COVID-19 as a chronic stressor and the importance of individual identity: A data-driven look at academic productivity during the pandemic.

The COVID-19 pandemic impacted personal and professional life. For academics, research, teaching, and service tasks were upended and we all had to navigate the altered landscape. However, some individuals faced a disproportionate burden, particularly academics with minoritized identities or those who were early career, were caregivers, or had intersecting identities. As comparative endocrinologists, we determine how aspects of individual and species-level variation influence response to, recovery from, and resilience in the face of stressors. Here, we flip that framework and apply an integrative biological lens to the impact of the COVID-19 chronic stressor on our endocrine community. We address how the pandemic altered impact factors of academia (e.g., scholarly products) and relatedly, how factors of impact (e.g., sex, gender, race, career stage, caregiver status, etc.) altered the way in which individuals could respond. We predict the pandemic will have long-term impacts on the population dynamics, composition, and landscape of our academic ecosystem. Impact factors of research, namely journal submissions, were altered by COVID-19, and women authors saw a big dip. We discuss this broadly and then report General and Comparative Endocrinology (GCE) manuscript submission and acceptance status by gender and geographic region from 2019 to 2023. We also summarize how the pandemic impacted individuals with different axes of identity, how academic institutions have responded, compile proposed solutions, and conclude with a discussion on what we can all do to (re)build the academy in an equitable way. At GCE, the first author positions had gender parity, but men outnumbered women at the corresponding author position. Region of manuscript origin mattered for submission and acceptance rates, and women authors from Asia and the Middle East were the most heavily impacted by the pandemic. The number of manuscripts submitted dropped after year 1 of the pandemic and has not yet recovered. Thus, COVID-19 was a chronic stressor for the GCE community.

The social environment alters neural responses to a lipopolysaccharide challenge.

Sick animals display drastic changes in their behavioral patterns, including decreased activity, decreased food and water intake, and decreased interest in social interactions. These behaviors, collectively called "sickness behaviors", can be socially modulated. For example, when provided with mating opportunities, males of several species show reduced sickness behaviors. While the behavior is known to change, how the social environment affects neural molecular responses to sickness is not known. Here, we used a species, the zebra finch, Taeniopygia guttata, where males have been shown to decrease sickness behaviors when presented with novel females. Using this paradigm, we obtained samples from three brain regions (the hypothalamus, the bed nucleus of the stria terminalis, and the nucleus taeniae) from lipopolysaccharide (LPS) or control treated males housed under four different social environments. Manipulation of the social environment rapidly changed the strength and co-expression patterns of the neural molecular responses to the immune challenge in all brain regions tested, therefore suggesting that the social environment plays a significant role in determining the neural responses to an infection. In particular, brains of males paired with a novel female showed muted immune responses to LPS, as well as altered synaptic signaling. Neural metabolic activity in response to the LPS challenge was also affected by the social environment. Our results provide new insights into the effects of the social environment on brain responses to an infection, thereby improving our understanding of how the social environment can affect health.

From mechanism to ecosystem: building bridges between ecoimmunology, psychoneuroimmunology and disease ecology.

Historically, the fields of ecoimmunology, psychoneuroimmunology and disease ecology have taken complementary yet disparate theoretical and experimental approaches, despite sharing critical common themes. Researchers in these areas have largely worked independently of one another to understand mechanistic immunological responses, organismal level immune performance, behavioral changes, and host and parasite/disease population dynamics, with few bridges across disciplines. Although efforts to strengthen and expand these bridges have been called for (and occasionally heeded) over the last decade, more integrative studies are only now beginning to emerge, with critical gaps remaining. Here, we briefly discuss the origins of these key fields, and their current state of integration, while highlighting several critical directions that we suggest will strengthen their connections into the future. Specifically, we highlight three key research areas that provide collaborative opportunities for integrative investigation across multiple levels of biological organization, from mechanisms to ecosystems: (1) parental effects of immunity, (2) microbiome and immune function and (3) sickness behaviors. By building new bridges among these fields, and strengthening existing ones, a truly integrative approach to understanding the role of host immunity on individual and community fitness is within our grasp.

The effect of infection risk on female blood transcriptomics.

