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| Neonatal Exposure to Sevoflurane in Mice Causes Deficits in Maternal Behavior Later in Adulthood | |
| Yumiko Takaenoki, M.D., Yasushi Satoh, Ph.D., Yoshiyuki Araki, M.D., Mitsuyoshi Kodama, M.D., Ph.D., Ryuji Yonamine, M.D., Shinya Yufune, M.D., Tomiei Kazama, M.D., Ph.D. | |
| ABSTRACT | |
| Background: In animal models, exposure to general anesthetics induces widespread increases in neuronal apoptosis in the developing brain. Subsequently, abnormalities in brain functioning are found in adulthood, long after the anesthetic exposure. These abnormalities include not only reduced learning abilities but also impaired social behaviors, suggesting pervasive deficits in brain functioning. But the underlying features of these deficits are still largely unknown. Methods: Six-day-old C57BL/6 female mice were exposed to 3% sevoflurane for 6 h with or without hydrogen (1.3%) as part of the carrier gas mixture. At 7–9 weeks of age, they were mated with healthy males. The first day after parturition, the maternal behaviors of dams were evaluated. The survival rate of newborn pups was recorded for 6 days after birth. Results: Female mice that received neonatal exposure to sevoflurane could mate normally and deliver healthy pups similar to controls. But these dams often left the pups scattered in the cage and nurtured them very little, so that about half of the pups died within a couple of days. Yet, these dams did not show any deficits in olfactory or exploratory behaviors. Notably, pups born to sevoflurane-treated dams were successfully fostered when nursed by control dams. Mice coadministered of hydrogen gas with sevoflurane did not exhibit the deficits of maternal behaviors. Conclusion: In an animal model, sevoflurane exposure in the developing brain caused serious impairment of maternal behav- iors when fostering their pups, suggesting pervasive impairment of brain functions including innate behavior essential to spe- cies survival. (Anesthesiology 2014; 120:403-15) | |
| A CCUMULATING evidence indicates that exposure | |
| What We Already Know about This Topic | |
| to general anesthetics at clinically effective concentra- tions induces widespread increases in neuronal apoptosis in the developing brain of a variety of animals ranging from rodents to rhesus monkeys.1–10 Furthermore, long after the anesthetic exposure, learning deficits are manifested later in adulthood1–5 even though a significant increase in neuro- nal apoptosis is no longer evident.11 The primary cause of these learning deficits in the adults is not fully understood, which hinders identification of the underlying pathophysiol- ogy. The impairment of brain function caused by neonatal exposure to sevoflurane is not specific to the learning deficit. We previously reported that neonatal exposure to sevoflu- rane induced a disturbance in social behaviors in mice that resembles those observed in subjects with autism.3 This evi- dence suggests that pervasive deficits in brain functioning may be induced. However, there is not enough evidence to support this hypothesis. | |
| Anesthetic exposure to neonatal animals results in increased programmed cell death in the brain and altered neurocognitive development | |
| The effects of this exposure on innate behavior are relatively unexplored | |
| What This Article Tells Us That Is New | |
| Female mouse pups exposed to sevoflurane anesthesia ex- hibited deficits in classic maternal behaviors after delivery, an effect which was prevented by coadministration of the antioxi- dant, hydrogen gas with sevoflurane | |
| Previous anesthesia exposure did not alter oxytocin or vaso- pressin release in the maternal mice after delivery | |
| behavioral task for mice in normal laboratory conditions. Although it is believed that maternal behavior is influenced by hormones,15,16 accumulating evidence suggests a specific hormonal condition is not necessary to induce maternal behaviors. For instance, even nonpregnant nulliparous mice can exhibit maternal behaviors when extensively exposed to pups17 although they are rarely maternal spontaneously and actively avoid pups.18 This evidence indicates that sensory stimuli provided by newborns are important in the rapid onset of maternal behaviors in mammals.19–22 | |
| Animals must adapt rapidly to changing environmental conditions. In mammals, pregnant females undergo fun- damental behavioral changes: the pattern of care by moth- ers to their offspring, which is called maternal behavior, is induced in female mothers. Maternal behavior is critical in rodents because pups are born deaf and blind. Neural mechanisms for maternal behavior have been studied most extensively in rodents,12–14 and it may be the most complex | |
| Recently, we found a high rate of mortality in pups born to female mice that were exposed to sevoflurane in their early | |
| Submitted for publication November 9, 2012. Accepted for publication August 29, 2013. From the Department of Anesthesiology, National | |
| Defense Medical College, Tokorozawa, Saitama, Japan. Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2014; 120:403-15 | |
| Anesthesiology, V 120 • No 2 | |
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| February 2014 | |
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| Maternal Behavior in Sevoflurane-treated Mice | |
