WSB1 Involvement in Prostate Cancer Progression.

Prostate cancer (PC) is polygenic disease involving many genes, and more importantly a host of gene-gene interactions, including transcriptional factors. The WSB1 gene is a transcriptional target of numerous oncoproteins, and its dysregulation can contribute to tumor progression by abnormal activation of targeted oncogenes. Using data from the Cancer Genome Atlas, we tested the possible involvement of WSB1 in PC progression. A multi-dimensional scaling (MDS) model was applied to clarify the association of WSB1 expression with other key genes, such as c-myc, ERG, Enhancer of Zeste 1 and 2 (EHZ1 and EZH2), WNT10a, and WNT 10b. An increased WSB1 expression was associated with higher PC grades and with a worse prognosis. It was also positively related to EZH1, EZH2, WNT10a, and WNT10b. Moreover, MDS showed the central role of WSB1 in influencing the other target genes by its central location on the map. Our study is the first to show a link between WSB1 expression and other genes involved in PC progression, suggesting a novel role for WSB1 in PC progression. This network between WSB1 and EZH2 through WNT/ß-catenin may have an important role in PC progression, as suggested by the association between high WSB1 expression and unfavorable prognosis in our analysis.

Steroid Hormones as Modulators of Emotional Regulation in Male Urogenital Cancers.

BACKGROUND: Tumors develop within an organism operating in a specific social and physical environment. Cortisol and dehydroepiandrosterone (DHEA), two of the most abundant steroid hormones in humans, are involved in both emotional regulation and the tumor progression. Several studies reported preclinical findings that DHEA can have preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, although the mechanisms of action are not yet defined. The main aim of current study was to investigate the relationship between psychological and physiological emotional regulation and cancer development. METHOD: This study assessed the quality of life of urogenital cancer male patients using several validated tools, including the Functional Assessment of Cancer Therapy-General and the Profile of Mood States. Saliva samples were collected to monitor peripheral activity of both cortisol and DHEA. It was hypothesized that patients with a better quality of life would have higher levels of the DHEA/cortisol ratios. RESULTS: We found that the quality of life was positively related to DHEA, but not cortisol levels. Negative mood increases were related to lower levels of DHEA. Logistic regression of the predictors of metastases indicated three main independent factors involved: DHEA, age, and cortisol. In other words, the higher the DHEA levels in comparison to cortisol levels, controlling for age, the lower the probability of metastases. CONCLUSION: Our results appear to support the hypothesis that emotional dysregulation mediated by DHEA/cortisol activity is a key factor in the probability of metastasis in urogenital cancers.

Proposal for a New Diagnostic Histopathological Approach in the Evaluation of Ki-67 in GEP-NETs.

INTRODUCTION: Studies have shown that the Ki-67 index is a valuable biomarker for the diagnosis, and classification of gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). We re-evaluated the expression of Ki-67 based on the intensity of the stain, basing our hypothesis on the fact that the Ki-67 protein is continuously degraded. BACKGROUND: The aim was to evaluate whether a new scoring method would be more effective in classifying NETs by reducing staining heterogeneity. METHODS: Patients with GEP-NET (n = 87) were analyzed. The classification difference between the two methods was determined. RESULTS: The classification changed significantly when the Ki-67 semiquantal index was used. The percentage of G1 patients increased from 18.4% to 60.9%, while the G2 patients decreased from 66.7% to 29.9% and the G3 patients also decreased from 14.9% to 9.2%. Moreover, it was found that the traditional Ki-67 was not significantly related to the overall survival (OS), whereas the semiquantal Ki-67 was significantly related to the OS. CONCLUSIONS: The new quantification was a better predictor of OS and of tumor classification. Therefore, it could be used both as a marker of proliferation and as a tool to map tumor dynamics that can influence the diagnosis and guide the choice of therapy.

Multi-Dimensional Scaling Analysis of Key Regulatory Genes in Prostate Cancer Using the TCGA Database.

