Disrupted development from head to tail: Pervasive effects of postnatal restricted resources on neurobiological, behavioral, and morphometric outcomes.

When a maternal rat nurtures her pups, she relies on adequate resources to provide optimal care for her offspring. Accordingly, limited environmental resources may result in atypical maternal care, disrupting various developmental outcomes. In the current study, maternal Long-Evans rats were randomly assigned to either a standard resource (SR) group, provided with four cups of bedding and two paper towels for nesting material or a limited resource (LR) group, provided with a quarter of the bedding and nesting material provided for the SR group. Offspring were monitored at various developmental phases throughout the study. After weaning, pups were housed in same-sex dyads in environments with SRs for continued observations. Subsequent behavioral tests revealed a sex × resource interaction in play behavior on PND 28; specifically, LR reduced play attacks in males while LR increased play attacks in females. A sex × resource interaction was also observed in anxiety-related responses in the open field task with an increase in thigmotaxis in LR females and, in the social interaction task, females exhibited more external rears oriented away from the social target. Focusing on morphological variables, tail length measurements of LR males and females were shorter on PND 9, 16, and 21; however, differences in tail length were no longer present at PND 35. Following the behavioral assessments, animals were perfused at 56 days of age and subsequent immunohistochemical assays indicated increased glucocorticoid receptors in the lateral habenula of LR offspring and higher c-Fos immunoreactivity in the basolateral amygdala of SR offspring. Further, when tail vertebrae and tail tendons were assessed via micro-CT and hydroxyproline assays, results indicated increased trabecular separation, decreased bone volume fraction, and decreased connectivity density in bones, along with reduced collagen concentration in tendons in the LR animals. In sum, although the restricted resources only persisted for a brief duration, the effects appear to be far-reaching and pervasive in this early life stress animal model.

Developmental Lead Exposure in Rats Causes Sex-Dependent Changes in Neurobiological and Anxiety-Like Behaviors that Are Improved by Taurine Co-treatment.

Lead (Pb2+) is a developmental neurotoxicant that causes alterations in the brain's excitation-to-inhibition (E/I) balance by disrupting the development of the GABAergic systems. These GABAergic disruptions have persistent neurobiological and neurobehavioral structure-function relationships that can be examined using animal models of Pb2+ exposure. Further, taurine, a GABA-AR agonist, has been shown to offer neuroprotection against neurodevelopmental Pb2+ exposure and senescence. The present study evaluated the effects of Pb2+ exposure (i.e., at 150 ppm and 1,000 ppm doses) on Long Evans hooded rats during the perinatal period of development on locomotor activity in the open field (OF) and anxiety-like behaviors in the elevated plus maze (EPM). This was followed by an examination of brain mass using an encephalization quotient (EQ) and isotropic fractionation (ITF) of total cells and the number of neurons and non-neuronal cells in the prefrontal cortex, hippocampus, and diencephalon. The results suggest that neurodevelopmental Pb2+ exposure caused persistent anxiety-like behaviors in both the OF and EPM with associated changes in EQ, but not ITF-determined cell density. Further, taurine treatment was observed to compensate for Pb2+ exposure in the behavioral assessments although precise neurobiological mechanisms remain unknown. Thus, more work is required to evaluate the role of taurine and other anxiolytic compounds in the alleviation of neurotoxicant-induced neurobehavioral syndromes and their associated neurobiological correlates.

The emotional impact of disrupted environmental contexts: Enrichment loss and coping profiles influence stress response recovery in Long-Evans rats.

With increasing rates of anxiety and mood disorders across the world, there is an unprecedented need for preclinical animal models to generate translational results for humans experiencing disruptive emotional symptoms. Considering that life events resulting in a perception of loss are correlated with depressive symptoms, the enrichment-loss rodent model offers promise as a translational model for stress-initiated psychiatric disorders. Additionally, predisposed temperament characteristics such as coping styles have been found to influence an individual's stress response. Accordingly, male rats were profiled as either consistent or flexible copers and assigned to one of three environments: standard laboratory housing, enriched environment, or enriched environment exposure followed by downsizing to standard laboratory cages (i.e., enrichment-loss group). Throughout the study, several behaviors were assessed to determine stress, social, and reward-processing responses. To assess recovery of the stress response, fecal samples were collected following the swim stress in 3-h increments to determine the recovery trajectory of corticosterone (CORT) and dehydroepiandrosterone (DHEA) metabolite levels. Upon death, neural markers of neuroplasticity including doublecortin, glial fibrillary acidic factor, and brain-derived neurotrophic factor were assessed via immunohistochemistry. Results indicated the flexible coping animals in the continuous enriched group had higher DHEA/CORT ratios (consistent with adaptive responses in past research); furthermore, the enrichment-loss animals exhibited a blunted CORT response throughout the assessments and enriched flexible copers had faster CORT recovery rates than consistent copers. Standard housed animals exhibited less exploratory behavior in the open field task and continuous enriched, flexible rats consumed more food rewards than the other groups. No differences in neuroplasticity neural markers were observed. In sum, the results of the present study support past research indicating the disruptive consequences of enrichment-loss, providing evidence that the model represents a valuable approach for the investigation of neurobiological mechanisms contributing to interindividual variability in responses to changing experiential landscapes.