| stage after birth. In this study, to examine the deficient sur- vival of pups, we investigated whether maternal behavior was impaired in these dams. These mice showed serious impair- ment of maternal behaviors when they fostered their pups although parturition was normal, which severely impaired the survival of their offspring. We hypothesized two possible mechanisms for impairment of maternal behaviors in these dams: circulating neurohormones, vasopressin and oxytocin, which are related to maternal behaviors,23–26 could have been altered by neonatal exposure to general anesthetics. Alter- natively, activation of central circuits underlying maternal behaviors could have been altered without a change in release of vasopressin and oxytocin into the circulation. Accumu- lating evidence suggests the existence of central circuit for maternal behaviors in the medial preoptic area (MPOA) in the rostral hypothalamus.19,27,28 In addition, we hypoth- esized that neonatal exposure to sevoflurane could have altered maternal behavior by a mechanism reversible by anti- oxidant: antioxidant reportedly mitigated behavioral deficits caused by neonatal exposure to general anesthetics.29,30 | |
| important difference was set at a 30% decrease from the baseline level in the control group. | |
| 3. Behavioral studies: control, sevoflurane, and sevo- flurane + hydrogen groups (n = 10–11 dams for each group); the primary outcome measure was latencies for pup retrieval; in the pup retrieval test, a minimum bio- logically important difference was set at a 30% increase from the baseline level in the control group. | |
| 4. Hormonal assay: control, hydrogen, sevoflurane, and sevoflurane + hydrogen groups (n = 4–5 dams for each group); a minimum biologically important difference was set as 30% decrease from the baseline level in the control group. Immunohistochemical study: control and sevoflurane groups (n = 5 dams for each group); a minimum bio- logically important difference was set at a 30% decrease from the baseline level in the control group. 5. In total, we prepared 160 female pups, which received anesthesia or hydrogen treatment at P6 (55 of control, 56 of sevoflurane, 40 of sevoflurane + hydrogen, and 9 of hydrogen groups). Among them, eight pups with sevoflurane and one pup with sevoflurane + hydrogen died during the treatment. Then, these siblings from the same litter were reunited and cohoused till the experiment (mice were similarly caged and housed in all groups). At 3 weeks of age, mice were weaned and allowed to further mature. At 7–9 weeks of age, female mice were mated with healthy males that had not been exposed to any anesthetic. Among them, 23 female mice did not get pregnant (eight of control, six of sevoflurane, five of sevoflurane + hydrogen, and four of hydrogen groups) and 1 control mouse died due to failure of delivery. These mice were excluded from the final analysis. Thus, for first delivery experiments, we used 46 control dams, 42 sevoflu- rane-treated dams, 34 sevoflurane + hydrogen–treated dams, and 5 hydrogen-treated dams. These mice were allocated as described above (1–5 in this section). | |
| Materials and Methods Animals All experiments were conducted according to the insti- tutional ethical guidelines for animal experiments of the National Defense Medical College and were approved by the Committee for Animal Research at National Defense Medi- cal College (Tokorozawa, Saitama, Japan). Inbred C57BL/6 mice were used in this study and maintained as described previously.5 | |
| Anesthesia and Hydrogen Treatment Sevoflurane anesthesia was carried out as described previously.5 In brief, on postnatal day 6 (P6), pups were placed in a humid chamber immediately after removal of mice from the maternal cage. A 3% concentration of sevoflurane was administered in 30% oxygen as the carrier gas. Control mice were exposed to 30% oxygen. Hydrogen gas (1.3%) was supplied as described previously.30 Total gas flow rate was 2 l/min. | |
| Among them, some dams were further analyzed for behavioral studies of parous dams: the same sets of mice for behavioral studies in first-time delivery were reused in behavioral studies in second-time (parous) delivery (control: 7 for survival rate and 11 for behavioral studies; sevoflurane- treated: 8 for survival rate and 10 for behavioral studies). | |
| Mouse Study Design In each experiment, siblings from the same litter were ran- domly allocated into one of the following groups so that each group was balanced on littermate. No obvious differ- ences (e.g., body size and weight) were observed within the litters, and there was no significant difference in mean body weight among the groups (data not shown). | |
| For paternal study experiments, 26 age-matched male mice were either subjected to anesthesia (n = 13) or control (n = 13) treatment at P6 (no mice died during the treatment). Siblings from the same litter were allocated into each group almost equally (i.e., groups were balanced on littermate). | |
| 1. Survival rate of delivered pups: control, sevoflurane, and sevoflurane + hydrogen groups (n = 17–19 dams for each group); a minimum biologically important dif- ference was set at a 30% decrease from the baseline level in the control group. | |
| Oxytocin and Vasopressin Assay Plasma concentrations of oxytocin and vasopressin in dams at 10 weeks of age were examined by enzyme-linked immu- nosorbent assay using commercially available kits (Oxytocin enzyme-linked immunosorbent assay kit and arg8-Vasopres- sin enzyme-linked immunosorbent assay kit; Enzo Life Sci- ences, Farmingdale, NY). Assays were performed according | |
| 2. Pup exchange test: control and sevoflurane groups (n = 6 dams for each group); a minimum biologically | |
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| to the manufacturer’s instructions. Blood samples were col- lected from the inferior vena cava within 6 h after parturition. | |
| sniff a pup for the first time and to return each pup to the nest were evaluated. | |
| Immunohistochemical Study Immunohistochemical studies using the anti-c-Fos antibody (rabbit polyclonal; sc-52; Santa Cruz Biotechnology, Santa Cruz, CA) were performed as previously described.30 Sam- ples were obtained within 6 h after parturition. The num- bers of immunoreactive cells were counted by an observer blinded to the groups. | |