Defenses against pathogens can take on many forms. For instance, behavioral avoidance of diseased conspecifics is widely documented. Interactions with these infectious conspecifics can also, however, lead to physiological changes in uninfected animals, an effect that is much less well understood. These changes in behavior and physiology are particularly important to study in a reproductive context, where they can impact reproductive decisions and offspring quality. Here, we studied how an acute (3 h) exposure to an immune-challenged male affected female blood transcriptomics and behavior. We predicted that females paired with immune-challenged males would reduce eating and drinking behaviors (as avoidance behaviors) and that their blood would show activation of immune and stress responses. We used female Japanese quail as a study system because they have been shown to respond to male traits, in terms of their own physiology and egg investment. Only two genes showed significant differential expression due to treatment, including an increase in the threonine dehydrogenase (TDH) transcript, an enzyme important for threonine breakdown. However, hundreds of genes in pathways related to activation of immune responses showed coordinated up-regulation in females exposed to immune-challenged males. Suppressed pathways revealed potential changes to metabolism and reduced responsiveness to glucocorticoids. Contrary to our prediction, we found that females paired with immune-challenged males increased food consumption. Water consumption was not changed by treatment. These findings suggest that even short exposure to diseased conspecifics can trigger both behavioral and physiological responses in healthy animals.

Sickness behaviors across vertebrate taxa: proximate and ultimate mechanisms.

There is nothing like a pandemic to get the world thinking about how infectious diseases affect individual behavior. In this respect, sick animals can behave in ways that are dramatically different from healthy animals: altered social interactions and changes to patterns of eating and drinking are all hallmarks of sickness. As a result, behavioral changes associated with inflammatory responses (i.e. sickness behaviors) have important implications for disease spread by affecting contacts with others and with common resources, including water and/or sleeping sites. In this Review, we summarize the behavioral modifications, including changes to thermoregulatory behaviors, known to occur in vertebrates during infection, with an emphasis on non-mammalian taxa, which have historically received less attention. We then outline and discuss our current understanding of the changes in physiology associated with the production of these behaviors and highlight areas where more research is needed, including an exploration of individual and sex differences in the acute phase response and a greater understanding of the ecophysiological implications of sickness behaviors for disease at the population level.

Wild mice with different social network sizes vary in brain gene expression.

BACKGROUND: Appropriate social interactions influence animal fitness by impacting several processes, such as mating, territory defense, and offspring care. Many studies shedding light on the neurobiological underpinnings of social behavior have focused on nonapeptides (vasopressin, oxytocin, and homologues) and on sexual or parent-offspring interactions. Furthermore, animals have been studied under artificial laboratory conditions, where the consequences of behavioral responses may not be as critical as when expressed under natural environments, therefore obscuring certain physiological responses. We used automated recording of social interactions of wild house mice outside of the breeding season to detect individuals at both tails of a distribution of egocentric network sizes (characterized by number of different partners encountered per day). We then used RNA-seq to perform an unbiased assessment of neural differences in gene expression in the prefrontal cortex, the hippocampus and the hypothalamus between these mice with naturally occurring extreme differences in social network size. RESULTS: We found that the neurogenomic pathways associated with having extreme social network sizes differed between the sexes. In females, hundreds of genes were differentially expressed between animals with small and large social network sizes, whereas in males very few were. In males, X-chromosome inactivation pathways in the prefrontal cortex were the ones that better differentiated animals with small from those with large social network sizes animals. In females, animals with small network size showed up-regulation of dopaminergic production and transport pathways in the hypothalamus. Additionally, in females, extracellular matrix deposition on hippocampal neurons was higher in individuals with small relative to large social network size. CONCLUSIONS: Studying neural substrates of natural variation in social behavior in traditional model organisms in their habitat can open new targets of research for understanding variation in social behavior in other taxa.

Baseline corticosterone is associated with parental care in virgin Japanese quail (Coturnix japonica).