Prostate cancer (PC) is a polygenic disease with multiple gene interactions. Therefore, a detailed analysis of its epidemiology and evaluation of risk factors can help to identify more accurate predictors of aggressive disease. We used the transcriptome data from a cohort of 243 patients from the Cancer Genome Atlas (TCGA) database. Key regulatory genes involved in proliferation activity, in the regulation of stress, and in the regulation of inflammation processes of the tumor microenvironment were selected to test a priori multi-dimensional scaling (MDS) models and create a combined score to better predict the patients' survival and disease-free intervals. Survival was positively correlated with cortisol expression and negatively with Mini-Chromosome Maintenance 7 (MCM7) and Breast-Related Cancer Antigen2 (BRCA2) expression. The disease-free interval was negatively related to the expression of enhancer of zeste homolog 2 (EZH2), MCM7, BRCA2, and programmed cell death 1 ligand 1 (PD-L1). MDS suggested two separate pathways of activation in PC. Within these two dimensions three separate clusters emerged: (1) cortisol and brain-derived neurotrophic factor BDNF, (2) PD-L1 and cytotoxic-T-lymphocyte-associated protein 4 (CTL4); (3) and finally EZH2, MCM7, BRCA2, and c-Myc. We entered the three clusters of association shown in the MDS in several Kaplan-Meier analyses. It was found that only Cluster 3 was significantly related to the interval-disease free, indicating that patients with an overall higher activity of regulatory genes of proliferation and DNA repair had a lower probability to have a longer disease-free time. In conclusion, our data study provided initial evidence that selecting patients with a high grade of proliferation and DNA repair activity could lead to an early identification of an aggressive PC with a potentials for metastatic development.

Back to nature: herbal treatment, environmental enrichment, and social play can protect against unpredictable chronic stress in Long-Evans rats (Rattus norvegicus).

The importance of integrative biobehavioral responses to complex challenges cannot be overlooked. In this study, the synergetic effects of icariin (a flavonoid present in the plant Epimedium brevicornum), natural enrichment (NaEn), and play behavior were investigated. Rats (n = 60) were assigned to standard housing or NaEn; these two groups were subsequently divided into controls, rats receiving icariin treatments, and rats receiving icariin and allowed to play with an individual from another cage. All rats were exposed to unpredictable mild stressors for 4 weeks. At the end of the treatment, a Forced Swim Task (FST) was conducted to assess emotional regulation during an inescapable acute challenge. Biological samples were collected weekly and before and after the FST to monitor endocrine changes. Corticosterone (CORT), dehydroepiandrosterone (DHEA), and testosterone (T) were assayed. We found that icariin had a significant effect on DHEA/CORT ratios and T levels. NaEn also had a significant effect on both CORT and DHEA, but not on T levels. Play did not appear to be significantly related to the endocrine changes. The strongest positive effects on emotional resilience were observed in NaEn rats that also received icariin. Our results confirmed that using multiple channels to stimulate adaptive responses can be effective in increasing the ability of an organism to face uncertainty. Considering how quickly our life can change due to unpredictable events, our data is instrumental to a better comprehension of the many aspects of integrative biobehavioral responses.

Gastrin-Releasing Peptide Receptor in Low Grade Prostate Cancer: Can It Be a Better Predictor Than Prostate-Specific Membrane Antigen?

The aim of the present study was to evaluate whether prostate cancer (PC) patients can be accurately classified on the bases of tissue expression of gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA). This retrospective study included 28 patients with PC. Formalin-fixed paraffin-embedded samples were used for diagnosis. Immunohistochemistry staining techniques were used to evaluate PSMA and GRPR expression (both number of cells expressed and % of area stained). To assess the independent associations among selected variables, a multi-dimensional scaling (MDS) analysis was used. It was found that the PSMA expression was inversely correlated with GRPR expression. Only the number of cells expressing GRPR was significantly related to the Gleason score. Both the percentage of area expressing GRPR and the number of cells expressing PSMA were close to reaching significance at the 0.05 level. MDS provided a map of the overall, independent association confirming that GRPR and PSMA represent inversely correlated measures of the same dimension. In conclusion, our data showed that GRPR expression should be evaluated in prostate biopsy specimens to improve our ability to detect PC with low grades at the earliest phases of development. Considering that GRPRs appear to be directly involved in the mechanisms of tumor proliferation, advancements in nuclear medicine radiotherapy can focus on this receptor to improve the therapeutic approach to PC. Further studies in our laboratory will investigate the molecular mechanisms of activation based on GRPR.

