Cage Mates Research Articles

Effects of Intermittent Harem Mating on Parturition-induced Stress and Success Rate of Weaning in C57BL/6JNarl Mice.

Improving the effectiveness of mating schemes for large-scale production of mice is an ongoing challenge in animal facilities. Continuous mating, which requires fewer breeding cages than intermittent mating, has traditionally been used to take advantage of postpartum estrus for efficient production. However, the continuous mating scheme lacks flexibility because it cannot immediately accommodate the reduced needs of mice when production levels are high. In this study, we compared reproductive performance, fecal corticosterone metabolite (FCM) level as a stress indicator, and mouse mortality between the continuous trio (CT) and intermittent quad (IQ) mating schemes. The weaning rates in the IQ scheme were higher than those in the CT scheme (98.8% compared with 85.3%). The FCM levels in IQ female breeders were lower during the first 5 d after parturition than those in CT female breeders. The FCM levels in postpartum females housed with 2 adult mice were significantly higher on days 1, 3, and 5 after giving birth than those of females housed alone. This suggests that the presence of cage mates may induce stress responses in postpartum females. Increasing the individual cage area did not reduce the FCM levels of female breeders when accompanied by cage mates after parturition. In addition, the incidence of dystocia and mortality was lower in IQ breeders than in CT breeders. In summary, this breeding trial suggests that compared with the continuous mating scheme, the intermittent mating scheme improves the welfare of postpartum females with normal breeding performance in the C57BL/6JNarl production colony.

Unravelling the mechanisms underlying the social interaction effects on the feed efficiency of rabbits

The feed consumption and feeding patterns of group-housed livestock and their productive outputs can be affected by interactions among group members, such as competition for feeder access and aggression. The impact of competition is especially significant when feed restriction is implemented during the fattening stage, a common practice in rabbit farms to reduce mortality from digestive disorders during this period. The overall aim was to quantify the importance of social interaction effects at the genetic and environmental level on feed efficiency, feeding behaviour and social ranking traits in rabbit populations having access to electronic feeders whilst they were housed in groups during fattening. This was done by quantifying novel feeding behaviour (FB) and social ranking (SR) traits and by estimating the genetic parameters and genetic correlations between all combinations of direct and social effects of these traits and residual feed intake (RFI), an indicator of feed efficiency. These effects were estimated in animals fed either ad libitum (AL) or on a time-based feed restriction (R) and were selected for feed efficiency on these feeding regimes for six generations. We found that there were substantial social genetic and social litter effects on RFI and FB traits, manifesting as antagonistic relationships between direct and social genetic effects. These effects were stronger amongst the R, as opposed to the AL animals. Despite these antagonistic relationships, the large social genetic effects resulted in substantial heritable variation available for selection of these traits, and therefore feeding behaviour could be changed by genetic selection, especially for R animals. The indicators of an animal’s SR were also heritable and subject to social genetic effects and therefore may respond to selection. However, the phenotypic population mean would not change, because such traits are context−specific. The animals that took most of the feeding resources and had priority access to the feeder had a higher RFI, that is, they were less efficient, but they made their cage mates more efficient. This is the first time that the genetic correlations between direct effects of RFI and direct effects of FB and SR traits, as well as between social effects of RFI and direct effects of FB traits and SR traits, have been quantified. Results could help to understand the mechanisms by which an animal exerts its influence on the feed efficiency of its cage mates under different feeding regimes and assist in the development of breeding strategies.

