Tolerability and age-dependent toxicokinetics following perinatal hydroxyurea treatment in Sprague Dawley rats.

Hydroxyurea (HU) is a valuable therapy for individuals with sickle cell anemia. With increased use of HU in children and throughout their lives, it is important to understand the potential effects of HU therapy on their development and fertility. Thus, studies were conducted to identify appropriate doses to examine long-term effects of prenatal and early postnatal HU exposure and to understand kinetics of HU at various life stages. Pregnant Sprague Dawley dams were administered HU (0-150 mg/kg/day) via oral gavage from gestation days 17 to 21 and during lactation. Pups were dosed with the same dose as their respective dam starting on postnatal day (PND) 10 and up to PND 34. There was minimal maternal toxicity, and no significant effects on littering at any dose of HU. Starting on ~PND 16, offspring displayed skin discoloration and alopecia at doses ≥75 mg/kg/day and lower body weight compared to controls at doses ≥100 mg/kg/day. Gestational transfer of HU was observed, but there was minimal evidence of lactational transfer. Our toxicokinetic studies suggest that the internal dose in offspring may be altered due to age, but not due to sex. The plasma area under the curve, a measure of systemic exposure, at doses tolerated by offspring was threefold to sevenfold lower than the internal therapeutic dose in humans. Therefore, strategies to establish clinically relevant exposures in animal studies are needed. Overall, these data are useful for the design of appropriate nonclinical studies in the future to evaluate the consequences of long-term HU treatment starting in childhood.

Invasive mammalian predators habituate to and generalize avian prey cues: a mechanism for conserving native prey.

Invasive mammalian predators can cause the decline and extinction of vulnerable native species. Many invasive mammalian predators are dietary generalists that hunt a variety of prey. These predators often rely upon olfaction when foraging, particularly at night. Little is understood about how prey odor cues are used to inform foraging decisions. Prey cues can vary spatially and temporally in their association with prey and can either reveal the location of prey or lead to unsuccessful foraging. Here we examine how two wild-caught invasive mammalian bird predator species (European hedgehogs Erinaceus europaeus and ferrets Mustela putorius furo) respond to unrewarded bird odors over successive exposures, first demonstrating that the odors are perceptually different using house mice (Mus musculus) as a biological olfactometer. We aim to test if introduced predators categorize odor cues of similar prey together, a tactic that could increase foraging efficiency. We exposed house mice to the odors using a standard habituation/dishabituation test in a laboratory setting, and wild-caught European hedgehogs and ferrets in an outdoor enclosure using a similar procedure. Mice discriminated among all bird odors presented, showing more interest in chicken odor than quail or gull odor. Both predator species showed a decline in interest toward unrewarded prey odor (i.e., habituation), but only ferrets generalized their response from one unrewarded bird odor to another bird odor. Hedgehog responses to unrewarded bird odors were highly variable between individuals. Taken together, our results reveal interspecific and intraspecific differences in response to prey odors, which we argue are a consequence of different diet breadth, life and evolutionary histories, and the conditions in each experiment. Generalization of prey odors may have enabled some species of invasive predators to efficiently hunt a range of intraguild prey species, for example, ground-nesting shorebirds. Olfactory manipulation of predators may be a useful conservation tool for threatened prey if it reduces the conspicuousness of vulnerable prey.

Modeling habituation of introduced predators to unrewarding bird odors for conservation of ground-nesting shorebirds.

