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Biology Department (H.I.), Washington and Lee University, Lexington, Virginia 24450; and Programs in Neuroscience (L.A.S., S.M.R., S.R.), Washington State University, Pullman, Washington 99164-6520
Address all correspondence and requests for reprints to: H. I’Anson, Department of Biology, Howe Hall, Washington and Lee University, Lexington, Virginia 24450. E-mail: iansonh{at}wlu.edu.
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Introduction |
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The sensors that regulate reproduction in response to glucose availability are most likely located in the lower brain stem, because infusion of very low doses of 2DG into the fourth ventricle will suppress pulsatile LH secretion in the rat (7). 2DG-induced glucoprivation also increases Fos-immunoreactivity (Fos-ir) in specific populations of catecholaminergic neurons of the brain stem (8, 9), suggesting that these neurons are activated by glucoprivation and may transmit glucoprivic signals to forebrain centers. This possibility is further supported by the observation that selective immunotoxic destruction of hindbrain norepinephrine (NE) and epinephrine (E) neurons with projections to the hypothalamic paraventricular nucleus (PVN) abolishes acute 2DG-induced feeding and Fos-ir in the PVN in rats (10).
In the present experiment, we hypothesized that hindbrain catecholamine (NE or E) neurons, in addition to their essential role in glucoprivic feeding, are also responsible for suppressing estrous cycles during glucoprivation. Our approach was to selectively destroy NE and E neurons projecting to the PVN by injecting a monoclonal dopamine ß-hydroxylase (dßh) antibody conjugated to the ribosomal toxin, saporin, into the PVN of normally cycling adult rats. Anti-dßh-saporin [dßh mouse monoclonal antibody conjugated to saporin (DSAP)] is selectively internalized in dßh-containing (NE and E) neurons, is readily internalized into nerve terminals, and is retrogradely transported (10, 11, 12, 13). Previously, we showed that injection of DSAP into the PVN selectively destroys cell bodies and terminals of hindbrain NE and E neurons that innervate the PVN injection site, without damaging NE and E neurons that do not project to the PVN (10). We used this same approach in the present study to examine the contribution of hindbrain NE and E neurons to reproductive function during normal conditions and during chronic glucoprivation.
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Materials and Methods |
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Experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by Washington State University animal care and use committee.
Surgical procedures
Rats were randomly assigned to two groups so that mean body weight was not different between groups (257 ± 3.4 and 257 ± 5.7 g). They were anesthetized and injections of DSAP (Chemicon International, Inc., Temecula, CA; 42 ng/200 nl in phosphate buffer, pH 7.4) or control solution containing an equivalent amount of unconjugated saporin (SAP, Advanced Targeting Systems, 8.82 ng/200 nl in phosphate buffer, pH 7.4) were made bilaterally in the PVN using a drawn glass capillary micropipette (30-micron tip diameter) connected to a microinjector (Picospritzer) with PE tubing (10). The delivery of solution was monitored microscopically. Two to 3 wk were allowed for degeneration of the affected neurons (11, 12), and daily vaginal cytological examination was resumed until the end of the study.
Acute glucoprivic feeding test
Loss of glucoprivic feeding is highly correlated with the selective deletion of NE and E terminals in the medial hypothalamus by DSAP (10). Therefore, a 2DG-induced feeding test was conducted as an independent measure of the efficacy of the DSAP lesion. Only DSAP rats with deficits in the 2DG-induced feeding test were used in the present study. For feeding tests, rats were given a weighed quantity of pelleted rat chow in their home cages at approximately 1000 h and injected sc with 2DG (Sigma, St. Louis, MO), 200 mg/kg, 1 ml/kg), or sterile saline (0.9%, 1 ml/kg). Remaining pellets and spillage were measured over the 4-h period immediately after the injection.
Chronic 2DG-induced glucoprivation
The acute glucoprivic feeding test revealed eight DSAP rats with a loss of glucoprivic feeding, and these rats were used in subsequent tests of reproductive function during normal and chronic glucoprivic conditions. At least two consecutive normal (4–5 d) cycles were recorded in the DSAP (n = 8) and SAP (n = 8) rats before the chronic 2DG-induced glucoprivation test. These rats were then injected sc with 200 mg/kg 2DG (Sigma) every 6 h for 72 h, beginning 1200 h on the day after estrus was detected by vaginal smear. This 2DG administration protocol has been shown to extend estrous cycles in a manner similar to 72-h food deprivation (4, 14). Daily food intake was monitored during the 72-h treatment period. Vaginal cytology and body weight were recorded daily between 1200 and 1300 h throughout the chronic 2DG administration and thereafter until an estrus smear was recorded.