Female behavior drives the formation of distinct social structures in C57BL/6J versus wild-derived outbred mice in field enclosures

BackgroundSocial behavior and social organization have major influences on individual health and fitness. Yet, biomedical research focuses on studying a few genotypes under impoverished social conditions. Understanding how lab conditions have modified social organizations of model organisms, such as lab mice, relative to natural populations is a missing link between socioecology and biomedical science.ResultsUsing a common garden design, we describe the formation of social structure in the well-studied laboratory mouse strain, C57BL/6J, in replicated mixed-sex populations over 10-day trials compared to control trials with wild-derived outbred house mice in outdoor field enclosures. We focus on three key features of mouse social systems: (i) territory establishment in males, (ii) female social relationships, and (iii) the social networks formed by the populations. Male territorial behaviors were similar but muted in C57 compared to wild-derived mice. Female C57 sharply differed from wild-derived females, showing little social bias toward cage mates and exploring substantially more of the enclosures compared to all other groups. Female behavior consistently generated denser social networks in C57 than in wild-derived mice.ConclusionsC57 and wild-derived mice individually vary in their social and spatial behaviors which scale to shape overall social organization. The repeatable societies formed under field conditions highlights opportunities to experimentally study the interplay between society and individual biology using model organisms.

The impact of cage dividers on mouse aggression, dominance and hormone levels.

Home cage aggression in group-housed male mice is a major welfare concern and may compromise animal research. Conventional cages prevent flight or retreat from sight, increasing the risk that agonistic encounters will result in injury. Moreover, depending on social rank, mice vary in their phenotype, and these effects seem highly variable and dependent on the social context. Interventions that reduce aggression, therefore, may reduce not only injuries and stress, but also variability between cage mates. Here we housed male mice (Balb/c and SWISS, group sizes of three and five) with or without partial cage dividers for two months. Mice were inspected for wounding weekly and home cages were recorded during housing and after 6h isolation housing, to assess aggression and assign individual social ranks. Fecal boli and fur were collected to quantify steroid levels. We found no evidence that the provision of cage dividers improves the welfare of group housed male mice; The prevalence of injuries and steroid levels was similar between the two housing conditions and aggression was reduced only in Balb/c strain. However, mice housed with cage dividers developed less despotic hierarchies and had more stable social ranks. We also found a relationship between hormone levels and social rank depending on housing type. Therefore, addition of cage dividers may play a role in stabilizing social ranks and modulating the activation of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, thus reducing phenotypic variability between mice of different ranks.

Novel phenotypes of feeding and social behaviour and their relationship with individual rabbit growth and feed efficiency

Due to the lack of a recording system for individual consumption of group-housed rabbits, published studies about feeding behaviour are based on information recorded at the group- and not at the individual level and periods covering only a few days or, in some cases, only part of a day. Such information could be used to inform rabbit management systems but cannot be used for genetic selection. We aimed to generate and use information from a novel automated feeder for group-housed rabbits to identify new phenotypes for individual animals that could be incorporated into breeding programs to improve feed efficiency and social behaviour under different feeding regimens. At 39 d of age, rabbits from 15 batches were placed in cages and fed ad libitum to become used to the electronic feeder. From 42 to 58–59 d, one group of 1 086 rabbits was fed ad libitum (AL), while another group of 1 134 rabbits was fed on a restricted feeding schedule (R) by limiting the feeding time to the period between 1800 and 0600 h of the following day. We implemented a reliable multivariate method to remove anomalous feeding behaviour records. We then defined novel traits for feeding behaviour that apply to both types of feeding regimes, and for social behaviour that indicates an animal’s rank within the cage hierarchy. We based these traits on feeder records and a biologically sound definition of a meal. Finally, we estimated the phenotypic correlations of those traits with growth and feed efficiency traits. Our findings demonstrate that variables about resource distribution among cage mates and an animal's priority for feed access were found to be good indicators of an animal's dominant or subordinate status within the cage. Based on results obtained in R animals (results were similar in AL animals), the most efficient animals were those that ate less frequently (phenotypic correlation with feed conversion ratio, rho = 0.6), and consumed smaller amounts per meal (rho = 0.7), spent less time at the feeder (rho = 0.4), and appeared to be subordinate, as they did not have priority access to the feeder (rho = −0.3), and had the smallest share of resources (range of rho = 0.2–0.6). We conclude that quantifying feeding and social behaviour traits can enhance the understanding of the mechanisms through which individuals exert their effects on the performance of their cage mates.