Foraging mammalian predators face a myriad of odors from potential prey. To be efficient, they must focus on rewarding odors while ignoring consistently unrewarding ones. This may be exploited as a nonlethal conservation tool if predators can be deceived into ignoring odors of vulnerable secondary prey. To explore critical design components and assess the potential gains to prey survival of this technique, we created an individual-based model that simulated the hunting behavior of three introduced mammalian predators on one of their secondary prey (a migratory shorebird) in the South Island of New Zealand. Within this model, we heuristically assessed the outcome of habituating the predators to human-deployed unrewarding bird odors before the bird's arrival at their breeding grounds, i.e., the predators were "primed." Using known home range sizes and probabilities of predators interacting with food lures, our model suggests that wide-ranging predators should encounter a relatively large number of odor points (between 10 and 115) during 27 d of priming when odor is deployed within high-resolution grids (100-150 m). Using this information, we then modeled the effect of different habituation curves (exponential and sigmoidal) on the probability of predators depredating shorebird nests. Our results show that important gains in nest survival can be achieved regardless of the shape of the habituation curve, but particularly if predators are fast olfactory learners (exponential curve), and even if some level of dishabituation occurs after prey become available. Predictions from our model can inform the amount and pattern in which olfactory stimuli need to be deployed in the field to optimize encounters by predators, and the relative gains that can be expected from reduced predation pressure on secondary prey under different scenarios of predator learning. Habituating predators to odors of threatened secondary prey may have particular efficacy as a conservation tool in areas where lethal predator control is not possible or ethical, or where even low predator densities can be detrimental to prey survival. Our approach is also relevant for determining interaction probabilities for devices other than odor points, such as bait stations and camera traps.

Food quality and conspicuousness shape improvements in olfactory discrimination by mice.

How animals locate nutritious but camouflaged prey items with increasing accuracy is not well understood. Olfactory foraging is common in vertebrates and the nutritional desirability of food should influence the salience of odour cues. We used signal detection analysis to test the effect of nutritional value relative to the conspicuousness of food patches on rates of foraging improvement of wild house mice Mus musculus searching for buried food (preferred peanuts or non-preferred barley). Olfactory cues were arranged to make food patches conspicuous or difficult to distinguish using a novel form of olfactory camouflage. Regardless of food type or abundance, mice searching for conspicuous food patches performed significantly better than mice searching for camouflaged patches. However, food type influenced how mice responded to different levels of conspicuousness. Mice searching for peanuts improved by similar rates regardless of whether food was easy or hard to find, but mice searching for barley showed significant differences, improving rapidly when food was conspicuous but declining in accuracy when food was camouflaged. Our results demonstrate a fundamental tenet of olfactory foraging that nutritional desirability influences rates of improvement in odour discrimination, enabling nutritious but camouflaged prey to be located with increasing efficiency.

Leaf odour cues enable non-random foraging by mammalian herbivores.

Searching for food is the first critical stage of foraging, and search efficiency is enhanced when foragers use cues from foods they seek. Yet we know little about food cues used by one major group of mammals, the herbivores, a highly interactive component of most ecosystems. How herbivores forage and what disrupts this process, both have significant ecological and evolutionary consequences beyond the animals themselves. Our aim was to investigate how free-ranging mammalian herbivores exploit leaf odour cues to find food plants amongst a natural and complex vegetation community. Our study system comprised the native "deer equivalent" of eastern Australian forests, the swamp wallaby Wallabia bicolor, and seedlings of Eucalyptus, the foundation tree genus in these ecosystems. We quantified how foraging wallabies responded to odour cues from plants manipulated in several ways: varying the quantity of visually concealed leaves, comparing damaged vs. undamaged leaves, and whole plants vs. those with suppressed cues. The rate of discovery of leaves by wallabies increased with odour cue magnitude, yet animals were extremely sensitive to even a tiny odour source of just a few leaves. Whole seedlings were discovered faster if their leaves were damaged. Wallabies found whole seedlings and those with suppressed visual cues equally rapidly, day and night. Seedlings with very little odour were discovered mainly by day, as nocturnal foraging success was severely disrupted. This study shows how leaf odour attracts mammalian herbivores to food plants, enabling non-random search for even tiny odour sources. As damaged leaves enhanced discovery, we suggest that the benefit of attracting natural enemies to invertebrate herbivores feeding on plants (potential "cry for help") may be offset by a cost-increased browsing by mammalian herbivores. This cost should be incorporated into multi-trophic plant-animal studies. Finally, the breakdown in capacity to find plants at night suggests substantial but unrecognized foraging costs to herbivores when abiotic factors, such as cold temperatures or pollution, reduce or degrade plant odour cues. We predict that an increasingly polluted world will alter the foraging success of mammalian herbivores, with significant ecological ramifications given that browsing can shape ecosystems.