Environmental enrichment modulates inflammation during development in long-evans rats (Rattus norvegicus).

It is unknown whether increased production of pro-inflammatory mediators during the life span is caused by aging per se or via the combination of a cumulative allostatic load due to life challenges. This study aimed to investigate the long-term effects of stress and environmental enrichment on the inflammatory status associated with aging in rats. Animals were assigned to the following five treatment groups: chronic stress with and without environmental enrichment; acute stress with and without environmental enrichment; control animals. Enrichment was provided as an open field containing novel objects (30 min three times per week). Animals assigned to chronic stress groups were exposed to predator sound stressors (e.g., hawk sound) for 30 min daily, while animals assigned to acute stress groups were exposed once a week for 30 min. The interaction between the hypothalamic-pituitary-adrenal axis and the immune system was investigated by measuring metabolized dehydroepiandrosterone (DHEA) levels and peripheral levels of the cytokines IL-6 and IL-10. Results suggested that inflamm-aging was more pronounced in animals with low DHEA levels, which in turn were affected by exposure to environmental enrichment and acute stress. This study showed that environmental enrichment and acute stress can significantly attenuate disruptions in DHEA production, consequently contributing to improved neuroimmune function of aging animals.

Postpartum environmental challenges alter maternal responsiveness and offspring development.

Because many threats exist in an animal's natural habitat, it is important to understand the impact of environmental challenges on maternal-offspring interactions and outcomes. In the current study, a rodent model incorporating the presence of restricted resources and an environmental threat (e.g. predator-related odors and sounds) was investigated. Specifically, pregnant females were assigned to one of four treatments: standard resources, without threat (SR; n = 7); standard resources plus threat (SR-T; n = 8); restricted resources, without threat (RR; n = 7); and restricted resources plus threat (RR-T; n = 6). Maternal rats were moved into the assigned conditions on postnatal day 2 and remained until pups were weaned. Following a standard pup retrieval task on postnatal days 2 and 6, maternal rats were exposed to a retrieval challenge task on postnatal day 8 in which each rat had to traverse a novel barrier to retrieve pups. For neurobiological measures of stress/resilience responsiveness, fecal samples were collected for detection of corticosterone and DHEA metabolites; additionally, immunohistochemistry was conducted on the maternal brains to indicate the presence of Neuropeptide Y (NPY) and Brain Derived Neurotrophic Factor (BDNF) immunoreactivity in the hippocampus, amygdala and hypothalamus. Pup development measures, including body weight and tail length, were also collected. Results suggest that maternal rats with restricted resources exhibited diminished maternal responsiveness that resulted in altered pup development measures; further, restricted resource rats exhibited endocrine markers of compromised emotional resilience (lower DHEA) and decreased neural markers of neuroplasticity (BDNF) and emotional resilience (NPY). Interestingly, predator threat affected various aspects of maternal-pup interactions but had no effect on neurobiological variables, suggesting that restricted resources had a more negative impact on maternal-related outcomes than the presence of predator threat.

What makes a long tail short? Testing Allen's rule in the toque macaques of Sri Lanka.

