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To compare the sequential evolution of lesions developed by resistant (A/Sn) and susceptible (B10.A) mice to Paracoccidioides brasiliensis infection we inoculated a virulent isolate of the fungus and collected the pancreas/peripancreatic omentum monthly (from 1 to 6 months) post infection. After fixation, tissue sections were stained by conventional methods for light microscopy to investigate the cellular composition, the extracellular matrix (ECM) patterns and the morphology of the yeasts in the lesions. In both strains, the fungal lesions were localized mostly in the omentum; a few lesions in the pancreatic parenchyma were observed, mostly in B10.A mice. In both strains, macrophages and plasmocytes were the predominant cells in all lesions, followed by neutrophils (PMN) and macrophages transformed into giant and epithelioid cells. Remarkable differences were observed between resistant and susceptible mice, specially related to the ECM structure of the granulomatous lesions. In A/Sn mice, from the 1st month on, the coexistence of two types of lesions was observed: one type showed a well-defined encapsulated nodule, constituted mainly of type I collagen. Neutrophils were abundant in areas of massive fungal destruction and few viable yeasts were observed. The other type showed residual characteristics, with sparse collagen deposits and presence of xantomatous-like macrophages, containing degenerated fungi. Such residual lesions predominated after the 2nd month and were the only type observed from the 4th month on, indicating the control of the infection. In B10.A mice, on the contrary, only one type of lesion was observed, showing less tendency to encapsulation and the formation of multiple small granulomatous foci, individualized by reticular type III collagen fibers. There were many plasmocytes in the periphery and large numbers of budding yeasts, with no evidence of fungal destruction. In the course of the infection the lesions progressively increased in number and size. Altogether, the comparative histopathological analysis demonstrates the influence of the genetic pattern of the host on the lesions developed by resistant and susceptible mice to P. brasiliensis infection. [ABSTRACT FROM AUTHOR]

Both maternal and fetal genetic factors influence variations in response to prenatal ethanol exposure. To assess the effect of maternal genotype on the incidence of ethanol teratogenesis, a reciprocal cross study was conducted in an animal mode using the relatively susceptible C57BL/6J (B6) and the relatively resistant DBA/2J (D2) inbred mice. This mating pattern produced four embryonic genotypes: true-bred B6B6 and D2D2 litters and hybrid B6D2 and D2B6 litters. To examine the role of maternal egg cytoplasm as the source of variation that could account for a maternal effect, B6D2 and D2B6 F1 females were mated back to B6 males, which produced two additional embryonic genotypes: B6D2.B6 and D2B6.B6. Dams were intubated with either 5.8 g/kg of ethanol or an isocaloric amount of maltose–dextrin on day 9 of pregnancy. On day 18 of pregnancy, dams were sacrificed, fetuses were removed, weighed, sexed, and examined for gross morphological malformations. Every other fetus within a litter was prepared for either skeletal or soft tissue analysis. Results showed a higher rate of teratogenesis in the B6D2 group compared to the genetically similar D2B6 group, which indicates an influence of maternal genotype on susceptibility to ethanol teratogenesis. The percentage of affected male and female fetuses did not differ, which suggests that sex-linked factors are not responsible for the maternal effect. The backcross B6D2.B6 and D2B6.B6 litters did not differ significantly for any measure of teratogenesis, suggesting that differences in maternally transmitted cytoplasmic material are not the cause of the maternal effect. Factors that could account for the maternal effect are differences in the maternal uterine environment and genomic imprinting. Separating maternal from fetal-mediated mechanisms responsible for susceptibility to ethahol teratogenesis is needed for identifying mothers and infants at risk. [ABSTRACT FROM AUTHOR]

The effect of multiple dose regimens of amantadine, reserpine, chlorpromazine alone or combined on liver alcohol (L-ADH) and aldehyde dehydrogenase (L-ALDH) was studied in three strains of mice. A strain-dependent difference between endogenous specific activity of these enzymes and their sensitivity to the agents studied was determined. The C57BL/6 mice showed most resistance to drug effect and possessed greater activity of mitochondrial L-ALDH isoenzymes and L-ADH than either ICR or BALB/C mouse strains, respectively. Amantadine induced both L-ADH and mitochondrial L-ALDH while reserpine inhibited them also as a function of mouse strain. Both reserpine- and chlorpromazine-mediated inhibition of albino ICR mouse L-ADH and BALB/C mitochondrial L-ALDH was alleviated by pretreatment with amantadine. This indicates antagonism between amantadine and these agents. The results suggest a genotypic sensitivity to drug action which may explain the individual sensitivity to the development of chlorpromazine and reserpine-produced side-effects, and the potency of amantadine in management of such drug-induced adverse reactions. [ABSTRACT FROM AUTHOR]