Increased olfactory search costs change foraging behaviour in an alien mustelid: a precursor to prey switching?

If generalist predators are to hunt efficiently, they must track the changing costs and benefits of multiple prey types. Decisions to switch from hunting preferred prey to alternate prey have been assumed to be driven by decreasing availability of preferred prey, with less regard for accessibility of alternate prey. Olfactory cues from prey provide information about prey availability and its location, and are exploited by many predators to reduce search costs. We show that stoats Mustela erminea, an alien olfactory predator in New Zealand, are sensitive to the search costs of hunting both their preferred rodent prey (mice) and a less desirable alternate prey (locust). We manipulated search costs for stoats using a novel form of olfactory camouflage of both prey, and found that stoats altered their foraging strategy depending on whether mice were camouflaged or conspicuous, but only when locusts were also camouflaged. Stoats gave up foraging four times more often when both prey were camouflaged, compared to when mice were conspicuous and locusts camouflaged. There were no differences in the foraging strategies used to hunt camouflaged or conspicuous mice when locusts were easy to find. Consequently, camouflaged mice survived longer than conspicuous mice when locusts were hard to find, but not when locusts were easy to find. Our results demonstrate that predators can integrate search costs from multiple prey types when making foraging decisions. Manipulating olfactory search costs to alter foraging strategies offers new methods for understanding the factors that foreshadow prey switching.

Exploiting olfactory learning in alien rats to protect birds' eggs.

Predators must ignore unhelpful background "noise" within information-rich environments and focus on useful cues of prey activity to forage efficiently. Learning to disregard unrewarding cues should happen quickly, weakening future interest in the cue. Prey odor, which is rapidly investigated by predators, may be particularly appropriate for testing whether consistently unrewarded cues are ignored, and whether such behavior can be exploited to benefit prey. Using wild free-ranging populations of black rats, Rattus rattus, an alien predator of global concern, we tested whether the application of bird-nesting odors before the introduction of artificial nests (odor preexposure), enhanced the survival of birds eggs (prey) compared with areas where prey and nesting odors were introduced concurrently. In areas where predators had encountered prey odor before prey being available, the subsequently introduced eggs showed 62% greater survival than in areas where prey and odor were introduced together. We suggest that black rats preexposed to prey odor learned to ignore the unrewarding cue, leading to a significant improvement in prey survival that held for the 7-d monitoring period. Exploiting rapid learning that underpins foraging decisions by manipulating sensory contexts offers a nonlethal, but effective approach to reducing undesirable predatory impacts. Techniques based on olfactory preexposure may provide prey with protection during critical periods of vulnerability, such as immediately following a prey reintroduction. These results also highlight the potential benefits to species conservation to be gained from a greater understanding of the cognitive mechanisms driving alien predator behavior within ecological contexts.

Olfactory misinformation provides refuge to palatable plants from mammalian browsing.

Mammalian herbivores browse palatable plants of ecological and economical value. Undesirable neighbours can reduce browsing to these plants by providing 'associational refuge', but they can also compete for resources. Here we recreated the informative odour emitted by undesirable plants. We then tested whether this odour could act as virtual neighbours, providing browsing refuge to palatable eucalyptus tree seedlings. We found that protection using this method was equivalent to protection provided by real plants. Palatable seedlings were 17-20 times more likely to be eaten by herbivores without virtual, or real, neighbours. Because many herbivores use plant odour to forage, virtual neighbours could provide a useful practical management approach to help protect valued plants.

Leveraging AI to improve evidence synthesis in conservation.

