Convergent generation of atypical prions in knockin mouse models of genetic prion disease.

Most cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action.

Effects of oxytocin receptor agonism on acquisition and expression of pair bonding in male prairie voles.

There is much interest in targeting the activity in the oxytocin system to regulate social bonding. However, studies with exogenous administration of oxytocin face the caveats of its low stability, poor brain permeability and insufficient receptor specificity. The use of a small-molecule oxytocin receptor-specific agonist could overcome these caveats. Prior to testing the potential effects of a brain-penetrant oxytocin receptor agonist in clinical settings, it is important to assess how such an agonist would affect social bonds in animal models. The facultatively monogamous prairie voles (Microtus ochrogaster), capable of forming long-term social attachments between adult individuals, are an ideal rodent model for such testing. Therefore, in a series of experiments we investigated the effects of the recently developed oxytocin receptor-specific agonist LIT-001 on the acquisition and expression of partner preference, a well-established model of pair bonding, in prairie voles. LIT-001 (10 mg/kg, intraperitoneal), as expected, facilitated the acquisition of partner preference when administered prior to a 4hr cohabitation. In contrast, while animals injected with vehicle after the 4hr cohabitation exhibited significant partner preference, animals that were injected with LIT-001 did not show such partner preference. This result suggests that OXTR activation during expression of pair bonding can inhibit partner preference. The difference in effects of LIT-001 on acquisition versus expression was not due to basal differences in partner preference between the experiments, as LIT-001 had no significant effects on expression of partner preference if administered following a shorter (2hr-long) cohabitation. Instead, this difference agrees with the hypothesis that the activation of oxytocin receptors acts as a signal of presence of a social partner. Our results indicate that the effects of pharmacological activation of oxytocin receptors crucially depend on the phase of social attachments.

Genome-wide relaxation of selection and the evolution of the island syndrome in Orkney voles.

Island populations often experience different ecological and demographic conditions than their counterparts on the continent, resulting in divergent evolutionary forces affecting their genomes. Random genetic drift and selection both may leave their imprints on island populations, although the relative impact depends strongly on the specific conditions. Here we address their contributions to the island syndrome in a rodent with an unusually clear history of isolation. Common voles (Microtus arvalis) were introduced by humans on the Orkney archipelago north of Scotland >5000 years ago and rapidly evolved to exceptionally large size. Our analyses show that the genomes of Orkney voles were dominated by genetic drift, with extremely low diversity, variable Tajima's D, and very high divergence from continental conspecifics. Increased d N/d S ratios over a wide range of genes in Orkney voles indicated genome-wide relaxation of purifying selection. We found evidence of hard sweeps on key genes of the lipid metabolism pathway only in continental voles. The marked increase of body size in Orkney-a typical phenomenon of the island syndrome-may thus be associated to the relaxation of positive selection on genes related to this pathway. On the other hand, a hard sweep on immune genes of Orkney voles likely reflects the divergent ecological conditions and possibly the history of human introduction. The long-term isolated Orkney voles show that adaptive changes may still impact the evolutionary trajectories of such populations despite the pervasive consequences of genetic drift at the genome level.

Epigenetic aging studies of pair bonding in prairie voles.

The quality of romantic relationships can predict health consequences related to aging. DNA methylation-based biomarkers of aging accurately estimate chronological age. We developed several highly accurate epigenetic aging clocks, based on highly conserved mammalian CpGs, for the socially monogamous prairie vole (Microtus ochrogaster). In addition, our dual-species human-vole clock accurately measured relative age and illustrates high species conservation of epigenetic aging effects. Next, we assessed how pair bonding impacts epigenetic aging. We did not find evidence that pair-bonded voles exhibit accelerated or decelerated epigenetic aging effects in blood, ear, liver, or brain tissue. Our epigenome wide association study identified CpGs in five genes strongly associated with pair bonding: Foxp4, Phf2, Mms22l, Foxb1, and Eif1ad. Overall, we present accurate DNA methylation-based estimators of age for a species of great interest to researchers studying monogamy in animals. We did not find any evidence that sex-naive animals age differently from pair-bonded animals.

