Amanda Kentner

Exposure to adverse childhood experiences (ACEs) is a risk factor for the development of psychiatric disorders in addition to cardiovascular associated diseases. This risk is elevated when the cumulative burden of ACEs is increased. Laboratory animals can be used to model the changes (as well as the underlying mechanisms) that result in response to adverse events. In this study, using male and female Sprague Dawley rats, we examined the impact of increasing stress burden, utilizing both two adverse early life experiences (parental/offspring high fat diet + limited bedding exposure) and three adverse early life experiences (parental/offspring high fat diet + limited bedding exposure + neonatal inflammation), on maternal care quality and offspring behavior. Additionally, we measured hormones and hippocampal gene expression related to stress. We found that the adverse perinatal environment led to a compensatory increase in maternal care. Moreover, these dams had reduced maternal expression of oxytocin receptor, compared to standard housed dams, in response to acute stress on postnatal day (P)22. In offspring, the two-hit and three-hit models resulted in a hyperlocomotor phenotype and increased body weights. Plasma leptin and hippocampal gene expression of corticotropin releasing hormone (Chrh)1 and Crhr2 were elevated (males) while expression of oxytocin was reduced (females) following acute stress. On some measures (e.g., hyperlocomotion, leptin), the magnitude of change was lower in the three-hit compared to the two-hit model. This suggests that multiple early adverse events can have interactive, and often unpredictable, impacts, highlighting the importance of modeling complex interactions amongst stressors during development.

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study, we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual pairwise discrimination (PD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the PD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a 'two-hit' stress model (MIA + loss of the social component of environmental enrichment [EE]), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in, delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right 'dose', early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built poorer quality nests, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers. Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluated c-Fos immunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA axis dysregulation. Our findings provide further evidence for the viability of EE interventions in maternal and pediatric settings.

The reproducibility and translation of neuroscience research is assumed to be undermined by introducing environmental complexity and heterogeneity. Rearing laboratory animals with minimal (if any) environmental stimulation is thought to control for biological variability but may not adequately test the robustness of our animal models. Standard laboratory housing is associated with reduced demonstrations of species typical behaviors and changes in neurophysiology that may impact the translation of research results. Modest increases in environmental enrichment (EE) mitigate against insults used to induce animal models of disease, directly calling into question the translatability of our work. This may in part underlie the disconnect between preclinical and clinical research findings. Enhancing environmental stimulation for our model organisms promotes ethological natural behaviors but may simultaneously increase phenotypic trait variability. To test this assumption, we conducted a systematic review and evaluated coefficients of variation (CVs) between EE and standard housed mice and rats. Given findings of suboptimal reporting of animal laboratory housing conditions, we also developed a methodological reporting table for enrichment use in neuroscience research. Our data show that animals housed in EE were not more variable than those in standard housing. Therefore, environmental heterogeneity introduced into the laboratory, in the form of enrichment, does not compromise data integrity. Overall, human life is complicated, and by embracing such nuanced complexity into our laboratories, we may paradoxically improve on the rigor and reproducibility of our research.

Maternal immune activation (MIA) has been identified as a significant risk factor for several neurodevelopmental disorders. We have previously demonstrated that postpubertal environmental enrichment (EE) rescues and promotes resiliency against MIA in male rats. Importantly, EE protocols have demonstrated clinical relevancy in human rehabilitation settings. Applying some of the elements of these EE protocols (e.g. social, physical, cognitive stimulation) to animal models of health and disease allows for the exploration of the mechanisms that underlie their success. Here, using a MIA model, we further investigate the rehabilitative potential of complex environments with a focus on female animals. Additionally, we expand upon some of our previous work by exploring genetic markers of synaptic plasticity and stress throughout several brain regions of both sexes. In the current study, standard housed female Sprague-Dawley rats were challenged with either the inflammatory endotoxin lipopolysaccharide (LPS; 100 μg/kg) or saline (equivolume) on gestational day 15. On postnatal day 50, male and female offspring were randomized into one of three conditions that differed in terms of cage size, number of cage mates (social stimulation) and enrichment materials. Spatial discrimination ability and social behavior were assessed six weeks later. Similar to our previously published work in males, our results revealed that a single LPS injection during mid gestation disrupted spatial discrimination ability in female rats. Postpubertal EE rescued this disruption. On the endocrine level, EE dampened elevations in plasma corticosterone that followed MIA, which may mediate EE's rehabilitative effects in female offspring. Within the prefrontal cortex, hippocampus, amygdala, and hypothalamus, MIA and EE altered the mRNA expression of several genes associated with resiliency and synaptic plasticity in both sexes. Overall, our findings provide further evidence that EE may serve as a therapeutic intervention for MIA-induced behavioral and cognitive deficits. Moreover, we identify some sexually dimorphic molecular mechanisms that may underlie these impairments and their rescue.

Despite the increasing attention to early life adversity and its long-term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later-life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota.

