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Departments of Physiology and Biophysics (S.M.K., G.S.F., S.M.S., R.A.S.), Obstetrics and Gynecology (D.K.C., R.A.S.) and Zoology (R.A.S.), University of Washington, Seattle, Washington 98195-7290; and Amgen, Inc. (J.W.B.), Thousand Oaks, California 91320
Address all correspondence and requests for reprints to: Dr. Robert A. Steiner, Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, Washington 98195-7290. E-mail: steiner{at}u.washington.edu.
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Introduction |
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-MSH (a cleavage product of the POMC precursor gene) and CART have been demonstrated to decrease FI and BW when administered centrally (8, 9, 10). Conversely, leptin decreases mRNA levels of the orexigenic neuropeptides NPY and AgRP (11, 12). All four of these neuropeptides are thought to be downstream effectors of leptin signaling within the hypothalamus and have been implicated in the regulation of energy homeostasis and reproduction (2, 13, 14, 15, 16). However, evidence suggests that other populations of neurons in the Arc, in addition to the ones mentioned above, are also targets for leptin, including neurons that synthesize galanin-like peptide (GALP). GALP is a 60-amino-acid neuropeptide that was recently isolated from porcine hypothalamus by virtue of its ability to bind and activate galanin receptors in vitro (17). GALP cDNAs have subsequently been cloned from pig, rat, mouse, macaque, and human (17, 18, 19). In all species studied to date, amino acids 9–21 of GALP are 100% homologous to the first thirteen amino acids of galanin, which are believed to confer biological activity to the galanin molecule (17, 18, 19, 20). GALP binds to galanin receptors in vitro, showing a higher affinity for GalR2 (IC50 = 0.24 nM) than for GalR1 (IC50 = 4.3 nM). In contrast, galanin binds to GalR1 and GalR2 with more similar affinities (IC50 = 0.1 nM and 0.48 nM, respectively) (17). GALP has a fairly restricted distribution pattern within the central nervous system (CNS), with the expression of GALP mRNA and protein in the forebrain being confined to the Arc and median eminence, as well as the neurohypophysis (21, 22, 23, 24).
The expression of GALP mRNA within the Arc is highly dependent upon an animal’s nutritional status. In the rat, levels of GALP mRNA are reduced by a 48-h fast, an effect that is reversed by concomitant treatment with leptin (21). In the leptin-deficient ob/ob mouse, GALP mRNA expression is virtually nondetectable but is restored to wild-type levels by central leptin administration (18). Furthermore, the vast majority (greater than 85%) of GALP-containing cells in the Arc coexpress Ob-R mRNA (19) or protein (24). These observations suggest that GALP neurons are downstream targets of leptin within the CNS, and thus might play an intermediary role in leptin’s ability to decrease FI and BW and stimulate reproductive hormone secretion. To test these hypotheses, we performed a series of experiments to evaluate the effects of central GALP treatment on FI, BW, and reproductive hormone levels in the mouse.
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Materials and Methods |
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Animals
Adult male C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME) were individually housed and were maintained on a 14-h light, 10-h dark dark cycle (lights on at 0500 h), unless otherwise noted. Male Sprague Dawley rats (B&K Universal, Kent, WA) were individually housed and were maintained on a 12-h light, 12-h dark cycle (lights on at 0600 h). All animals had access to standard rodent chow and water ad libitum, unless stated otherwise. In each experiment, animals were weight-matched before being divided into treatment groups. All procedures were approved by the Animal Care Committee of the School of Medicine of the University of Washington in accordance with the NIH Guide for Care and Use of Laboratory Animals.
Intracerebroventricular (ICV) injections
Freehand ICV injections were performed as previously described (25), with a few modifications. Briefly, mice were anesthetized with isoflurane (Abbott Laboratory, North Chicago, IL) delivered by a vaporizer (Veterinary Anesthesia Systems, Bend, OR). Upon achieving a surgical plane of anesthesia, a small hole was bored in the skull 1 mm lateral and 0.5 mm posterior to bregma with a Hamilton syringe attached to a 27-gauge needle fitted with polyethylene tubing, leaving 3.5 mm of the needle tip exposed. Once the initial hole was made, all subsequent injections were made at the same site. Mice were allowed to recover for at least 2 d before treatment. For ICV injections, mice were anesthetized with isoflurane for a total of 2–3 min, during which time 3 µl solution were slowly and continuously injected into the lateral ventricle. The needle remained inserted for approximately 30 sec after injection to minimize backflow up the needle track. Mice typically recovered from the anesthesia within 3 min after the injection.