Neurobiological effects of a probiotic-supplemented diet in chronically stressed male Long-Evans rats: Evidence of enhanced resilience.

Probiotics that regulate the microbiome-gut-brain axis and provide mental health benefits to the host are referred to as psychobiotics. Preclinical studies have demonstrated psychobiotic effects on early life stress-induced anxiety- and depression-related behavior in rodents; however, the specific mechanisms remain ill-defined. In the current study, we investigated the effects of probiotic supplementation on neurobiological responses to chronic stress in adult male Long-Evans rats. Twenty-four rats were randomly assigned to probiotic (PB) or vehicle control (VEH) groups, then to either chronic unpredictable stress (CUS) or no-stress control (CON) conditions within each group (n = 6/subgroup). We hypothesized that PB supplementation would reduce markers of anxiety and enhance emotional resilience, especially in the CUS animals. In the cognitive uncertainty task, a nonsignificant trend was observed indicating that the PB-supplemented animals spent more time oriented toward the food reward than VEH animals. In the open-field task, CUS-PB animals spent more time in the center of the arena than CUS-VEH animals, an effect not observed between the two CON groups. In the swim task, the PB animals, regardless of stress assignment, exhibited increased floating, suggesting a conserved response in a challenging context. Focusing on the endocrine measures, higher dehydroepiandrosterone (DHEA)-to-corticosterone fecal metabolite ratios, a correlate of emotional resilience, were observed in PB animals. Further, PB animals exhibited reduced microglia immunoreactivity in the basolateral amygdala, possibly indicating a neuroprotective effect of PB supplements in this rodent model. These results provide evidence that PB supplementation interacts with stress exposure to influence adaptive responses associated with endocrine, neural, and behavioral indices of anxiety.

Cytoarchitectural characteristics associated with cognitive flexibility in raccoons.

With rates of psychiatric illnesses such as depression continuing to rise, additional preclinical models are needed to facilitate translational neuroscience research. In the current study, the raccoon (Procyon lotor) was investigated due to its similarities with primate brains, including comparable proportional neuronal densities, cortical magnification of the forepaw area, and cortical gyrification. Specifically, we report on the cytoarchitectural characteristics of raccoons profiled as high, intermediate, or low solvers in a multiaccess problem-solving task. Isotropic fractionation indicated that high-solvers had significantly more cells in the hippocampus (HC) than the other solving groups; further, a nonsignificant trend suggested that this increase in cell profile density was due to increased nonneuronal (e.g., glial) cells. Group differences were not observed in the cellular density of the somatosensory cortex. Thionin-based staining confirmed the presence of von Economo neurons (VENs) in the frontoinsular cortex, although no impact of solving ability on VEN cell profile density levels was observed. Elongated fusiform cells were quantified in the HC dentate gyrus where high-solvers were observed to have higher levels of this cell type than the other solving groups. In sum, the current findings suggest that varying cytoarchitectural phenotypes contribute to cognitive flexibility. Additional research is necessary to determine the translational value of cytoarchitectural distribution patterns on adaptive behavioral outcomes associated with cognitive performance and mental health.

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.

In search of optimal resilience ratios: Differential influences of neurobehavioral factors contributing to stress-resilience spectra.

The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal's position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.

Avoiding Beach's Boojum Effect: Enhancing bench to bedside translation with field to laboratory considerations in optimal animal models.

Pioneering comparative neuroendocrinologist Frank Beach cautioned researchers of the dangers of investing too much research energy in a single species (i.e., the laboratory rat) in the pursuit of limited behavioral investigations (e.g., learning) in his 1950 article entitled The snark was a boojum. Over a half-century later, behavioral neuroscientists continue to focus disproportionately on rodent models and, although exciting cutting-edge neuroscience techniques are currently utilized, the sophistication of behavioral approaches often lag behind these neurobiological methodological tools. The predictable, sterile laboratory environments, referred to as niceties by Beach, also present challenges to the investigation of relevant, species-specific responses to unpredictable natural environments. As more attention is directed to these methodological issues, fundamental information about nervous systems, as well as the translational value of studies utilizing various animal models, will be enhanced.

Maternal-induced shifts in allostatic demands: Reproductive experience alters emotional and cognitive biobehavioral responses in rats (Rattus norvegicus).

The arrival and subsequent care of offspring require abrupt shifts in biobehavioral responses in mammalian mothers. In the current study, female rats with one reproductive experience [primiparous (PRIM) rats, n = 8] or no reproductive experience [nulliparous (NULL) rats, n = 8] were assessed in a dry land maze to determine both learning acquisition and responses to uncertainty/prediction errors during the probe trial. Additionally, rats were observed in a swim task and an open field arena to assess responsiveness to varied environmental challenges. Results indicated that the PRIM rats investigated more previously baited wells during the probe trial (on-task behavior) whereas the NULL rats exhibited more peripheral-oriented rearing responses (off-task behavior). Further, a nonsignificant trend was observed indicating more dive responses in the PRIM animals. Focusing on endocrine markers, the PRIM animals had higher DHEA/CORT ratios than the NULL animals following the probe trial. Finally, PRIM animals had less hippocampal glucocorticoid receptor immunoreactivity and more hippocampal BDNF immunoreactivity than NULL animals. In sum, behavioral, endocrine and neural markers suggest that PRIM rats exhibit long-lasting modifications to stress responsivity.