Allen's rule (1877) predicts ecogeographical anatomical variation in appendage proportions as a function of body temperature regulation. This phenomenon has been tested in a variety of animal species. In macaques, relative tail length (RTL) is one of the most frequently measured appendages to test Allen's rule. These studies have relied on museum specimens or the invasive and time-consuming capturing of free-ranging individuals. To augment sample size and lessen these logistical limitations, we designed and validated a novel noninvasive technique using digitalized photographs processed using LibreCAD, an open-source 2D-computer-aided design (CAD) application. This was used to generate pixelated measurements to calculate an RTL equivalent, the Tail to Trunk Index (TTI) = (tail [tail base to anterior tip] pixel count/trunk [neck to tail base] pixel count). The TTI of 259 adult free-ranging toque macaques (Macaca sinica) from 36 locations between 7 and 2,087 m above sea level (m.a.s.l.) was used in the analysis. Samples were collected from all three putative subspecies (M. s. sinica, aurifrons, and opisthomelas), at locations representing all altitudinal climatic zones where they are naturally distributed. These data were used to test whether toque macaque tail length variation across elevation follows Allen's rule, predicting that RTL decreases with increasing elevation and lower temperature. Our results strongly supported this prediction. There was also a statistically significant, negative correlation between elevation and annual average temperature. The best predictor for the TTI index was elevation. Significant subspecies differences in RTL are linked in part to their ecological and altitudinal niche separation, but overall the variation is seen as the species' adaptation to climate. The method developed for the quick morphometric assessment of relative body proportions, applicable for use on unhabituated free-ranging animals, widens the range of materials available for research studying morphological characteristics and their evolution in primates.

Forest fragments become farmland: Dietary Response of wild chimpanzees (Pan troglodytes) to fast-changing anthropogenic landscapes.

Behavioral flexibility, including an ability to modify feeding behavior, is a key trait enabling primates to survive in forest fragments. In human-dominated landscapes, unprotected forest fragments can become progressively degraded, and may be cleared entirely, challenging the capacity of primates to adjust to the changes. We examined responses of wild chimpanzees (Pan troglodytes schweinfurthii) to major habitat change: that is, clearance of forest fragments for agriculture. Over 7 years, fragments in Bulindi, Uganda, were reduced in size by 80%. We compared the chimpanzees' diet at the start and end of this period of rapid deforestation, using data derived mainly from fecal analysis. Similar to other long-term study populations, chimpanzees in Bulindi have a diverse diet comprising over 169 plant foods. However, extensive deforestation seemed to impact their feeding ecology. Dietary changes after fragment clearance included reduced overall frugivory, reduced intake of figs (Ficus spp.; formerly a dietary "staple" for these chimpanzees), and reduced variety of fruits in fecal samples. Nevertheless, the magnitude of most changes was remarkably minor given the extent of forest loss. Agricultural fruits increased in dietary importance, with crops accounting for a greater proportion of fruits in fecal samples after deforestation. In particular, cultivated jackfruit (Artocarpus heterophyllus) became a "staple" food for the chimpanzees but was scarcely eaten before fragment clearance. Crops offer some nutritional benefits for primates, being high in carbohydrate energy and low in hard-to-digest fiber. Thus, crop feeding may have offset foraging costs associated with loss of wild foods and reduced overall frugivory for the chimpanzees. The adaptability of many primates offers hope for their conservation in fragmented, rural landscapes. However, long-term data are needed to establish whether potential benefits (i.e. energetic, reproductive) of foraging in agricultural matrix habitats outweigh fitness costs from anthropogenic mortality risk for chimpanzees and other adaptable primates.

Immunomodulatory Effects of Stress and Environmental Enrichment in Long-Evans Rats (Rattus norvegicus).

Stress can influence the secretion of neuroendocrine mediators, thereby exposing immune cells to altered signaling and interactions. Here we investigated the synergetic effect of stress and environmental enrichment on the immune response of Long-Evans rats. Subjects (n = 46) were assigned to 5 treatment groups: acute compared with chronic stress with or without environmental enrichment, plus an unmanipulated control group. Animals also were classified as active, passive, and flexible copers according to back-test assessment. Rats were exposed to enrichment in an open-field containing objects in different areas for 30 min 3 times each week, thus modeling the effects of a temporary increase in environmental stimuli. Animals assigned to chronic stress groups were exposed to predator sound stressors for 30 min daily, whereas animals assigned to acute stress groups were exposed once each week. After 7 wk, a dermal punch biopsy was administered to activate the immune response, after which rats were challenged through a forced swim test. Biologic samples were collected to measure corticosterone, dehydroepiandrosterone (DHEA), oxytocin, testosterone, and the cytokines IL6 and IL10. Rats exposed to chronic stress had lower DHEA:corticosterone ratios, suggesting increased allostatic load. Enrichment exposure modulated these effects, lowering overall corticosterone and testosterone levels and increasing DHEA and oxytocin levels in animals exposed to the predator sound. The immune response was decreased in rats exposed to chronic stress, but the effect of environmental enrichment helped to mitigate the negative influence on cells producing IL6. Combining acute stress and exposure to an enriched environment returned a healthier profile in terms of both immune activation and stress regulation. By using a multidimensional scaling model, we found that a combination of 'good' stress and exposure to brief sessions of enriching stimuli can reliably predict health in Long-Evans rats.

