsignificantly higher than control in photostimulated birds. Permission from (8).
Chronic CaRT administration in passerines has been shown to decrease territorialaggression, parental care, and activity (2, 46, 54). It is not known whether thesechanges are mediated through cytosolic or membrane corticosteroid receptors.However, behavioral responses to rapid surges in CaRT are often in direct contrastto those induced by chronic caRT application. For example, in white-crownedsparrows, rapid infusion of CaRT increased perch-hopping activity (6), whereasCaRT implants decreased the same activity (2). In several mammalian systems,rapid glucocorticoid infusion increases reproductive behavior (29, 45), whereaschronic glucocorticoid application inhibits it (9, 15). Also in mammals, chronicCaRT tends to decrease aggressive behaviors (30), while rapid infusion of caRTincreases them (18, 22). It is possible that the membrane and intracellularcorticosteroid receptors mediate very different behaviors within the stress response.Conversely, most CaRT -induced behaviors may be mediated thrqugh themembrane receptor, but a neuroendocrine background of high CaRT (as occUrswith CaRT implant and chronic stress) may alter the biological action of thereceptor.
Seasonality in behaviorIn White-crowned sparrows, behavioral sensitivity to rapid CaRT increase changeswith photoperiod (8). The increase in perch-hopping due to rapid CaRT infusiononly occurs in long-day, photo stimulated sparrows. The same CaRT applicationhas no effect on short-day, photosensitive sparrows (Fig. 4). In .these sparrows,baseline total CaRT, CBG, .nd rate of caRT increase after CaRT ingestion arenot affected by photoperiod, suggesting that the change in sensitivity to CaRT is
Avian Endocrinology 9
due to a change at the level of the target cell, possibly in the number of membranecorticosteroid receptors. Few other studies have examined seasonal changes inbehavioral sensitivity to CaRT. In part, this may be due to the difficulty indetermining ,hormonal effects on behaviors that change seasonally (e.g. songproduction or aggression).
ConclusionsIt is clear now, based mostly on data from John Wingfield's laboratory, that inbirds the adrenocortical response to stress is modulated seasonally. Recent studiessuggest that other characteristics of the stress response pathway, including CBGcapacity, receptor number, and behavioral response to corticosteroids, also changeseasonally. This covariation of multiple components may have interesting effectson the system as a whole. For example, studies of multiple components in Housesparrows suggest that seasonal regulation of the stress response does not mimicregulation of the adrenocortical response to stress; CBG levels change in concertwith hormone levels, resulting in no seasonal change in estimated plasmaconcentrations of free CaRT. Changes in CBG, in most passerines studied, seem totrack changes in total CaRT, possibly diminishing seasonal changes in free CaRT.Furthermore, the extent to which the CBG-CORT complex plays an active role inthe 'stress response is unknown; there may be CBG receptors that are seasonallyregulated. Future studies of CBG should focus on both free CaRT levels underdifferent environmental conditions, and the possibility that CBG itself can effectphysiological and behavioral changes in response to stress.
A second emerging observation is that the targets of corticosteroids, themembrane and intracellul'Pc,r receptors, are differentially regulated fromcorticosteroids, and also from each other. For example, in House sparrows,intracellular corticosteroid receptors are higher during nesting when CaRT levelsare highest, but membrane corticosteroid receptors show the opposite pattern. Theindependent regulation of the intracellular and membrane corticosteroid receptorsmay allow for greater control of sensitivity to a stressor on a season- and tissue-specific basis. For example, metabolic sensitivity to stress could increase duringnesting as a result of higher concentrations of intracellular receptors in the liver,whereas rapid behavioral sensitivity to stress could decrease during nesting, as aresult of lower concentrations of membrane receptors in discrete areas in the brain.This hypothesis could be tested by radioligand binding studies that measureseasonal changes in receptor number in discrete areas, and by behavioral orphysiological studies measuring seasonal changes in sensitivity to increasingCaRT.
With the broad base of literature on the modulation of the adrenocorticalresponse to stress, it is now possible to focus experiments further downstream,integrating experiments on plasma binding globulins, corticosteroid receptors, andbehavior to gain a fuller understanding of the functional significance of the stressresponse at an organismallevel.