Immunohistochemistry and quantification of dßh-immunoreactive cell bodies
At the conclusion of testing, rats were killed rapidly by injection of a lethal dose of pentobarbital sodium (300 mg/kg ip; Abbott Laboratories, North Chicago, IL). They were transcardially perfused with 0.1 M PBS (pH 7.4) followed by 4% formalin in 0.1 M PBS (pH 7.4) and 2 h post fixation. Brains were then cryoprotected overnight in 25% sucrose and sectioned on a cryostat. Coronal sections (40 microns in thickness) of the brain stem and hypothalamus were cut in multiple sets. Hindbrain sections were processed for immunocytochemical detection of dßh. Immunohistochemical staining was done using standard avidin-biotin-peroxidase techniques described previously (9). Briefly, sections were treated with 50% ethanol for 30 min, then washed (3 x 5 min) in 0.1 M PB, and incubated for 45 min in 10% normal horse serum made in Tris sodium phosphate buffer (TPBS, pH 7.4) with 0.05% thimerosol. The blocking solution was removed from the tissue, and the sections were incubated for 48 h in mouse monoclonal anti-dßh (Chemicon, 1:100,000) made in 10% normal horse serum-TPBS. The primary antibody was removed, and the sections were washed and incubated in biotinylated donkey antimouse IgG (1:500 in 1% normal horse serum-TPBS, Jackson ImmunoResearch Laboratories, West Grove, PA). After 24 h, the tissue was washed (3 x 10 min), incubated with Extravidin-peroxidase (Sigma, 1:1500 in TPBS) overnight, washed again (3 x 10 min), and reacted for visualization of dßh-ir using nickel-intensified diaminobenzidine in the peroxidase reaction to produce a black reaction product. Sections were then mounted on slides and cover-slipped for microscopic evaluation. All antibodies used in the experiment were titrated before use to determine optimal concentrations. Standard controls for specificity of the primary antibody were used, including the incubation of the tissue with normal instead of immune serum and preincubation of the immune serum with the antigen before its application to tissue. Histological sections used in figures were captured using a Nikon photomicroscope equipped with a digital camera (RS Photometrics; Roper Scientific Inc., Tucson, AZ) and linked to a computer running CoolSNAP software (Roper Scientific Inc.). Plates of multiple sections were assembled using Adobe Photoshop (Adobe Systems Inc., San Jose, CA). Brightness only was altered digitally in some cases.
The distribution of NE (A1–A6) and E (C1–C3) cell bodies has been described in detail (15, 16, 17, 18, 19). To determine the effectiveness of PVN DSAP injections in lesioning NE and E neurons, dßh-ir cell bodies were quantified at representative levels through hindbrain cell groups A1, C1, and A2, which provide the major NE/E innervation of the PVN (20, 21) and where the majority of cell bodies project to the medial hypothalamus. To assess the selectivity of the DSAP lesion for PVN-projecting NE/E neurons, groups A5 and A7 were also analyzed. Cell groups A5 and A7 do not innervate the PVN and therefore are not damaged by PVN DSAP injections. However, these cell groups are more vulnerable to intraventricular DSAP injection than A1 and C1 (11). Therefore, loss of cell numbers in A1 and C1 with normal cell numbers in A5 and A7 cell groups provides evidence that DSAP injections did not leak or diffuse into the ventricular system. One of three sets of anatomically matched hindbrain sections from each rat was used for quantification. Immunoreactive cells in five anatomically matched sections, sampling the extent of each of the cell groups (specified below), were counted bilaterally for each rat. The mean number of cells per section was calculated from these five sections for each cell group for each rat and averaged across the rats in each treatment group. All immunoreactive cells were counted, regardless of the presence of a cell nucleus. No correction factor for double counting was applied because of the use of relatively thick sections for the quantification. For purposes of quantification, dßh-ir cell bodies in the ventrolateral medulla were considered as four separate groups, referred to here as A1, A1/C1, C1m, and C1r, anatomically defined as described below. Approximate anatomical levels (mm caudal to bregma) of each quantified area were determined from Paxinos and Watson (15) and are included below. Cells designated as A1 were those found between the decussation of the pyramids and the calamus scriptorius (14.60–14.30 mm). At this level of the ventrolateral medulla, the dßh-ir cell bodies are predominantly NE-containing. Cells designated as A1/C1 were those found between the calamus scriptorius and obex (the rostral border of the area postrema) (14.30–13.68 mm), where NE and E cell bodies have an overlapping distribution. Cells referred to as C1m (the middle portion of C1) were those located in the ventrolateral medulla between obex and the caudal border of nucleus prepositus, a region containing predominantly E cell bodies (13.68–12.30 mm). Cells referred to as C1r (the rostral portion of C1) were those lying between nucleus prepositus and the caudal border of the facial nucleus (12.30–11.80 mm). The latter cells are entirely E-containing; but because many or most project to the spinal cord and not to the PVN, these were not counted. A2 cells were counted in the nucleus of the solitary tract from the level of the calamus scriptorius through the caudal half of the area postrema (14.30–13.80 mm), caudal to the appearance of C2 neurons. Cell group A5 was quantified at the level of the caudal locus coeruleus, at the exit of cranial nerve 7 from the ventral brain stem (10.30–9.80 mm), and A7 was assessed at the level of the Kölliker-Fuse nucleus (9.16–8.72 mm). Hypothalamic sections were examined for the presence of dßh-ir terminals. However, because immunoreactivity does not provide a reliable basis for quantification of terminals, dßh-ir terminals were not quantified.