Genetic admixture drives climate adaptation in the bank vole.

Genetic admixture introduces new variants at relatively high frequencies, potentially aiding rapid responses to environmental changes. Here, we evaluate its role in adaptive variation related to climatic conditions in bank voles (Clethrionomys glareolus) in Britain, using whole-genome data. Our results reveal loci showing excess ancestry from one of the two postglacial colonist populations inconsistent with overall admixture patterns. Notably, loci associated with climate adaptation exhibit disproportionate amounts of excess ancestry, highlighting the impact of admixture between colonist populations on local adaptation. The results suggest strong and localized selection on climate-adaptive loci, as indicated by steep clines and/or shifted cline centres, during population replacement. A subset, including a haemoglobin gene, is associated with oxidative stress responses, underscoring a role of oxidative stress in local adaptation. Our study highlights the important contribution of admixture during secondary contact between populations from distinct climatic refugia enriching adaptive diversity. Understanding these dynamics is crucial for predicting future adaptive capacity to anthropogenic climate change.

Identification of spontaneous age-related cataract in Microtus fortis. / ä¸œæ–¹ç”°é¼ è‡ªå‘æ€§å¹´é¾„ç›¸å ³æ€§ç™½å† éšœçš„é‰´å®š.

OBJECTIVES: Age-related cataract is the most common type of adult cataract and a leading cause of blindness. Currently, there are few reports on the establishment of animal models for age-related cataract. During the experimental breeding of Microtus fortis (M. fortis), we first observed that M. fortis aged 12 to 15 months could naturally develop cataracts. This study aims to explore the possibility of developing them as an animal model for age-related cataract via identifing and analyzing spontaneous cataract in M. fortis. METHODS: The 12-month-old healthy M. fortis were served as a control group and 12-month-old cataractous M. fortis were served as an experimental group. The lens transparency was observed using the slit-lamp biomicroscope. Hematoxylin and eosin staining was used to detect pathological changes in the lens. Biochemical detection methods were applied to detect blood routine, blood glucose levels, the serum activities of superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in both groups. Finally, real-time RT-PCR was used to detect the transcription levels of cataract-related genes in the lens of 2 groups. RESULTS: Compared with the control group, the lens of cataract M. fortis showed severely visible opacity, the structure of lens was destroyed seriously, and some pathological damage, such as swelling, degeneration/necrosis, calcification, hyperplasia, and fiber liquefaction were found in lens epithelial cells (LECs). The fibrous structure was disorganized and irregularly distributed with morgagnian globules (MGs) aggregated in the degenerated lens fibers. There was no statistically significant difference in blood glucose levels between the experimental and control groups (P>0.05). However, white blood cell (WBC) count (P<0.05), lymphocyte count (P<0.01), and lymphocyte ratio (P<0.05) were significantly decreased, while neutrophil percentage (P<0.05) and monocyte ratio (P<0.01) were significantly increased. The serum activities of SOD and GSH-Px (both P<0.05) were both reduced. The mRNAs of cataract-related genes, including CRYAA, CRYBA1, CRYBB3, Bsfp1, GJA3, CRYBA2, MIP, HspB1, DNase2B, and GJA8, were significantly downregultaed in the lenses of the experimental group (all P<0.05). CONCLUSIONS: There are significant differences in lens pathological changes, peroxidase levels, and cataract-related gene expression between cataract and healthy M. fortis. The developed cataract spontaneously in M. fortis is closely related to age, the cataract M. fortis might be an ideal animal model for the research of age-related cataract.

Molecular evolution of Hokkaido virus, a genotype of Orthohantavirus puumalaense, among Myodes rodents.