Locomotor activity responses to sub-hypnotic doses of ethanol (ETOH) were assessed in selected lines of mice (LS and SS), inbred strains, and their F1 hybrids. Data were obtained as photocell beam interruptions in a 15-min test for a dose range of 0 to 2.75 or 3.5 g/kg for LS and SS mice, respectively. Biphasic dose-response curves were obtained for LS and SS mice with the SS mice showing a sedative limb of the dose-response curve shifted to the right. The effects of 2.0 g/kg ETOH were also assessed in a diallel cross of the selected LS/SS lines and C57BL/6Abg and MOLD/RkAbg inbred strains. The 2.0 g/kg dose produced a wide range of responses, from sedation in C57BL/6Abg mice to extreme activation in SS and MOLD/RkAbg mice, and no effect in LS mice. The responses of F1 hybrids reflected a typical pattern of partial dominance, with heterosis in some crosses. When present, dominance was in the direction of greater locomotor activation. These patterns were confirmed by biometrical genetic analysis of the 4 × 4 diallel cross of the two lines and the two inbred strains. The data indicate that loci in addition to those responsible for selection for sedative sensitivity in LS and SS mice can influence locomotor activation produced by sub-hypnotic ETOH doses, and that SS and MOLD mice show locomotor activation for different genetic reasons. [ABSTRACT FROM AUTHOR]

To assess genetic factors determining sensitivity to streptozotocin-induced diabetes in inbred strains of mice, a genetic analysis of streptozotocin-sensitive C57BL/6J and streptozotocin-resistant C3H/HeJ mice was performed. One week after a single dose of streptozotocin (200 mg/kg body weight), differences in plasma glucose concentration were marked between male mice of the C57BL/6J and C3H/HeJ strains ( p<0.001). To determine the number of genes responsible for the difference, F male progeny of a cross between parental strains were produced, and found to be streptozotocin resistant like C3H/HeJ parents. F mice were, therefore, backcrossed with streptozotocin-sensitive C57BL/6J mice (Backcross: F♂ ♂ X C57BL/6J ♀ ♀). The plasma glucoses of backcrossed male mice ( n=41) following streptozotocin treatment appeared to segregate into two populations, half like the C57BL/6J parent, and half like the F parent. Statistical analysis of the data revealed that the data fit a model with two distributions better than one with a single distribution, suggesting a single major gene responsible for the difference in streptozotocin susceptibility. This hypothesis was also supported by the observation that streptozotocin sensitivity in 12 recombinant inbred strains of C57BL/6J and C3H/HeJ mice appeared to segregate into two classes. Resistance to streptozotocin induced diabetes in F mice suggested that the expression of this gene is recessive, although X-chromosome linked inheritance could not be excluded. Efforts to map the streptozotocin-sensitivity gene revealed lack of right linkage to several loci including the H-2 locus. If inherited differences in the ability to resist a B-cell toxin play a role in genetic susceptibility to diabetes in man, then mapping the streptozotocin-susceptibility gene in mice may provide a means to evaluate the role of a putative homologous locus in the aetiology of diabetes in man. [ABSTRACT FROM AUTHOR]