| Evaluation of Parental Behavior Parental behavior of virgin male mice toward pups was eval- uated for 20 min. At the beginning, each mouse was put in one corner of a cage and three new born pups were placed in different corners of the same cage as described in the pup retrieval test. Latencies to sniff a pup for the first time and the numbers of males which committed attacks toward pups were evaluated. If any of the pups was attacked during the test, all pups were removed immediately and this subject was considered as “attack.” | |
| Behavioral Studies On the morning of parturition, maternal behaviors were examined. Maternal behavioral studies using first-time mothers were performed at 10–12 weeks of age. The same sets of female mice were reused in the maternal behavioral studies for second-time (parous) mothers: those mice were mated again at 19–25 weeks of age, and maternal behav- iors were examined at 22–28 weeks of age. Paternal behav- ioral studies using male mice were performed at 11 weeks of age. Survival rate (percentage of the number of pups at the indicated day compared with that at birth) was recorded until P6. In each experiment, observation was made by the same observer who was blinded to the groups. All appara- tus used in this study was made by O’Hara & CO., LTD. (Tokyo, Japan). | |
| Pup Exchange Test The pup exchange test was conducted as described previ- ously with some modifications.14 Pups born to a female dam couple (a dam with sevoflurane exposure at P6 and a control), which were born on the same day, were exchanged within 12 h after delivery. The number of surviving pups was evaluated for 6 days after birth. | |
| Olfactory Test The olfactory test was conducted as described previously.3 | |
| Statistical Analysis Statistical analysis was performed using GraphPad Prism 5 (GraphPad Software Inc., La Jolla, CA). Comparisons of the means of each group were performed using Student t test, one-way ANOVA followed by Bonferroni post hoc test, and two-way ANOVA followed by Bonferroni post hoc test. Comparisons of the survival rate until P6 were performed using a log-rank (Mantel-Cox) test. We did not exclude any data in this study. P values of less than 0.05 were considered statistically significant. Values are presented as the mean ± SEM in bar graphs. | |
| Evaluation of Maternal Behavior Pregnant females were individually housed for a few days before parturition and examined for maternal behavior on the morning of parturition. The number of pups with milk in their digestive tract and that of poorly cleaned pups (with pla- centa, amniotic membrane, or umbilical cords) was recorded on that day. Nest quality was also evaluated at the same time using the score system described previously31 with some modifications: grade 3, shaped like a deep hollow surrounded by high banks; grade 2, a hollow with medium-height banks; grade 1, flat with low banks, but still discrete; grade 0, no depression in bedding with no banks. Each new dam was also evaluated for time spent crouching over pups and the percentage of newborns scattered for 20 min with minimal disturbance as described previously.32 The percentage of scat- tered pups was expressed as a percentage with respect to time. We calculated the percentage of scatter as follows for each pup: (duration of scatter/total time observed (20 min) × 100). We then calculated the average for each group. These evalua- tions were carried out before the pup retrieval test. | |
| Results Survival Was Significantly Impaired in Pups Born to Mothers Exposed to Sevoflurane in Their Early Stage after Birth Female mice were exposed to 3% sevoflurane for 6 h and allowed to mature. These female mice appeared to grow nor- mally and could bear pups. But we found that about half of their pups died within 2 days after birth, whereas pups born to control mice (without exposure to sevoflurane) showed more than 80% survival rate at 6 days after birth (fig. 1). A log-rank analysis confirmed the difference, indicating a significantly lower survival rate in pups from sevoflurane- treated dams compared with those from control dams (P < 0.0001). The number of delivered pups in sevoflurane- treated dams was not significantly differ from control dams (sevoflurane group, n = 110 from 17 dams; control group, n = 124 from 19 dams), indicating that parturition was nor- mal in sevoflurane-treated dams. | |
| Pup Retrieval Test The pup retrieval test was performed essentially as described previously.14 Before the test, pups were separated from dams for 30 min. At the beginning, each mouse was put in one corner of a cage and three of her pups were placed in differ- ent corners of the same cage. The cages were continuously observed for 10 min with minimal disturbance. Latencies to | |
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| Maternal Behavior in Sevoflurane-treated Mice | |
| returned to the nest by a dam using mouth grip. Sevoflu- rane-treated dams displayed a significantly longer latency to retrieve the pups than control dams (fig. 3, A–C; t test, sevoflurane-treated dams vs. control dams, t = 2.25, P < 0.05 [first retrieval]; t = 2.33, P < 0.05 [second retrieval]; and t = 2.78, P < 0.05 [complete retrieval]). The impairment of retrieval was not caused by failure of the dams to detect the pups, because latency to approach and sniff a pup for the first time was indistinguishable between sevoflurane-treated and control dams (fig. 3D; t test, sevoflurane-treated dams vs. control dams, t = 0.52, P > 0.05). Furthermore, the olfac- tory test showed that olfactory function was also normal in sevoflurane-treated dams (fig. 3E; t test, sevoflurane-treated dams vs. control dams, t = 0.10, P > 0.05). These results indi- cated that exploratory and investigative behaviors toward pups were normal in sevoflurane-treated dams, yet they were unable to effectively perform maternal behaviors. | |