AcknowledgmentsWe would like to thank J.1 A Woods for editorial assistance. Much of the author'swork cited here was su:J:Iported by NSF grants IBN 9604200 to M Orchinik, and aPostdoctoral Research Fellowship In Biosciences Related To The Environment toCW Breuner.
10 Seasonality of corticosterone binding. Breuner and Orchinik
References1 Astheimer LB, Buttemer WA & Wingfield JC (1994) Gender and seasonal differences in
adrenal response to ACTH challenge in an arctic passerine, Zonotrichia leucophrys gambelii.General and Comparative Endocrinology 94 33-43
2 Astheimer. LB, Buttemer WA & Wingfield JC (1992) Interactions of corticosterone withfeeding, activity and metabolism in passerine birds. Ornis Scandinavica 23355-365
3 Astheimer LB, Buttemer WA & Wingfield JC (1995) Seasonal and acute changes inadrenocortical responsiveness in an arctic-breeding bird. Hormones and Behavior 29 442-457
4 Barsano CP & Baumann G (1989) Editorial: simple algebraic and graphic methods for theapportionment of hormone (and receptor) into bound and free fractions in binding equilibria; orhow to calculate bound and free hormone? Endocrinology 124 1101-1106
5 Beaudry C, Bellabarba D & Lehoux J-G (1983) Corticosteroid receptors in the kidney of chickembryo 1. Nature and properties of corticosterone receptor. General and ComparativeEndocrinology 50
6 Breuner CW, Greenberg AL & Wingfield JC (1998) Non-invasive corticoster<;>ne treatmentrapidly increases activity in Gambel's white-crowned sparrow (Zonotrichia leucophrysgambelil). General and Comparative Endocrinology 111 386-394
7 Breuner CW & Orchinik M Membrane and intracellular corticosteroid receptors are seasonallyregulated in the house sparrow brain. s-~~ :S, nt\AV'D~~ CI\}.~ i>(, rt'\ (J~.sS
8 Breuner CW & Wingfield JC (2000) Rapid behavioral response to corticosterone varies withphotoperiod and dose. Hormones and Behavior 37 23-30
9 de Cantanzaro D (1987) Alteration of estrogen-induced lordosis through central administrationof corticosterone in adrenalectomized-ovariectomized rats. Neuroendocrinology 46 468-474
10 Deviche P, Breuner C & Orchinik M Testosterone, corticosterone, and photoperiod interact toregu.late free s~eroid hormone levels in avian plasma. S-I~~ q ~r;- J ,'t1 f~~S
11 Devlche P, Wmgfield JC & Sharp PJ (2000) Year-class differences m the reproducnve system,plasma prolactin and corticosterone concentrations, and onset of prebasic molt in male dark-eyed juncos (Junco hyemalis) during the breeding period. General and ComparativeEndocrinology 118 425-435
12 Diamond DM, Bennett MC, Fleshner M & Rose GM (1992) Inverted-U relationship betweenthe level of peripheral corticosterone and the magnitude of hippocampal primed burstpotentiation. Hippocampus 2421-430
13 DiBattista JA, Mehdi AZ & Sandor T (1985) A profile of the intestinal mucosal corticosteroidreceptors in the domestic duck. General and Comparative Endocrinology 59 31-49
14 Ekins R (1990) Measurement of free hormones in blood. Endocrine Reviews 115-4615 Everitt BJ & Herbert J (1971) The effects of dexamethasone and androgens on sexual
receptivity of female rhesus monkeys. Journal of Endocrinology 51575-58816 Fassler R, Schauenstein K, Kromer G, Schwarz S & Wick G (1986) Elevation of corticosteroid-
binding globulin in obese strain (OS) chickens: possible implications for the disturbedimmunoregulation and the development of spontaneous autoimmune thyroiditis. Journal ofImmunology 136 3657-3661
17 Fassler R, Schwarz S, Dietrich H & Wick G (1986) Sex steroid and glucocorticoid receptors inthe bursa of fabricius of obese strain chickens spontaneously developing autoimmunethryroiditis. Journal of Steroid Biochemistry 24405-411
18 Haller J, Albert I & Makara GB (1997) Acute behavioral effects of corticosterone lackspecificity but show marked context-dependency. Journal of Neuroendocrinology 9 ~15-518
19 Hammond GL (1995) Potential functions of plasma steroid-binding proteins. Trends inEndocrinology and Metabolism 6298-30420 Hammond GL, Smith CL, Paterson NAM & Sibbald WJ (1990) A role for corticosteroid- .-