Data analyses
The effect of chronic 2DG treatment on body weight of SAP and DSAP rats was determined by comparing the body weight for each rat just before the first 2DG injection (d 0) with body weight on each successive day of treatment, using a two-factor ANOVA for repeated measures and Tukey’s test for post hoc comparisons. The same statistical tests were used to compare acute glucoprivic feeding responses and total daily food intake during chronic 2DG treatment. The frequencies of animals with normal (4–5 d) cycles were analyzed by the R x C test of independence using the G statistic (Statview, SAS Institute, Cary, NC). Comparisons resulting in a P < 0.05 were considered significant. Data are presented as mean ± SE of the mean.
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Results |
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). SAP and DSAP rats ate similar amounts of food in the 4-h saline baseline test (1.4 ± 0.3 and 1.4 ± 0.3 g, respectively). 2DG increased food intake significantly above the baseline intake in SAP rats (3.6 ± 0.3 g; P < 0.001, compared with saline baseline) but not in DSAP rats (1.3 ± 0.3 g; P = 0.77, compared with saline baseline).
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Body weights did not differ significantly between SAP and DSAP rats on d 0 at the start of chronic 2DG treatment or at any time during chronic 2DG treatment (Fig. 2). However, 2DG produced significant weight loss in both groups (d 0 vs. d 3, P < 0.05 for both groups). Before chronic 2DG treatment, 24-h food intake was 16.5 ± 0.5 and 17.7 ± 0.8 g for SAP and DSAP rats, respectively. In both SAP and DSAP groups, daily food intake declined significantly during the chronic 2DG treatment (P < 0.001; Fig. 3). The reduction in total daily food intake during the three treatment days was slightly greater in the DSAP rats (d 1 vs. d 2, P < 0.04; d 1 vs. d 3, P < 0.004) than the SAP rats (d 1 vs. d 3, P < 0.025). However, daily food intake did not differ between groups on any day.
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, left panel) was extended by chronic 2DG treatment in the SAP rats (P < 0.001) but not in the DSAP rats (P = 0.35). Rats with extended cycles had more days of diestrus than a normal 4- to 5-d cycle and did not have more days of estrus. In addition, Fig. 4 (right panel) shows that fewer SAP than DSAP rats had normal 4- to 5-d cycles during 2DG treatment (one of eight SAP rats vs. seven of eight DSAP rats, P < 0.002).
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Neither SAP nor DSAP injections produced detectable nonspecific damage. However, PVN DSAP injections produced a significant loss of dßh-ir cell bodies in the A1, A1/C1, and C1m areas (Table 1). Cell numbers in A2 were also reduced by PVN DSAP, but to a lesser extent than for the ventrolateral cell groups, as noted previously (10). DSAP did not reduce cell body number in cell groups A5 and A7 that do not innervate the PVN (Table 1). In addition to loss of cell bodies, PVN DSAP injection caused profound depletion of dßh-immunoreactive terminals and fibers in the PVN and throughout the medial hypothalamus. The photomicrographs in Fig. 5 depict dßh-ir of SAP- and DSAP-injected animals in representative sections from the A1/C1 region of the brain stem (Fig. 5, A and B) and from the PVN (Fig. 5, C and D), median eminence (ME) (Fig. 5, E and F), and medial preoptic area/medial septum-diagonal band (MPOA/MS-DB) area (Fig. 5, G and H).