Glucocorticoids (GCs) are thought to impact reproductive success, and ultimately fitness. In this study we focus specifically on the relationship between GCs and parental care. Captive bred Japanese quail (Coturnix japonica) do not show spontaneous parental care behavior, however this behavior can be induced through a sensitization procedure. We investigated how the GC status of Japanese quail relates to parental care in animals of both sexes exposed or not to a chick sensitization treatment. To assess GC status, we obtained baseline plasma and feather cort samples, and used the HPA-axis function test to assess stress responsiveness by examining the response to a standardized stressor as well as negative feedback efficacy through dexamethasone injection. Next, birds were either exposed to chicks overnight in a small enclosure (sensitization treatment) or were enclosed but not exposed to chicks (control). The following morning, adult behaviors were filmed in the presence of a fresh set of chicks for 20 min. A final serum GC sample was obtained to assess if exposure to novel chicks was perceived as stressful. In control animals, baseline GCs were associated with increased total parental care duration and decreased latency to first parental care event. Interestingly, the opposite relationship was found in the sensitization group. Finally, exposure to novel chicks was not associated with an increase in corticosterone in either group. Overall it appears that baseline GCs are correlated with parental care in captive bred Japanese quail, and that the relationship changes direction depending on whether or not sensitization has occurred.

A selfish genetic element linked to increased lifespan impacts metabolism in female house mice.

Gene drive systems can lead to the evolution of traits that further enhance the transmission of the driving element. In gene drive, one allele is transmitted to offspring at a higher frequency than the homologous allele. This has a range of consequences, which generally include a reduction in fitness of the carrier of the driving allele, making such systems 'selfish'. The t haplotype is one such driver, found in house mice. It is linked to a reduction in litter size in matings among heterozygous animals, but also to increased lifespan in wild females that carry it. Here, we tested whether carrying the t haplotype was associated with altered resting metabolic rate (RMR). We show that females carrying the t haplotype decrease RMR as they increase in size, compared with wild-type females or males of either genotype. Our study elucidates a plausible mechanism by which a selfish genetic element increases lifespan.

Why are behavioral and immune traits linked?

Through behavior, animals interact with a world where parasites abound. It is easy to understand how behavioral traits can thus have a differential effect on pathogen exposure. Harder to understand is why we observe behavioral traits to be linked to immune defense traits. Is variation in immune traits a consequence of behavior-induced variation in immunological experiences? Or is variation in behavioral traits a function of immune capabilities? Is our immune system a much bigger driver of personality than anticipated? In this review, I provide examples of how behavioral and immune traits co-vary. I then explore the different routes linking behavioral and immune traits, emphasizing on the physiological/hormonal mechanisms that could lead to immune control of behavior. Finally, I discuss why we should aim at understanding more about the mechanisms connecting these phenotypic traits.

LPS and neuroinflammation: a matter of timing.

Lipopolysaccharide (LPS) administration has been repeatedly shown to elicit central inflammation, regardless of the route of administration. In a recent study, Tiwari et al. (Inflammopharmacology 10.1007/s10787-016-0274-3 , 2016) dispute the potential of peripheral administration of LPS to induce neuroinflammation. Here, I summarise literature indicating that the neuroinflammatory effects of LPS are time dependent, and suggest that their findings can be explained by the time at which they chose to measure neuroinflammation.

When is it socially acceptable to feel sick?

Disease is a ubiquitous and powerful evolutionary force. Hosts have evolved behavioural and physiological responses to disease that are associated with increased survival. Behavioural modifications, known as 'sickness behaviours', frequently involve symptoms such as lethargy, somnolence and anorexia. Current research has demonstrated that the social environment is a potent modulator of these behaviours: when conflicting social opportunities arise, animals can decrease or entirely forgo experiencing sickness symptoms. Here, I review how different social contexts, such as the presence of mates, caring for offspring, competing for territories or maintaining social status, affect the expression of sickness behaviours. Exploiting the circumstances that promote this behavioural plasticity will provide new insights into the evolutionary ecology of social behaviours. A deeper understanding of when and how this modulation takes place may lead to better tools to treat symptoms of infection and be relevant for the development of more efficient disease control programmes.

Balancing Act: an Interdisciplinary Exploration of Trade-offs in Reproducing Females.