Experiment 1: dose-response
Mice received two ICV injections (1800 h and 0800 h the following day) of either aCSF (n = 7) or 1 nmol (n = 6), 5 nmol (n = 8), or 10 nmol GALP (n = 5). FI, BW, and rectal temperature were measured 24 h after the first injection.
Experiment 2: long-term GALP treatment
Mice received two ICV injections/d (0800 h and 1800 h) for 4.5 d, with the first injection occurring at 1800 h (d 0). Mice were treated with either aCSF (n = 8) or 5 nmol GALP (n = 8). FI and BW were monitored daily.
Experiment 3: locomotor activity
Mice were group-housed (four per cage) and were maintained on a 12-h light, 12-h dark cycle (lights on at 0700 h). Either aCSF (n = 7) or 5 nmol GALP (n = 8) was injected ICV twice daily (0800 h and 1800 h) for 4.5 d, with the first injection occurring at 1800 h. Locomotor activity was measured by placing the mice in individual transparent Plexiglas cages (40 x 20 x 20 cm) surrounded by aluminum frames equipped with infrared beams (San Diego Instruments, San Diego, CA). Activity levels were monitored for 14 h overnight (starting at 1830 h) after the first and ninth injections. Activity levels are expressed as the number of ambulations (two consecutive beam breaks) recorded in each 30-min interval, as well as the total number of ambulations over the entire 14-h observation period.
Experiment 4: conditioned taste aversion
Mice were placed on a water restriction schedule, during which time they received two water bottles per cage from 0830–0900 h and from 1400–1900 h each day for 7 d. Food and water intake were measured daily. On d 8, the mice received a single bottle of water containing 0.15% saccharin (Sigma, St. Louis, MO) at 0830 h. Bottle position in the cage was randomized. The saccharin water was removed 30 min later, and then the mice received an ICV injection of either aCSF (n = 9) or 5 nmol GALP (n = 8). A third group of mice received an ip injection (2% BW) of 0.15 M LiCl (J. T. Baker, Inc., Phillipsburg, NJ) dissolved in saline (n = 4). The mice were allowed to recover for 48 h, during which time they were still water restricted. Food and water intake returned to preinjection levels in all treatment groups within 48 h. After 48 h, the mice received two bottles (one containing water and the other containing 0.15% saccharin water, with bottle position randomized) at 0830 h. Fluid intake was measured from each bottle after 2 h. Data are expressed as saccharin preference ratios (SPR = volume of saccharin water consumed/total fluid volume consumed during the 2-h period).
Experiment 5: time-course
Mice received a single ICV injection of either aCSF (n = 7) or 5 nmol GALP (n = 7) at 1800 h. FI was measured 2, 4, 6, 8, 14, and 24 h post injection, and BW was measured 14 and 24 h post injection.
Experiment 6: morning GALP injection in mice
Mice received a single ICV injection of either aCSF (n = 8) or 5 nmol GALP (n = 8) at 0900 h. FI was measured after 1 and 2 h, and both FI and BW were measured 24 h post injection.
Experiment 7: morning GALP injection in rats
Rats (320–350 g) were anesthetized with an injection (0.1 ml/100 g BW, im) of a ketamine (100 mg/ml)/xylazine (20 mg/ml)/acepromazine maleate (10 mg/ml) cocktail. The animals were placed in a stereotaxic instrument with the incisor bar positioned 3 mm below the horizontal plane that intersected the center of the ear bars. A permanent stainless steel cannula was implanted into the third ventricle at 0 mm from midline, -2.2 mm caudal to bregma, and -7.5 mm ventral to dura (26). The animals were allowed to recover for 8 d before treatment, during which time they were handled daily. On d 9, the rats received a single injection of either aCSF or 5 nmol GALP at 0900 h. Injections were delivered in a volume of 3 µl over the course of 2 min. FI was measured 1, 2, and 24 h post injection; BW was measured 24 h post injection. The experiment was repeated 4 d later in a cross-over design, such that each animal received both treatments (n = 10 per treatment). Correct cannula placement was determined by injecting 0.5 nmol NPY 2 d after the first round of injections. Only rats that increased baseline FI by at least 4 g during the first hour after NPY treatment were included in the study.