The insulin resistance produced by the recessive db mutation has led to more severe diabetes in C57BL/KsJ mice relative to that in C57BL/6J mice, suggesting genetic differences between the two strains affecting insulin production or insulin action. To assess these parameters blood glucose, serum insulin, pancreatic insulin, and proinsulin mRNA were measured in both normal and diabetic (db/db) KsJ and 6J strains. The mice were compared at 5 weeks of age, prior to the development of insulin lack known to occur with age in KsJ db/db mice. As a further provocation to insulin production, another group of the normal and db/db mice were given dexamethasone for 4 days. In normal mice there were no strain differences in blood glucose, serum insulin, pancreatic insulin, or proinsulin mRNA. Dexamethasone, presumably by augmenting insulin resistance, induced increases in serum insulin and proinsulin mRNA to the same extent in KsJ and 6J mice. In db/db mice, while blood glucose, serum insulin, and proinsulin mRNA were considerably higher than in normal mice, there were no strain differences observed. After dexamethasone the db/db mice exhibited strain differences which included higher blood glucose and higher serum insulin levels in KsJ mice. These findings were compatible with greater insulin resistance in KsJ than in 6J db/db mice. While dexamethasone treatment increased serum insulin in KsJ db/db mice, there was no augmentation of proinsulin mRNA in either strain, suggesting a limit to the insulin synthesis. Analysis of serum insulin/glucose and proinsulin mRNA/glucose ratios demonstrated a dexamethasone-induced increase in serum insulin/glucose in normal and diabetic mice of both strains. An increase in dexamethasone induced proinsulin mRNA/glucose ratio was observed in all but the KsJ db/db mice. This analysis suggested that although insulin secretion in KsJ db/db mice was augmented, the capacity for insulin synthesis had been exceeded. A limitation of insulin production at the level of insulin synthesis might explain the enhanced diabetes susceptibility of this strain. [ABSTRACT FROM AUTHOR]

Proliferation of islet cells may compensate for both an increased peripheral insulin resistance and islet cell destruction but the capacity for regeneration may be genetically determined. For the latter reason, glucose-stimulated islet cell replication was estimated in both inbred C57BL/6J (BL/6) and C57BL/KsJ (BL/Ks) mice. Islets isolated from both strains were exposed to high concentrations of glucose in vitro or in vivo for a prolonged time period. This was achieved either by culturing the islets free-floating in a high glucose concentration medium for 3 days or implanting the islets intrasplenically in insufficient numbers to cure alloxan-diabetic syngeneic recipients. In both strains high glucose concentration culture was found to increase the autoradiographic labelling index of the islets but the replicatory activity decreased with age. The proliferative rate of the islet cells of the BL/6 mice was about twice as high as that of the BL/Ks mice irrespective of age and glucose concentration. Likewise, the labelling index of intrasplenic BL/6 islets implanted into alloxan-diabetic mice was twice as high as that of the islets implanted into alloxan-diabetic BL/Ks mice. The replicatory activity of the latter islets did not differ statistically from that of islets implanted into non-diabetic control BL/Ks mice. No differences in the rates of proinsulin and total protein biosynthetic rates were observed between high glucose concentration-cultured islets of the two mouse strains. The present results indicate that the proliferative response of pancreatic islets to a prolonged glucose stimulation may be genetically determined. This may play a significant role in the development of different diabetic syndromes both in laboratory animals and man. [ABSTRACT FROM AUTHOR]

Hepatic glucokinase activity in the C3H/He strain of mice is about twice that in the C58 strain. Genetic analysis of hybrids and back-crosses indicates control of activity by a single codominant gene. The adaptations of activity that occur when animals of the two strains are starved, fed a carbohydrate-free diet or made streptozotocin-diabetic are similar in the two strains. In almost all the situations tested, plasma insulin concentrations were higher in the C3H/He strain than in the C58 strain. On the assumption that insulin plays some role in the synthesis of glucokinase, the possible association between the plasma insulin concentration and hepatic glucokinase activity in mice in which plasma glucose concentrations are similar is discussed. The twofold difference in glucokinase activity between the two strains is associated with only minor differences in glucose tolerance and insulin response to a glucose load. [ABSTRACT FROM AUTHOR]

The behavioral performance of inbred mouse strains was examined in animal models of anxiety to evaluate the potential contribution of genetic factors to fear-motivated behaviors. The preference that randomly bred mice and rats exhibit for the enclosed as opposed to the open arms of an elevated maze has been considered a fear-motivated behavior. Pronounced differences were observed in this measure among 16 inbred mouse strains. An estimate of the proportion of the variance attributable to between-strain differences, ν, revealed that 78% and 69% of the variance in time and number of entries in the open arms of an elevated maze, respectively, can be attributed to genetic factors. In contrast, only 27% and 42% of the variance could be attributed to between-strain differences in ambulatory activity in the open field and elevated maze, respectively. Furthermore, performance in the elevated maze was predictive of behavior in other animal models of anxiety. Thus, significant negative correlations were observed among inbred mouse strains between the percent time spent in the open arms of the elevated maze and amplitude of an acoustic startle response ( r=−0.88m P<0.01) or latency to initiate chow consumption in a hyponeophagia paradigm ( r=−0.71, P<0.05). These results indicate that genetic factors substantially contribute to fear motivated behaviors in these animal models of anxiety. The use of such inbred mouse strains may provide a novel approach to investigate the biochemical and genetic bases of fear. [ABSTRACT FROM AUTHOR]