Trade-offs resulting from the high demand of offspring production are a central focus of many subdisciplines within the field of biology. Yet, despite the historical and current interest on this topic, large gaps in our understanding of whole-organism trade-offs that occur in reproducing individuals remain, particularly as it relates to the nuances associated with female reproduction. This volume of Integrative and Comparative Biology (ICB) contains a series of papers that focus on reviewing trade-offs from the female-centered perspective of biology (i.e., a perspective that places female reproductive biology at the center of the topic being investigated or discussed). These papers represent some of the work showcased during our symposium held at the 2024 meeting of the Society for Integrative and Comparative Biology (SICB) in Seattle, Washington. In this roundtable discussion, we use a question-and-answer format to capture the diverse perspectives and voices involved in our symposium. We hope that the dialogue featured in this discussion will be used to motivate researchers interested in understanding trade-offs in reproducing females and provide guidance on future research endeavors.

The effects of different inspired oxygen fractions on gas exchange and Tei-index of myocardial performance in propofol-anesthetized dogs.

OBJECTIVE: To evaluate the influence of different inspired oxygen fractions (FiO2) on pulmonary oxygen exchange and Tei-index of myocardial performance in propofol-anesthetized dogs. STUDY DESIGN: Prospective crossover, randomized, experimental trial. ANIMALS: Eight adult dogs weighing 8.6 ± 1.8 kg. METHODS: The animals were anesthetized on five occasions, receiving either an FiO2 = 1.0 (F100), 0.8 (F80), 0.6 (F60), 0.4 (F40) or 0.21 (F21). Propofol was used for induction (6.45 ± 0.69 mgkg(-1) IV) followed by a continuous rate infusion (CRI, 0.7 mgkg(-1) minute(-1)). The dogs breathed spontaneously. The initial measurements of arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), arterial hemoglobin saturation (SaO2), heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), stroke index (SI), pre-ejection period (PEP) and left ventricular ejection time (LVET) were performed 30 minutes after beginning the CRI (T0) and then, at 15-minute intervals (T15-T60). From these measurements the following were calculated; alveolar oxygen partial pressure (PAO2), alveolar-arterial oxygen gradient (AaDO2), arterial oxygen partial pressure/inspired oxygen fraction ratio (PaO2/FiO2), arterial-to-alveolar oxygen tension ratio (PaO2/PAO2), respiratory index (RI), oxygen delivery (D·O2), PEP/LVET ratio, isovolumic relaxation time (IVRT) and Tei-index. RESULTS: At T30, PaCO2 in F100 was higher than in F21. The AaDO2 mean in F100 was greater than in other treatments. PaO2/FiO2 in F21 was lower than F100 and F80 at T0 and than in F80 and F60 at T15. At T15, PaO2/PAO2 and RI in F100 were higher than in F80, F60 and F21. At T30, PaO2/PAO2 in F21 was lower than in F100 and F60. At T30, PEP/LVET in F100 was higher than F80, F40 and F21, which was lower than F80 and F40. CONCLUSION: The Tei-index and cardiovascular parameters are not affected by different FiO2. CLINICAL RELEVANCE: An FiO2 of 1.0 and 0.21 impaired respiratory efficiency.

Responding to infection affects more than just the host.

An infection triggers a dramatic suite of changes in host physiology and behavior. While seemingly localized, the host response affects many other organisms, both within and beyond the boundaries of the host's body, with far-reaching ecological implications. Here, I call for more awareness and integration of those potential 'off-host' effects.

Female presence does not increase testosterone but still ameliorates sickness behaviours in male Japanese quail.

Infections can dramatically modify animal behaviour. The extent of these changes depends on an animal's environment. It has been proposed that testosterone modulates the suppression of behavioural symptoms of sickness under certain reproductive contexts. To further understand the role played by testosterone in modulating sickness behaviours under reproductive contexts, we studied a species, the Japanese quail, in which female exposure rapidly decreases circulating testosterone in males. Males received either an immune challenge (lipopolysaccharide - LPS) or a control injection and their behaviours, mass change and testosterone levels were quantified in the presence or absence of a female. Both the presence of a female and LPS treatment reduced testosterone levels. LPS-treated males maintained in isolation expressed expected sickness behaviours, including increased resting (quantified as crouching) and decreased food and water intake. Despite the reduction in testosterone, when paired with females LPS-treated males showed similar amounts of mating behaviours to controls and reduced crouching. In sum, even under very low levels of testosterone, male quail had reduced sickness behaviours when exposed to females, indicating that testosterone may not be key in modulating sickness behaviours, at least in this species.

