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Background Ischemic heart disease and the resulting heart failure continue to carry high morbidity and mortality, and a breakthrough in our understanding of this disorder is needed. The adult spiny mouse (Acomys cahirinus) has evolved the remarkable capacity to regenerate full-thickness skin tissue, including microvasculature and cartilage, without fibrosis or scarring. We hypothesized that lack of scarring and resulting functional regeneration also applies to the adult Acomys heart. Methods and results We compared responses of the Acomys heart to CD1 outbred Mus heart following acute left anterior descending coronary artery ligation to induce myocardial infarction. Both Acomys and Mus hearts showed decreased ejection fraction (EF) after ligation. However, Acomys hearts showed significant EF recovery to pre-ligation values over four weeks. Histological analysis showed comparable infarct area 24-h after ligation with a similar collateral flow in both species' hearts, but subsequently, Acomys displayed reduced infarct size, regenerated microvasculature, and increased cell proliferative activity in the infarcted area. Conclusions These observations suggest that adult Acomys displays remarkable cardiac recovery properties after acute coronary artery occlusion and may be a useful model to understand functional recovery better. Translational perspective Adult Acomys provides a novel mammalian model to further investigate the cardioprotective and regenerative signaling mechanisms in adult mammals. This opens the door to breakthrough treatment strategies for the injured myocardium and help millions of patients with heart failure secondary to tissue injury with irreversible damage.

The nonapeptides vasopressin (VP) and oxytocin (OT) are present in some form in most vertebrates. VP and OT play critical roles in modulating physiology and are well-studied for their influences on a variety of social behaviors, ranging from affiliation to aggression. Their anatomical distributions have been mapped for numerous species across taxa, demonstrating relatively strong evolutionary conservation in distributions throughout the basal forebrain and midbrain. Here we examined the distribution of VP-immunoreactive (-ir) and OT-ir neurons in a gregarious, cooperatively breeding rodent species, the spiny mouse (Acomys cahirinus), for which nonapeptide mapping does not yet exist. Immunohistochemical techniques revealed VP-ir and OT-ir neuronal populations throughout the hypothalamus and amygdala of males and females that are consistent with those of other rodents. However, a novel population of OT-ir neurons was observed in the median preoptic nucleus of both sexes, located dorsally to the anterior commissure. Furthermore, we found widespread sex differences in OT neuronal populations, with males having significantly more OT-ir neurons than females. However, we observed a sex difference in only one VP cell group – that of the bed nucleus of the stria terminalis (BST), a VP neuronal population that exhibits a phylogenetically widespread sexual dimorphism. These findings provide mapping distributions of VP and OT neurons in Acomys cahirinus. Spiny mice lend themselves to the study of mammalian cooperation and sociality, and the nonapeptide neuronal mapping presented here can serve as a basic foundation for the study of nonapeptide-mediated behavior in a group of highly social rodents.

The aim of this study was to determine the effects of ß-hydroxy-ß-methylbutyrate (HMB) supplementation during pregnancy on postpartum bone tissue quality by assessing changes in trabecular and compact bone as well as in hyaline and epiphyseal cartilage. The experiment was carried out on adult 6-month-old female spiny mice (Acomys cahirinus) divided into three groups: pregnant control (PregCont), pregnant HMB-treated (supplemented with 0.02 g/kg b.w of HMB during the second trimester of pregnancy, PregHMB), and non-pregnant females (NonPreg). Cross-sectional area and cortical index of the femoral mid-shaft, stiffness, and Young modulus were significantly greater in the PregHMB group. Whole-bone mineral density was similar in all groups, and HMB supplementation increased trabecular number. Growth plate cartilage was the thinnest, while the articular cartilage was the thickest in the PregHMB group. HMB supplementation increased the content of proteoglycans in the articular cartilage and the percentage of immature collagen content in metaphyseal trabeculae and compact bone. In summary, dietary HMB supplementation during the second trimester of pregnancy intensifies bone metabolic processes and prevents bone loss during pregnancy.

Environmental risk factors that operate at foetal or neonatal levels increase the vulnerability to schizophrenia, plausibly via stress-immune activation that perturbs the epidermal growth factor (EGF) system, a system critical for neurodevelopment. We investigated potential associations between environmental insults and immune and EGF system changes through a maternal immune activation (MIA) model, using the precocial spiny mice (Acomys cahirinus). After mid-gestation MIA prepubescent offspring showed elevated NF-κB1 protein in nucleus accumbens, decreased EGFR in caudate putamen and a trend for increased PI3K-110δ in ventral hippocampus. Thus, prenatal stress may cause a heightened NF-κB1-mediated immune attenuation of EGF system signalling.

Considering the negative effects of glucocorticoid treatment, especially during fetal development it is important to investigate effectors decreasing such disadvantages. The aim of this study was to investigate the effect of prenatally administered dexamethasone (Dex), a synthetic glucocorticoid, on the histomorphometry of the femur in the offspring of spiny mice. The study was performed on 24 pregnant spiny mice. The time of the experiment included the prenatal period between the 20th day of gestation until birth (pregnancy lasts on average of 36–38 days). The mice from the experimental group received dexamethasone per os in a dose of 125 mg/kg birth weight daily. At the end, the newborns from the experimental and control group were weighted and euthanized. Maternal Dex treatment resulted in a 17% decrease in birth weight in newborns. Dex administration significantly reduced the thickness of the hypertrophy zone of the growth plate by 34% and total thickness by 8,7%. In addition, Dex decreased the number of cells in the articular cartilage by 27% and significantly decreased their diameter by 5%. Dex also affected the structure and spatial distribution of thick and thin collagen fibers, lowering the proportion of thin fibers compared with the control group. Moreover, Dex treatment considerably lowered the amount of proteoglycans in articular and growth cartilages. Exposure to glucocorticoids in pregnant spiny mice affects cartilage development by accelerating maturity of collagen fibers and growth plate, presumably along with further disruption of longitudinal growth of long bones.

The spiny mouse, Acomys cahirinus, is an adult mammal capable of remarkable feats of scar-free tissue regeneration after damage to several organs including the skin and the heart. Here we investigate the regenerative properties of the skeletal muscle of A. cahirinus tibialis anterior in comparison to the lab mouse, Mus musculus. The A. cahirinus TA showed a similar distribution of myosin heavy chain fibre types and a reduced proportion of oxidative fibres compared to M. musculus. There were differences in the matrix components of the TA with regard to collagen VI and the biomechanical properties. A. cahirinus TA regenerated faster with a more rapid induction of embryonic myosin and higher levels of dystrophin than in M. musculus fibres. There were lower levels of inflammation (NF-kB), fibrosis (TGFβ-1, collagens) and higher levels of the anti-inflammatory cytokine Cxcl12. There was a difference in macrophage profile between the two species. After multiple rounds of muscle regeneration the M. musculus TA failed to regenerate muscle fibres and instead produced a large numbers of adipocytes whereas the A. cahirinus TA regenerated perfectly. This clearly improved regeneration performance can be explained by differing levels of growth factors such as adiponectin between the two species.