Viruses in the genus Orthohantavirus within the family Hantaviridae cause human hantavirus infections and represent a threat to public health. Hokkaido virus (HOKV), a genotype of Orthohantavirus puumalaense (Puumala virus; PUUV), was first identified in Tobetsu, Hokkaido, Japan. Although it is genetically related to the prototype of PUUV, the evolutionary pathway of HOKV is unclear. We conducted a field survey in a forest in Tobetsu in 2022 and captured 44 rodents. Complete coding genome sequences of HOKVs were obtained from five viral-RNA-positive rodents (four Myodes rufocanus bedfordiae and one Apodemus speciosus). Phylogenetic analysis revealed a close relationship between the phylogenies and geographical origins of M. rufocanus-related orthohantaviruses. Comparison of the phylogenetic trees of the S segments of orthohantaviruses and the cytochrome b genes of Myodes species suggested that Myodes-related orthohantaviruses evolved in Myodes rodent species as a result of genetic isolation and host switching.

Re-wiring of the bonded brain: Gene expression among pair bonded female prairie voles changes as they transition to motherhood.

Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade-off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu-opioids (oprm1a), and kappa-opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC-NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long-term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade-off associated with increased emotional investment in offspring, while also maintaining a pair bond.

Testicular histomorphometric patterns and spermatogenesis dynamics of Oecomys bicolor tomes, 1860 (Rodentia: Cricetidae).

Although the order Rodentia does not present a high risk of extinction compared to mammals as a whole, several families demonstrate high levels of threat and/or data deficiency, therefore highlighting the need for targeted research and the application of ecological and reproductive data to the development of conservation actions. The order Rodentia, the largest among mammals, includes 9 families, and the family Cricetidae is the most diverse of the Brazilian rodents. In Brazil, 12 of the 16 genera of Oecomys are found. Oecomys bicolor is known in Brazil as the 'arboreal rat' and is, found in dry, deciduous and tropical forests. The mean body weight of Oecomys bicolor was 35.8 g and the gonadal, tubular and epithelial somatic indexes were, 0.53%, 0.47% and 0.37%, respectively. Seminiferous tubules volume density was 89.72% and the mitotic and meiotic indexes corresponded to 8.59 and 2.45 cells, respectively, and the yield of spermatogenesis was 23.83 cells. The intertubular compartment represented 10.28% of the testis parenchyma and around 5% of the interstitial space was occupied by Leydig cells, whose number per gram of testis was 11.10 × 107 cells. By evaluating the biometric and histomorphometric characteristics of the testis, there is evidence that this species has a high investment in reproduction. Due to the high contribution of the seminiferous epithelium and the intertubular compartment in this species, compared to the others of the same family, it is possible to infer that the species Oecomys bicolor has a promiscuous reproductive behaviour.

Adaptive responses to habitat change: Theory and tests with field experiments.

Habitat loss and change are often implicated as the primary causes of species extinction. Although any population can be instantly imperiled by catastrophe, most habitat loss occurs gradually, thus enabling affected individuals an adaptive advantage to occupy the best of their dwindling opportunities. I demonstrate how to infer the advantage between two habitats for any density and frequency-dependent strategy of habitat selection. I explore the concept of an Adaptive Dispersal Strategy Landscape to reveal the Evolutionarily Stable Strategy separately for ideal-free and ideal preemptive habitat selectors. Both solutions reveal an initially counterintuitive expectation that individuals living at high density gain insufficient adaptive advantage to disperse from a deteriorating habitat. Adaptive dispersal is constrained at high density because habitats of better quality are fully occupied. I test the theory with measures of movement and foraging in crossover experiments on a seminatural population of meadow voles. The experiment allowed the voles to choose among patches and between enclosures in which I differentially manipulated food and shelter. Although photographs from an infrared camera documented voles venturing from one habitat to the other, none became resident. Voles preferentially foraged in the richer of the two enclosures, even when I reversed treatments, and they foraged more in patches protected by mulched straw. The adaptive advantage of dispersal using a surrogate fitness proxy based on the voles' giving-up densities mirrored that generated by theory. The convergence between theory and experiment yields much-needed insight into our ability to test, predict, and hopefully resolve, the ecological, evolutionary, and conservation consequences of habitat loss.