Epizootic of enterocolitis and clostridial overgrowth in NSG and NSG-related mouse strains.

While the immunodeficient status of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) and NSG-related mice provides utility for numerous research models, it also results in increased susceptibility to opportunistic pathogens. Over a 9-week period, a high rate of mortality was reported in a housing room of NSG and NSG-related mice. Diagnostics were performed to determine the underlying etiopathogenesis. Mice submitted for evaluation included those found deceased (n = 2), cage mates of deceased mice with or without diarrhea (n = 17), and moribund mice (n = 8). Grossly, mice exhibited small intestinal and cecal dilation with abundant gas and/or digesta (n = 18), serosal hemorrhage and congestion (n = 6), or were grossly normal (n = 3). Histologically, there was erosive to ulcerative enterocolitis (n = 7) of the distal small and large intestine or widespread individual epithelial cell death with luminal sloughing (n = 13) and varying degrees of submucosal edema and mucosal hyperplasia. Cecal dysbiosis, a reduction in typical filamentous bacteria coupled with overgrowth of bacterial rods, was identified in 18 of 24 (75%) mice. Clostridium spp. and Paeniclostridium sordellii were identified in 13 of 23 (57%) and 7 of 23 (30%) mice, respectively. Clostridium perfringens (7 of 23, 30%) was isolated most frequently. Toxinotyping of C. perfringens positive mice (n = 2) identified C. perfringens type A. Luminal immunoreactivity to several clostridial species was identified within lesioned small intestine by immunohistochemistry. Clinicopathologic findings were thus associated with overgrowth of various clostridial species, though direct causality could not be ascribed. A diet shift preceding the mortality event may have contributed to loss of intestinal homeostasis.

The Goldilocks Principle: Balancing Familiarity and Novelty in the Selection of Play Partners in Groups of Juvenile Male Rats

Like many mammals, rats frequently engage in play fighting as juveniles, an activity that influences the development of socio-cognitive skills. Most studies that assess play are based on staged dyadic encounters, implying that some average quantity and quality of play are sufficient to produce these developmental effects. However, there are individual differences, with some rats not only preferring to play more, but also to have more physical contact than others. Given that rats have individual differences in play, it raises the possibility that rats might express these preferences when playing in groups. To determine whether rats form partner preferences, trials were conducted in which a focal rat was given the opportunity to play with three partners of varying familiarity. One partner was a cage mate, another was housed on the other side of a transparent and perforated divider and so familiar, but not a prior play partner, and the third was a stranger from another cage. A total of 36 focal rats, between 30-36 days of age, were tested and video recorded in 20-minute trials following 2.5 h of social isolation. Focal rats expressed a preference for neighbors over both strangers and cage mates, indicating that balancing between familiarity and novelty influences social play partner preferences. Mechanisms by which this preference might have been established, such as dominance relationships, weight differences, and congruency of play style, were investigated, but none were correlated with the preferences expressed. This group dynamics perspective provides a novel approach to studying play, and more generally, provides insights into social exploration and decision-making.

Wildtype peers rescue social play and 50-kHz ultrasonic vocalization deficits in juvenile female Cacna1c heterozygous rats.