Excessive exposure to glucocorticoids can alter ovarian function by modulating oogenesis, folliculogenesis and steroidogenesis. The aim of the present study was to examine the effects of dexamethasone (DEX) administered during pregnancy on folliculogenesis and corpus luteum development in the postpartum spiny mouse ovary. DEX (125 μg kg-1 body weight per day) was applied to pregnant spiny mouse from day 20 of gestation to parturition. The obtained ovaries were fixed and used for immunohistochemistry and TEM analysis. The expression of proteins related to apoptosis (caspase-3, Bax, Bcl-2) and autophagy (Beclin1, Lamp1) as well as PCNA and GR receptors were evaluated by western-blot. In comparison with DEX-treated group a higher percentage of TUNEL positive granulosa and luteal cells was observed in the control group. These data were consistent with changes in caspase-3 and Bax expression, which increased in the control and decreased after DEX exposure. In turn, the proliferation index and PCNA expression were higher in the DEX-treated group. Moreover, the higher level of Beclin1, Lamp1, anti-apoptotic Bcl-2 protein and GR was observed in the DEX-treated females than in the control group. Beclin1 and Lamp1 were strongly expressed in luteal cells which exhibited an autophagic ultrastructure. Surprisingly, DEX augmented the number of ovarian follicles and corpora lutea, which resulted in a significant increase in ovarian weight. These findings suggest that DEX exerts anti-apoptotic action on granulosa layer and stimulates follicular maturation. Moreover, DEX induces autophagy in luteal cells promoting cell survival rather than cell death, which can prolong the corpus luteum life span.

The pattern of ovulation in mammals is generally considered to be either spontaneous or induced by coitus. The present study aimed to assess the pattern of ovulation in the southern African spiny mice (Acomys spinosissimus). Females were divided into three treatments differing in the degree of contact with a male. Control females had no contact with males, separated females had only chemical, auditory and visual contact with a male as the sexes were separated with wire mesh and paired females had full contact with a vasectomized male and copulations were possible. Each treatment consisted of seven females and the ovarian mass, the number of primary, secondary/tertiary and Graafian follicles as well as presence of corpora lutea were compared between the three treatments. Faecal progestagen metabolite (FPM) concentrations were analyzed for every second day throughout the experiment and they were used to determine luteal phases and oestrous cycles. Corpora lutea were found in both the control and the paired treatment indicating that ovulation also occurred in the absence of coitus. There was also no effect of treatment on ovarian mass or follicle numbers. In contrast, only females in the separated and paired treatments exhibited luteal phases and oestrous cycles. Especially at the beginning of the experiment, FPM concentrations were higher in those two groups than the control. The results indicate that A. spinosissimus appears to ovulate spontaneously, although physical as well as olfactory male cues appear to be of great importance to enhance reproductive efforts of females.

For spiny mice, detailed long-term data on reproductive endocrine function is lacking, as limited blood volumes make frequent collections of individual plasma samples for hormone monitoring impractical. To provide the necessary tools in order to fill this gap, this study examined the suitability of two enzyme immunoassays for monitoring male and female reproductive function in the southern African spiny mouse (Acomys spinosissimus) based on faecal hormone analysis. Fourteen non-pregnant and one pregnant female and 24 male spiny mice were wild-caught and subsequently monitored under controlled conditions. Thirteen of the 14 non-pregnant females revealed elevated faecal progestagen metabolite concentrations with eight individuals showing indications of a luteal phase. Two females showed two post-ovulatory luteal phases with estimated cycle lengths of 16 and 18 days, respectively. The pregnant female had an elevated (231%) mean faecal progestagen metabolite level compared with the overall mean baseline hormone concentration determined for the 14 non-pregnant females. Males exposed to a long photoperiod, simulating summer-related breeding activity, exhibited a 47.8% increase in faecal androgen metabolite levels compared with males exposed to a short photoperiod. Collectively, the data demonstrated that reproductive endocrine function can be monitored in male and female spiny mice by measuring respective faecal hormone metabolites.

Introduction Elevated maternal glucocorticoids during human pregnancy suppress fetal growth, more so if the fetus is male. The synthetic glucocorticoid dexamethasone (DEX) is known to affect placental glucose transport, but whether this also affects placental glycogen stores has not been investigated. Method We examined the short and long term consequences of a single, 60 h exposure to DEX at mid gestation on the glycogen pathway in the placenta of the spiny mouse, with a focus on identifying sex-dependent differences in expression of genes involved in glycogen cell formation ( PCDH12 ), and regulation of glycogen synthesis ( GSK3B , GYS1 , GBE1 , FOXO1 , UGP2 ). Results Placentas from female fetuses had increased amounts of glycogen on day 25 of gestation (term is 39 days) as identified by positive Periodic acid Schiff (PAS) reaction staining. DEX administration initially reduced expression of GSK3B , GYS1 , GBE1 , FOXO1 , UGP2 in both male and female placentas, but reduced histologically detectable glycogen storage in placentas of female fetuses only. The DEX-induced reduction in expression of GSK3B and UGP2 persisted until day 37 of gestation, an effect that was significantly greater in the male placenta. Discussion/conclusion We conclude that constitutive placental glycogen storage is regulated in pregnancy in a sex-dependant manner, and that glucocorticoids such as DEX induce sex-dependent changes in glycogen storage. Placental glycogen metabolism and its response to glucocorticoids may contribute to the different sensitivities of male and female fetuses to the effects of maternal illness and stress in utero .

We have previously reported that maternal creatine supplementation protects the neonate from hypoxic injury. Here, we investigated whether maternal creatine supplementation altered expression of the creatine synthesis enzymes (arginine:glycine amidinotransferase [AGAT], guanidinoaceteate methyltransferase [GAMT]) and the creatine transporter (solute carrier family 6 [neurotransmitter transporter, creatine] member 8: SLC6A8) in the term offspring. Pregnant spiny mice were fed a 5% creatine monohydrate diet from midgestation (day 20) to term (39 days). Placentas and neonatal kidney, liver, heart, and brain collected at 24 hours of age underwent quantitative polymerase chain reaction and Western blot analysis. Maternal creatine had no effect on the expression of AGAT and GAMT in neonatal kidney and liver, but mRNA expression of AGAT in brain tissues was significantly decreased in both male and female neonates born to mothers who were fed the creatine diet. SLC6A8 expression was not affected by maternal dietary creatine loading in any tissues. Maternal dietary creatine supplementation from midgestation in the spiny mouse did not alter the capacity for creatine synthesis or transport.

Animals show daily rhythms in most bodily functions, resulting from the integration of information from an endogenous circadian clock and external stimuli. These rhythms are adaptive and are expected to be related to activity patterns, i.e., to be opposite in diurnal and nocturnal species. Melatonin is secreted during the night in all mammalian species, regardless of their activity patterns. Consequently, in diurnal species the nocturnal secretion of melatonin is concurrent with the resting phase, whereas in nocturnal species it is related to an increase in activity. In this research, we examined in three diurnal and three nocturnal rodent species whether a daily rhythm in anxiety-like behavior exists; whether it differs between nocturnal and diurnal species; and how melatonin affects anxiety-like behavior in species with different activity patterns. Anxiety-like behavior levels were analyzed using the elevated plus-maze. We found a daily rhythm in anxiety-like behavior and a significant response to daytime melatonin administration in all three nocturnal species, which showed significantly lower levels of anxiety during the dark phase, and after melatonin administration. The diurnal species showed either an inverse pattern to that of the nocturnal species in anxiety-like behavior rhythm and in response to daytime melatonin injection, or no rhythm and, accordingly, no response to melatonin.