binding globulin in delivery of cortiso] to activated neutrophils. Journal of ClinicalEndocrinology and Metabolism 71 34-39
21 Hammond GL, Smith CL, Underhill CM & Nguyen VTT (1990) Interaction betweencorticosteroid binding globulin and activated leukocytes in vitro. Biochemical and BiophysicalResearch Communication 172 272-177
22 Hayden-Hixson DM & F' ris CF (1991) Steroid-specific regulation of agonistic responding inthe anterior hypothalamlols of male hamsters. Physiology and Behavior 50 793-799
23 Hryb DJ, Khan MS, Romas NA & Rosner W (1986) Specific binding of human corticosteroid-binding globulin to cell membranes. Proceedings of the National Academy of Sciences 83 3253
Avian Endocrinology 11
24 Hsu BR-S, Siiteri PK & Kuhn RW (1986) Interactions between corticosteroid-binding globulin(CBG) and target tissues. In Binding Proteins of Steroid Hormones, pp. 577-592. Forest MG &Pugeat, M. (Eds), Eurotext, London
25 Kavaliers M, Perrot-Sinal TS & Ossenkopp KP (1997) Corticosterone rapidly reduces malepreference for the odors of estrous female mice. Society for Neuroscience, abstracts 2 185
26 Klukowski"LA, Cawthorn 1M, Ketterson ED & Nolan Jr. V (1997) Effects of experimentallyelevated testosterone on plasma corticosterone and corticosteroid-binding globulin in dark-eyedjuncos (Junco hyemalis). General and Comparative Endocrinology 108141-151
27 Kovacs GL, Telegdy G & Lissak K (1977) Dose-dependent action of corticosteroids on brainserotonin content and passive avoidance behavior. Hormones and Behavior 8155-165
28 Kovacs KJ, Westphal HM & Pecze1y P (1989) Distribution of glucocorticoid receptor-likeimmunoreactivity in the brain, and its relation to CRF and ACTH immunoreactivity in thehypothalamus of the Japanese quail, Coturnix coturnixjaponica. Brain Research 505 239-245
29 Kubli-Garfias C (1990) Chemical structure of corticosteroids and its relationship with theiracute induction of lordosis in the female rat. Hormones and Behavior 24 443-449
30 Leshner AI, Korn SJ, Mixon JF, Rosenthal C & Besser AK (1980) Effects of corticosterone onsubmissiveness in mice: some temporal and theoretical considerations. Physiology andBehavior 24 283-288
31 Mendel CM (1989) The free hormone hypothesis: a physiologically based mathematical model.Endorcrine Reviews 10 232-274
32 Nakhla AM, Khan MS & Rosner W (1988) Induction of adenylate cyclase in a mammarycarcinoma cell line by human corticosteroid-binding globulin. Biochemical and BiophysicalResearch Communication .1531012
33 Orchinik M, Matthews L & Gasser PJ (2000) Distinct specificity for corticosteroid binding sitesin amphibian cytosol, neuronal membranes, and plasma. General and ComparativeEndocrinology 118 284-301
34 Orchinik M, Murray TF & Moore FL (1991) A corticosteroid receptor in neuronal membranes.Science 2521848-1851
36 Romero LM, Ramenofsky M & Wingfield JC (1997) Season and migration alters thecorticosterone response to capture and handling in an arctic migrant, the white-crownedsparrow (Zonotrichia leucophrys gambelil). Comparative Biochemistry and Physiology 116C171-177
37 Romero LM, Soma KK & Wingfield JC (1998) Changes in pituitary and adrenal sensitivitiesallow the snow bunting (plectrophenax nivalis), an Arctic-breeding song bird, to modulatecorticosterone release seasonally. Journal of Comparative Physiology B-Biochemical Systemicand Environmental Physiology 168 353-358
38 Romero LM, Soma KK & Wingfield JC (1998) Hypotha1amic-pituitary-adrenal axis changesallow seasonal modulation of corticosterone in a bird. American Journal of Physiology-Regulatory Integrative and Comparative Physiology 43 R1338-R1344
39 Romero LM & Wingfield JC (1999) Alterations in hypothalamic-pituitary-adrenal functionassociated with captivity in Gambel's white-crowned sparrows (Zonotrichia leucophrysgambelii). Comparative Biochemistry and Physiology B 122 13-20
40 Romero LM & Wingfield JC (1998) Seasonal changes in adrenal sensitivity alter corticosteronelevels in Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii). ComparativeBiochemistry and Physiology C 119 31-36 ":-.