Experiment 8: reproductive hormones
Mice were handled daily for 2 wk before treatment. Mice received a single ICV injection of either aCSF (n = 9) or 5 nmol GALP (n = 8) between 0800 h and 0830 h. The mice were lightly anesthetized with isoflurane 30 min later and were then brought to a separate room. Blood was obtained by a combination of orbital bleed and by collecting trunk blood after cervical dislocation and rapid decapitation. Sera were stored at -20 C for hormone measurements.
RIAs
Serum LH and FSH concentrations were measured with reagents obtained from NIH. For LH, the antiserum used was anti-rLH-S-11 and the standard was rLH-RP3. The assay sensitivity was 0.2 ng/ml and the intraassay coefficient of variation was 7%. For FSH, the antiserum used was anti-rFSH-S-11 and the standard was rFSH-RP2. The assay sensitivity was 1.0 ng/ml and the intraassay coefficient of variation was 6%. Testosterone was measured with a double antibody kit (ICN Biomedicals, Inc., Costa Mesa, CA). The assay sensitivity was 0.02 ng/ml, and the intraassay coefficient of variation was 3%. All hormones were measured in single assays.
Statistical analysis
All data are expressed as a mean ± SEM for each group. Differences between groups were assessed by one-way or two-way ANOVA. When the ANOVA indicated significant differences, Fisher’s post hoc test was used to identify differences between individual treatment groups. Two group comparisons were performed using Student’s t test. Differences were considered significant when P < 0.05.
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Results |
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) and BW (Fig. 1B) when measured 24 h after the first injection, with significant decreases in FI and BW occurring with injection of 5 or 10 nmol GALP. At 24 h after the first injection, rectal temperature was depressed in the mice that received 10 nmol GALP (P < 0.005 vs. vehicle-treated mice) but was unaffected by either 1 or 5 nmol GALP (data not shown). In addition to reducing FI and BW, treatment with the higher doses of GALP had pronounced effects on motor behavior. The mice treated with 5 or 10 nmol GALP consistently remained immobile for a longer period of time than the vehicle-treated mice (i.e. they did not appear to recover from the anesthesia as quickly as the vehicle-treated animals). Within the first hour post injection, tremors were often observed in the mice that received 10 nmol GALP. There was no evidence of tremors associated with either the 1- or 5-nmol doses.
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) and BW (Fig. 2B). At 24 h after the first injection (d 1), FI and BW were significantly reduced in the GALP-treated mice (P < 0.005 and P < 0.05 vs. vehicle-treated mice, respectively). However, at 48 h after the first injection (d 2), FI and BW no longer differed between the vehicle- and GALP-treated groups. FI recovered to baseline levels in the GALP-treated mice by d 2, whereas BW took longer to return to pretreatment levels. FI was significantly elevated in the GALP-treated mice on d 4 (P < 0.05 compared with vehicle-treated mice).
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), locomotor activity was significantly suppressed by 5 nmol GALP (P < 0.005 vs. vehicle-treated mice). Following the first injection, there was very little evidence of movement in the GALP-treated mice until the final few hours of the observation period, coinciding with the timing of the lights coming on (Fig. 3B). Surprisingly, locomotor activity was significantly elevated in the GALP-treated mice during the 14-h period following the ninth injection (P < 0.005 vs. vehicle-treated mice). After the ninth injection, the GALP-treated mice were immobile for approximately 4 h but then became increasingly hyperactive for the remainder of the observation period.
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). Using a two-bottle paradigm, we observed that ICV treatment with vehicle did not appear to induce a CTA, as evidenced by a high saccharin preference ratio (SPR) in the vehicle-treated group (SPR = 0.83 ± 0.03). Another group of mice received an ip injection of LiCl, an emetic drug that is well known to elicit the formation of a CTA in rodents. As expected, the LiCl-treated mice had a low SPR (SPR = 0.12 ± 0.06; P < 0.0001 vs. vehicle-treated mice), indicating that LiCl treatment induced the formation of a CTA. Mice that received an ICV injection of 5 nmol GALP also formed a strong CTA (SPR=0.02 ± 0.01; P < 0.0001 vs. vehicle-treated mice).