Healthy brain development depends on early social practices and experiences. The risk gene CACNA1C is implicated in numerous neuropsychiatric disorders, in which key characteristics include deficits in social functioning and communication. Recently, we reported sex-dependent impairments in social behavior and ultrasonic vocalizations (USV) in juvenile heterozygous Cacna1c+/- (HET) rats. Specifically, HET females displayed increases in rough-and-tumble play that eliminated the typically observed sex difference between male and female rats. Interestingly, female wild-type Cacna1c+/+ (WT) pairs also showed a similar increase in social play when housed with HET females, suggesting their behavior may be influenced by HET cage mates. This indicates that the genetic makeup of the social environment related to Cacna1c can influence social play, yet systematic studies are lacking. In the present study, we housed juvenile females in MIXED- or SAME-genotype cages and tested them in a social play paradigm with a same- and opposite-genotype partner. The results show that the early social environment and the genotype of the play partner influence social play and 50-kHz USV emission. Experience with a WT play partner appears necessary for HET females to show comparable levels of play and 50-kHz USV emission. Same-genotype HET pairs played less and emitted fewer 50-kHz USV than same-genotype WT or opposite-genotype pairs; however, we found that the decrease in social play and 50-kHz USV in HET pairs can be rescued by playing with a WT partner. The effect was particularly prominent when the first play partner was WT, as we found it increased play and 50-kHz USV emission in all subsequent interactions with ensuing partners. These findings suggest that the genetic makeup related to the social environment and/or social peers influences social play in Cacna1c+/- haploinsufficient rats. Specifically, our results show that WT peers can rescue behavior and communication alterations in Cacna1c female rats. Our findings have important implications because they show that the genetic makeup of the social environment can divulge phenotypic changes in genetic rat models of neuropsychiatric disorders.

The Social Relationship of Mice: The Influence of Sex and Status of Mice to the Approach Behavior toward Their Cage Mate

Based on the statistics given by health report that interpersonal violence is among the leading causes of death for people aged 15-44 years worldwide. In order to explore the reasons of violent behavior occurrence, this article uses rodent as experiment subject and resident-intruder paradigm to conduct a 2x2 experiment. The experiment will measure whether sex or status will be significant on the effect of aggression occurrence and affiliative duration and number of cells count on their medial amygdala. The result of the experiment shows that male exhibit a higher level of aggression toward intruders compared to females. But for females, more afflilative behavior shown in the test toward their conspecifics. And male do have a larger cell counts in their medial amygdala, there is no evidence that these variables are caused driven by sex, status and sex: status interaction.

Deletion of Endogenous Neuregulin-4 Limits Adaptive Immunity During Interleukin-10 Receptor-Neutralizing Colitis.

Growth factors are essential for maintenance of intestinal health. We previously showed that exogenous neuregulin-4 (NRG4) promotes colonocyte survival during cytokine challenge and is protective against acute models of intestinal inflammation. However, the function(s) of endogenous NRG4 are not well understood. Using NRG4-/- mice, we tested the role of endogenous NRG4 in models of colitis skewed toward either adaptive (interleukin-10 receptor [IL-10R] neutralization) or innate (dextran sulfate sodium [DSS]) immune responses. NRG4-/- and wild-type cage mate mice were subjected to chronic IL-10R neutralization colitis and acute DSS colitis. Disease was assessed by histological examination, inflammatory cytokine levels, fecal lipocalin-2 levels, and single cell mass cytometry immune cell profiling. Homeostatic gene alterations were evaluated by RNA sequencing analysis from colonic homogenates, with real-time quantitative polymerase chain reaction confirmation in both tissue and isolated epithelium. During IL-10R neutralization colitis, NRG4-/- mice had reduced colonic inflammatory cytokine expression, histological damage, and colonic CD8+ T cell numbers vs wild-type cage mates. Conversely, in DSS colitis, NRG4-/- mice had elevated cytokine expression, fecal lipocalin-2 levels, and impaired weight recovery. RNA sequencing showed a loss of St3gal4, a sialyltransferase involved in immune cell trafficking, in NRG4-null colons, which was verified in both tissue and isolated epithelium. The regulation of St3gal4 by NRG4 was confirmed with ex vivo epithelial colon organoid cultures from NRG4-/- mice and by induction of St3gal4 in vivo following NRG4 treatment. NRG4 regulates colonic epithelial ST3GAL4 and thus may allow for robust recruitment of CD8+ T cells during adaptive immune responses in colitis. On the other hand, NRG4 loss exacerbates injury driven by innate immune responses.

Examination of Horizontal Transmission of Nippostrongylus brasiliensis in Mice to Assess Biosecurity Risks.