Exposure of the embryo or fetus to perturbations in utero can result in intrauterine growth restriction, a primary risk factor for the development of adult disease. However, despite similar exposures, males and females often have altered disease susceptibility or progression from different stages of life. Fetal growth is largely mediated by the placenta, which, like the fetus is genetically XX or XY. The placenta and its associated trophoblast lineages originate from the trophectoderm (TE) of the early embryo. Rodent models (rat, mouse, spiny mouse), have been used extensively to examine placenta development and these have demonstrated the growth trajectory of the placenta in females is generally slower compared to males, and also shows altered adaptive responses to stressful environments. These placental adaptations are likely to depend on the type of stressor, duration, severity and the window of exposure during development. Here we describe the divergent developmental pathways between the male and female placenta contributing to altered differentiation of the TE derived trophoblast subtypes, placental growth, and formation of the placental architecture. Our focus is primarily genetic or environmental pertur bations in rodent models which show altered placental responsiveness between sexes. We suggest that perturbations during early placental development may have greater impact on viability and growth of the female fetus whilst those occurring later in gestation may preferentially affect the male fetus. This may be of great relevance to human pregnancies which result from assisted reproductive technologies or complications such as pre-eclampsia and diabetes.

BackgroundAdvances in research relating to menstruation and associated disorders (such as endometriosis and pre-menstrual syndrome) have been hindered by the lack of an appropriate animal model. Thus, many aspects of this phenomenon remain poorly understood limiting the development of efficacious treatment for women. Menstruating species account for only 1.5% of mammals, and less than 0.09% of these are non-primates. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents.ObjectiveHere we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus).Study DesignVirgin female spiny mice (n=14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles in our in-house colony at Monash Medical Centre, Clayton, Australia. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and ELISA assay of progesterone (n=5 / stage of the menstrual cycle). Normally distributed data are reported as the mean ± standard error and significant differences calculated using a one-way ANOVA. Non-normal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test.ResultsMean cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase, when plasma progesterone peaked at ~102.1 ng/mL and the optical density for prolactin immunoreactivity was strongest. The spiny mouse undergoes spontaneous decidualisation, demonstrating for the first time menstruation in a rodent.ConclusionThe spiny mouse is the first rodent species known to menstruate and provides an unprecedented natural non-primate model to study the mechanisms of menstrual shedding and repair, and may be useful in furthering our understanding of human specific menstrual and pregnancy associated diseases.

Maternal antenatal creatine supplementation protects the brain, kidney, and diaphragm against the effects of birth asphyxia in the spiny mouse. In this study, we examined creatine's potential to prevent damage to axial skeletal muscles.Pregnant spiny mice were fed a control or creatine-supplemented diet from mid-pregnancy, and 1 d before term (39 d), fetuses were delivered by c-section with or without 7.5 min of birth asphyxia. At 24 h or 33 ± 2 d after birth, gastrocnemius muscles were obtained for ex-vivo study of twitch-tension, muscle fatigue, and structural and histochemical analysis.Birth asphyxia significantly reduced cross-sectional area of all muscle fiber types (P0.05), and increased fatigue caused by repeated tetanic contractions at 24 h of age (P0.05). There were fewer (P0.05) Type I and IIa fibers and more (P0.05) Type IIb fibers in male gastrocnemius at 33 d of age. Muscle oxidative capacity was reduced (P0.05) in males at 24 h and 33 d and in females at 24 h only. Maternal creatine treatment prevented all asphyxia-induced changes in the gastrocnemius, improved motor performance.This study demonstrates that creatine loading before birth protects the muscle from asphyxia-induced damage at birth.

The placenta is the intermediary between the mother and fetus, and its primary role is to provide for the appropriate growth of the fetus. A suboptimal in utero environment has been shown to differentially affect the health of offspring, depending on their sex. Here we show that excess maternal glucocorticoids administered in midgestation (Day 20, 0.5 gestation in the spiny mouse) for 60 h, have persisting effects on the placenta that differ by fetal sex, placental region, and time after glucocorticoid exposure. Dexamethasone (DEX) exposure altered placental structure and mRNA expression from male and female fetuses both immediately (Day 23) and 2 wk posttreatment (Day 37). The immediate consequences (Day 23) of DEX were similar between males and females, with reductions in the expression of IGF1, IGF1R, and SLC2A1 in the placenta. However, by Day 37, the transcriptional and structural response of the placenta was dependent on the sex of the fetus, with placentas of male fetuses having an increase in GCM1 expression, a decrease in SLC2A1 expression, and an increase in the amount of maternal blood sinusoids in the DEX-exposed placenta. Female placentas, on the other hand, showed increased SLC2A1 and MAP2K1 expression and a decrease in the amount of maternal blood sinusoids in response to DEX exposure. We have shown that the effect of a brief glucocorticoid exposure at midgestation has persisting effects on the placenta, and this is likely to have ongoing and dynamic effects on fetal development that differ for a male and female fetus.

This study was designed to determine follicular atresia in the newborn and the prepubertal spiny mouse. We analyzed the processes of follicle loss using classical markers of apoptosis (TUNEL reaction, active caspase-3) and autophagy (Lamp1). Numerous small clear vacuoles and autophagosomes as well as strong Lamp1 staining were observed in dying oocytes of all follicle types, especially of the primordial and primary ones. Active caspase 3 and the TUNEL reaction were detected only in the granulosa cells of large secondary and antral follicles. The expression of apoptosis and autophagy markers was also changing during the prepubertal period. Western blot analysis indicated that at the moment of birth, females undergo an increased rate of follicular atresia mediated by autophagy, while apoptosis is the dominant form of ovarian atresia in consecutive postnatal days. On the basis of these observations, we concluded that apoptosis and autophagy are involved in follicular atresia and these processes are cell and developmental stage-specific.

Studies of human neonates, and in animal experiments, suggest that birth asphyxia results in functional compromise of the hippocampus, even when structural damage is not observable or resolves in early postnatal life. The aim of this study was to determine if changes in hippocampal function occur in a model of birth asphyxia in the precocial spiny mouse where it is reported there is no major lesion or infarct. Further, to assess if, as in human infants, this functional deficit has a sex-dependent component. At 37 days gestation (term=39 days) spiny mice fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5min of in utero asphyxia causing systemic acidosis and hypoxia. At 5 days of age hippocampal function was assessed ex vivo in brain slices, or brains were collected for examination of structure or protein expression. This model of birth asphyxia did not cause infarct or cystic lesion in the postnatal day 5 (P5) hippocampus, and the number of proliferating or pyknotic cells in the hippocampus was unchanged, although neuronal density in the CA1 and CA3 was increased. Protein expression of synaptophysin, brain-derived neurotrophic factor (BDNF), and the inositol trisphosphate receptor 1 (IP(3)R1) were all significantly increased after birth asphyxia, while long-term potentiation (LTP), paired pulse facilitation (PPF), and post-tetanic potentiation (PTP) were all reduced at P5 by birth asphyxia. In control P5 pups, PPF and synaptic fatigue were greater in female compared to male pups, and after birth asphyxia PPF and synaptic fatigue were reduced to a greater extent in female vs. male pups. In contrast, the asphyxia-induced increase in synaptophysin expression and neuronal density were greater in male pups. Thus, birth asphyxia in this precocial species causes functional deficits without major structural damage, and there is a sex-dependent effect on the hippocampus. This may be a clinically relevant model for assessing treatments delivered either before or after birth to protect this vulnerable region of the developing brain.