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). FI remained significantly reduced at all subsequent time points (P < 0.001 vs. vehicle-treated mice at all post-injection time points). BW was significantly decreased in the GALP-treated mice 14 h post injection (P < 0.05 vs. vehicle-treated mice) but no longer differed from the vehicle-treated group by the 24-h time point (data not shown).
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). FI (Fig. 6B) and BW (Fig. 6C) in the GALP-treated group were significantly reduced 24 h post injection (P < 0.05 vs. vehicle-treated mice). Lower doses of GALP (0.2 and 1 nmol) also tended to reduce FI during the first hour post injection compared with vehicle treatment, although the differences did not reach statistical significance (data not shown). Although no formal measures of locomotor activity were made in this experiment, treatment with 1 nmol GALP appeared to have minimal effects on motor behavior and the 0.2 nmol dose appeared to be sub-threshold for any detectable motor effects. Although the morning FI measurements in all treatment groups were only slightly above the level of detection, there was no evidence of stimulation of FI at these lower doses of GALP, even in the absence of pronounced effects on motor activity.
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Experiment 7: morning GALP injection in rats
To confirm the earlier report by Matsumoto et al. (29) of GALP’s acute stimulatory effect on FI in the rat, rats were given a single third ventricle injection of vehicle or 5 nmol GALP at 0900 h. FI was significantly elevated in the GALP-treated group during the first hour post injection (P < 0.05 vs. vehicle-treated rats) but did not differ between the two groups during the second hour (Fig. 7A). Despite the initial increase in FI with GALP treatment, FI (Fig. 7B) and BW (Fig. 7C) were significantly reduced in the GALP-treated rats 24 h post injection (P < 0.005 and P < 0.05 vs. vehicle-treated rats, respectively). Motor behavior did not appear to be altered in the rats by administration of 5 nmol GALP.
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). 30 min following an ICV injection of either vehicle or 5 nmol GALP, serum levels of LH and testosterone were significantly higher in the GALP-treated mice compared with the vehicle-treated group (P < 0.0005). Serum levels of FSH were modestly elevated in the GALP-treated animals, but the difference did not reach statistical significance (P = 0.06 vs. vehicle-treated mice).
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Discussion |
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Matsumoto et al. (29) recently demonstrated that in the rat, central GALP administration stimulates FI during the first 90 min post injection, suggesting that GALP is orexigenic. This observation seems to be counterintuitive, considering reports that the expression of GALP mRNA is up-regulated by leptin, a hormone that acts centrally to reduce FI. The expression of orexigenic neuropeptides, such as NPY and AgRP, is generally inhibited by leptin and induced by fasting and leptin deficiency (13, 14). In contrast, the expression of GALP mRNA is reduced in cases of fasting and leptin deficiency, in a manner similar to that of the anorectic peptides -MSH and CART (14). In an attempt to reconcile our observations in the mouse with previous reports that GALP stimulates FI in the rat, we investigated the effects of GALP on short-term FI in the mouse, in the event that we might have been overlooking an acute stimulatory effect of GALP on FI. However, when mice were injected with GALP in the morning, we observed a reduction in FI during the first hour following the injection. Although mice eat very little food during the daytime, it is possible to observe a statistically significant increase in acute FI in the morning. In our hands, we have observed an approximately 2-fold increase in FI in mice 1 h following an ICV injection of NPY in the morning (unpublished observations). Furthermore, the use of isoflurane anesthesia before and during the ICV injection of NPY did not block the increase in FI in that study; thus, we would conclude that the use of isoflurane was unlikely to have masked a possible stimulatory effect of GALP on FI in the present study.
The observation that GALP had no discernible stimulatory effect on FI in the mouse, in contrast to a previously published report of GALP’s effects on FI in the rat, initially raised the concern that the GALP we were using might display differences in biological activity and/or potency compared with the GALP preparation used by Matsumoto et al. (29). Therefore, we tested the bioactivity of our GALP within a different physiological context. Central GALP administration has been shown to acutely stimulate LH secretion in the male rat (30). We reasoned that if the GALP we were using was bioactive, we would likely observe an increase in LH secretion in mice following GALP administration, as is the case in the rat. Indeed, we found that ICV treatment with our GALP preparation acutely increased circulating levels of both LH and testosterone in male mice, thus corroborating results in the rat and confirming the efficacy of our GALP preparation.