Enriched Environment Exposure Enhances Social Interactions and Oxytocin Responsiveness in Male Long-Evans Rats.

Both social and physical stimuli contribute to the complexity of an animal's environment, influencing biobehavioral responses to subsequent challenges. In the current study, male Long-Evans rats were randomly assigned to an isolate (ISO), social control (SC) or social enriched (SE) group (n = 8 per group). The SC and SE conditions were group housed with the SE group exposed to physical enrichment stimuli that were natural as opposed to manufactured (e.g., hollowed out log instead of plastic hiding place). On three occasions during their 40-day enriched environment exposure, night/dark phase videos were obtained for 1 h during the early part of the dark phase. During this time, the SE animals exhibited significantly more social grooming with no differences between the SE and SC in the frequency of play or self-grooming bouts. Subsequently, all animals were assessed in social interaction and problem-solving escape tasks during the last week of the enriched environment exposure. SE rats exhibited increased digging bouts toward the restrained conspecific in the social interaction task whereas the other groups exhibited more escape responses. In the problem-solving task, SE animals exhibited a decreased latency to cross the barrier to escape from the predator odor (i.e., cat urine and fur). Neural analyses indicated increased oxytocin-immunoreactive (OT-ir) tissue in the SE supraoptic and paraventricular nuclei of the hypothalamus compared to the other groups. Interestingly, blood samples indicated lower peripheral corticosterone (CORT) and higher OT levels in the ISO animals when compared to the SC and SE animals, an effect retrospectively attributed to separation anxiety in the SE and SC animals in preparation for histology procedures. When the behavioral, neural and endocrine data were visualized as a multifaceted dataset via a multidimensional scaling analysis, however, an association between social enrichment and higher OT involvement was observed in the SE animals, as well as heightened stress responsivity in the ISO and SC groups. In sum, the SE animals exhibited a facilitation of social responses, problem-solving ability and OT immunoreactive responsiveness. These findings provide new information about the influences of both physical and social stimuli in dynamic and enriched environments.

Physiologic Correlates of Interactions between Adult Male and Immature Long-tailed Macaques (Macaca fascicularis).

Interactions between adult males and immature members of the same species are rare in most mammals; in contrast, an estimated 40% of primate species are characterized by an involvement of males in the social life of infants and juveniles. The proximate mechanisms of male-infant interactions are largely unstudied, and very few direct benefits for males have been proposed, especially in uniparental species in which the identity of the male parent is uncertain. In this study, we aimed to assess the relationship among behavioral and physiologic stress, health, and various affiliative behaviors initiated by adult males toward infants and juveniles in long-tailed macaques. We hypothesized that males that spent more time with infants and juveniles would have lower physiologic and social stress and better health than males with less interaction. We observed 2 troops of macaques with established social hierarchies (n = 18 in troop 1 and n = 8 in troop 2), each occupying a stable area within the enclosure, for more than 200 h. Fecal samples were used to assess cortisol levels as a measure of physiologic stress, and blood samples were collected to measure oxytocin levels as an index of social responsiveness. Our results indicated that male affiliative behavior directed toward immature animals was significantly higher in the troop characterized by more social conflicts; midranking males interacted more with infants than high- and low-ranking males in both troops. Furthermore, the DHEA:cortisol ratio, a physiologic index of resilience and coping, was positively correlated with males' affiliative responses, suggesting a neuroprotective role of male-infant interactions. In summary, our data support a proximate mechanism of alloparenting or paternal behavior in uniparental species. Interacting with infants and juveniles could provide an immediate neurobiologic benefit to adult males by facilitating adaptive coping responses to social tensions.