The spiny mouse Acomys cahirinus produces well-developed pups although it is a relatively small mammal (45 g). We envisioned two opposing hypotheses on the effect of early weaning on the growth rate of pups. The first predicts little effect since the increase in energy intake of dams above non-reproducing females is relatively low, suggesting that pups consume a large portion of their energy as solid food, and the pups are very well developed at birth. The second predicts a substantial effect since the ‘index of precociality’, that is the energy intake for maintenance of a pup as a proportion of that predicted for a rodent of its body mass, falls within values for altricial rodents, suggesting an extended maternal dependence of the young. To test these hypotheses, we measured the growth rate and food intake of pups weaned after either 7, 14, 21 or 28 days. Only three of 12 pups weaned after 7 days survived and, consequently, the latter hypothesis was supported. All pups weaned at 14–28 days survived. There was a significant decrease in growth rate during the first day after weaning in pups weaned at 7, 14 and 21 days but not after 28 days, suggesting that pups did not require parental care by day 28. Peak growth rate in pups weaned at 14 days occurred in the second week but occurred in the third week in pups weaned at 21 and 28 days. In spite of these differences, pups in all treatments had similar body mass at 64 days, indicating compensatory growth. We concluded that pups of A. cahirinus are precocial from a morphological aspect in that they are well developed at birth but altricial from a nutritional aspect in that they require extended maternal support.

The desert-adapted spiny mouse has a significantly lower glomerular number, increased glomerular size, and a more densely packed renal papillae compared with the similar-sized laboratory-adapted C57BL/6 mouse. In the present study we examined the functional consequences of these structural differences in young adult male spiny and C57BL/6 mice and detailed the impact of 1 wk of a high-salt (10% wt/wt NaCl) diet. Basal food and water intake, urine and feces production, and urinary electrolyte concentrations were not different between species, although urinary urea concentrations were higher in spiny mice ( P < 0.05). On normal salt, MAP of the anesthetized spiny mouse was ∼18 mmHg lower, effective renal plasma flow (ERPF) was 40% lower ( P < 0.001), and glomerular filtration rate (GFR) tended to be lower than in the C57BL/6 mouse. On the high-salt diet, both species had similar 24-h NaCl excretions; but C57BL/6 mice required a significantly increased amount of water (lower urine NaCl concentration) than the spiny mice. Filtration fraction was greater in both species on the high-salt diet. Spiny mice had greater GFR and ERPF after the high-salt diet, whereas the C57BL/6 mouse showed little change in GFR. The ability of the spiny mouse to tolerate a significantly higher plasma osmolality after salt, measured by a decreased drinking response, and the ability to increase ERPF at a lower MAP are features that allow this species to conserve water more efficiently than can be done in the C57BL/6 mouse. These features are important, particularly since the desert mouse has a smaller kidney, with fewer nephrons.

Synthesis of dehydroepiandrosterone (DHEA) by the fetal adrenal gland is important for placental oestrogen production, and may also be important for modulating the effects of glucocorticoids on the developing brain. We have preciously shown that the enzymes and accessory proteins needed for DHEA synthesis-cytochrome P450 enzyme 17α-hydroxylase/17,20 lyase (P450c17), cytochrome-b5 (Cytb5), 3β-hydroxysteroid dehydrogenase (3βHSD)-are expressed in the adrenal gland from 30 days gestation, and DHEA, cortisol and aldosterone are present in fetal plasma from this time. Explant culture of fetal adrenal tissue showed that the spiny mouse adrenal gland, can synthesize and secrete DHEA from at least 0.75 of gestation, and suggest that DHEA may have an important role(s) in placental biosynthesis of oestrogens and in modulating the actions of glucocorticoids in the developing brain in this species. Post-natally, increased immuno-expression of P450c17 and Cytb5 expression in the zona reticularis of the adrenal gland and a significant increase in the synthesis and secretion of DHEA in plasma from 8 to 20 days of age in the spiny mouse, are representative of a period of high adrenal androgen production consistent with the human phenomenon of adrenarche. The studies summarised in this review also show that DHEA is produced de novo in the developing brain of the spiny mouse. These results showed that the spiny mouse brain can indeed produce DHEA from pregnenolone in a time-dependant manner, and coupled with the identification of P450c17 and Cytb5 protein in several regions of the brain, support the idea that DHEA is an endogenous neuro-active steroid in this species. Together, the studies outlined in this review indicate that the androgen DHEA is an important hormone of adrenal and Central Nervous System (CNS) origin in the fetal and postnatal spiny mouse. Disturbance of the development of these fetal tissues, and/or of the relationship between the fetal adrenal gland and placenta during pregnancy, may have significant consequences for fetal development, placental function, and maturation of the brain. It is proposed that such disturbances of normal adrenal function could account for some of the neuropathologies that arise in juvenile and adult offspring following illness and stress experienced by the mother during pregnancy.

Background Pregnancy induces adaptations in maternal metabolism to meet the increased need for nutrients by the placenta and fetus. Creatine is an important intracellular metabolite obtained from the diet and also synthesised endogenously. Experimental evidence suggests that the fetus relies on a maternal supply of creatine for much of gestation. However, the impact of pregnancy on maternal creatine homeostasis is unclear. We hypothesise that alteration of maternal creatine homeostasis occurs during pregnancy to ensure adequate levels of this essential substrate are available for maternal tissues, the placenta and fetus. This study aimed to describe maternal creatine homeostasis from mid to late gestation in the precocial spiny mouse. Methods Plasma creatine concentration and urinary excretion were measured from mid to late gestation in pregnant (n = 8) and age-matched virgin female spiny mice (n = 6). At term, body composition and organ weights were assessed and tissue total creatine content determined. mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and the creatine transporter (CrT1) were assessed by RT-qPCR. Protein expression of AGAT and GAMT was also assessed by western blot analysis. Results Plasma creatine and renal creatine excretion decreased significantly from mid to late gestation (P < 0.001, P < 0.05, respectively). Pregnancy resulted in increased lean tissue (P < 0.01), kidney (P < 0.01), liver (P < 0.01) and heart (P < 0.05) mass at term. CrT1 expression was increased in the heart (P < 0.05) and skeletal muscle (P < 0.05) at term compared to non-pregnant tissues, and creatine content of the heart (P < 0.05) and kidney (P < 0.001) were also increased at this time. CrT1 mRNA expression was down-regulated in the liver (

This study was designed to determine the expression pattern of estrogen receptor (ER) subtypes in the Acomys cahirinus ovarian cells during its postnatal development. Immunohistochemical studies revealed the presence of ERalpha and ERbeta in germinal epithelium cells and interstitial tissue. Both these ER subtypes were also seen in granulosa cells and oocytes of growing follicles, however, the level of ERbeta expression was higher in comparison with ERalpha. In contrast to ERbeta, ERalpha protein was also present in theca cells. The expression of ERs increased with animals' age, but it decreased during follicular maturation. Moreover, the immunolocalization of ER subtypes in luteal cells showed that not ERbeta, but ERalpha expression is up-regulated throughout corpus luteum development. These immunohistochemical studies demonstrate, for the first time, that ERalpha is also expressed in the mouse granulosa cells and it may be a mediator of estrogen action in granulosa cells proliferation and differentiation.