T(r)icky Environments: Higher Prevalence of Tick-Borne Zoonotic Pathogens in Rodents from Natural Areas Compared with Urban Areas.

Background: Urban areas are unique ecosystems with stark differences in species abundance and composition compared with natural ecosystems. These differences can affect pathogen transmission dynamics, thereby altering zoonotic pathogen prevalence and diversity. In this study, we screened small mammals from natural and urban areas in the Netherlands for up to 19 zoonotic pathogens, including viruses, bacteria, and protozoan parasites. Materials and Methods: In total, 578 small mammals were captured, including wood mice (Apodemus sylvaticus), bank voles (Myodes glareolus), yellow-necked mice (Apodemus flavicollis), house mice (Mus musculus), common voles (Microtus arvalis), and greater white-toothed shrews (Crocidura russula). We detected a wide variety of zoonotic pathogens in small mammals from both urban and natural areas. For a subset of these pathogens, in wood mice and bank voles, we then tested whether pathogen prevalence and diversity were associated with habitat type (i.e., natural versus urban), degree of greenness, and various host characteristics. Results: The prevalence of tick-borne zoonotic pathogens (Borrelia spp. and Neoehrlichia mikurensis) was significantly higher in wood mice from natural areas. In contrast, the prevalence of Bartonella spp. was higher in wood mice from urban areas, but this difference was not statistically significant. Pathogen diversity was higher in bank voles from natural habitats and increased with body weight for both rodent species, although this relationship depended on sex for bank voles. In addition, we detected methicillin-resistant Staphylococcus aureus, extended-spectrum beta-lactamase/AmpC-producing Escherichia coli, and lymphocytic choriomeningitis virus for the first time in rodents in the Netherlands. Discussion: The differences between natural and urban areas are likely related to differences in the abundance and diversity of arthropod vectors and vertebrate community composition. With increasing environmental encroachment and changes in urban land use (e.g., urban greening), it is important to better understand transmission dynamics of zoonotic pathogens in urban environments to reduce potential disease risks for public health.

Body temperature and locomotor activity of social subterranean mole voles (Ellobius talpinus) in winter.

To find out whether a social subterranean rodent-the northern mole vole (Ellobius talpinus)-hibernates in winter, nine individuals from Southern Siberia were captured in late autumn and implanted with loggers [that constantly recorded body temperature (Tb) and locomotor activity] and then released. Eight of them were recaptured the following spring. From October to April, the animals' Tb never dropped below 33 °C, although cosinor analysis revealed a decrease in mesor values and in the amplitude of daily fluctuations of Tb and activity in winter months. Spectral density of circadian rhythms of both indexes also diminished in winter. The magnitude of Tb and fluctuations of activity differed between the two studied familial groups, probably due to their unequal numbers of individuals, which could affect the total heat production. The levels and patterns of temperature and activity fluctuations observed in winter rule out the possibility of hibernation in this species.

Steppe lemmings and Chinese hamsters as new potential animal models for the study of the Leishmania subgenus Mundinia (Kinetoplastida: Trypanosomatidae).