Profiling coping strategies in male and female rats: Potential neurobehavioral markers of increased resilience to depressive symptoms.

Coping strategies have been associated with differential stress responsivity, perhaps providing a valuable neurobiological marker for susceptibility to the emergence of depressogenic symptoms or vulnerability to other anxiety-related disorders. Rats profiled with a flexible coping phenotype, for example, exhibit increased neurobiological markers of emotional regulation compared to active and passive copers (Bardi et al., 2012; Lambert et al., 2014). In the current study, responses of male and female rats to prediction errors in a spatial foraging task (dry land maze; DLM) were examined after animals were exposed to chronic unpredictable stress (CUS). Brains were processed following the DLM training/assessment for fos-activation patterns and several measures of neuroplasticity in relevant areas. Behavioral responses observed during both the CUS and DLM phases of testing suggested that males and females employ different means of gathering information such as increased ambulatory exploration in males and rear responses in females. Fecal samples collected during baseline and following CUS swim exposure revealed higher corticosterone (CORT) in active copers, whereas flexible copers had higher dehydroepiandrosterone (DHEA) and DHEA/CORT ratios, both indications of enhanced emotional regulation. Focusing on the neural analysis, flexible copers exhibited fewer fos-immunoreactive cells in the basolateral amygdala and a trend toward lower activation in the insula while encountering the prediction error associated with the DLM probe trial. Coping profiles also differentially influenced markers of neuroplasticity; specifically, flexible copers exhibited higher levels nestin-immunoreactivity (ir). Further, less hippocampal glucocorticoid receptor-ir was observed in the flexible copers than the active and passive copers. In sum, flexible coping rats exhibited evidence of emotional resilience as indicated by several neurobiological measures; however, despite increased rates of depression and related symptoms reported in human females, sex effects weren't as pervasive as coping strategy profiles in the analysis of neurobiological markers employed in the current study.

Gastrointestinal parasite infections and self-medication in wild chimpanzees surviving in degraded forest fragments within an agricultural landscape mosaic in Uganda.

Monitoring health in wild great apes is integral to their conservation and is especially important where they share habitats with humans, given the potential for zoonotic pathogen exchange. We studied the intestinal parasites of wild chimpanzees (Pan troglodytes schweinfurthii) inhabiting degraded forest fragments amid farmland and villages in Bulindi, Uganda. We first identified protozoan and helminth parasites infecting this population. Sixteen taxa were demonstrated microscopically (9 protozoa, 5 nematodes, 1 cestode, and 1 trematode). DNA sequence analysis enabled more precise identification of larval nematodes (e.g. Oesophagostomum stephanostomum, O. bifurcum, Strongyloides fuelleborni, Necator sp. Type II) and tapeworm proglottids (genus Bertiella). To better understand the ecology of infections, we used multidimensional scaling analysis to reveal general patterns of association among parasites, climate, and whole leaf swallowing-a prevalent self-medicative behaviour at Bulindi linked to control of nodular worms (Oesophagostomum spp.). Prevalence of parasites varied with climate in diverse ways. For example, Oesophagostomum sp. was detected in faeces at higher frequencies with increasing rainfall but was most clearly associated with periods of low temperature. Certain parasites occurred together within chimpanzee hosts more or less frequently than expected by chance. For example, the commensal ciliate Troglodytella abrassarti was negatively associated with Balantidium coli and Oesophagostomum sp., possibly because the latter taxa make the large intestine less suitable for T. abrassarti. Whole leaves in faeces showed independent associations with the prevalence of Oesophagostomum sp., Strongyloides sp., and hookworm by microscopic examination, and with egestion of adult O. stephanostomum by macroscopic inspection. All parasites identified to species or genus have been reported in wild chimpanzees inhabiting less-disturbed environments than Bulindi. Nevertheless, several disease-causing taxa infecting these chimpanzees are potentially transmissible between apes and humans (e.g. rhabditoid and strongyle nematodes), underscoring the importance of identifying and reducing risks of pathogen exchange in shared landscapes.