Mice are commonly infected with Nippostrongylus brasiliensis (Nb) to study their immune responses. However, biosecurity measures have not been established for housing Nb-infected mice and rats. Transmission reportedly does not occur when infected mice are cohoused with naive mice. To test this, we inoculated female NOD. Cg-Prkdcscid Il2rgtm1Wjl /Sz(NSG;n = 12) and C57BL/6J (B6;n = 12) mice with 750 Nb L₃ larvae. These mice were then cohoused with naïve NSG ( n = 24) and B6 ( n = 24) mice (1 infected and 2 naïve mice per cage (24 cages) for 28 d in static microisolation cages that were changed every 14 d. We also did several studies to determine the conditions that favor horizontal transmission. First, we assessed in vitro development to the L₃ stage of Nb egg-containing fecal pellets maintained under 4 environmental conditions (dry, moist, soiled bedding, and control). Second, we assessed infection of naïve NSG mice ( n = 9) housed in microisolation cages that contained soiled bedding spiked with infective L₃ larvae (10,000/cage). Third, we gavaged NSG mice ( n = 3) with Nb eggs to model the potential for infection after coprophagy. We found that naïve NSG (9 of 24) and B6 (10 of 24) mice cohoused with an infected cagemate passed Nb eggs in feces as early as 1 d after cohousing and intermittently thereafter for varying periods. This shedding was presumably the result of coprophagy because adult worms were not detected in the shedding mice at euthanasia. Although eggs developed in vitro into L₃ larvae under moist and control environmental conditions, none of the NSG mice housed in cages with L₃ -spiked bedding or gavaged with eggs became infected with Nb. These findings indicate that infectious horizontal transmission does not occur when mice are housed with Nb-shedding cage mates in static microisolation cages with a 14-d cage-changing interval. Results from this study can be used to inform biosecurity practices when working with Nb-infected mice.

Poststress social isolation exerts anxiolytic effects by activating the ventral dentate gyrus

After aversive stress, people either choose to return to their previously familiar social environment or tend to adopt temporary social withdrawal to buffer negative emotions. However, which behavior intervention is more appropriate and when remain elusive. Here, we unexpectedly found that stressed mice experiencing social isolation exhibited less anxiety than those experiencing social contact. Within the first 24 h after returning to their previous social environment, mice experienced acute restraint stress (ARS) displayed low social interest but simultaneously received excessive social disturbance from their cage mates, indicating a critical time window for social isolation to balance the conflict. To screen brain regions that were differentially activated between the poststress social isolation and poststress social contact groups, we performed ΔFosB immunostaining and found that ΔFosB + signals were remarkably increased in the vDG of poststress social isolation group compared with poststress social contact group. There were no significant differences between the two groups in the other anxiety- and social-related brain regions, such as prelimbic cortex, infralimbic cortex, nucleus accumbens, etc. These data indicate that vDG is closely related to the differential phenotypes between the poststress social isolation and poststress social contact groups. Electrophysiological recording, further, revealed a higher activity of vDG in the poststress social isolation group than the poststress social contact group. Chemogenetically inhibiting vDG excitatory neurons within the first 24 h after ARS completely abolished the anxiolytic effects of poststress social isolation, while stimulating vDG excitatory neurons remarkably reduced anxiety-like behaviors in the poststress social contact group. Together, these data suggest that the activity of vDG excitatory neurons is essential and sufficient to govern the anxiolytic effect of poststress social isolation. To the best of our knowledge, this is the first report to uncover a beneficial role of temporal social isolation in acute stress-induced anxiety. In addition to the critical 24-h time window, activation of vDG is crucial for ameliorating anxiety through poststress social isolation.

Infrared thermography for non-invasive measurement of social inequality aversion in rodents and potential usefulness for future animal-friendly studies.

