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.

Assessment of the mode of action underlying development of liver lesions in mice following oral exposure to HFPO-DA and relevance to humans.

HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate) is a short-chain polyfluorinated alkyl substance (PFAS) used in the manufacture of some types of fluorinated polymers. Like many PFAS, toxicity studies with HFPO-DA indicate the liver is the primary target of toxicity in rodents following oral exposure. Due to the structural diversity of PFAS, the mode of action (MOA) can differ between PFAS for the same target tissue. There is significant evidence for involvement of peroxisome proliferator-activated receptor alpha (PPARα) activation based on molecular and histopathological responses in the liver following HFPO-DA exposure, but other MOAs have also been hypothesized based on limited evidence. The MOA underlying the liver effects in mice exposed to HFPO-DA was assessed in the context of the Key Events (KEs) outlined in the MOA framework for PPARα activator-induced rodent hepatocarcinogenesis. The first 3 KEs (ie, PPARα activation, alteration of cell growth pathways, and perturbation of cell growth/survival) are supported by several lines of evidence from both in vitro and in vivo data available for HFPO-DA. In contrast, alternate MOAs, including cytotoxicity, PPARγ and mitochondrial dysfunction are generally not supported by the scientific literature. HFPO-DA-mediated liver effects in mice are not expected in humans as only KE 1, PPARα activation, is shared across species. PPARα-mediated gene expression in humans produces only a subset (ie, lipid modulating effects) of the responses observed in rodents. As such, the adverse effects observed in rodent livers should not be used as the basis of toxicity values for HFPO-DA for purposes of human health risk assessment.

Rodent Model Preclinical Assessment of PEGylated Block Copolymer Targeting Cognition and Oxidative Stress Insults of Alzheimer's Disease.

Misfolded peptide amyloid beta (Aß42), neurofibrillary tangles of hyper-phosphorylated tau, oxidative damage to the brain, and neuroinflammation are distinguished determinants of Alzheimer's disease (AD) responsible for disease progression. This multifaceted neurodegenerative disease is challenging to cure under a single treatment regime until the key disease determinants are traced for their sequential occurrence in disease progression. In an early report, a novel side-chain tripeptide containing PEGylated block copolymer has been tested thoroughly in vitro and in silico for the early inhibition of Aß42 aggregation as well as degradation of preformed Aß42 fibril deposits. The present study demonstrates a preclinical assessment of the PEGylated block copolymer in colchicine-induced AD-mimicking rodent model. The colchicine-induced Wistar rats receiving an intranasal delivery of the block copolymer at a daily dosage of 100 µg/kg and 200 µg/kg body weights, respectively, for 14 days manifested a notable attenuation of behavioral deficit pattern, oxidative stress, and neurotransmitters' deficiency as compared to the untreated ones. The current study also reports the ameliorative property of the PEGylated compound for progressive neuroinflammation and decreased mitochondrial bioenergetics in astrocytoma cell line, viz., U87. A closer look into the drug mechanism of action of a compact 3D PEGylated block copolymer confirmed its disintegrative interaction with Aß42 fibril via in silico simulation. The results obtained from this study signify the potential of the novel PEGylated block copolymer to ameliorate the cognitive decline and progressive oxidative insults in AD and may envision a successful clinical phase trial. The amelioration of disease condition of colchicine-induced AD rat. Initially the rat has given colchicine via stereotaxic surgery which led to a mimicking condition of AD including neuronal death in hippocampal CA1 region. After recovery from the surgery, the rat was treated with the PEGylated block copolymer through intranasal delivery, and this has led to the decrease in neuronal death in hippocampal CA1 region. The mechanism of drug action has shown by the separation of monomer chains of Aß42.

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions.

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy.

Multi-elemental exposure assessment through concentrations in hair of free-ranging capybaras (Hydrochoerus hydrochaeris Linnaeus, 1766) in the Atlantic Forest remnants, Northeast of Brazil.