Natural-enriched environments lead to enhanced environmental engagement and altered neurobiological resilience.

The mammalian brain has evolved in close synchrony with the natural environment; consequently, trends toward disengagement from natural environments in today's industrialized societies may compromise adaptive neural responses and lead to psychiatric illness. Investigations of rodents housed in enriched environments indicate enhanced neurobiological complexity; yet, the origin of these stimuli, natural vs. manufactured, has not been sufficiently explored. In the current study, groups of rats were exposed to one of three environments: (1) a standard environment with only food and water, (2) an artificial-enriched environment with manufactured stimuli and (3) a natural-enriched environment with natural stimuli. Results indicated that, during the dark phase, natural-enriched animals exhibited longer durations interacting with objects than the artificial-enriched group; further, the natural-enriched group engaged in more social behavior than the other two groups. Both enriched groups exhibited less anxiety in response to a novel object but the natural-enriched rats exhibited less anxiety-typical behavior in response to a predator odor than the other groups. Less fos activation in the amygdala was observed in both enriched groups following a water escape task whereas an increase in fos activation in the nucleus accumbens was observed in the natural-enriched animals. Thus, the current findings indicate the potential importance of exposure to complex environments, especially natural-like habitats, in the maintenance of emotional health, perhaps providing a buffer against the emergence of anxiogenic responses.

Paternal retrievals increase testosterone levels in both male and female California mouse (Peromyscus californicus) offspring.

The importance of maternal care on offspring development has received considerable attention, although more recently, researchers have begun to focus on the significance of paternal contributions. In the monogamous and bi-parental California mouse, fathers provide high levels of care, and therefore serve as a model system for studying paternal effects on behavior and underlying neuroendocrine mechanisms. Paternal retrievals in this species influence long term changes in brain (expression of arginine vasopressin-AVP) and behavior (aggression and parenting) in adult male offspring. Further, paternal retrievals induce a transient increase in testosterone (T) in male offspring, which is thought to mediate the relationship between paternal retrievals and AVP expression. Although the father-son relationship has been well characterized, few studies have examined father-daughter interactions. In California mice, paternal retrievals increase aggression in female offspring. Although T has been implicated in the regulation of female aggression, it remains unclear whether T may underlie long-term changes in female offspring aggression in response to paternal retrievals. In the current study, we examined the influence of paternal retrievals on T in both male and female offspring. Retrievals were manipulated experimentally by displacement of the pup and trunk blood was collected from retrieved, non-retrieved, and non-manipulated (baseline) pups. We found that fathers expressed similar levels of retrievals towards sons and daughters, and that T levels were elevated in retrieved, as compared to non-retrieved offspring. Similar to what has been previously described in male offspring and replicated here, female offspring that were retrieved had higher T levels than non-retrieved females. Neither females nor males experienced a change in corticosterone levels in response to retrievals suggesting offspring do not mount a stress response to paternal care. Therefore, our data suggest that paternal retrievals may serve similar functions in shaping adult behavior in both male and female offspring via modulation of hormone levels.

Reproductive experiential regulation of cognitive and emotional resilience.

Adaptation virtually defines survival. For mammals, arguably, no other developmental milestone is exemplified by--nor more reliant on--the sudden and dramatic behavioral alterations observed in the maternal female, which rapidly must undergo change in order to express a large suite of proper and effective maternal behaviors. As pregnancy progresses, as well as during lactation, when pup cues are rich and rampant, the female is literally transformed from an organism that actively avoided offspring-related signals, to one highly motivated by those same cues to build nests, be attracted to pups and to retrieve, group, groom, crouch-over, care for, and protect, the young. Ancillary responses such as reference memory, spatial learning, foraging (including predation), and boldness improve in mothers compared to virgins. Such modifications arise early and are persistent, with neural benefits that last well into senescence. Evolutionarily, such enhancements have likely reduced the maternal burdens associated with sheltering and feeding the vulnerable young; collectively, this strengthens the mother's/parent's reproductive fitness and that of the pups in which all this effort is invested. Of the many behaviors that change as a function of pending or concurrent maternity, therefore, what is the role of modifications to resilience, the ability to withstand the numerous, unpredictable, and threatening environmental events that the mother/parent must daily, indeed, multiply daily, face and thwart in order to bring the offspring from pups to fully functioning adults. We explore these questions, and their connections, here in a multi-disciplinary manner focused on the constellation of change that summates to fundamentally alter the female for the rest of her life. Behavior, brain, neurochemistry and genes are fundamentally changed as the substrate for reproduction unfolds and expresses its inherent plasticity.