| Fig. 1. Neonatal exposure to sevoflurane in female mice caused insufficient survival of their pups. Pup survival rate was assessed for 6 days using 110 (born to sevoflurane- treated dams [n = 17]) and 124 pups (born to control dams [n = 19]). About half of the pups born to sevoflurane-treated dams died, whereas pups born to control dams showed >80% surviving rate. | |
| Maternal Nurturing Was Impaired in Mice Exposed to Sevoflurane in Their Early Stage after Birth The number of pups that did not have milk in their diges- tive tracts was increased in pups born to sevoflurane-treated dams when compared with pups born to control dams (fig. 2, A and B). However, the ratio of poorly cleaned pups was indistinguishable between them (fig. 2C). | |
| Survival Deficits of the Pups Lay Entirely with Dams The reduced pup survival was likely caused by the impair- ment of maternal behaviors in sevoflurane-treated dams. To confirm whether the high mortality rate of pups born to sevo- flurane-treated dams was caused by dams or pups, we carried out the pup exchange test. In this test, pups born to sevoflu- rane-treated dams were successfully fostered when nursed by control dams (fig. 4A). But, more than half of pups born to control dams died when nursed by sevoflurane-treated dams (fig. 4A). A log-rank analysis indicated that the survival rate of pups nurtured by sevoflurane-treated dams was significantly lower than the survival rate of pups nurtured by control dams during the 6 days after birth (P < 0.0001). In addition, the pups born to 3% sevoflurane-treated dams but nursed by control dams had milk in their digestive tracts, whereas pups born to controls but nursed by sevoflurane-treated mice did not (fig. 4B). Thus, we concluded that the sevoflurane-treated dams caused the survival deficit of the pups. | |
| Furthermore, to assess whether the excess mortality of pups born to sevoflurane-treated dams was caused by defects in nurturing, we investigated maternal behaviors in sevoflu- rane-treated dams. Around the time of delivery, mice usu- ally prepare a high-walled, corner nest, which is significantly different from the flat, centrally located, sleeping pad of the nonpregnant female.20 Because these features are characteris- tic of maternal females, the evaluation of nest quality is often used as an indicator of maternal behavior.20 We found that sevoflurane-treated dams exhibited incomplete nest building compared with control dams (fig. 2, D–G). Comparison of the nest quality scores confirmed the difference, indicating the significant difference between sevoflurane-treated dams and controls (fig. 2G; t test, t = 3.32, P < 0.01). In addition, we examined the ratio of scattered pups as another indicator of maternal behavior.32,33 We found that the ratio of scat- tered pups out of the nest was significantly higher in the sevoflurane-treated dams (fig. 2H; t test, sevoflurane-treated group vs. control group, t = 2.17, P < 0.05). | |
| Maternal Behavior Was Not Impaired in Second-time Parous Dams that Were Exposed to Sevoflurane in Their Early Stage after Birth Subsequent to the first delivery, mice usually show a perma- nently enhanced rate of induction of maternal behaviors20 although the underlying mechanism is largely unknown. Therefore, we investigated whether maternal behaviors were also impaired in second-time parous mice that were exposed to sevoflurane at P6. We found that pup survival rate was indistinguishable between the sevoflurane-treated second-time parous dams and the second-time parous con- trol dams during the 6 days after birth (fig. 5). A log-rank analysis indicated that the survival rate of pups nurtured by sevoflurane-treated second-time parous dams was not sig- nificantly different from those of control dams during the 6 days after birth (P > 0.05). Majority of pups born to parous dams exposed to sevoflurane were cleaned and had milk in their digestive tracts, similar to pups born to parous control | |
| When all pups are in the nest, the dam normally hov- ers over them, allowing pups to suckle (crouching). We found that sevoflurane-treated dams exhibited a significantly shorter duration of crouching compared with control dams (fig. 2I; t test, sevoflurane-treated dams vs. control dams, t = 3.84, P < 0.01). | |
| Maternal behavior was further evaluated by the pup retrieval test, which is frequently used to measure maternal behavior.14,32,34,35 In the test, we monitored the response of dams to three pups placed in different corners of the cage for 10 min. Pups that wander from the nest are usually | |
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| Fig. 2. Neonatal exposure to sevoflurane in mice caused deficits in maternal behaviors later in adulthood. The aspects of maternal behaviors were assessed on the day of parturition. The same sets of mice were used in all tests shown in figure 2 (control dams, n = 11; sevoflurane-treated dams, n = 10). (A) Pups nursed by control dams (Cont) had milk in their digestive tract (arrow), whereas pups nursed by sevoflurane-treated dams (Sevo) did not. (B) Ratio of pups with or without milk in the digestive tract. (C) Ratio of cleaned or poorly cleaned pups. (D–F) Representative images of nests made by sevoflurane-treated mice and controls. (D) A control dam built a crater-like hollow with high banks, and no pups were scattered outside of the nest. (E) When the dam was removed from the nest, pups under the crouching dam in the deep bottom were apparent. Sevoflurane-treated dams built much shallower or flat nests. (F) Significantly more pups were scattered outside of the nest. (G) The nest quality scores (grade 0–3). (H) Percentage of scattered pups outside of the nest. (I) Time spent crouching over the pups in the nest. *P < 0.05, **P < 0.01 (t test). | |