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Discussion |
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The failure of chronic glucoprivation to suppress estrous cylicity in DSAP-injected rats is not likely to be attributable to nonspecific pathology resulting from the injection. We have shown previously, using a variety of functional, histological, and histochemical indicators, that the DSAP lesion is highly specific for dßh-containing neurons (10, 25, 26). In a small percentage of cases where the microinjector tract can be identified by small hemosiderin deposits, the tissue surrounding the injection site appears normal. Animals in the present study were not sick or underweight and exhibited normal cycles after DSAP injection surgery that were not different from estrous cycles of untreated rats or of saporin-treated rats. These normal estrous cycles can only be produced if the underlying neuroendocrine axis remains functional. PVN DSAP injection does cause a number of specific deficits related to the multiple functions of NE/E neurons, such as a reduction in corticosterone secretion in response to the glucose deficit (25), and we cannot rule out the possibility that the failure of chronic glucoprivation to suppress estrous cylicity in DSAP-injected rats is secondary to one of these deficits. However, even if this is so, our data nevertheless indicate an essential role for NE/E neurons in the response of the reproductive axis to chronic glucoprivation.
Although microinjections of DSAP were directed at the PVN, these injections caused severe depletion of dßh-ir throughout the medial hypothalamus, including the PVN, ME, and MPOA/MS-DB. The extent of the denervation throughout the medial hypothalamus is of course related, in part, to the diffusion of the DSAP from the injection site. However, because DSAP is retrogradely transported from the injection site and ultimately destroys the neurons that internalize it, all of the innervation derived from the processes of those same neurons will be eliminated. Therefore, the pattern and extent of the denervation produced by injection of DSAP into a particular site is determined by the collateralization patterns of the neurons innervating the injection site. Thus, the profound denervation of the PVN, ME, and MPOA/MS-DB produced by PVN DSAP injections may reflect extensive innervation of these medial hypothalamic sites by collaterals of a common cell population. A number of studies have demonstrated that most of the NE and E innervation of the hypothalamus, including the PVN, ME, and MPOA/MS-DB, originates from cell groups A1, A2, and C1 (27, 28, 29), which collateralize extensively throughout the medial hypothalamus and were severely reduced by our DSAP injection.
Because the denervation associated with our DSAP lesion included the entire medial hypothalamic region, we are not able to determine from our results which denervated area is the most critical for suppression of estrous cycles during chronic glucoprivation. Additional work will be required to address this important question. The complete denervation of NE and E terminals in the MPOA/MS-DB regions is noteworthy, however, because earlier work has demonstrated an involvement of NE neurons in estrous cyclicity and ovulation (see Ref. 30 for review). Acute studies have shown both stimulatory and inhibitory effects of NE on LH pulse frequency in the rat (31, 32), whereas NE seems to be important in generation of the LH surge (33, 34, 35, 36, 37). Therefore, it is interesting that DSAP injections eliminated dßh-ir in the MPOA/MS-DB, where GnRH-containing neurons reside, as well as in the PVH and ME, without altering estrous cyclicity in our rats. This strongly indicates that the hindbrain catecholamine innervation of these areas is not required for normal ovulation and estrous cycles. Our data are in agreement with studies that show a complete recovery of LH secretion after pharmacological or lesion-induced disruption of ascending NE pathways (38, 39, 40, 41). Further, LH pulses are not altered after complete hypothalamic deafferentation in the rat (42, 43, 44). Perhaps this points to a permissive role for NE and E neurons in the regulation of GnRH secretion that can be compensated for by other neuronal pathways.
Previous studies have shown that neuropeptide Y (NPY) afferents to the hypothalamus from the hindbrain derive almost entirely from neurons that coexpress either NE or E (45). Nearly all rostrally projecting C1 (E-containing) neurons coexpress NPY. A smaller percentage of A1 (NE-containing) neurons coexpress NPY, but those that do are concentrated in the rostral part of the cell group, in the area of A1/C1 overlap. A2 neurons do not coexpress NPY. Because dßh-ir neurons in areas A1, A1/C1, and C1m were almost totally eliminated by the PVN DSAP injection, we can conclude that the major source of hypothalamic NPY innervation from the hindbrain, as well as the major source of NE and E innervation, was eliminated. Thus, the loss of hindbrain NPY afferents to the medial hypothalamus may be involved in the deficits we report here. However, we have observed that NPY terminals in the MPOA/MS-DB and PVN are not abolished by PVN DSAP injection (unpublished data), consistent with the fact that NPY-containing neurons with cell bodies in the arcuate nucleus also innervate these structures (28, 46, 47).