One of the significant factors that affect brain dopamine function is the activity of tyrosine hydroxylase (TH), the first and rate-limiting enzyme in catecholamine biosynthesis. For the analysis of the genetically determined role of dopamine function and TH in behavior and in the regulatory mechanisms of the mesotelencephalic dopamine system we devised a novel genetic strategy (Vadasz; Mouse Genome 88:16–18; 1990). We hypothesized that phenotypic introgression and recombinant fixation could ensure the transfer of Quantitative Trait Loci (QTL) from one strain onto the genetic background of another strain, and new, genetically very similar quasi-congenic strains could be created that would carry individual QTLs, or QTLs in various combinations. Here we summarize the construction of the first set of QTL Introgression strains, and present evidence that QTLs that are responsible for the continuous variation of mesencephalic tyrosine hydroxylase activity (TH/MES), have been transferred onto the C57BL/6By (B6) strain background from BALB/cJ (C) and CXBI (I) donor strains with high and low TH/MES, respectively. The QTL transfer was carried out in two directions by repeated backcross-intercross cycles with concomitant selection for the extreme high and low expressions of TH/MES in replicates, resulting in four QTL Introgression lines. Analysis of regional brain TH activities in the course of the QTL introgression indicated that (a) TH activity in B6.I lines showed quite limited heritability, (b) TH/MES was not highly correlated with striatal TH, and (c) the control of hypothalamic and olfactory tubercle TH activities was largely independent from that of TH/MES. Examination of the open-field (OF) behavior data demonstrated that TH activity did not correlate significantly with OF behavior. After 5 backcross-intercross cycles, TH/MES in each replicate line was still significantly different from that of the B6 background strain. A genomewide scanning of microsatellite markers in the QTL introgression lines demonstrated that about 96% of the markers were of background (B6) type. These results indicate the successful transfer of TH/MES QTLs. After the QTL transfer phase of the experiment altogether more than 100 new RQI strains were initiated in the QTL Introgression lines by strict brother × sister mating. After fixing the introgressed QTLs, ten of the inbred RQI strains were tested for TH/MES. The results showed that in one of the new RQI strains TH/MES was restored to a level that is characteristic to the C donor strain, while TH/MES values in some other strains were between those of the background and donor strains, confirming our hypothesis that phenotypic introgression and recombinant fixation can ensure a virtually complete transfer of QTLs. We conclude from this study that complex, continuously distributed neural traits can successfully be subjected to QTL introgression, and the results raise the possibility that the RQI method can be efficiently applied for gene mapping of complex neural and behavioral traits even if their phenotypic expression is sensitive to confounding developmental and environmental variations, genetic interactions, and genotype-environment interactions. [ABSTRACT FROM AUTHOR]

Reciprocal crosses were made between AKR/J, a 1,2-dimethylhydrazine (DMH)-resistant mouse strain, and SWR/J, a sensitive strain. The F1 hybrids were tested with DMH and methylazoxymethanol (MAM), two colon carcinogens. Either DMH (20 mg/kg body weight) or MAM (35 mg/kg body weight), a metabolic derivative of DMH, was injected weekly for 10 weeks. In each group of 35 mice, 10 were injected with tritiated thymidine (25 μCi) 1 week after the sixth injection of DMH and MAM for the evaluation of proliferative characteristics and the number of foci of dysplasia occuring in 325 μm of distal colonic mucosa. At 27 weeks after the first injection of the carcinogen, the colons of remaining mice were opened longitudinally and the number of tumors enumerated. Compared with DMH-treated mice, the number of foci of dysplasia per mouse, the percentage of tumor-bearing mice, the number of tumors per animal, and the number of tumors per tumor-bearing animal induced by MAM were severalfold higher. This would suggest the presence of a gene(s) repressing metabolism of DMH to MAM. Moreover, differences in response to the carcinogens were observed between the sexes. In contrast to males, females treated with both DMH and MAM had significantly greater numbers of tumors per animal, tumors per tumor-bearing mice, and a greater proliferative response with extension of S-phase cells to the upper third and luminal surface of crypts. Among males, those with the X/Y heritage appeared more resistant than X/Y males, particularly in their response to MAM. A twofold difference in the number of foci of dysplasia per mouse, tumors per animal, and the number of tumors per tumor-bearing animals was seen. Analyses of the response to DMH and MAM by F1 reciprocal hybrids of the AKR and SWR strains have shown a complex inheritance pattern governing susceptibility to DMH. Resistance to the carcinogen is provided by at least two specific repressor genes, one governing metabolism of carcinogen from DMH to MAM, and the other controlled by gender. Genetic factors contributed by the AKR female appear to convey additional resistance to male progeny, suggesting more than one gender-related gene. [ABSTRACT FROM AUTHOR]