We determined water budget in the reproducing female common spiny mouse (Acomys cahirinus) offered ad libitum millet seeds and water. We hypothesized that the proportional increase in water input in lactating mice compared with nonreproducing mice would be greater than the proportional increase in energy intake, given that more water would be required for higher heat production and for milk production. Females gave birth to 1 or 2 offspring; results of water budget and energy intake did not differ among litter sizes and were combined. Lactating females increased water input and energy intake by 59.1% and 35.2%, respectively, compared with nonreproducing females, confirming our hypothesis. Milk production (1.04 ml/day) accounted for 29% of the difference in water output between lactating and nonreproducing spiny mice.

We hypothesized that energy intake of lactating females is the main factor determining growth of the young and that use of maternal energy reserves is less important when food is available in abundance. We studied reproducing female common spiny mouse (Acomys cahirinus) offered millet seeds and water ad libitum. Females gave birth to 1 or 2 young, and growth rate was similar between litters of 1 infant and 2 infants combined. In addition, energy intake of the 2 groups of females was similar. Lactating females increased energy intake by 45% (per g0.75) over that of nonreproducing females. Energy intake and change in body mass of the lactating female each explained about 50% of the variance in infant growth and, therefore, our hypothesis was not supported. Energy intake and change in body mass of the lactating female together explained approximately 76% of the variance in growth of young.

The pronounced increase in the protein/mRNA ratio of ammonia-metabolising enzymes in rat liver in the last prenatal week represents a clear example of a post-transcriptional level of control of gene expression. Both the underlying mechanism, namely an increase in translational efficiency of the mRNA and/or enhanced stability of the protein, and its importance for perinatal adaptation are unknown. We investigated this process in spiny mouse liver, because the comparison of rat and spiny mouse can discriminate adaptively from developmentally regulated processes in the perinatal period. We focused on glutamine synthetase (GS) because of the conveniently small size of its mRNA. Prenatally, GS enzyme activity slowly accumulated to approximately 1.3 U x g-1 liver at birth and postnatally more rapidly to 5.5 U x g-1 at 2 weeks. Both phases of enzyme accumulation obeyed exponential functions. Western-blot analysis showed that changes in GS activity reflected changes in GS protein content. GS mRNA content of the liver was 45 fmol x g-1 at 2 weeks before birth and slowly declined to approximately 25 fmol x g-1 at 2 weeks after birth. The GS protein/mRNA ratio increased 2.5-fold prenatally and sixfold postnatally. Analysis of prenatal and postnatal polysome profiles revealed no evidence of GS mRNA-containing ribonucleoprotein particles. Instead, GS mRNAs were (fully) occupied by 12 ribosomes, indicating regulation at the level of elongation. The kinetics of GS protein accumulation, in conjunction with GS mRNA content, are consistent with an approximately sixfold increase in its rate of synthesis at birth as the result of a corresponding stimulation of the rate of elongation.

Beta-adrenergic stimulation induces melatonin synthesis and non-shivering thermogenesis (NST) in rodents. The golden spiny mouse, Acomys russatus is a nocturnal species capable of diurnal activity when coexisting with its congenitor the common spiny mouse A. cahirinus. We have investigated the impact of beta-adrenergic blockade on 6-sulphatoxymelatonin (6-SMT--a metabolite and index of melatonin production) and body temperature (Tb) daily rhythms in male A. russatus. Mice were acclimated to an ambient temperature (Ta) of 28 degrees C, under two photoperiod regimes (16L:8D; 8L:16D). The daily rhythms of Tb and urinary 6-SMT were measured for a period of 30 h at intervals of 4 h. Propranolol (4.5 mg/kg, i.p.) was administered one hour before lights went off (i.e. when beta blockade does not affect NST in this species) and both variables were measured for another 30 h. The beta blocker markedly augmented melatonin output of A. russatus under both photoperiod regimes. The elevation in melatonin secretion was accompanied with an increase in Tb of only 16L:8D-acclimated mice (i.e. shorten duration of melatonin peak). However, in 8L:16D-acclimated mice, a phase advance of about 4 h was noted in 6-SMT daily rhythm. These results indicate that the role of sympathetic innervation in regulation of melatonin synthesis in A. russatus differs from that in the rat. In addition, these data are compatible with the hyperthermic action of melatonin in this species. Therefore, it is suggested that in A. russatus, other neural pathways are involved in its pineal regulation.

1. 1. The effects of photoperiod (16L:8D; 8L:16D) and melatonin treatment (50 μg for seven days) on daily rhythms of body temperature ( T b ) were studied in golden spiny mice Acomys russatus , kept at a constant ambient temperature of 28°C. 2. 2. Results show different patterns of daily T b rhythms under the different photoperiod regimes. As a response to melatonin, mice under both photoperiods increased T b while rhythm percentage decreased. A phase shift of about 10 h in T b acrophase was noted in mice acclimated to 8L:16D. 3. 3. Differences in the patterns of T b daily rhythms under the different photoperiod regimes, and difference in response to melatonin, may result from higher endogenous melatonin levels in long scotophase acclimated mice.

Synthesis of the androgen dehydroepiandrosterone (DHEA) by the fetal adrenal gland is important for placental estrogen production and may also be important for modulating the effects of glucocorticoids on the developing brain. The presence of cortisol in spiny mouse (Acomys cahirinus) blood led us to determine whether the adrenal gland of this precocial rodent also synthesized DHEA. Cytochrome P450 enzyme 17α-hydroxylase/17,20-lyase (P450c17), cytochrome-b5 (Cytb5), and 3β-hydroxysteroid dehydrogenase (3βHSD) were detected in the adrenal gland from 30 days gestation (term = 39 days), and DHEA, cortisol, and aldosterone were detected in fetal plasma from this time. Plasma DHEA concentrations increased 4-fold, whereas cortisol concentrations decreased from day 30 of gestation until the day of birth. Explant culture of fetal adrenal tissue showed that DHEA was produced from exogenous pregnenolone, and thus, the DHEA in the fetal circulation is likely to be of fetal origin. Clear zonation of the fetal adrenal cortex was evident by 38 days gestation when expression of Cytb5 was present throughout the cortex, and coexpression of P450c17 and Cytb5 occurred in the zona reticularis and fasciculata. 3βHSD was expressed in the cortex from at least 30 days gestation and decreased as term approached, consistent with the fall of cortisol in late gestation in this species. These results show that the spiny mouse adrenal gland, like that of the human fetus, can synthesize and secrete DHEA from at least 30 days (relative gestation length, 30 days of a 39-day gestation, 0.76) of gestation, and DHEA may have important roles in placental biosynthesis of estrogens and in modulating the actions of glucocorticoids in the developing brain in this species.