To further examine whether mice and rats exhibit differential feeding responses to acute GALP treatment, we administered GALP to rats. We confirmed the occurrence of a transient stimulatory effect of GALP on FI in the rat, yet also observed a significant decrease in FI and BW 24 h later, as we have demonstrated in the mouse. These findings corroborate a recent report by Lawrence et al. (32) demonstrating that FI and BW are reduced 24 h following a single ICV injection of GALP in the rat. One possible explanation for the disparate effects of GALP on FI between the 1- and 24-h intervals in the rat may be that GALP activates different neural pathways over the short and long term. It is conceivable that GALP’s rapid stimulatory effect on FI reflects an activation of galanin receptors, perhaps mimicking the orexigenic effect of central galanin administration in the rat. This supposition is supported by the observation that GALP’s acute stimulatory effect on FI in the rat is similar in its time-course to that of galanin (29). However, over a more extended time interval GALP might activate a different population of receptors (either another galanin receptor subtype or perhaps a yet-to-be-identified GALP-specific receptor), resulting in the activation of neural circuits that ultimately decrease FI and BW. If this were the case, the different response of the rat and the mouse to an acute GALP challenge might be attributable to the inaccessibility of exogenously administered GALP to orexigenic galaninergic pathways in the mouse, or perhaps to the absence of orexigenic galaninergic pathways in the mouse (which do exist in the rat) (33). The fact that there was no apparent stimulatory effect of galanin on acute FI in the mouse supports these arguments.
Centrally administered GALP elicits temporary immobility in the rat (29). In the present study, spontaneous locomotor activity was reduced in mice after both acute and long-term GALP treatment. Compared with a single GALP injection, locomotor activity was suppressed for a shorter duration after long-term GALP treatment and was subsequently followed by pronounced hyperactivity. We did not measure activity levels at any intermediate time points during the course of long-term GALP treatment, so we do not know precisely when during the 3-d window this shift in motor response occurred. The physiological significance of this response is not immediately apparent. One possibility is that endogenous GALP is involved in the generation of circadian rhythms and/or sleep/wake cycling, as was recently shown to be the case with the orexins, a family of hypothalamic neuropeptides that is also implicated in regulating feeding behavior (34). On the other hand, it is possible that GALP’s effects on motor behavior occur as a consequence of widespread diffusion of GALP following ICV injection. Galanin receptors are widely distributed throughout the CNS, including regions involved in motor function (35), and thus it is conceivable that the ICV injection of GALP leads to activation of receptors that ordinarily do not receive input from GALP neurons.
Given the acute suppressive effect of GALP treatment on locomotor activity, it is plausible that the reduced FI observed following ICV GALP treatment is a consequence of impaired motor function. Similar concerns have been raised about the specificity of CART’s inhibitory effect on FI. Central administration of CART(55–102) reduces FI in rats but also causes movement-associated tremors and aberrant body postures (8, 36). Additional experiments have provided support for the argument that CART has specific effects on feeding behavior that are independent of its effects on motor function. Central administration of CART antiserum significantly increases night-time feeding in rats (8), and ICV administration of CART(42–89) induces Fos expression in regions of the brain that are involved in the regulation of FI, including several hypothalamic nuclei (37). When similar experiments are performed with GALP, they should help to elucidate whether the effects of exogenous GALP on FI are specific to modulation of central feeding pathways. Although we did not formally measure locomotor activity with doses of GALP lower than 5 nmol in this study, doses of both 0.2 and 1 nmol GALP had minimal effects on gross motor function, yet we still observed a trend for reduced FI at these lower doses. A transient suppression of locomotor activity occurred after both the first and ninth GALP injections during long-term treatment with GALP, but FI was suppressed only during d 1 of the 4.5-d treatment period. This suggests that changes in FI cannot be entirely explained by reduced levels of motor activity immediately after the GALP injection.