Infrared thermography is a method that detects thermal radiation energy and can measure the body surface temperature of animals from a distance. While rectal temperature has traditionally been used to measure animals' core temperature, thermal imaging can avoid the stress and potential rise of body temperature deriving from handling of the animals. Additionally, being non-invasive and contactless, thermal imaging allows free movement of the animals. The validity of this technique as a psychophysiological method has been proven in a series of stress-induced hyperthermia (SIH) studies of mice under social inequality conditions. Restraint in a holder elicits SIH in mice. A restrained mouse surrounded by freely moving cage mates displays increased SIH suggesting that social inequality enhances the stress. Social inequality can be examined also in unrestrained mice, in particular through unequal distribution of food. In this protocol, a food-deprived mouse is given a small piece of cheese, while its cage mate is given a large piece of cheese. This inequity causes SIH, suggesting social inequality aversion in mice. Thus, social inequality in different situations similarly increased SIH. Importantly, in future studies infrared thermography could also be used to evaluate emotional arousal states different from stress (for example to assess reactivity to rewards or in social and sexual preference tests). Moreover, the technique could be used to investigate also cognitive arousal induced by novelty. Indeed, infrared thermography could be a particularly useful tool for animal-friendly studies of cognition and emotion in rodents.

Evaluation of Cage Mate-induced Postsurgical Trauma in Mice.

Although mice are social animals, individual housing is sometimes requested after surgery. We questioned whether pair-housing mice after surgery resulted in greater trauma to the surgical site as compared with single housing. We further evaluated the effect of individual housing after surgery on the wellbeing of mice that had previously been pair-housed. Female C57Bl/6 mice (age, 6 to 8 wk) were housed as follows: group A, individually housed before and after surgery (n = 10; all 10 mice underwent surgery); group B, pair-housed before surgery but individually housed after surgery (n = 10; all 10 mice received surgery); group C, pair-housed before and after surgery (n = 20; 10 mice underwent surgery but their cage mates did not); and group D, pair-housed before and after surgery (n = 10; all 10 mice underwent surgery). Dependent variables were body weight, body condition, grimace based on real-time scoring, nest building, time to incorporate into nest test (TINT) score, wound trauma score, and missing wound clips. Weight was significantly different between groups A and C both before and after surgery. Mean nest building scores were significantly higher for pair-housed (groups C and D) than for individually housed mice (groups A and B) after surgery while TINT scores were significantly higher for these same groups both before and after surgery. Mean values for body condition, grimace score, wound score, and number of wound clips missing did not differ significantly between any groups either before or after surgery. Taken together, these results suggest that pair housing mice after surgery benefited their wellbeing but did not increase trauma to the surgical incision site or disturb wound clips as compared with individually housed mice. Furthermore, separating previously pair-housed mice (group B) did not affect these measures as compared with individually housed mice (Group A) either before or after surgery.

Multi-Influenza HA Subtype Protection of Ferrets Vaccinated with an N1 COBRA-Based Neuraminidase.

The influenza neuraminidase (NA) is a promising target for next-generation vaccines. Protection induced by vaccination with the computationally optimized broadly reactive NA antigen (N1-I COBRA NA) was characterized in both influenza serologically naive and pre-immune ferret models following H1N1 (A/California/07/2009, CA/09) or H5N1 (A/Vietnam/1203/2004, Viet/04) influenza challenges. The N1-I COBRA NA vaccine elicited antibodies with neutralizing ELLA activity against both seasonal and pandemic H1N1 influenza, as well as the H5N1 influenza virus. In both models, N1-I COBRA NA-vaccinated ferrets that were challenged with CA/09 virus had similar morbidity (weight loss and clinical symptoms) as ferrets vaccinated with the CA/09 HA control vaccine. There were significantly reduced viral titers compared to the mock-vaccinated control animals. Ferrets vaccinated with N1-I COBRA NA or Viet/04 NA vaccines were protected against the H5N1 virus infection with minimal clinical symptoms and negligible weight loss. In contrast, ferrets vaccinated with the CA/09 NA vaccine lost ~10% of their original body weight with 25% mortality. Vaccination with either HA or NA vaccines did not inhibit contact transmission of CA/09 virus to naïve cage mates. Overall, the N1-I COBRA vaccine elicited protective immune responses against both H1N1 and H5N1 infections and partially mitigated disease in contact-transmission receiving ferrets. These results indicate that the N1-I COBRA NA performed similarly to the CA/09 HA and NA positive controls. Therefore, the N1-I COBRA NA alone induces protection against viruses from both H5N1 and H1N1 subtypes, indicating its value as a vaccine component in broadly protective influenza vaccines.