Systematic evidence syntheses (systematic reviews and maps) summarize knowledge and are used to support decisions and policies in a variety of applied fields, from medicine and public health to biodiversity conservation. However, conducting these exercises in conservation is often expensive and slow, which can impede their use and hamper progress in addressing the current biodiversity crisis. With the explosive growth of large language models (LLMs) and other forms of artificial intelligence (AI), we discuss here the promise and perils associated with their use. We conclude that, when judiciously used, AI has the potential to speed up and hopefully improve the process of evidence synthesis, which can be particularly useful for underfunded applied fields, such as conservation science.

The ethics of intervening in animal behaviour for conservation.

Conservation behaviour is a growing field that applies insights from the study of animal behaviour to address challenges in wildlife conservation and management. Conservation behaviour interventions often aim to manage specific behaviours of a species to solve conservation challenges. The field is often viewed as offering approaches that are less intrusive or harmful to animals than, for example, managing the impact of a problematic species by reducing its population size (frequently through lethal control). However, intervening in animal behaviour, even for conservation purposes, may still raise important ethical considerations. We discuss these issues and develop a framework and a decision support tool, to aid managers and researchers in evaluating the ethical considerations of conservation behaviour interventions against other options.

A mechanistic understanding of prebaiting to improve interaction with wildlife management devices.

BACKGROUND: Prebaiting is a technique involving early deployment of 'unarmed' devices (e.g. baits and traps) to increase efficacy of wildlife management. Although commonly used, the mechanisms by which prebaiting works are poorly understood. We propose three mechanisms by which prebaiting may increase device interaction probabilities; (1) overcoming neophobia towards novel devices, (2) a 'trickle in' effect increasing time for animals to encounter devices; and (3) social information transfer about rewards associated with devices. We conducted a survey of 100 articles to understand how prebaiting has been used. We then tested our proposed prebaiting mechanisms using a global pest (black rats, Rattus rattus) examining how uniquely marked free-living rats responded to a common yet novel monitoring technique (tracking tunnels). RESULTS: No studies in our dataset tested how prebaiting functioned. Most studies (61%) did not propose a mechanism for prebaiting, but overcoming neophobia was most commonly mentioned. We only found partial support for the overcoming neophobia hypothesis in our field test. We found the dominant mechanism operating in our system to be the 'trickle in' effect with the proportion of individuals visiting the device increasing over time. We found no support for social information transfer as a mechanism of prebaiting. CONCLUSION: Applying a mechanistic understanding of how prebaiting functions will improve the efficacy of management devices. Our results suggest that prebaiting allows time for more rats to encounter a device, hence surveys in our system would benefit from long prebaiting periods. © 2021 Society of Chemical Industry.

Misinformation tactics protect rare birds from problem predators.

Efficient decision-making integrates previous experience with new information. Tactical use of misinformation can alter choice in humans. Whether misinformation affects decision-making in other free-living species, including problem species, is unknown. Here, we show that sensory misinformation tactics can reduce the impacts of predators on vulnerable bird populations as effectively as lethal control. We repeatedly exposed invasive mammalian predators to unprofitable bird odors for 5 weeks before native shorebirds arrived for nesting and for 8 weeks thereafter. Chick production increased 1.7-fold at odor-treated sites over 25 to 35 days, with doubled or tripled odds of successful hatching, resulting in a 127% increase in modeled population size in 25 years. We demonstrate that decision-making processes that respond to changes in information reliability are vulnerable to tactical manipulation by misinformation. Altering perceptions of prey availability offers an innovative, nonlethal approach to managing problem predators and improving conservation outcomes for threatened species.

Generative models, linguistic communication and active inference.