This study aimed to determine the mineral profile of hair samples of free-ranging capybaras (Hydrochoerus hydrochaeris) in remnants of the Atlantic Forest located in the Northeast of Brazil, and to evaluate the effects of origin, gender and age of the animals on their mineral accumulation in hair. Twenty hair samples from animals of different areas, genders and ages were prepared using microwave-assisted digestion, employing 5 mL of HNO3 and 2.5 mL of H2SO4 for 100 mg of sample. Digestion efficiency was assessed by residual carbon content. The digested samples were analyzed by inductively coupled plasma optical emission spectrometry (ICP OES). Principal component analysis (PCA) was performed considering the composition data of 11 elements (Al, Ca, Cd, Co, Cr, Cu, Fe, K, Mn, Mo, and Na). The digestion method applied was efficient and the most abundant elements with their respective concentration ranges in mg kg-1 were Al (396-2746), Ca (36-3420), Fe (476-51180), K (115-4843), and Na (72-473). ANOVA and PCA differentiated among the capybaras regarding age (adults) and origin (A3), both associated with higher concentrations of Al, Cd, Fe, and K. Although a higher metal bioaccumulation was observed in adult animals, it is important to highlight that this result could have been affected by diet and physiological parameters. The results suggest that A3 was the most anthropized remnant area due to agricultural and urban influences. Multi-elemental determination in hair can be used as a non-invasive method to assess heavy metal contamination in capybaras.

PHA-induced inflammation is not energetically costly in the subterranean rodent Ctenomys talarum (tuco-tucos).

Immune activity has been proposed to be associated with substantial costs, due to trade-offs with other functions or activities that share common resources and contribute to an animal's fitness. However, direct estimates of the cost of mounting an immune response are few and have been performed mainly in birds. Thus, further work is needed to clarify the relative costs of different components of the immune system and the role of environmental and life-history traits in modulating the costs of resistance. Within the components of immunity, inflammation is considered to be associated with a larger energetic expenditure. Here, we evaluated the energetic cost of the inflammatory response to phytohemagglutinin (PHA) in a wild population of a subterranean rodent, Ctenomys talarum, and the trade-offs between immune activity and reproduction. C. talarum develops an inflammatory response to PHA, but contrary to our predictions, this response was not associated with an increase in oxygen consumption regardless of reproductive status or sex. Our study shows that an immune challenge may not always result in a detectable energetic cost. We discuss the possibility that other currencies could be underlying the cost, such as micro-or macronutrients requirements, autoimmunity or oxidative stress.

How does evolutionary variation in Basal metabolic rates arise? A statistical assessment and a mechanistic model.

Metabolic rates are related to the pace of life. Hence, research into their variability at global scales is of vital importance for several contemporary theories in physiology, ecology, and evolution. Here we evaluated the effect of latitude, climate, primary productivity, habitat aridity, and species trophic habits, on mass-independent basal metabolic rates (BMRs) for 195 rodent species. The aims of this article were twofold. First, we evaluated the predictive power of different statistical models (via a model selection approach), using a dimensional reduction technique on the exogenous factor matrix to achieve a clear interpretation of the selected models. Second, we evaluated three specific predictions derived from a recently proposed hypothesis, herein called the "obligatory heat" model (OHM), for the evolution of BMR. Obtained results indicate that mean/minimum environmental temperature, rainfall/primary productivity and, finally, species trophic habits are, in this order, the major determinants of mass-independent BMR. Concerning the mechanistic causes behind this variation, obtained data agree with the predictions of the OHM: (1) mean annual environmental temperature was the best single predictor of residual variation in BMR, (2) herbivorous species have greater mass-independent metabolic rates, and tend to be present at high-latitude cold environments, than species in other trophic categories.

Development of a versatile enzyme immunoassay for non-invasive assessment of glucocorticoid metabolites in a diversity of taxonomic species.