An open-source head-fixation and implant-protection system for mice

Mice are widely used in neuroscience experiments, which often require head-fixation and attachment of skull-mounted hardware. For many experiments, these components must remain intact over weeks to months, ideally with animals group housed. Many labs have designed ad-hoc head-fixation systems, which is an inefficient process. For example, when reinventing these solutions in our lab, we faced challenges with group housing, wherein mice would chew and damage implanted cannulas and electrodes of their cage mates. We performed several non-trivial design iterations to solve this problem, and present the most successful designs as an open-source collection. The designs include a standard mounting headbar compatible with most skull-mounted hardware, a snap-on protective mouse hat (headhat) to prevent mice from chewing the hardware, and a head-fixation station to facilitate common experimental procedures. We provide 3D-printing files, detail vendors and software used to make the components of the system, and provide editable design files for maximum flexibility to individual lab requirements.

Combined effect of traditional Chinese herbal-based formulations Jing Si herbal tea and Jing Si nasal drop inhibits adhesion and transmission of SARS-CoV2 in diabetic SKH-1 mice.

Multiple studies show increased severity of SARS-CoV2-infection in patients with comorbidities such as hypertension and diabetes. In this study, we have prepared two herbal-based formulations, a pleiotropic herbal drink (Jin Si Herbal Tea, JHT) and a nasal drop (Jin Si nasal drop, JND), to provide preventive care against SARS-CoV2 infection. The effect of JHT and JND was determined in SARS-CoV2-S-pseudotyped lentivirus-infected bronchial and colorectal cell lines and in SKH-1 mouse models. For preliminary studies, ACE2 receptor abundant bronchial (Calu-3) and colorectal cells (Caco-2) were used to determine the effect of JHT and JND on the host entry of various variants of SARS-CoV2-S-pseudotyped lentivirus. A series of experiments were performed to understand the infection rate in SKH-1 mice (6 weeks old, n = 9), find the effective dosage of JHT and JND, and determine the combination effect of JHT and JND on the entry and adhesion of various variant SARS-CoV2-S-pseudotyped lentiviruses, which included highly transmissible delta and gamma mutants. Furthermore, the effect of combined JHT and JND was determined on diabetes-induced SKH-1 mice against the comorbidity-associated intense viral entry and accumulation. In addition, the effect of combined JHT and JND administration on viral transmission from infected SKH-1 mice to uninfected cage mate mice was determined. The results showed that both JHT and JND were effective in alleviating the viral entry and accumulation in the thorax and the abdominal area. While JHT showed a dose-dependent decrease in the viral load, JND showed early inhibition of viral entry from day 1 of the infection. Combined administration of 48.66mg of JHT and 20µL of JND showed rapid reduction in the viral entry and reduced the viral load (97-99%) in the infected mice within 3 days of treatment. Moreover, 16.22mg of JHT and 20µL JND reduced the viral infection in STZ-induced diabetic SKH-1 mice. Interestingly, combined JHT and JND also inhibited viral transmission among cage mates. The results, therefore, showed that combined administration of JHT and JND is a novel and an efficient strategy to potentially prevent SARS-CoV2 infection.