This paper presents a biologically plausible generative model and inference scheme that is capable of simulating communication between synthetic subjects who talk to each other. Building on active inference formulations of dyadic interactions, we simulate linguistic exchange to explore generative models that support dialogues. These models employ high-order interactions among abstract (discrete) states in deep (hierarchical) models. The sequential nature of language processing mandates generative models with a particular factorial structure-necessary to accommodate the rich combinatorics of language. We illustrate linguistic communication by simulating a synthetic subject who can play the 'Twenty Questions' game. In this game, synthetic subjects take the role of the questioner or answerer, using the same generative model. This simulation setup is used to illustrate some key architectural points and demonstrate that many behavioural and neurophysiological correlates of linguistic communication emerge under variational (marginal) message passing, given the right kind of generative model. For example, we show that theta-gamma coupling is an emergent property of belief updating, when listening to another.

Leveraging Motivations, Personality, and Sensory Cues for Vertebrate Pest Management.

Managing vertebrate pests is a global conservation challenge given their undesirable socio-ecological impacts. Pest management often focuses on the 'average' individual, neglecting individual-level behavioural variation ('personalities') and differences in life histories. These differences affect pest impacts and modify attraction to, or avoidance of, sensory cues. Strategies targeting the average individual may fail to mitigate damage by 'rogues' (individuals causing disproportionate impact) or to target 'recalcitrants' (individuals avoiding standard control measures). Effective management leverages animal behaviours that relate primarily to four core motivations: feeding, fleeing, fighting, and fornication. Management success could be greatly increased by identifying and exploiting individual variation in motivations. We provide explicit suggestions for cue-based tools to manipulate these four motivators, thereby improving pest management outcomes.

Second waves, social distancing, and the spread of COVID-19 across the USA.

We recently described a dynamic causal model of a COVID-19 outbreak within a single region. Here, we combine several of these (epidemic) models to create a (pandemic) model of viral spread among regions. Our focus is on a second wave of new cases that may result from loss of immunity-and the exchange of people between regions-and how mortality rates can be ameliorated under different strategic responses. In particular, we consider hard or soft social distancing strategies predicated on national (Federal) or regional (State) estimates of the prevalence of infection in the population. The modelling is demonstrated using timeseries of new cases and deaths from the United States to estimate the parameters of a factorial (compartmental) epidemiological model of each State and, crucially, coupling between States. Using Bayesian model reduction, we identify the effective connectivity between States that best explains the initial phases of the outbreak in the United States. Using the ensuing posterior parameter estimates, we then evaluate the likely outcomes of different policies in terms of mortality, working days lost due to lockdown and demands upon critical care. The provisional results of this modelling suggest that social distancing and loss of immunity are the two key factors that underwrite a return to endemic equilibrium.

Deadly intentions: naïve introduced foxes show rapid attraction to odour cues of an unfamiliar native prey.

Introduced predators have caused declines and extinctions of native species worldwide, seemingly able to find and hunt new, unfamiliar prey from the time of their introduction. Yet, just as native species are often naïve to introduced predators, in theory, introduced predators should initially be naïve in their response to novel native prey. Here we examine the response of free-living introduced red foxes (Vulpes vulpes) to their first encounter with the odour cues of a novel native prey, the long-nosed bandicoot (Perameles nasuta). Despite no experience with bandicoots at the study site, foxes were significantly more interested in bandicoot odour compared to untreated controls and to a co-evolved prey, the black rat (Rattus rattus). So what gives introduced predators a novelty advantage over native prey? Such neophilia towards novel potential food sources carries little costs, however naïve native prey often lack analogous neophobic responses towards novel predators, possibly because predator avoidance is so costly. We propose that this nexus between the costs and benefits of responding to novel information is different for alien predators and native prey, giving alien predators a novelty advantage over native prey. This may explain why some introduced predators have rapid and devastating impacts on native fauna.

Research Priorities from Animal Behaviour for Maximising Conservation Progress.

Poor communication between academic researchers and wildlife managers limits conservation progress and innovation. As a result, input from overlapping fields, such as animal behaviour, is underused in conservation management despite its demonstrated utility as a conservation tool and countless papers advocating its use. Communication and collaboration across these two disciplines are unlikely to improve without clearly identified management needs and demonstrable impacts of behavioural-based conservation management. To facilitate this process, a team of wildlife managers and animal behaviour researchers conducted a research prioritisation exercise, identifying 50 key questions that have great potential to resolve critical conservation and management problems. The resulting agenda highlights the diversity and extent of advances that both fields could achieve through collaboration.