Leishmania, the dixenous trypanosomatid parasites, are the causative agents of leishmaniasis currently divided into four subgenera: Leishmania, Viannia, Sauroleishmania, and the recently described Mundinia, consisting of six species distributed sporadically all over the world infecting humans and/or animals. These parasites infect various mammalian species and also cause serious human diseases, but their reservoirs are unknown. Thus, adequate laboratory models are needed to enable proper research of Mundinia parasites. In this complex study, we compared experimental infections of five Mundinia species (L. enriettii, L. macropodum, L. chancei, L. orientalis, and four strains of L. martiniquensis) in three rodent species: BALB/c mouse, Chinese hamster (Cricetulus griseus) and steppe lemming (Lagurus lagurus). Culture-derived parasites were inoculated intradermally into the ear pinnae and progress of infection was monitored for 20 weeks, when the tissues and organs of animals were screened for the presence and quantity of Leishmania. Xenodiagnoses with Phlebotomus duboscqi were performed at weeks 5, 10, 15 and 20 post-infection to test the infectiousness of the animals throughout the experiment. BALB/c mice showed no signs of infection and were not infectious to sand flies, while Chinese hamsters and steppe lemmings proved susceptible to all five species of Mundinia tested, showing a wide spectrum of disease signs ranging from asymptomatic to visceral. Mundinia induced significantly higher infection rates in steppe lemmings compared to Chinese hamsters, and consequently steppe lemmings were more infectious to sand flies: In all groups tested, they were infectious from the 5th to the 20th week post infection. In conclusion, we identified two rodent species, Chinese hamster (Cricetulus griseus) and steppe lemming (Lagurus lagurus), as candidates for laboratory models for Mundinia allowing detailed studies of these enigmatic parasites. Furthermore, the long-term survival of all Mundinia species in steppe lemmings and their infectiousness to vectors support the hypothesis that some rodents have the potential to serve as reservoir hosts for Mundinia.

Habitat type modulates sharp body mass oscillations in cyclic common vole populations.

Cyclic rodent populations exhibit pronounced changes in body mass associated with the population cycle phase, long-known as Chitty effect. Although Chitty effect is a common epiphenomenon in both America and Europe, there is still incomplete evidence about the generality of these patterns across the entire range of most species. Moreover, despite decades of research, the underlying factors driving Chitty effect remains poorly understood. Here, we examined the influence of intrinsic and extrinsic factors that may underlie observed patterns in vole size variation in the Iberian common vole Microtus arvalis asturianus. We weighed and measured 2816 adult voles that were captured during 6 trapping periods. Vole numbers and body mass showed strong period- and phase-related variation both in females and males, demonstrating marked Chitty effect in the studied population. Body mass of adult males correlated with body length, evidencing that heavier males are also structurally larger. Statistical models showed that probability of occurrence of large-sized vole (> 37 g) was significantly more likely in reproductive males, during increase and peak phases, and it was modulated by habitat, with crop fields and field margins between crops showing an increased likelihood. We suggest an effect of the habitat on vole body mass mediated by predation.

Changes in the structural and functional state of the thyroid gland of small mammals when exposed to low-intensity chronic radiation.

The study gives a morphofunctional assessment of the state of the thyroid gland of tundra voles (Microtus oeconomus Pall.) in conditions of an increased radiation background (the Ukhta district of the Komi Republic (Russia) and the 30-km zone of the Chernobyl NPP), as well as in an experiment with chronic external gamma irradiation in the low dose range. The work summarizes the experience of more than 35 years of field and laboratory research. The authors have noted the high sensitivity of the thyroid gland to chronic radiation against the general irradiation of the organism both in natural conditions and in the experiment. The repeatability of the observed effects in voles from natural populations and the comparability of some effects with the morphological changes occurring in animals after exposure to ionizing radiation in the experiment indicates the radiation nature of these effects. The tundra voles living in conditions of increased radiation background have been identified for a greater variety of morphological rearrangements in the thyroid parenchyma than the experimental animals. The complex and ambiguous nature of the thyroid gland responses to radiation exposure indicates the possibility of a significant increase in the risk of negative effects of ionizing radiation in contrast with the expected results of biological effects' extrapolation from high to low doses.

Experimental manipulation of food availability and macroparasite prevalence reveal differential effects on space use in wild rodents.