Updated vaccine protects against SARS-CoV-2 variants including Omicron (B.1.1.529) and prevents transmission in hamsters

Current COVID-19 vaccines are based on prototypic spike sequences from ancestral 2019 SARS-CoV-2 strains. However, the ongoing pandemic is fueled by variants of concern (VOC) escaping vaccine-mediated protection. Here we demonstrate how immunization in hamsters using prototypic spike expressed from yellow fever 17D (YF17D) as vector blocks ancestral virus (B lineage) and VOC Alpha (B.1.1.7) yet fails to fully protect from Beta (B.1.351). However, the same YF17D vectored vaccine candidate with an evolved antigen induced considerably improved neutralizing antibody responses against VOCs Beta, Gamma (P.1) and the recently predominant Omicron (B.1.1.529), while maintaining immunogenicity against ancestral virus and VOC Delta (B.1.617.2). Thus vaccinated animals resisted challenge by all VOCs, including vigorous high titre exposure to the most difficult to cover Beta, Delta and Omicron variants, eliminating detectable virus and markedly improving lung pathology. Finally, vaccinated hamsters did not transmit Delta variant to non-vaccinated cage mates. Overall, our data illustrate how current first-generation COVID-19 vaccines may need to be updated to maintain efficacy against emerging VOCs and their spread at community level.

Crosstalk of Alzheimer's disease-phenotype, HPA axis, splenic oxidative stress and frailty in late-stages of dementia, with special concerns on the effects of social isolation: A translational neuroscience approach.

Coping with emotional stressors strongly impacts older people due to their age-related impaired neuroendocrine and immune systems. Elevated cortisol levels seem to be associated with an increased risk of cognitive decline and dementia. In Alzheimer’s disease (AD), alterations in the innate immune system result in crosstalk between immune mediators and neuronal and endocrine functions. Besides, neuropsychiatric symptoms such as depression, anxiety, or agitation are observed in most patients. Here, we studied the psychophysiological response to intrinsic (AD-phenotype) and extrinsic (anxiogenic tests) stress factors and their relation to liver, kidneys, heart, and spleen oxidative status in 18-months-old female gold-standard C57BL/6 mice and 3xTg-AD mice model for AD. The emotional, cognitive, and motor phenotypes were assessed under three different anxiogenic conditions. Survival, frailty index, and immunoendocrine status (corticosterone levels and oxidative stress of peripheral organs) were evaluated. Genotype differences in neuropsychiatric-like profiles and cognitive disfunction in 3xTg-AD females that survived beyond advanced stages of the disease persisted despite losing other behavioral and hypothalamic–pituitary–adrenal (HPA) physiological differences. A secondary analysis studied the impact of social isolation, naturally occurring in 3xTg-AD mice due to the death of cage mates. One month of isolation modified hyperactivity and neophobia patterns and disrupt the obsessive-compulsive disorder-like digging ethogram. Frailty index correlated with spleen organometrics in all groups, whereas two AD-specific salient functional correlations were identified: (1) Levels of corticosterone with worse performance in the T-maze, (2) and with a lower splenic GPx antioxidant enzymatic activity, which may suppose a potent risk of morbidity and mortality in AD.

Socially Transferred Stress Experience Modulates Social Affective Behaviors in Rats

Social communication of affective states between individuals, as well as actual experiences, influences their internal states and behaviors. Although prior stress experiences promote empathy-like behaviors, it remains unclear whether the social transmission of stress events modulates these behaviors. Here, we provide evidence that transferred stress experiences from cage mates modulate socioaffective approach-avoidance behaviors in rats. Male Wistar-Imamichi rats were assigned to one of five experimental groups (Control (n = 15); no shock with shocked cage mates (n = 15); low (0.1 mA, n = 15), middle (0.5 mA, n = 14), and high shock (1.0 mA, n = 14)). Except for the naïve and housed with stressed mate groups, rats received two foot-shocks (5 s for each). The next day, the subjects were allowed to explore two unfamiliar conspecifics; one was a naïve, while the other was a distressed conspecific that received two foot-shocks (1.0 mA, 5 s) immediately before the test. Rats that were housed with stressed mates, as well as those that experienced a higher intensity of foot-shocks, were more likely to approach, while naïve rats avoided, a distressed conspecific. These results suggest that socially transferred stress shifts socioaffective response styles from avoidance to approach toward a stressed conspecific in rats.