Parity modifies endocrine hormones in urine and problem-solving strategies of captive owl monkeys (Aotus spp.).

Parental behavior modifies neural, physiologic, and behavioral characteristics of both maternal and paternal mammals. These parenting-induced modifications extend to brain regions not typically associated with parental responses themselves but that enhance ancillary responses, such as foraging efficiency and predator avoidance. Here we hypothesized that male and female owl monkeys (Aotus spp.) with reproductive experience (RE) would demonstrate more adaptive ancillary behavioral and neuroendocrine responses than those of their nonRE counterparts. To assess cognitive skills and coping flexibility, we introduced a foraging strategy task, including a set of novel objects (coin holders) marked with different symbols representing different food rewards, to the animals. To assess endocrine responses, urine samples were assayed for cortisol and dehydroepiandrosterone (DHEA) levels and their ratios to determine physiologic measures of emotional regulation in RE and nonRE owl monkeys. Compared with nonRE monkeys, experienced parents had higher DHEA:cortisol ratios after exposure to habituation training and on the first day of testing in the foraging task. Both hormones play critical roles in the stress response and coping mechanisms, and a high DHEA:cortisol ratio usually indicates increased coping skills. In addition, RE monkeys exhibited more efficient foraging responses (by 4-fold) than did the nonRE mating pairs. We conclude that RE modifies relevant behavioral and hormonal responses of both maternal and paternal owl monkeys exposed to a challenging cognitive paradigm. Corroborating previous research demonstrating adaptive modifications in foraging efficiency and emotional responses in reproductively experienced rodents, the current results extend these findings to a monogamous primate species.

The mother as hunter: significant reduction in foraging costs through enhancements of predation in maternal rats.

In previous laboratory investigations, we have identified enhanced cognition and reduced stress in parous rats, which are likely adaptations in mothers needing to efficiently exploit resources to maintain, protect and provision their immature offspring. Here, in a series of seven behavioral tests on rats, we examined a natural interface between cognition and resource gathering: predation. Experiment 1 compared predatory behavior (toward crickets) in age-matched nulliparous mothers (NULLs) and postpartum lactating mothers (LACTs), revealing a highly significant enhancement of predation in LACT females (mean = -65s in LACTs, vs. -270s in NULLs). Experiment 2 examined the possibility that LACTs, given their increased metabolic rate, were hungrier, and thus more motivated to hunt; doubling the length of time of food deprivation in NULLs did not decrease their predatory latencies. Experiments 3-5, which examined sensory regulation of the effect, indicated that olfaction (anosmia), audition (blockade with white noise), and somatosensation (trimming the vibrissae) appear to play little role in the behavioral enhancement observed in the LACTs; Experiment 6 examined the possibility that visual augmentations may facilitate the improvements in predation; testing LACTs in a 0-lux environment eliminated the behavioral advantage (increasing their latencies from -65s to -212s), which suggests that temporary augmentation to the visual system may be important, and with hormone-neural alterations therein a likely candidate for further study. In contrast, testing NULLS in the 0-lux environment had the opposite effect, reducing their latency to catch the cricket (from -270s to -200s). Finally, Experiment 7 examined the development of predatory behavior in Early-pregnant (PREG), Mid-PREG, and Late-PREG females. Here, we observed a significant enhancement of predation in Mid-PREG and Late-PREG females--at a time when maternity-associated bodily changes would be expected to diminish predation ability--relative to NULLs. Therefore, as with the increasing reports of enhancements to the maternal brain, it is apparent that meaningful behavioral adaptations occur that likewise promote the survival of the mother and her infants at a crucial stage of their lives.