| dams (fig. 6, A and B). Sevoflurane-treated parous dams also exhibited nest quality scores similar to parous control dams (fig. 6C; t test, sevoflurane-treated dams vs. control dams, t = 0.61, P > 0.05). The ratio of scattered pups was not sig- nificantly different between sevoflurane-treated parous dams and parous control dams (fig. 6D; t test, sevoflurane-treated group vs. control group, t = 0.93, P > 0.05). Time spent crouching was also indistinguishable between them (fig. 6E; t test, sevoflurane-treated dams vs. control dams, t = 0.36, P > 0.05). | |
| t = 0.07, P > 0.05 [first retrieval]; t = 0.06, P > 0.05 [second retrieval]; and t = 0.04, P > 0.05 [complete retrieval]). The latency to approach and sniff a pup for the first time was also indistinguishable between them (fig. 7B; t test, sevoflurane- treated dams vs. control dams, t = 0.83, P > 0.05). These results indicated that maternal behaviors of parous dams were indistinguishable regardless of sevoflurane exposure in their early stage after birth. | |
| Parental Behaviors Were Impaired in Male Mice That Were Exposed to Sevoflurane in Their Early Stage after Birth Accumulating evidence suggests that the neural circuit for maternal behavior exists in males as well as female mice.20 | |
| In the pup retrieval test, sevoflurane-treated parous dams displayed latencies to retrieve the pups similar to controls (fig. 7A; t test, sevoflurane-treated dams vs. control dams, | |
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| Fig. 4. The pup exchange test demonstrated that the re- duced survival of pups lay entirely with dams. Pups were cross-fostered by sevoflurane-treated dams and control dams. (A) Six paired sevoflurane-treated and control dams that produced six to nine pups each were exchanged within 12 h after delivery. Pup survival rate was assessed for 6 days using 44 (born to sevoflurane-treated dams but nursed by control dams) and 45 pups (born to control dams but nursed by sevoflurane-treated dams). (B) Pups born to sevoflurane- treated dams had milk in the digestive tract (arrow) when nursed by control mice (Cont), whereas pups born to con- trol dams had no milk in the digestive tract when nursed by sevoflurane-treated dams (Sevo). | |
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| Hydrogen Coadministration Mitigated Impairments of Maternal Behavior Caused by Sevoflurane Exposure in Their Early Stage after Birth We recently showed that the antioxidative effects of molecu- lar hydrogen gas suppressed neurotoxicity caused by neo- natal exposure to anesthetics in the developing brain.30 Hydrogen gas can be easily supplied as part of the carrier gas mixture during anesthesia. Thus, we sought to investigate whether coadministration of hydrogen gas with sevoflurane could effectively suppress impairments of maternal behaviors caused by neonatal anesthetic exposure. | |
| Fig. 3. Pup retrieval responses were impaired in sevoflurane- exposed, first-time dams on the day of parturition. Same sets of dams for figure 2 were used. At the beginning, each dam was put in one corner of a cage and three of her pups were placed in different corners of the same cage. (A and B) Representative images of dams in the retrieval test at 2 min. (A) Control dams retrieved all pups within a couple of minutes. (B) But majority of pups born to sevoflurane-treated dams were still scattered out- side of the nest at 2 min (right). (C) Latency to retrieve each pup by sevoflurane-treated dams or control dams. (D) Latency to sniff a pup for the first time. (E) The olfactory test. *P < 0.05 (t test). | |
| The survival deficits of pups born to dams exposed to sevoflurane at P6 was prevented by coadministration of 1.3% hydrogen gas with sevoflurane (fig. 9). A log-rank anal- ysis indicated that pup survival rate was indistinguishable between the control dams and the sevoflurane + hydrogen– treated dams (P > 0.05). Furthermore, a log-rank analysis | |
| In some rodents, behavior toward the young is essentially the same for each sex.36,37 To investigate whether parental behavior is impaired by neonatal exposure to sevoflurane, sevoflurane-treated virgin male mice were exposed to three newborn pups for 20 min. The latency to approach and sniff a pup for the first time was indistinguishable regard- less of neonatal exposure to sevoflurane (fig. 8A; t test, sevo- flurane-treated male vs. control male, t = 0.37, P > 0.05). But we observed that some of sevoflurane-treated males bit pups within a few minutes after exposure to newborn pups, whereas control males did not commit attacks (fig. 8B). Thus, nurturing behaviors were impaired in male mice simi- lar to first-time mothers. | |
| Fig. 5. Maternal behavior was not impaired in parous dams that were exposed to sevoflurane at P6. Pup survival rate was assessed for 6 days using 59 pups (born to sevoflurane-treat- ed parous [second-time] dams [n = 8]) and 48 (born to control parous [second-time] dams [n = 7]). | |
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| Fig. 6. Maternal behaviors in sevoflurane-treated parous dams were normal. The aspects of maternal behaviors were assessed on the day of parturition. Same sets of mice were used in all tests shown in figure 6 (parous control dams, n = 11; sevoflurane- treated parous dams, n = 10). (A) The ratio of pups with or without milk in the digestive tract. (B) The ratio of cleaned or poorly cleaned pups. (C) The nest quality scores (grade 0–3). (D) Percentage of scattered pups outside of the nest. (E) Time spent crouching over the pups in the nest. | |
| also indicated that the pup survival rate of the sevoflurane + hydrogen–treated dams was significantly higher than that of the sevoflurane-treated dams (P < 0.0001). | |
| between them (fig. 10B). Furthermore, we found that the sevoflurane + hydrogen–treated dams exhibited a normal nest-building score (fig. 10C), a normal ratio of scattered pups in their home cage (fig. 10D), and a normal duration of crouching (fig. 10E) compared with those of the con- trol dams. A one-way ANOVA followed by Bonferroni post hoc test confirmed these findings, indicating no significant | |