The central administration of GALP elicited the formation of a strong CTA in mice. The induction of a CTA has been used for several decades as a behavioral assay to ascertain whether a particular substance might be toxic or cause visceral illness in rodents. One interpretation of experiment 4 is that central administration of 5 nmol GALP produces a pharmacological toxicity, and this explains its inhibitory effects on feeding and BW. Notwithstanding, there has been an ongoing debate about the interpretation of CTA studies. Several investigators have proposed that the formation of a CTA may not reflect either toxicity or illness, nor does it prove that the administered substance is truly aversive to the subject (27, 38, 39). Many drugs that elicit the formation of a CTA in an experimental setting do not appear to cause nausea or visceral illness and are even self-administered by animals, such as morphine and cocaine (39). It is also worth noting that not all agents that elicit a CTA reduce FI. The central administration of NPY results in the formation of a CTA in the rat, despite its simultaneous ability to markedly stimulate FI (40). Given the uncertainty of interpreting the results of CTA experiments, it is conceivable that the induction of a CTA by central GALP treatment does not reflect simple toxicity. Perhaps the central administration of GALP modulates the activity of neural pathways that are normally activated under aversive circumstances, thus leading to the formation of a CTA. Alternatively, if ICV GALP treatment does indeed have aversive properties, it might be argued that such an effect may still be physiologically relevant, in the sense that aversion may simply lie at one extreme of the range of appetitive behavior.
In addition to confirming the biopotency of our GALP preparation, the observation that central GALP administration stimulates the secretion of reproductive hormones suggests that GALP is involved in the neuroendocrine control of reproduction. GALP-immunoreactive fibers are found in close apposition to a subset of GnRH neurons in the medial preoptic area and the bed nucleus of the stria terminalis, and ICV GALP administration induces Fos expression in GnRH neurons (24, 30). GALP’s stimulatory effect on LH secretion in the rat is blocked by pretreatment with a GnRH receptor antagonist, suggesting that exogenous GALP treatment stimulates LH secretion via a GnRH-dependent mechanism (30). These observations implicate a role for GALP in modulating the hypothalamic-pituitary-gonadal axis in the rat. The present demonstration that central GALP treatment increases serum LH and testosterone concentrations in the mouse suggests that GALP has a modulatory effect on the reproductive axis of this species as well as the rat.
We have demonstrated here that central administration of GALP decreases FI and BW in the mouse and the rat. Together with previous demonstrations that the expression of GALP mRNA is up-regulated by leptin, the present observations are consistent with GALP playing a physiological role in the regulation of energy homeostasis. However, it is conceivable that the observed reduction in FI following central GALP treatment is not due to a specific action of GALP on neural circuits controlling feeding but is instead secondary to impaired motor behavior and/or aversive properties of ICV GALP treatment. Additional experiments will be necessary to further resolve questions about the specificity of GALP’s effects on feeding behavior. The effects of GALP on FI appear to be species dependent because we (and others) have shown that GALP acutely stimulates FI in the rat but not in the mouse. We have also demonstrated a stimulatory effect of GALP on reproductive hormone secretion in the mouse. Together, these observations support the argument that GALP is a downstream effector of leptin’s actions within the CNS. Furthermore, the putative involvement of GALP in the regulation of both feeding and reproduction implicates GALP as a potential molecular link between these two physiological processes.
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Acknowledgments |
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Footnotes |
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Abbreviations: aCSF, Artificial cerebrospinal fluid; AgRP, agouti-related protein; Arc, arcuate nucleus; BW, body weight; CART, cocaine- and amphetamine-regulated transcript; CNS, central nervous system; CTA, conditioned taste aversion; FI, food intake; GALP, galanin-like peptide; ICV, intracerebroventricular; NPY, neuropeptide Y; Ob-R, leptin receptor; POMC, proopiomelanocortin; SPR, saccharin preference ratio.
Received September 18, 2002.
Accepted for publication December 3, 2002.
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References |
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-MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression. Am J Physiol Regul Integr Comp Physiol 279:R695–R703
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M. L. Heiman and M. A. Statnick Galanin-Like Peptide Functions More Like Leptin than Like Galanin Endocrinology, November 1, 2003; 144(11): 4707 - 4708. [Full Text] [PDF]
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K. R. Hansen, S. M. Krasnow, M. A. Nolan, G. S. Fraley, |
) or 5 nmol GALP (
). Mice received two ICV injections/d for 4.5 d. Solid black bars indicate duration of treatment. *, P < 0.05; **, P < 0.005 vs. vehicle-treated mice.