41 Rosner W (1990) The functions of corticosteroid-binding globulin and sex hormone-bindingglobulin: recent advances. Endocrine Reviews 11 80-91
42 Saldanha CJ, Schlinger BA & Clayton NS (2000) Rapid effects of corticosterone on cacherecovery in mountain chickadees (Parus gambelz). Hormones and Behavior 37109-115
43 Sandi C & Rose SPR (1997) Training-dependent biphasic effects of corticosterone in memoryformation for a passive avoidance task in chicks. Psychopharmacology 133 152-160
44 Sandi C, Venero C & Guaza C (1996) Novelty-related rapid locomotor effects of corticosteronein rats. European Journal "{Neuroscience 8 794-800
45 Schiml PA & Rissman I.' (1999) Cortisol facilitates induction of sexual behavior in the femalemusk shrew (Suncus murinus). Behavioral Neuroscience 113 166-175
12 Seasonality of corticosterone binding. Breuner and Orchinik
46 Silverin B (1986) Corticosterone-binding proteins and behavioral effects of high plasma levelsof corticosterone during the breeding period in the pied flycatcher. General and ComparativeEndocrinology 64 67-74
47 Strel'chyonok OA & A vvakumov GV (1983) Evidence for the presence of specific binding sitesfor transcortin in human liver plasma membranes. Biochimica et Biophysica-ACTA 755 514
48 Towle AC & Sze PY (1983) Steroid binding to synaptic plasma membrane: Differential bindingof glucocorticoids and gonadal steroids. Journal of Steroid Biochemistry 18 135-143
49 Trueba M, lbarrola I, Ogiza K, Marino A & Macarulla 1M (1991) Specific binding sites forcorticosterone in isolated cells and plasma membrane from rat liver. Journal of MembraneBiology 120 115-124
50 Wingfield JC (1994) Modulation of the adrenocortical response to stress in' birds. InPerspectives in Comparative Endocrinology, pp, 520-528. KG Davey, E Peter and SS Tobe(Eds), National Research Council Canada, Ottawa
51 WingfieldJC & Farner DS (1978) The annual cycle of plasma irLH and steroid hormones inferal populations of the white-crowned sparrow, Zonotrichia leucophrys gambelii. Biology ofReproduction 191046-1056
52 Wingfield JC, Matt KS & Farner DS (1984) Physiologic properties of steroid hormone-bindingproteins in avian blood. General and Comparative Endocrinology 53 281-292
53 Wingfield JC, O'Reilly KM & Astheimer LB (1995) Modulation of the adrenocorticalresponses to acute stress in arctic birds: A possible ecological basis. American Zoologist 35285-294
54 Wingfield JC & Silverin B (1986) Effects of corticosterone on territorial behavior of free-livingmale song sparrows, Melospiza melodia. Hormones and Behavior 20405-417
55 Wingfield JC, Vleck CM & Moore MC (1992) Seasonal changes of the adrenocortical responseto stress in birds of the sonoran desert. Journal of Experimental Zoology 264 419-428