| The number of pups that did not have milk in their digestive tracts was indistinguishable between the control group and sevoflurane + hydrogen–treated dams (fig. 10A). The ratio of poorly cleaned pups was also indistinguishable | |
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| Fig. 7. Pup retrieval responses were normal in sevoflurane-treated parous mice. Same sets of dams for figure 6 were used. (A) Latency to retrieve each pup by sevoflurane-treated parous dams and parous control dams. (B) Latency to sniff a pup for the first time. | |
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| Plasma Concentrations of Oxytocin and Vasopressin Were Not Significantly Changed in Sevoflurane-treated Dams Oxytocin and vasopressin are known to be implicated in the induction of maternal behaviors.23–26 It is possible that neo- natal exposure to anesthetics might alter the release of these hormones, leading to the impairment of maternal behav- ior. Therefore, we sought to examine whether the plasma concentration levels of oxytocin and vasopressin could be disrupted in sevoflurane-treated dams by the use of enzyme- linked immunosorbent assay. Furthermore, to exclude the possibility that the exposure to hydrogen gas per se counter- acts perturbations in hormonal levels, we also examined the plasma concentration levels of these hormones in hydrogen- treated mice. We found that there was no significant change in plasma oxytocin concentration on the day of parturition when comparing control, sevoflurane, hydrogen, and sevo- flurane + hydrogen groups (fig. 12A). A two-way ANOVA confirmed this, indicating no significant main effect of sevo- flurane treatment (F = 0.005, P > 0.05) and of hydrogen treatment (F = 0.012, P > 0.05). The interaction between sevoflurane and hydrogen treatment was not significant as well (F = 0.446, P > 0.05). | |
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| Fig. 8. Parental behaviors were impaired in male mice that were exposed to sevoflurane at P6. Each mouse (control group: n = 13; sevoflurane-treated group: n = 13) was put in one corner of a cage, and three pups from healthy dams were placed in different corners of the same cage. (A) Latency to sniff a pup for the first time. (B) Percentage of attacking and not attacking male mice. | |
| differences between sevoflurane + hydrogen–treated dams and controls in these tests (fig. 10, C–E; F and P values are presented below each panel; post hoc test, P > 0.05 for each test). In the pup retrieval test, the sevoflurane + hydro- gen–treated dams performed similar to the control dams (fig. 11A). A one-way ANOVA followed by Bonferroni post hoc test confirmed this, indicating no significant difference between sevoflurane + hydrogen–treated dams and controls in each retrieval (fig. 11A; F and P values are presented below each panel; post hoc test, P > 0.05 for each retrieval). We did not detect significant differences in the analysis for laten- cies to approach and to sniff a pup for the first time among groups (fig. 11B; one-way ANOVA, F = 0.19, P > 0.05). Olfaction abilities were also indistinguishable among groups (fig. 11C; one-way ANOVA, F = 0.008, P > 0.05). Together, it can be concluded that concomitant hydrogen inhalation significantly mitigated impairment of maternal behaviors caused by neonatal exposure to sevoflurane. | |
| Similarly, there was no significant change in plasma vaso- pressin concentration on the day of parturition when com- paring control, sevoflurane, hydrogen, and sevoflurane + hydrogen groups (fig. 12B). A two-way ANOVA confirmed this, indicating no significant main effect of sevoflurane treatment (F = 0.018, P > 0.05) and of hydrogen treat- ment (F = 1.194, P > 0.05). The interaction between sevo- flurane and hydrogen treatment was not significant as well (F = 0.206, P > 0.05). Therefore, we concluded that neither neonatal exposure to sevoflurane nor to hydrogen altered the blood concentration levels of oxytocin and vasopressin when fostering their pups. | |
| The Number of c-Fos–Immunopositive Cells Decreased in the MPOA in Sevoflurane-treated Dams Modification of neurons in the MPOA in the rostral hypo- thalamus is required to express maternal behaviors.19,27,28 It was reported that when a mouse takes care of pups, c-Fos is induced in the MPOA.38,39 Thus, we set out to quantify the number of c-Fos–immunopositive cells in the MPOA from maternal dams when fostering their pups. In sevoflurane- treated dams, the number of c-Fos–immunopositive cells was significantly reduced in the MPOA when compared with control dams (fig. 13, A and B; t test, sevoflurane-treated dams vs. control dams, t = 6.92, P < 0.001). This finding suggested that neonatal exposure to sevoflurane disrupted neural mechanism to induce maternal behavior. | |
| Fig. 9. Hydrogen coadministration mitigated the deficient sur- vival rate in pups caused by sevoflurane exposure to dams in their early stage after birth. Pup survival rate was assessed for 6 days using 124 (born to control dams [n = 19]), 110 (born to sevoflurane-treated dams [n = 17]), and 128 pups (born to sevoflurane + hydrogen-treated dams [n = 19]). The same data for the control group and sevoflurane-treated group in figure 1 are reused. | |
| Discussion | |
| In this study, we showed that sevoflurane exposure in the developing brain of female mice caused serious impair- ment of maternal behaviors when fostering their pups although parturition was normal. Furthermore, survival | |