Mice of the C57BL/6J and CBA/HT6J inbred strains and their F hybrid were investigated at 67, 202, 463, and 711 days of age to determine how genetic differences affected aging patterns of renal function and morphology. The three genotypes differed significantly in their body and kidney weights and their kidney to body weight ratios. These differences reflected functional capacities, and renal hypertrophy appeared to be an attempt to compensate for functional losses with age. The glomerular filtration rate (GFR) decreased in both inbred strains with age but remained constant in the F hybrid mice. There was a significant strain difference in GFR, but this difference disappeared when the GFR was considered in relation to the kidney weight. Thus the strain difference appeared to reflect differences in ability to compensate for loss of function by increasing kidney size. Osmolarities and sodium clearances decreased with age and increased with renal hypertrophy, but plasma levels were constant. Histopathological changes with age appeared to be correlated with functional changes. [ABSTRACT FROM PUBLISHER]

Following weekly i.m. injections of gold(I) disodium thiomalate (GST), mice of strains A.SW and C57BL/6 develop adverse immune reactions, whereas DBA/2 mice do not. We have studied the pharmaco-toxicokinetics of gold in these strains under chronic GST treatment. Our results indicate that the susceptible strains A.SW and C57BL/6 accumulate significantly higher gold concentrations in the liver and spleen compared to the resistant strain DBA/2. In the kidney of DBA/2 mice, gold concentrations persisted at a plateau level, whereas in A.SW and, particularly, C57BL/6 mice early peaks of gold concentrations were followed by a transient decrease, suggestive of tubular toxicity. Whereas splenic T and B cells failed to contain measurable gold concentrations in all three strains, splenic and peritoneal macrophages contained relatively high levels, more so in the susceptible strain C57BL/6 than in the resistant DBA/2 strain. This finding is consistent with the concept that macrophages play an important role in both the adverse and the beneficial effects of gold drugs. [ABSTRACT FROM PUBLISHER]

Study Objectives: Sleep is an important biological process that is perturbed in numerous diseases, and assessment of its substages currently requires implantation of electrodes to carry out electroencephalogram/electromyogram (EEG/EMG) analysis. Although accurate, this method comes at a high cost of invasive surgery and experts trained to score EEG/EMG data. Here, we leverage modern computer vision methods to directly classify sleep substages from video data. This bypasses the need for surgery and expert scoring, provides a path to high-throughput studies of sleep in mice., Methods: We collected synchronized high-resolution video and EEG/EMG data in 16 male C57BL/6J mice. We extracted features from the video that are time and frequency-based and used the human expert-scored EEG/EMG data to train a visual classifier. We investigated several classifiers and data augmentation methods., Results: Our visual sleep classifier proved to be highly accurate in classifying wake, non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) states, and achieves an overall accuracy of 0.92 ± 0.05 (mean ± SD). We discover and genetically validate video features that correlate with breathing rates, and show low and high variability in NREM and REM sleep, respectively. Finally, we apply our methods to noninvasively detect that sleep stage disturbances induced by amphetamine administration., Conclusions: We conclude that machine learning-based visual classification of sleep is a viable alternative to EEG/EMG based scoring. Our results will enable noninvasive high-throughput sleep studies and will greatly reduce the barrier to screening mutant mice for abnormalities in sleep., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Abstract Background The aim of this study was to investigate the effects of prenatal alcohol exposure on radial-maze learning and hippocampal neuroanatomy, particularly the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields, in three inbred strains of mice (C57BL/6J, BALB/cJ, and DBA/2J). Results Although we anticipated a modification of both learning and IIPMF sizes, no such effects were detected. Prenatal alcohol exposure did, however, interfere with reproduction in C57BL/6J animals and decrease body and brain weight (in interaction with the genotype) at adult age. Conclusion Prenatal alcohol exposure influenced neither radial maze performance nor the sizes of the IIPMF terminal fields. We believe that future research should be pointed either at different targets when using mouse models for Fetal Alcohol Syndrome (e.g. more complicated behavioral paradigms, different hippocampal substructures, or other brain structures) or involve different animal models.