Maternal Responses in the Face of Infection Risk.

When animals are sick, their physiology and behavior change in ways that can impact their offspring. Research is emerging showing that infection risk alone can also modify the physiology and behavior of healthy animals. If physiological responses to environments with high infection risk take place during reproduction, it is possible that they lead to maternal effects. Understanding whether and how high infection risk triggers maternal effects is important to elucidate how the impacts of infectious agents extend beyond infected individuals and how, in this way, they are even stronger evolutionary forces than already considered. Here, to evaluate the effects of infection risk on maternal responses, we exposed healthy female Japanese quail to either an immune-challenged (lipopolysaccharide [LPS] treated) mate or to a healthy (control) mate. We first assessed how females responded behaviorally to these treatments. Exposure to an immune-challenged or control male was immediately followed by exposure to a healthy male, to determine whether treatment affected paternity allocation. We predicted that females paired with immune-challenged males would avoid and show aggression towards those males, and that paternity would be skewed towards the healthy male. After mating, we collected eggs over a 5-day period. As an additional control, we collected eggs from immune-challenged females mated to healthy males. We tested eggs for fertilization status, embryo sex ratio, as well as albumen corticosterone, lysozyme activity, and ovotransferrin, and yolk antioxidant capacity. We predicted that immune-challenged females would show the strongest changes in the egg and embryo metrics, and that females exposed to immune-challenged males would show intermediate responses. Contrary to our predictions, we found no avoidance of immune-challenged males and no differences in terms of paternity allocation. Immune-challenged females laid fewer eggs, with an almost bimodal distribution of sex ratio for embryos. In this group, albumen ovotransferrin was the lowest, and yolk antioxidant capacity decreased over time, while it increased in the other treatments. No differences in albumen lysozyme were found. Both females that were immune-challenged and those exposed to immune-challenged males deposited progressively more corticosterone in their eggs over time, a pattern opposed to that shown by females exposed to control males. Our results suggest that egg-laying Japanese quail may be able to respond to infection risk, but that additional or prolonged sickness symptoms may be needed for more extensive maternal responses.

Hemodynamic effects of butorphanol in desflurane-anesthetized dogs.

OBJECTIVE: To evaluate the effects of butorphanol on cardiopulmonary parameters in dogs anesthetized with desflurane and breathing spontaneously. STUDY DESIGN: Prospective, randomized experimental trial. ANIMALS: Twenty dogs weighing 12 ± 3 kg. METHODS: Animals were distributed into two groups: a control group (CG) and butorphanol group (BG). Propofol was used for induction and anesthesia was maintained with desflurane (10%). Forty minutes after induction, the dogs in the CG received sodium chloride 0.9% (0.05 mL kg(-1) IM), and dogs in the BG received butorphanol (0.4 mg kg(-1) IM). The first measurements of body temperature (BT), heart rate (HR), arterial pressures (AP), cardiac output (CO), cardiac index (CI), central venous pressure (CVP), stroke volume index (SVI), pulmonary arterial occlusion pressure (PAOP), mean pulmonary arterial pressure (mPAP), left ventricular stroke work (LVSW), systemic (SVR) and pulmonary (PVR) vascular resistances, respiratory rate (f(R) ), and arterial oxygen (PaO(2) ) and carbon dioxide (PaCO(2) ) partial pressures were taken immediately before the administration of butorphanol or sodium chloride solution (T0) and then at 15-minute intervals (T15-T75). RESULTS: In the BG, HR, AP, mPAP and SVR decreased significantly from T15 to T75 compared to baseline. f(R) was lower at T30 than at T0 in the BG. AP and f(R) were significantly lower than in the CG from T15 to T75. PVR was lower in the BG than in the CG at T30, while PaCO(2) was higher compared with T0 from T30 to T75 in the BG and significantly higher than in the CG at T30 to T75. CONCLUSIONS AND CLINICAL RELEVANCE: At the studied dose, butorphanol caused hypotension and decreased ventilation during desflurane anesthesia in dogs. The hypotension (from 86 ± 10 to 64 ± 10 mmHg) is clinically relevant, despite the maintenance of cardiac index.