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| Fig. 10. Hydrogen coadministration mitigated impairments of maternal behavior caused by sevoflurane exposure to dams in their early stage after birth. The aspects of maternal behaviors were assessed on the day of parturition. Same sets of mice were used in all tests shown in figure 10 (control dams, n = 11; sevoflurane-treated dams, n = 10; sevoflurane + hydrogen coadmin- istered dams, n = 10). The same data for the control dams and sevoflurane-treated dams in figure 2 are reused. (A) Ratio of pups with or without milk in the digestive tract. (B) Ratio of cleaned or poorly cleaned pups. (C) The nest quality score (grade 0–3). (D) Percentage of scattered pups outside of the nest. (E) Time spent crouching over the pups in the nest. Comparisons were performed using a one-way ANOVA followed by Bonferroni post hoc test. F and P values are presented below each panel. *P < 0.05, **P <0.01, ***P < 0.001. | |
| (placentophagia).20 Because these behaviors are char- acteristic of maternal females, some researchers classify them as one of maternal behaviors. However, from the dam’s perspective, afterbirth materials contain attractive substances such as placental opioid-enhancing factor that potentiate the antihyperalgesic properties of endogenous opioids.20 Thus, cleaning pup is not a maternal behavior in the sense of pup-directed caretaking behavior. | |
| rate was severely impaired in pups born to sevoflurane- treated dams. Pup exchange test showed that the sur- vival impairment of the pups lay entirely with dams. Taken together, deficits in maternal behavior of sevoflu- rane-treated dams caused the impaired survival of their offspring. The deficits in maternal behavior in sevoflu- rane-treated virgin females were not attributed to the secondary effect of other changes such as locomotor or olfactory functions because exploratory and investiga- tive behaviors toward pups were normal in these dams. It should be noted that all dams, irrespective of sevo- flurane treatment, promptly approached pups when the pups were placed outside the nest, indicating that neo- natal exposure to sevoflurane might not cause an inabil- ity to detect sensory cues emanating from pups. We did not find significant difference in pup-cleaning behavior between sevoflurane-treated dams and controls. At deliv- ery, normal dams usually devote an inordinate amount of attention to birth material and ingest the afterbirth | |
| We found that blood concentrations of oxytocin and vasopressin were not significantly changed in sevoflurane- treated dams compared with controls when fostering their pups. However, some studies reported that neonatal expo- sure to general anesthetics increased proinflammatory cyto- kines and stress hormones shortly after the anesthesia.40–44 Because some hormones are known to play important roles in neuronal development,45,46 we cannot exclude the pos- sibility that neonatal exposure to general anesthetics could cause impairment to hormone dynamics shortly after the anesthesia, which might affect neuronal development. | |
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| Fig. 12. Plasma concentrations of oxytocin and vasopressin were not significantly changed in sevoflurane-treated dams. (A) Levels of plasma oxytocin concentration (control dams, n = 5; sevoflurane-treated dams, n = 4; sevoflurane and hy- drogen–treated dams, n = 5; and hydrogen-treated dams, n = 5). (B) Levels of plasma vasopressin (control dams, n = 5; sevoflurane-treated dams, n = 4; sevoflurane and hydrogen– treated dams, n = 4; and hydrogen-treated dams, n = 5). | |
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| density protein-95 in the hippocampus.40 Because postsyn- aptic density protein-95 is a candidate molecule implicated in synaptic plasticity,49,50 neonatal exposure to anesthetics might impair synaptic plasticity, which is required to mod- ulate neuronal circuit. Thus, one might speculate that the impairment of the hippocampus was involved in the impair- ment of maternal behaviors in sevoflurane-treated dams. Fur- thermore, it was reported that lesions in the hippocampus disrupted maternal behavior in rats although the underlying mechanism was largely unknown.51 However, some studies reported that limbic structures including the hippocampus are important but not essential for maternal behavior.52–54 One might also speculate that the defect in maternal behav- iors was secondary to learning or memory deficits in sevoflu- rane-treated mice. However, a defect in maternal behavior is not necessarily indicative of these deficits. Indeed, there are mice that have deficits in maternal behaviors but not in learn- ing and memory. For instance, mice lacking the immediate early gene fosB showed deficits in maternal behaviors but not in learning ability.13 | |
| Fig. 11. Pup retrieval responses were mitigated in sevoflu- rane + hydrogen–treated dams. Same sets of dams for fig- ure 10 were used. The same data for the control dams and sevoflurane-treated dams in figure 3 are reused. (A) Latency to retrieve pups by sevoflurane-treated dams, sevoflurane + hydrogen–treated dams and control dams. (B) Latency to sniff a pup for the first time. (C) The olfactory test. Comparisons were performed using a one-way ANOVA followed by Bonfer- roni post hoc test. F and P values are presented below each panel. *P < 0.05, **P < 0.01. | |
| We found that the number of c-Fos–immunoreactive cells was significantly decreased in the MPOA from sevo- flurane-treated dams when compared with controls. Accu- mulating evidence indicates that the MPOA in the rostral hypothalamus plays critical roles in the induction of mater- nal behavior.19,27,28 Stimulation from pups converges on the MPOA, and it activates neurons in the MPOA. Then, the activated neurons induce the expression of transcription fac- tors such as c-Fos and its homolog FosB. These transcription factors are known to be essential for the facilitation of mater- nal behaviors.13,31,34 Thus, the reduced induction of c-Fos in the MPOA suggested that neonatal exposure to anesthet- ics impaired neuronal mechanism that plays critical role in maternal behavior. | |