High levels of maternal glucocorticoids during pregnancy can alter the developmental trajectory of some fetal organs. These perturbations are often more profound for the male fetus and have been attributed to passage of glucocorticoids through the placenta. However, the effect of excess glucocorticoids on the placenta itself is less well understood and, particularly, whether this is affected by fetal sex. Expression of genes involved in placental patterning, apoptosis, and nutrient transfer, along with their response to maternal administration of dexamethasone (DEX), has previously been shown to be dependent on fetal sex in the spiny mouse. Here we describe the placental spatiotemporal expression of genes important for branching morphogenesis (WNT4, BMP4, GREM1, TGFB1, KDR, VEGFA). Furthermore, we report that compared to TGFB1 expression in the female labyrinth, expression of TGFB1 in the male labyrinth was higher, and earlier peaks in expression levels of VEGFA (Day 19 placenta [male] vs. Day 37 labyrinth [female]) and KDR (Day 19 placenta [male] vs. Day 20 labyrinth [female]) were observed. Administration of DEX to pregnant dams for 60 h commencing at mid-gestation caused significantly different, sex-related changes in expression of genes that were constitutively different before DEX treatment (e.g., KDR, TGFB1) and those that were not (i.e., VEGFA, WNT4). Similarly, some genes which displayed similar expression profiles across gestation for both sexes also showed similar responses to DEX (e.g., BMP4), while others did not (i.e., GREM1). These results showed that constitutive and glucocorticoid-induced changes in expression of genes involved in branching morphogenesis may be influenced by fetal/placental sex and that fundamental differences exist between a male and female placenta.

The golden spiny mouse Acomys russatus is a rock dwelling rodent which lives in extremely arid and hot habitats. In Israel it is nocturnal except in areas in which it coexists with the common spiny mouse A. cahirinus. In such places it is diurnal. The daily rhythms of body temperature (Tb) and oxygen consumption (VO2) were compared in mice acclimated to two different photoperiod regimes in the laboratory: 8L:16D (short day) and 16L:8D (long day) at a constant ambient temperature. The daily rhythms of VO2 and of Tb in A. russatus were found to differ greatly under long and short photoperiod. Both parameters peaked at lights-out under both photoperiod regimes. In short day acclimated mice the effect of transmitter implantation was also studied. VO2 values at night were lower after implanting. The results of this study show that Tb and VO2 rhythms are altered by the lighting regimes. Seasonal acclimatization of thermoregulatory mechanisms in the golden spiny mouse are partly induced by changes in photoperiodicity.

This study was designed to determine whether prenatal dexamethasone treatment has an effect on follicular development and atresia in the ovary of spiny mouse (Acomys cahirinus) offspring. Dexamethasone (125 µg kg–1 bodyweight per day) was administered to pregnant spiny mice from Day 20 of gestation to parturition. The processes of follicle loss were analysed using classical markers of apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling reaction, active caspase-3) and autophagy (Lamp1). The present study indicated that dexamethasone reduced the pool of healthy primordial follicles. Moreover, the oocytes from these follicles showed intensive caspase-3 and Lamp1 staining. Surprisingly, dexamethasone caused an increase in the number of secondary follicles; however, most of these follicles were characterised by extensive degeneration of the oocyte and caspase-3 and Lamp1 labelling. Western-blot analysis indicated that the glucocorticoid receptor as well as apoptosis and autophagy markers were more strongly expressed in the DEX-treated group than in the control. On the basis of these findings, we have concluded that dexamethasone impairs spiny mouse folliculogenesis and enhances follicular atresia through induction of autophagy or combined autophagy and apoptosis.

Acute kidney injury (AKI) is a major complication for infants following an asphyxic insult at birth. We aimed to determine if kidney structure and function were affected in an animal model of birth asphyxia and if maternal dietary creatine supplementation could provide an energy reserve to the fetal kidney, maintaining cellular respiration during asphyxia and preventing AKI.Pregnant spiny mice were maintained on normal chow or chow supplemented with creatine from day 20 gestation. On day 38 (term ~39 d), pups were delivered by cesarean section (c-section) or subjected to intrauterine asphyxia. Twenty-four hours after insult, kidneys were collected for histological or molecular analysis. Urine and plasma were also collected for biochemical analysis.AKI was evident at 24 h after birth asphyxia, with a higher incidence of shrunken glomeruli (P0.02), disturbance to tubular arrangement, tubular dilatation, a twofold increase (P0.02) in expression of Ngal (early marker of kidney injury), and decreased expression of the podocyte differentiation marker nephrin. Maternal creatine supplementation prevented the glomerular and tubular abnormalities observed in the kidney at 24 h and the increased expression of Ngal.Maternal creatine supplementation may prove useful in ameliorating kidney injury associated with birth asphyxia.

It has been hypothesized that male fetuses down regulate placental growth during periods of accelerated fetal growth. We aimed to investigate this, and determine whether sexual dimorphism was apparent in the spiny mouse placenta. We hypothesized that expression of fetal growth promoters would be higher in placentas of males, whereas genes involved in placental structural development would be more highly expressed in placentas of females.Spiny mouse dams, a precocial rodent with an in utero endocrine milieu dissimilar from other rodents, but akin to humans, were sacrificed at gestational ages 15-37 (term = 39 days). Placentas were collected and processed for histology or qPCR analysis of selected genes (GCM1, MAP2K1, SLC2A1, NR3C1, IGF1, IGF1R).Fetal and placental weights were similar for both sexes. Placentas of female fetuses had less spongy zone (P(SEX)0.0001), and more labyrinth (P(SEX)0.0001) than males. Early placenta and labyrinth expression of SLC2A1 was higher in males than females (P(SEX)0.05). Labyrinthine IGF1R remained constant until term in the female, compared with male where expression increased until term. Peak MAP2K1 expression occurred earlier in the male placenta than the female. Spongy zone SLC2A1 remained constant until term in the female, compared with male where expression increased until term.The spiny mouse is a species that exhibits sexually dimorphic placental development. We suggest that these sex differences in placental gene expression and structure may underlie or compound the male vulnerability to a sub-optimal in utero environment.

Sufficient amounts of water and food are important cues for reproduction in an unpredictable environment. We previously demonstrated that increased osmolarity levels, or exogenous vasopressin (VP) treatment halt reproduction of desert adapted golden spiny mice Acomys russatus. In this research we studied gonad regulation by VP and food restriction (FR) in desert adapted common spiny mouse (A. cahirinus) males, kept under two different photoperiod regimes-short (SD-8L:16D) and long (LD-16L:8D) days. Mice were treated with VP, FR, and VP+FR for three weeks. Response was assessed from changes in relative testis mass, serum testosterone levels and mRNA receptor gene expression of VP, aldosterone and leptin in treated groups, compared with their controls. SD-acclimation increased testosterone levels, VP treatment decreased expression of aldosterone mRNA receptor in the testes of SD-acclimated males. FR under SD-conditions resulted in testosterone decrease and elevation of VP- receptor gene expression in testes. Aldosterone receptor mRNA expression was also detected in WAT. These results support the idea that water and food availability in the habitat may be used as signals for activating the reproductive system through direct effects of VP, aldosterone and leptin on the testes or through WAT by indirect effects.