Evaluation of the developmental toxicity of formamide in New Zealand white rabbits.

Naturally mated female New Zealand White (NZW) rabbits (24/group) received formamide (35, 70, or 140 mg/kg/day) or vehicle (1 ml/kg deionized/distilled water) by gavage on gestational days (GD) 6 through 29. The study was conducted using a 2-replicate design. Maternal food consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. One and four maternal deaths occurred at the low and high doses, respectively. Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140-mg/kg/day dose groups, respectively. Other clinical signs associated with formamide exposure were minimal: primarily reduced or absent fecal output at the high dose (2-13 animals/day). Also at the high dose, maternal body weight was significantly depressed on GD 21, 24, and 27 (87-90% of the control value); maternal body weight gain was significantly reduced for GD 12 to 15, 18 to 21, and 21 to 24 (treated animals gained less than 1 g, or lost up to 100 g). In addition, maternal body weight gain was reduced at the middle dose for GD 18 to 21. Maternal body weight gain, corrected for gravid uterine weight, was unaffected. Relative maternal food consumption in the high-dose group was 34-59% of control intake from GD 12 through GD 24, but was comparable to controls thereafter. At termination (GD 30), confirmed-pregnant females (9-20 per group) were evaluated for clinical status, liver weights, and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. Maternal liver weight (absolute or relative to body weight) was unaffected by treatment, but gravid uterine weight at the high dose was 71% of the control value. A significantly increasing trend was noted for the percent non-live implants per litter. In addition, although not statistically significant from the control group, the values for the percent late fetal deaths per litter and percent non-live implants per litter in the 140-mg/kg/day group were higher than maximum historical values, suggesting an increase in late gestational deaths in the surviving high-dose animals. Formamide decreased the mean number of live fetuses per litter at the high dose to 66% of the control value. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose; mean female fetal body weight was also decreased, although the difference did not reach statistical significance. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations in animals surviving to scheduled necropsy. In summary, the no-observed-adverse-effect level (NOAEL) for maternal toxicity was 70 mg/kg/day and the lowest-observed-adverse-effect level (LOAEL) was 140 mg/kg/day under the conditions of this study. Similarly, the NOAEL for developmental toxicity was 70 mg/kg/day and the LOAEL was 140 mg/kg/day.

Developmental neurotoxicity of 3,3',4,4'-tetrachloroazobenzene with thyroxine deficit: Sensitivity of glia and dentate granule neurons in the absence of behavioral changes.

Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3',4,4'-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3'- triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND)4-21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations.

Predators are attracted to the olfactory signals of prey.

BACKGROUND: Predator attraction to prey social signals can force prey to trade-off the social imperatives to communicate against the profound effect of predation on their future fitness. These tradeoffs underlie theories on the design and evolution of conspecific signalling systems and have received much attention in visual and acoustic signalling modes. Yet while most territorial mammals communicate using olfactory signals and olfactory hunting is widespread in predators, evidence for the attraction of predators to prey olfactory signals under field conditions is lacking. METHODOLOGY/PRINCIPAL FINDINGS: To redress this fundamental issue, we examined the attraction of free-roaming predators to discrete patches of scents collected from groups of two and six adult, male house mice, Mus domesticus, which primarily communicate through olfaction. Olfactorily-hunting predators were rapidly attracted to mouse scent signals, visiting mouse scented locations sooner, and in greater number, than control locations. There were no effects of signal concentration on predator attraction to their prey's signals. CONCLUSIONS/SIGNIFICANCE: This implies that communication will be costly if conspecific receivers and eavesdropping predators are simultaneously attracted to a signal. Significantly, our results also suggest that receivers may be at greater risk of predation when communicating than signallers, as receivers must visit risky patches of scent to perform their half of the communication equation, while signallers need not.