| How does neonatal exposure to general anesthetics cause impairment of maternal behaviors in mice? Although the molecular, cellular, and neurological mechanisms are largely unknown, accumulating evidence indicated that expression of maternal behaviors seems to require change of the neu- ral circuit in the brain.34 Generally, once virgin females are sensitized by extensive exposure to pups, maternal behaviors last for at least several days without further pup exposure. Therefore, the experience of pup exposure may be important to elicit changes in the neural circuit for maternal behav- iors, which modify maternal responsiveness in a long-lasting manner. Taking this into consideration, one possible expla- nation for the impairment of maternal behavior in sevoflu- rane-treated mice is that the neural circuit indispensable for this type of behavior might be stunted in these mice. But the mothering experience at the first delivery might add an additional redundant route, via memory, to the process of activating the maternal neural circuit. Thus, second-time | |
| The hippocampus plays critical roles in multiple brain functions including working memory, which is required to do complex cognitive tasks.47,48 Hippocampus is known to be vulnerable to neonatal exposure to general anesthetics. For instance, it was reported that neonatal exposure to general anesthetics reportedly decreased the expression of postsynaptic | |
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| Fig. 13. The number of c-Fos–immunopositive cells in the medial preoptic area (MPOA) decreased in sevoflurane-treated dams on the day of parturition. (A) Immunohistochemical staining for c-Fos in the MPOA (control dams: n = 5; sevoflurane-treated dams: n = 5). Scale bars: 250 μm. (B) Quantification of the immunohistochemical staining. ***P < 0.001 (t test). | |
| parous dams could foster pups irrespective of sevoflurane exposure. An alternative explanation is that stimuli ema- nating from newborn pups might not sufficiently activate the maternal neural circuit in the sevoflurane-treated mice: because of the failure to change the neural circuit effectively in sevoflurane-treated dams, they could not overcome the threshold to express maternal behavior. However, the par- tial change of the maternal neural circuit induced at the first delivery might contribute to overcome the threshold at the second delivery. In both cases, the adaptation to induce maternal behavior might depend on finely tuned neuronal mechanisms in the circuit for maternal behavior. It should be noted that the capacity to learn still remained in sevo- flurane-treated mice because maternal behavior deficit was no longer apparent after the birth of the second litter. This is consistent with a report that environmental enrichment reversed anesthetic-induced memory impairments in the rat developing brain almost completely even when instituted with substantial delay.55 | |
| Although there are interpretative limitations to translate ani- mal models to humans, an understanding of the neurobio- logical basis for the deficits of maternal behavior caused by neonatal exposure to sevoflurane is important in psychiatric medicine and would be helpful for ensuring safer anesthesia in pediatric medicine. | |
| In conclusion, sevoflurane exposure in the mouse devel- oping brain causes serious impairment of maternal behav- iors when the females foster their pups although parturition is normal. We previously showed that neonatal exposure to sevoflurane caused impairments of social behaviors that resemble those observed in autism.3 Together with the previous reports, it may be concluded that in an animal model, neonatal exposure to general anesthetics causes pervasive deficits in brain functioning including even an innate behavior that is essential to species survival. Further molecular neuropathological investigations are necessary to fully explain the diverse behavioral alterations caused by neonatal exposure to general anesthetics. | |
| It was reported that oxidative stress was involved in anesthetic-induced neurotoxicity in the developing brain.29 Hydrogen has recently received attention as an effective antioxidant because of its small size and electrically neutral properties, enabling it to reach target organs easily, to diffuse across cell membranes rapidly, and to penetrate the blood– brain barrier for the protection of neurons.56 We previously showed that coadministation of hydrogen gas significantly suppressed the increase in neuroapoptosis and subsequently mitigated the deficits in social behaviors as well as learn- ing deficits caused by neonatal exposure to sevoflurane.30 In the current study, we show that coadministration of hydrogen gas significantly reduced impairment of mater- nal behaviors caused by neonatal exposure to sevoflurane, suggesting further potential of hydrogen coadministration for therapeutic use. | |
| Acknowledgments The authors thank Ms. Kiyoko Takamiya and Mrs. Yuko Ogura (Department of Anesthesiology, National Defense Medical College, Tokorozawa, Saitama, Japan) for excellent technical help in this study. | |
| This work was supported by Japan Society for the Pro- motion of Science ( JSPS; Tokyo, Japan); grant numbers 22500304, 23791734, 25861404, and 25293331. | |
| Competing Interests The authors declare no competing interests. | |
| Correspondence Address correspondence to Dr. Satoh: Department of Anes- thesiology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359–8513, Japan. wndlt3@gmail.com. Informa- tion on purchasing reprints may be found at www.anesthe- siology.org or on the masthead page at the beginning of this issue. ANeSTheSIOlOgY’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. | |
| Similarities in the maternal behaviors of humans and rodents suggest an existence of a general neural circuit for these behaviors. In humans, child abuse and neglect are global problems with serious life-long consequences, includ- ing increased likelihood for a wide range of mental disorders. | |
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