Although acute glucoprivation increased food intake in SAP controls, chronic glucoprivation did not do so. The loss of responsiveness to glucoprivation during repeated 2DG administration or after repeated bouts of insulin-induced hypoglycemia is known as hypoglycemia unawareness and has been reported previously in both humans and rats (48, 49, 50, 51). However, in the present experiment, as well as in previous work (4), not only was the stimulation of food intake by 2DG suppressed during chronic glucoprivation, but food intake was suppressed below basal levels. This indicates that mechanisms in addition to those causing hypoglycemia unawareness may contribute to the reduction of intake. Additional mechanisms that may contribute include a reduction in metabolic rate during chronic systemic 2DG or generalized behavioral suppression attributable to reduction in brain glucose metabolism. Perhaps reduced food intake is associated with a change in energy-partitioning strategy. An acute increase in food intake would imply an increase in foraging activity, whereas the decrease in food intake associated with chronic glucoprivation would suggest a decrease in foraging activity and associated movements. Such a change in energy-partitioning strategy has been noted in developing house mice where exercise and temperature were manipulated to mimic differing metabolic challenges (52). House mice choose to run more wheel revolutions to obtain enough food for normal growth and timing of puberty only if ambient temperature is quite high (23 C). At lower ambient temperatures (9 C) the mice remain in their nests, resulting in inhibited growth and delayed puberty onset. In our study, PVN DSAP injection did not abolish the decline in food intake induced by chronic glucoprivation, suggesting that ascending catecholaminergic pathways are not involved in the decline in food intake. Perhaps other neuronal pathways are stimulated when metabolic challenges become more intense. Previous studies have shown that spinally projecting catecholaminergic neurons mediate adrenal-medullary secretion in response to acute glucoprivation, thus providing evidence of divergent pathways for regulation of energy homeostasis (10).
Animals in the wild are unlikely to be subjected to 2DG-induced glucoprivation, but they are likely to be in a state of negative energy balance from time to time. Chronic 2DG-induced glucoprivation extends estrous cycle length in rats in a manner similar to that of food deprivation (14). Because both food deprivation and acute 2DG-induced glucoprivation suppress LH pulse frequency (6, 24), we hypothesize that central glucoprivation underlies the suppressive effects of both treatments on the reproductive axis. Further, because DSAP injections into the PVN eliminate the suppressive effects of chronic glucoprivation on the reproductive axis, we would expect a similar elimination of the suppressive effects of food deprivation in DSAP-injected rats. On the other hand, feeding in response to acute glucoprivation is abolished by PVN DSAP injections, but feeding in response to mild or acute food deprivation induced by an overnight fast is not attenuated (10). Therefore we cannot assume, without further experimentation, that chronic 2DG and chronic food deprivation are equivalent in their effects on the reproductive axis. We intend to test this hypothesis in future studies using this model.
The present findings, in combination with previous work, support the hypothesis that NE and E neurons providing afferent innervation of the PVN transmit crucial signals associated with glucoprivation from hindbrain glucoreceptive sites to forebrain brain sites where reproductive function is controlled. Activation of NE and E neurons by glucoprivation inhibits estrous cycling. Suppression of estrous cycles during periods of energy deficit can be thought of as an adaptive response that contributes to metabolic homeostasis by suppressing reproductive function under circumstances that would be adverse for survival of the adult female and potential offspring. The inhibitory control of estrous cycles by hindbrain catecholamine neurons in response to glucoprivation is therefore a control that subserves the overall conservation and reallocation of energy required by glucose deficit. Previous results with DSAP indicate that hindbrain catecholamine neurons are essential for several glucoregulatory responses, including increased feeding, adrenal medullary secretion, and corticosterone secretion in response to glucoprivation, as well as for increased AGRP and NPY gene expression in response to glucoprivation (10, 26, 53, 54). These data therefore further extend the role of hindbrain catecholamine neurons in energy homeostasis to include the inhibition of estrous cycles during chronic glucoprivation.
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Acknowledgments |
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Footnotes |
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Abbreviations: dßh, Dopamine ß-hydroxylase; 2DG, 2-deoxy-D-glucose; DSAP, dopamine ß-hydroxylase mouse monoclonal antibody conjugated to saporin; E, epinephrine; -ir, immunoreactivity; ME, median eminence; MPOA/MS-DB, medial preoptic area/medial septum-diagonal band; NE, norepinephrine; NPY, neuropeptide Y; PVN, paraventricular nucleus; SAP, unconjugated saporin; TPBS, Tris sodium phosphate buffer.
Received February 27, 2003.
Accepted for publication June 27, 2003.
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References |
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immunoreactivity in the brain catecholaminergic neurons in ovariectomized rats. Neurosci Lett 299:109–112[CrossRef][Medline]
2-Adrenergic receptors are involved in the suppression of luteinizing hormone release during acute fasting in the ovariectomized estradiol-primed rat. Neuroendocrinology 56:724–728[Medline]
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