Mice of the BALB/cJ strain have more dopamine neurons than mice of the CBA/J strain. We now report that BALB/cJ mice have less circulating and pituitary prolactin than CBA/J mice, a relationship expected from the difference in tuberoinfundibular dopamine neuron number. [ABSTRACT FROM AUTHOR]

Recruitment of brite/beige cells, known as browning of white adipose tissue (WAT), is an efficient way to turn an energy-storing organ into an energy-dissipating one and may therefore be of therapeutic value in combating obesity. However, a comprehensive understanding of the regulatory mechanisms mediating WAT browning is still lacking. Here, we exploit the large natural variation in WAT browning propensity between inbred mouse strains to gain an inclusive view of the core regulatory network coordinating this cellular process. Combining comparative transcriptomics, perturbation-based validations, and gene network analyses, we present a comprehensive gene regulatory network of inguinal WAT browning, revealing up to four distinct regulatory modules with key roles for uncovered transcriptional factors, while also providing deep insights into the genetic architecture of brite adipogenesis. The presented findings therefore greatly increase our understanding of the molecular drivers mediating the intriguing cellular heterogeneity and plasticity of adipose tissue. • The browning capacity of white adipose tissue is under complex genetic control • Genetic architecture of brite adipogenesis is built from several genetic models • Dozens of Ucp1 regulating factors are validated • A core browning regulatory network with four distinct regulatory modules is revealed Browning of white fat, which turns an energy-storing organ into an energy-dissipating one, holds promise for the development of novel therapeutics against obesity. By exploiting intrinsic mouse strain variation and applying a systems-genetics approach, Li et al. reveal a comprehensive gene regulatory network that controls this browning process. [ABSTRACT FROM AUTHOR]

GABA type-A (GABA-A) receptors containing the α2 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair deletion located in an intron adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR- Cas9 -mediated gene editing on a B6J genetic background completely restored brain levels of GABRA2 protein and mRNA. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the Gabra2 gene is of critical importance to molecular genetic studies in neurobiological research because this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by GABRA2 function.

The present study was designed to investigate the correlation between the spatial and temporal aspects of immune responses and genetic heterogeneity in the progression of peripheral neuropathic pain. To address this issue, we first screened four inbred mouse strains (C57BL/6J, C3H/He, DBA/2, and A/J mice) to identify high- and low-responder strains to mechanical hypersensitivity induced by partial sciatic nerve ligation (pSNL). Among these strains, the C57BL/6J strain showed the highest vulnerability to pSNL-induced mechanical hypersensitivity, whereas the C3H/HeSlc strain was most resistant. C3H/HeSlc mice exhibited a significant increase in CD206-immunoreactivity (anti-inflammatory macrophages) in the dorsal root ganglia (DRG) at 3 and 7 days, and lower Iba1-immunoreactivity (microglia) in the spinal cord from 3 to 14 days after pSNL than C57BL/6J mice. These phenomena might be associated with a decrease in the production of inflammatory factors (interleukin-1β, interleukin-6, and CX3CL1) in the DRG and the poor responsiveness of spinal microglia (i.e. microglial production of IL1β, CCL2, and TNFα) against CX3CL1 in C3H/HeSlc mice. Behavioral experiments using bone marrow (BM) chimeric mice derived by crossing C3H/HeSlc and C57BL/6J strains showed that the strength of mechanical hypersensitivity 3 days following pSNL was inversely correlated with the increase in the ratio of anti-inflammatory/pro-inflammatory DRG macrophages, which was based on the BM-derived hematopoietic cells from donor mice. By contrast, the intensity of Iba1-immunoreactivity (microglia) in the spinal cord was dependent on the phenotypes of recipient mice, but not affected by the phenotypes of BM-derived donor hematopoietic cells. These findings suggest that the strain-specific aspects of DRG macrophages and spinal microglia might be related to the early and late phases of pSNL-induced mechanical hypersensitivity, respectively. This study presents a greater understanding of the differences in neuropathic pain among genetically heterogeneous inbred mouse strains, and provides further insights into the spatial and temporal roles of the immune system in the pathogenesis of neuropathic pain., (Copyright © 2018 Elsevier Inc. All rights reserved.)