Neurotranscriptomic changes associated with chick-directed parental care in adult non-reproductive Japanese quail.

For many species, parental care critically affects offspring survival. But what drives animals to display parental behaviours towards young? In mammals, pregnancy-induced physiological transformations seem key in preparing the neural circuits that lead towards attraction (and reduced-aggression) to young. Beyond mammalian maternal behaviour, knowledge of the neural mechanisms that underlie young-directed parental care is severely lacking. We took advantage of a domesticated bird species, the Japanese quail, for which parental behaviour towards chicks can be induced in virgin non-reproductive adults through a sensitization procedure, a process that is not effective in all animals. We used the variation in parental responses to study neural transcriptomic changes associated with the sensitization procedure itself and with the outcome of the procedure (i.e., presence of parental behaviours). We found differences in gene expression in the hypothalamus and bed nucleus of the stria terminalis, but not the nucleus taeniae. Two genes identified are of particular interest. One is neurotensin, previously only demonstrated to be causally associated with maternal care in mammals. The other one is urocortin 3, causally demonstrated to affect young-directed neglect and aggression in mammals. Because our studies were conducted in animals that were reproductively quiescent, our results reflect core neural changes that may be associated with avian young-directed care independently of extensive hormonal stimulation. Our work opens new avenues of research into understanding the neural basis of parental care in non-placental species.

Immune-Endocrine Links to Gregariousness in Wild House Mice.

Social interactions are critically important for survival and impact overall-health, but also impose costs on animals, such as exposure to contagious agents. The immune system can play a critical role in modulating social behavior when animals are sick, as has been demonstrated within the context of "sickness behaviors." Can immune molecules affect or be affected by social interactions even when animals are not sick, therefore serving a role in mediating pathogen exposure? We tested whether markers of immune function in both the blood and the brain are associated with gregariousness, quantified as number of animals interacted with per day. To do this, we used remote tracking of social interactions of a wild population of house mice (Mus musculus domesticus) to categorize animals in terms of gregariousness. Blood, hair, brain and other tissue samples from animals with extreme gregariousness phenotypes were collected. We then tested whether the levels of three important cytokines (TNF-α, IFN-γ and IL-1ß) in the serum, cortex and hypothalamus of these animals could be explained by the gregariousness phenotype and/or sex of the mice. Using the hair as a long-term quantification of steroid hormones, we also tested whether corticosterone, progesterone and testosterone differed by social phenotype. We found main effects of gregariousness and sex on the serum levels of TNF-α, but not on IFN-γ or IL-1ß. Brain gene expression levels were not different between phenotypes. All hair steroids tended to be elevated in animals of high gregariousness phenotype, independent of sex. In sum, elements of the immune system may be associated with gregariousness, even outside of major disease events. These results extend our knowledge of the role that immune signals have in contributing to the regulation of social behaviors outside periods of illness.

Bispectral index in dogs at three intravenous infusion rates of propofol.

OBJECTIVE: To establish the correlation between the bispectral index (BIS) and different rates of infusion of propofol in dogs. Study design Prospective experimental trial. ANIMALS: Eight adult dogs weighing 6-20 kg. METHODS: Eight animals underwent three treatments at intervals of 20 days. Propofol was used for induction of anesthesia (10 mg kg(-1) IV), followed by a continuous rate infusion (CRI) at 0.2 mg kg(-1) minute(-1) (P2), 0.4 mg kg(-1) minute(-1) (P4) or 0.8 mg kg(-1) minute(-1) (P8) for 55 minutes. The BIS values were measured at 10, 20, 30, 40, and 50 minutes (T10, T20, T30, T40, and T50, respectively) after the CRI of propofol was started. Numeric data were submitted to analysis of variance followed by Tukey test (p < 0.05). RESULTS: The BIS differed significantly among groups at T40, when P8 was lower than P2 and P4. At T50, P8 was lower than P2. The electromyographic activity (EMG) in P2 and P4 was higher than P8 at T40 and T50. CONCLUSIONS: An increase in propofol infusion rates decreases the BIS values and EMG.