Clinically, treatment options where fetal distress is anticipated or identified are limited. Allopregnanolone is an endogenous steroid, that positively modulates the GABA(A) receptor, and that has anti-apoptotic and anti-excitotoxic actions, reducing brain damage in adult animal models of brain injury. We sought to determine if prophylactic treatment of the pregnant female with a single dose of this steroid could reduce birth asphyxia-induced losses in hippocampal function at 5 days of age (P5) in spiny mouse neonates (Acomys cahirinus). At 37 days gestation (term=39 days) and 1h before inducing birth asphyxia, spiny mice dams were injected subcutaneously (0.2 ml) with either 3mg/kg allopregnanolone or 20% w/v β-cyclodextrin vehicle. One hour later, fetuses were either delivered immediately by caesarean section (control group) or exposed to 7.5 min of in utero asphyxia, causing acidosis and hypoxia. At P5, ex vivo hippocampal plasticity was assessed, or brains collected to determine cell proliferation (proliferating cell nuclear antigen; PCNA) or calcium channel expression (inositol trisphosphate receptor type 1; IP(3)R1) using immunohistochemistry. Allopregnanolone partially prevented the decrease in long term potentiation at P5, and the asphyxia-induced increase in IP(3)R1 expression in CA1 pyramidal neurons. There was no effect of allopregnanolone on the asphyxia induced impairment of the input/output (I/O) curve and paired-pulse facilitation (PPF). In control birth pups, maternal allopregnanolone treatment caused significant changes in short term post-synaptic plasticity and also reduced hippocampal proliferation at P5. These findings show that allopregnanolone can modulate hippocampal development and synaptic function in a normoxic or hypoxic environment, possibly by modifying calcium metabolism. Best practice for treatment dose and timing of treatment will need to be carefully considered.

Acomys, also called spiny mice, were once used as a diabetes model. We have recently demonstrated that the closest relatives to the Acomys, members of the family Gerbillinae, lack the transcription factor Pdx-1. Therefore, we sought to determine if members of this family also lack Pdx-1, and describe the pancreatic morphology in three different species of Acomys: Acomys cahirinus (Egyptian spiny mouse), Acomys cilicicus (Asia Minor spiny mouse) and Acomys dimidiatus (eastern spiny mouse). We successfully cloned the Acomys Pdx-1 gene and we demonstrate by immunocytochemistry that the Pdx-1 protein is expressed in the pancreatic insulin immunoreactive cells and in a subset of the somatostatin cells. The basic islet structure is very similar to other rodents - with the insulin cells in the center, and glucagon, somatostatin, PP and occasional PYY cells in the periphery. No ghrelin or CART cells were identified. Nkx6.1 was localized specifically to the insulin immunoreactive cells, while Nkx2.2 was found in all endocrine cells except the somatostatin immunoreactive cells. Both MafA and MafB were expressed in the islets; MafA being specific for the insulin cells, while MafB was primarily in the glucagon cells but also found in some insulin cells. Isl-1 was localized in all endocrine cell types. In conclusion, the closest relatives to the Gerbils express a Pdx-1 protein that is 90% similar to other rodents but also has a unique 3 amino acid insert compared to other species. During the evolution of the spiny mice and the gerbils, it appears that the Pdx-1 gene was lost.

This study describes the localization of androgen (AR) and progesterone (PR) receptors in the developing ovary in the spiny mouse. The immunohistochemical analysis showed for the first time the expression of AR and PR proteins in the ovary as early as in one day-old females. Both AR and PR were present in germinal epithelium cells, stromal cells as well as in the granulosa and theca layer of ovarian follicles. On days 7, 14, 21, 30, 60 and 90, the distribution of AR and PR depended on the stage of follicular development rather than on the animal's age. A novel observation was that PR protein was detected not only in granulosa cells of preovulatory follicles, but also in the growing and early antral follicles. It was demonstrated that there is a different pattern of AR and PR immunoexpression throughout folliculogenesis. In contrast to AR, whose expression decreased during follicular development, the PR immunostaining increased during this time. It is concluded that androgens and progesterone may play an important role in the early stage of follicular development in the spiny mouse.

Evolutionary transitions between nocturnal and diurnal patterns of adaptation to the day-night cycle must have involved fundamental changes in the neural mechanisms that coordinate the daily patterning of activity, but little is known about how these mechanisms differ. One reason is that information on these systems in very closely related diurnal and nocturnal species is lacking. In this study, we characterize the suprachiasmatic nucleus (SCN), the primary brain structure involved in the generation and coordination of circadian rhythms, in two members of the genus Acomys with very different activity patterns, Acomys russatus (the golden spiny mouse, diurnal) and Acomys cahirinus (the common spiny mouse, nocturnal). Immunohistochemical techniques were used to label cell bodies containing vasoactive intestinal polypeptide (VIP), vasopressin (VP), gastrin-releasing peptide (GRP) and calbindin (CalB) in the SCN, as well as two sets of inputs to it, those containing serotonin (5-HT) and neuropeptide Y (NPY), respectively. All were present in the SCN of both species and no differences between them were seen. On the basis of neuronal phenotype, the SCN was organized into three basic regions that contained VIP-immunoreactive (-ir), CalB-ir and VP-ir cells, in the ventral, middle and dorsal SCN, respectively. In the rostral SCN, GRP-ir cells were in both the VIP and the CalB cell regions, and in the caudal area they were distributed across a portion of each of the other three regions. Fibers containing NPY-ir and serotonin (5-HT)-ir were most concentrated in the areas containing VIP-ir and CalB-ir cells, respectively. The details of the spatial relationships among the labeled cells and fibers seen here are discussed in relation to different approaches investigators have taken to characterize the SCN more generally.

1. 1. A comparison was made of the mechanical performance of heart muscle from mouse, an atricial mammal, with corticosterone as glucocorticoid and spiny mouse ( Acomys cahirinus ), a precocial mammal, with cortisol as glucocorticoid. 2. 2. Force-frequency responses were negative in mouse and positive in spiny mouse. 3. 3. During recovery, there was a gradual increase and an overshoot in the mouse, while in the spiny mouse there was an initial enhanced response, diminishing gradually with time. 4. 4. High calcium concentration inhibited contractile tension in mouse heart, while it was positively inotropic in spiny mouse heart. Changes in the concentration of calcium did not change the patterns of force-frequency response. 5. 5. Lowering the experimental temperature increased the time course and amplitude of the tension curve. However, various parameters exhibited different temperature sensitivity. 6. 6. There was a significant difference in the levels of circulating cortisol between male and female spiny mice. 7. 7. It is proposed that the differences in the mechanical responses of mouse and spiny mouse hearts may be explained in terms of the effects of the specific glucocorticoid hormone on the development of the sodium-calcium exchanger.

Background Creatine synthesis takes place predominately in the kidney and liver via a two-step process involving AGAT (L-arginine:glycine amidinotransferase) and GAMT (guanidinoacetate methyltransferase). Creatine is taken into cells via the creatine transporter (CrT), where it plays an essential role in energy homeostasis, particularly for tissues with high and fluctuating energy demands. Very little is known of the fetal requirement for creatine and how this may change with advancing pregnancy and into the early neonatal period. Using the spiny mouse as a model of human perinatal development, the purpose of the present study was to comprehensively examine the development of the creatine synthesis and transport systems. Results The estimated amount of total creatine in the placenta and brain significantly increased in the second half of pregnancy, coinciding with a significant increase in expression of CrT mRNA. In the fetal brain, mRNA expression of AGAT increased steadily across the second half of pregnancy, although GAMT mRNA expression was relatively low until 34 days gestation (term is 38–39 days). In the fetal kidney and liver, AGAT and GAMT mRNA and protein expression were also relatively low until 34–37 days gestation. Between mid-gestation and term, neither AGAT or GAMT mRNA or protein could be detected in the placenta. Conclusion Our results suggest that in the spiny mouse, a species where, like the human, considerable organogenesis occurs before birth, there appears to be a limited capacity for endogenous creatine synthesis until approximately 0.9 of pregnancy. This implies that a maternal source of creatine, transferred across the placenta, may be essential until the creatine synthesis and transport system matures in preparation for birth. If these results also apply to the human, premature birth may increase the risk of creatine deficiency., BMC Developmental Biology, 9 (1), ISSN:1471-213X

Ultrasound was used to measure growth of the spiny mouse fetus throughout gestation and to record Doppler measurements of heart rate and umbilical blood flow to monitor fetal blood supply and wellbeing. Female spiny mice were anesthetized on 6 occasions throughout pregnancy. Ultrasound was performed with a Philips HDI 5000 machine using a compact linear CL15-7 transducer. Fetal heart rate and growth parameters increased across gestation. Blood flow through the umbilical artery and vein showed increasing velocity over gestation, and reduced resistance index. Blood flow through the ductus venosus also increased in velocity over gestation; however the resistance index remained constant. We have determined changes in umbilical blood flow throughout pregnancy in the spiny mouse, which resemble those seen in human pregnancy. We also confirm that ultrasound can be used as a valuable, non-invasive technique for measuring fetal growth and wellbeing in the spiny mouse.