Research Highlight: Mistrick, J., Veitch, J. S. M., Kitchen, S. M., Clague, S., Newman, B. C., Hall, R. J., Budischak, S. A., Forbes, K. M., & Craft, M. E. (2024). Effects of food supplementation and helminth removal on space use and spatial overlap in wild rodent populations. Journal of Animal Ecology. http://doi.org/10.1111/1365-2656.14067. The spread of pathogens has been of long-standing interest, even before dramatic outbreaks of avian influenza and the coronavirus pandemic spiked broad public interest. However, the dynamics of pathogen spread in wild populations are complex, with multiple effects shaping where animals go (their space use), population density and, more fundamentally, the resultant patterns of contacts (direct or indirect) among individuals. Thus, experimental studies exploring the dynamics of contact under different sets of conditions are needed. In the current field study, Mistrick et al. (2024) used a multifactorial experimental design, manipulating food availability and individual pathogen infection state in wild bank voles (Clethrionomys glareolus). They found that while food availability, individual traits and seasonality can affect how far individual voles moved, the degree of overlap between individual voles remained largely the same despite a high variation in population density-which itself was affected by food availability. These results highlight how biotic and abiotic factors can shape patterns of space use and balance the level of spatial overlap through multiple pathways.

The function of brown adipose tissue at different sites of the body in Brandt's voles during cold acclimation.

Ambient temperatures have great impacts on thermoregulation of small mammals. Brown adipose tissue (BAT), an obligative thermogenic tissue for small mammals, is localized not only in the interscapular depot (iBAT), but also in supraclavicular, infra/subscapular, cervical, paravertebral, and periaortic depots. The iBAT is known for its cold-induced thermogenesis, however, less has been paid attention to the function of BAT at other sites. Here, we investigated the function of BAT at different sites of the body during cold acclimation in a small rodent species. As expected, Brandt's voles (Lasiopodomys brandtii) consumed more food and reduced the body mass gain when they were exposed to cold. The voles increased resting metabolic rate and maintained a relatively lower body temperature in the cold (36.5 ± 0.27 °C) compared to those in the warm condition (37.1 ± 0.36 °C). During cold acclimation, the uncoupling protein 1 (UCP1) increased in aBAT (axillary), cBAT (anterior cervical), iBAT (interscapular), nBAT (supraclavicular), and sBAT (suprascapular). The levels of proliferating cell nuclear antigen (PCNA), a marker for cell proliferation, were higher in cBAT and iBAT in the cold than in the warm group. The pAMPK/AMPK and pCREB/CREB were increased in cBAT and iBAT during cold acclimation, respectively. These data indicate that these different sites of BAT play the cold-induced thermogenic function for small mammals.

Characterization of oxytocin and vasopressin receptors in the Southern giant pouched rat and comparison to other rodents.

Vasopressin and oxytocin are well known and evolutionarily ancient modulators of social behavior. The distribution and relative densities of vasopressin and oxytocin receptors are known to modulate the sensitivity to these signaling molecules. Comparative work is needed to determine which neural networks have been conserved and modified over evolutionary time, and which social behaviors are commonly modulated by nonapeptide signaling. To this end, we used receptor autoradiography to determine the distribution of vasopressin 1a and oxytocin receptors in the Southern giant pouched rat (Cricetomys ansorgei) brain, and to assess the relative densities of these receptors in specific brain regions. We then compared the relative receptor pattern to 23 other species of rodents using a multivariate ANOVA. Pouched rat receptor patterns were strikingly similar to hamsters and voles overall, despite the variation in social organization among species. Uniquely, the pouched rat had dense vasopressin 1a receptor binding in the caudate-putamen (i.e., striatum), an area that might impact affiliative behavior in this species. In contrast, the pouched rat had relatively little oxytocin receptor binding in much of the anterior forebrain. Notably, however, oxytocin receptor binding demonstrated extremely dense binding in the bed nucleus of the stria terminalis, which is associated with the modulation of several social behaviors and a central hub of the social decision-making network. Examination of the nonapeptide system has the potential to reveal insights into species-specific behaviors and general themes in the modulation of social behavior.

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease.

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.