Endocrinology is a useful tool for conservation biologists and animal managers, and measuring glucocorticoids can help understand biological mechanisms associated with species decline and animal welfare. The current study describes the development and optimization of a glucocorticoid enzyme immunoassay (EIA) to non-invasively assess adrenal activity in a variety of taxa. The antiserum (CJM006) was raised in rabbits to a corticosterone-3-CMO-BSA immunogen and used in a standard competitive EIA system. However, the EIA initially produced results with unacceptably high inter-assay variation, attributed to consistent patterns observed within the optical density of developing plates. To determine the cause of this variability, a number of factors were examined using synthetic corticosterone standard and endogenous faecal extract, including: plate type (Nunc MaxiSorp® II versus Immulon IB plates); the use of non-specific secondary antibody; type (artificial versus natural) and presence (light versus dark) of light during incubation; plate loading temperature (4°C versus room temperature); and substrate reagent temperature (4°C versus room temperature). Results indicated that variability was associated with plate location effects, which were not initially detected because control samples were always run in the same positions across plates. Light and temperature were the two major factors that affected EIA reliability. For this assay, the standard protocol required slight modification, with the optimal protocol using Nunc MaxiSorp® plates, room temperature substrate reagents and dark incubation conditions. Following optimization, this EIA was then validated biochemically for 38 species, through parallel displacement curves and interference assessment tests of faecal and urine samples. Additionally, biological validation was performed opportunistically in a subset of species, with use of this EIA demonstrating significant elevations in faecal glucocorticoid metabolites following potentially challenging events. In summary, this glucocorticoid EIA cross-reacts with excreted glucocorticoid metabolites across a wide range of taxa, including ungulates, primates, felids, birds, rodents and amphibians. We conclude that when used with optimal reagent and incubation conditions, this EIA will be useful for non-invasive monitoring of adrenal activity in a wide range of wildlife species.

High rates of energy expenditure and water flux in free-ranging Point Reyes mountain beavers Aplodontia rufa phaea.

We measured water flux and energy expenditure in free-ranging Point Reyes mountain beavers Aplodontia rufa phaea by using the doubly labeled water method. Previous laboratory investigations have suggested weak urinary concentrating ability, high rates of water flux, and low basal metabolic rates in this species. However, free-ranging measurements from hygric mammals are rare, and it is not known how these features interact in the environment. Rates of water flux (210+/-32 mL d(-1)) and field metabolic rates (1,488+/-486 kJ d(-1)) were 159% and 265%, respectively, of values predicted by allometric equations for similar-sized herbivores. Mountain beavers can likely meet their water needs through metabolic water production and preformed water in food and thus remain in water balance without access to free water. Arginine-vasopressin levels were strongly correlated with rates of water flux and plasma urea : creatinine ratios, suggesting an important role for this hormone in regulating urinary water loss in mountain beavers. High field metabolic rates may result from cool burrow temperatures that are well below lower critical temperatures measured in previous laboratory studies and suggest that thermoregulation costs may strongly influence field energetics and water flux in semifossorial mammals.

Cardiac magnetic resonance imaging in small rodents using clinical 1.5 T and 3.0 T scanners.

Cardiac magnetic resonance (CMR) imaging can provide noninvasive, high resolution images of heart anatomy, viability, perfusion, and function. However, the adoption of clinical CMR imaging protocols for small rodents has been limited due to the small heart size and rapid heart rates. Therefore, most CMR studies in small rodents have been performed on non-clinical, high-field MR magnets. Because such high-field systems are not readily available at most institutions, the technical aspects that are needed to perform CMR on clinical 1.5 T and 3.0 T MR scanners are presented in this paper. Equipment requirements are presented, and a comprehensive description of the methods needed to complete a CMR exam including the animal preparation, imaging, and image analysis are discussed. In addition, the advanced applications of myocardial tagging and delayed-contrast-enhanced imaging are reviewed for the assessment of regional contractile function and myocardial viability, respectively.

Cost of living in free-ranging degus (Octodon degus): seasonal dynamics of energy expenditure.

Animals process and allocate energy at different seasons at variable rates, depending on their breeding season and changes in environmental conditions and resulting physiological demands. Overall total energy expenditure, in turn, should either increase in some seasons due to special added demands (e.g. reproduction) or it could simply remain at about the same level, in which case the animals must show compensatory rebalancing of other expenditures that can be reduced. To test for the alternative hypotheses of seasonal variability or compensation, we measured total daily energy expenditure (DEE) in free-living degus (Octodon degus) at four seasons and followed this with determinations of basal metabolic rate (BMR) in the laboratory in the same individuals. DEE varied seasonally but was only significantly different (lower) in summer (non-breeding season), with a DEE:BMR ratio of only 1.6, whereas autumn, winter and spring DEE values were statistically indistinguishable from one another and showed DEE:BMR ratios ranging from 1.9 to 2.2. Our values of DEE in the field fall within the broad range of allometric expectation for herbivorous mammals in general, but the ratios of DEE:BMR are lower than expected. This, together with the lack of strong major shifts in total levels of DEE, suggests that degus are showing compensatory shifts among various categories of energy expenditure that allow them to manage their overall energy balance by minimizing total expenditure.