Increased dietary salinity suppressed reproduction of the xeric adapted golden spiny mouse, Acomys russatus. Testicular and uterine mass were reduced, suppressed spermatogenesis and vaginal closure were observed. The anti-diuretic hormone, vasopressin (VP), was suggested to mediate such effects. However, increased dietary salinity did not affect reproductive status of a mesic adapted population of the common spiny mouse, A. cahirinus. In the present study, the effect of exogenous VP on the reproductive status and energy balance of both males and females of A. russatus and of a mesic population of A. cahirinus was tested. Vasopressin (Sigma, 50 µg/kg) was injected intraperitoneally in three-day intervals for four weeks. In VP-treated A. russatus, spermatogenesis was significantly suppressed while the change in testis mass did not show significant difference. Both control and VP-treated females lost body mass (Wb) significantly and the latter also exhibited a higher energy expenditure compared to their male counterparts. VP did not affect reproductive status in both sexes of A. cahirinus. Also it did not have a significant effect on Wb, energy intake, and energy expenditure in this species. Our results support the idea that VP mediates the effects of increased diet salinity on reproduction in A. russatus. The results also reinforce previous knowledge that different physiological systems could be integrated by a single biochemical signal.

We studied levels of fecal glucocorticoid metabolites (GCM) in a social rodent — Egyptian spiny mouse. As breeding adults are socially dominant over subadults, and adolescent males are driven away by the dominant males, we addressed the question whether animals within extended families are stressed differently depending upon their social category. In addition, we evaluated whether there are differences between non-commensal (outdoor) and commensal (adapted to human settlements) populations. Concentrations of fecal GCM were assessed from samples collected in a special cage that allowed continuous individual sampling of undisturbed mice housed as a semi-natural social unit. First we performed an ACTH challenge test to validate two enzyme immunoassays (EIA): a 5α-pregnane-3β,11β,21-triol-20-one EIA and an 11-oxoetiocholanolone EIA to measure a group of fecal GCM in this species. Next we monitored concentrations of fecal GCM in 68 individuals belonging to 10 family groups and two populations. Commensal spiny mice showed higher fecal GCM levels than non-commensal ones. No effect of age (i.e., social dominance) and only a small effect of sex (in the commensal population only, with males exhibiting lower values) on fecal GCM levels were found. On the other hand, considerable variations in measured fecal GCM between family groups were revealed, indicating that the social settings of the particular group play an important role.

Male adult spiny mice (Acomys cahirinus) were acutely challenged with a single dose of regular insulin or saline vehicle SC; either food intake, meal frequency and meal duration, or stomach emptying were then measured. Meal frequency, as well as amount eaten, was significantly higher over a 6-hr period following both 10 and 30 U/kg of insulin than following vehicle injection. Meal duration remained essentially the same across all conditions. When 30 U/kg of insulin was administered either 15 min prior to, or immediately after, a solid food meal, stomach emptying (as measured by dry weight of recovered stomach contents) was accelerated relative to vehicle controls. These data are generally consistent with and extend the comparative literature suggesting a possible link between rate of stomach emptying and insulin-induced hyperphagia in some species.

We investigated the effects of maternal glucocorticoid exposure in the spiny mouse, a precocial species with a relatively long gestation, few offspring, and in which nephrogenesis is complete before birth. We hypothesized that exposure of the fetus to glucocorticoids before the formation of glomeruli would result in adult hypertensive offspring with fewer nephrons. Furthermore, we hypothesized that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at midgestation ( day 20) delivered dexamethasone (dex; 125 μg/kg) or saline for 60 h. Females were killed at day 23 of gestation and kidneys were frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 wk of age, blood pressure was measured in the offspring for 1 wk before nephron number was determined using unbiased stereology. Males and females exposed to dex had significantly fewer nephrons (male: saline: 7,870 ± 27, dex: 6,878 ± 173; female: saline: 7,526 ± 62, dex: 5,886 ± 382; P < 0.001) compared with controls. Dex had no effect on basal blood pressure. Fetal kidneys collected at day 23 of gestation from dex-exposed mothers showed increased mRNA expression of BMP4 ( P < 0.05), TGF-β1( P < 0.05), genes known to inhibit branching morphogenesis and gremlin ( P < 0.01), an antagonist of BMP4, compared with saline controls. This study shows for the first time an upregulation of branching morphogenic genes in the fetal kidney in a model of excess maternal glucocorticoids that leads to a nephron deficit in the adult. This study also provides evidence that a reduced nephron number does not necessarily lead to development of hypertension.

The spiny mouse is relatively mature at birth. We hypothesized that like other organs, the kidney may be more developed in the spiny mouse at birth, than in other rodents. If nephrogenesis is complete before birth, the spiny mouse may provide an excellent model with which to study the effects of an altered intrauterine environment on renal development. Due to its desert adaptation, the spiny mouse may have a reduced cortex-to-medulla ratio but an equivalent total nephron number to the C57/BL mouse. Kidneys were collected from fetal and neonatal spiny mice and sectioned for gross examination of metanephric development. Kidneys were collected from adult spiny mice (10 wk of age), and glomerular number, volume, and cortex-to-medulla ratios were determined using unbiased stereology. Nephrogenesis is complete in spiny mouse kidneys before birth. Metanephrogenesis begins at ∼ day 18, and by day 38 of a 40-day gestation, the nephrogenic zone is no longer present. Spiny mice have a significantly ( P < 0.001) lower total nephron number compared with C57/BL mice, although the total glomerular volume is similar. The cortex-to-medulla ratio of the spiny mouse is significantly ( P < 0.01) smaller. The spiny mouse is the first rodent species shown to complete nephrogenesis before birth. This makes it an attractive candidate for the study of fetal and neonatal kidney development and function. The reduced total nephron number and cortex-to-medulla ratio in the spiny mouse may contribute to its ability to highly concentrate its urine under stressful conditions (i.e., dehydration).

Circadian locomotor rhythms were examined in adult common spiny mice, Acomys cahirinus. Spiny mice demonstrated nocturnal activity, with onset of activity coinciding promptly with onset of darkness. Re-entrainment to 6-h delays of the light-dark cycle was accomplished faster than to 6-h advances. Access to running wheels yielded significant changes in period and duration of daily activity. Novelty-induced wheel running had no effect on phase of activity rhythms. Circadian responses to light at various times of the circadian cycle were temporally similar to those observed in other nocturnal rodent species. No gender differences were observed in any of the parameters measured.