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.

Changes in behavior and brain immediate early gene expression in male threespined sticklebacks as they become fathers.

Motherhood is a period of intense behavioral and brain activity. However, we know less about the neural and molecular mechanisms associated with the demands of fatherhood. Here, we report the results of two experiments designed to track changes in behavior and brain activation associated with fatherhood in male threespined stickleback fish (Gasterosteus aculeatus), a species in which fathers are the sole providers of parental care. In experiment 1, we tested whether males' behavioral reactions to different social stimuli depends on parental status, i.e. whether they were providing parental care. Parental males visited their nest more in response to social stimuli compared to nonparental males. Rates of courtship behavior were high in non-parental males but low in parental males. In experiment 2, we used a quantitative in situ hybridization method to compare the expression of an immediate early gene (Egr-1) across the breeding cycle - from establishing a territory to caring for offspring. Egr-1 expression peaked when the activities associated with fatherhood were greatest (when they were providing care to fry), and then returned to baseline levels once offspring were independent. The medial dorsal telencephalon (basolateral amygdala), lateral part of dorsal telencephalon (hippocampus) and anterior tuberal nucleus (ventral medial hypothalamus) exhibited high levels of Egr-1 expression during the breeding cycle. These results help to define the neural circuitry associated with fatherhood in fishes, and are consistent with the hypothesis that fatherhood - like motherhood - is a period of intense behavioral and neural activity.

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.

Neuromolecular responses to social challenge: common mechanisms across mouse, stickleback fish, and honey bee.

Certain complex phenotypes appear repeatedly across diverse species due to processes of evolutionary conservation and convergence. In some contexts like developmental body patterning, there is increased appreciation that common molecular mechanisms underlie common phenotypes; these molecular mechanisms include highly conserved genes and networks that may be modified by lineage-specific mutations. However, the existence of deeply conserved mechanisms for social behaviors has not yet been demonstrated. We used a comparative genomics approach to determine whether shared neuromolecular mechanisms could underlie behavioral response to territory intrusion across species spanning a broad phylogenetic range: house mouse (Mus musculus), stickleback fish (Gasterosteus aculeatus), and honey bee (Apis mellifera). Territory intrusion modulated similar brain functional processes in each species, including those associated with hormone-mediated signal transduction and neurodevelopment. Changes in chromosome organization and energy metabolism appear to be core, conserved processes involved in the response to territory intrusion. We also found that several homologous transcription factors that are typically associated with neural development were modulated across all three species, suggesting that shared neuronal effects may involve transcriptional cascades of evolutionarily conserved genes. Furthermore, immunohistochemical analyses of a subset of these transcription factors in mouse again implicated modulation of energy metabolism in the behavioral response. These results provide support for conserved genetic "toolkits" that are used in independent evolutions of the response to social challenge in diverse taxa.

Reexamining syphilis: an update on epidemiology, clinical manifestations, and management.

OBJECTIVE: To review the epidemiology, clinical features, diagnosis, and treatment of syphilis. DATA SOURCES: Studies and reviews were abstracted from MEDLINE (1950-April 2007) using the search term syphilis. All papers were cross-referenced to identify additional studies and reviews for inclusion. STUDY SELECTION AND DATA EXTRACTION: Pertinent original research articles, review articles, and book chapters were evaluated. DATA SYNTHESIS: Syphilis is a spirochetal disease that has plagued mankind for centuries. Following a low incidence of syphilis in the US for the last 2 decades, rates are now increasing both in the US and other parts of the world. Once acquired, syphilis can pass through 4 distinct stages of disease: primary syphilis, secondary syphilis, latent syphilis, and tertiary syphilis, with each stage being characterized by different symptoms and levels of infectivity. Diagnosis is made primarily by serologic assays with nontreponemal tests such as the Venereal Disease Research Laboratory and the Rapid Plasma Reagin assay used for screening. Treponemal tests including the Treponema pallidum particle agglutination and the fluorescent treponemal antibody absorption test are then used for confirmation. Recommended treatment regimens are based largely on uncontrolled trials and clinical experience. Penicillin is the treatment of choice, with the preparation and treatment duration varying for different stages. Benzathine penicillin is the treatment of choice for all stages of syphilis except neurosyphilis, for which aqueous crystalline penicillin or procaine penicillin is used due to the central nervous system penetration of these formulations. Coinfection with both syphilis and HIV occurs frequently due to common risk factors. These 2 diseases interact with each other, making both diagnosis and treatment more complicated. CONCLUSIONS: Clinicians should be aware of the signs and symptoms of syphilis as well as current guidelines for the management and treatment of this disease.