Both basic and clinical research support the use of tactile stimulation to rescue several neurobiobehavioral consequences that follow early life stress. Here, using a translational rodent model of the neonatal intensive care unit (NICU), we tested the individual prophylactic potential of a variety of sensory interventions including tactile (brushing pups with a paint brush to mimic maternal licking), auditory (a simulated lactating rat dam heart beat), and olfactory (a series of aroma therapy scents) stimulation. The NICU model was developed to mimic not only the reduced parental contact that sick infants receive (by isolating rat pups from their litters), but also the nosocomial infections and medical manipulations associated with this experience (by utilizing a dual lipopolysaccharide injection schedule). Each of the neurobiobehavioral consequences observed were dissociable between isolation and inflammation, or required a combined presentation ('two hits') of the neonatal stressors. Sprague-Dawley rats exposed to these early life stressors presented with sex-specific disruptions in both separation-induced ultrasonic vocalization (USV) distress calls (males & females) and juvenile social play USVs (males only). All three sensory enhancement interventions were associated with the rescue of potentiated distress calls while olfactory stimulation was protective of social vocalizations. Female rats exposed to early life stress experienced precocious puberty and shifts in the hypothalamic GnRh axis; sensory enrichment counter-acted the advanced pubertal onset. Animals that underwent the NICU protocol also displayed maturational acceleration in terms of the loss of the rooting reflex in addition to hyperalgesia, a reduced preference for a novel conspecific, blunted basal plasma corticosterone and reduced hippocampal glucocorticoid receptor expression. These alterations closely simulated the clinical effects of early life adversity in terms of disruptions in the hypothalamic pituitary "stress" axis, social communication and engagement, tactile system processing, and accelerated maturation. Moreover, sensory enrichment attenuated many of these behavioral and neurophysiological alterations, and even slowed maturation. Overall, this supports the translatability of our novel rodent model and its potential utility in understanding how brain maturation and quality of early life experiences may interact to shape the integrity of stress and sensory system development. Future work must determine the appropriate modalities and parameters (e.g. patterning, timing) for effective sensory enrichment interventions

The 2017 American College of Neuropychopharmacology (ACNP) conference hosted a Study Group on 4 December 2017, Establishing best practice guidelines to improve the rigor, reproducibility, and transparency of the maternal immune activation (MIA) animal model of neurodevelopmental abnormalities. The goals of this session were to (a) evaluate the current literature and establish a consensus on best practices to be implemented in MIA studies, (b) identify remaining research gaps warranting additional data collection and lend to the development of evidence-based best practice design, and (c) inform the MIA research community of these findings. During this session, there was a detailed discussion on the importance of validating immunogen doses and standardizing the general design (e.g., species, immunogenic compound used, housing) of our MIA models both within and across laboratories. The consensus of the study group was that data does not currently exist to support specific evidence-based model selection or methodological recommendations due to lack of consistency in reporting, and that this issue extends to other inflammatory models of neurodevelopmental abnormalities. This launched a call to establish a reporting checklist focusing on validation, implementation, and transparency modeled on the ARRIVE Guidelines and CONSORT (scientific reporting guidelines for animal and clinical research, respectively). Here we provide a summary of the discussions in addition to a suggested checklist of reporting guidelines needed to improve the rigor and reproducibility of this valuable translational model, which can be adapted and applied to other animal models as well

Early life exposure to a low security setting, characterized by a scarcity of resources and limited food access, increases the risk for psychiatric illness and metabolic dysfunction. We utilized a translational rat model to mimic a low security environment and determined how this manipulation affected offspring behavior, metabolism, and puberty. Because food insecurity in humans is associated with reduced access to healthy food options the "low security" rat manipulation combined a Western diet with exposure to a limited bedding and nesting manipulation (WD-LB). In this setting, dams were provided with limited nesting materials during the pups' early life (P2-P10). This manipulation was contrasted with standard rodent caging (SD) and environmental enrichment (EE), to model "medium security" and "high security" environments, respectively. To determine if transitioning from a low to high security environment improved outcomes, some juvenile WD-LB offspring were exposed to EE. Maternal care was impacted by these environments such that EE dams engaged in high quality care when on the nest, but spent less time on the nest than SD dams. Although WD-LB dams excessively chased their tails, they were very attentive to their pups, perhaps to compensate for limited resources. Offspring exposed to WD-LB only displayed subtle changes in behavior. However, WD-LB exposure resulted in significant metabolic dysfunction characterized by increased body weight, precocious puberty and alterations in the hypothalamic kisspeptin system. These negative effects of WD-LB on puberty and weight regulation were mitigated by EE exposure. Collectively, these studies suggest that both compensatory maternal care and juvenile enrichment can reduce the impact of a low security environment. Moreover, they highlight how utilizing diverse models of resource (in)stability can reveal mechanisms that confer vulnerability and resilience to early life stress

Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.

Methods for understanding the neurocircuitry of ethologically relevant behaviors have advanced substantially ; however renovations to standard animal laboratory housing, in the form of enhanced enrichment, have lagged behind. This is despite evidence that environmental enrichment (EE) reduces stress, stereotypy, and promotes healthy species typical behaviors. While many scientists express interest for increased EE as a standard for animal caging systems, there are concerns that its effects on brain, behavior, and cognition are not well characterized. In the present study, male and female Sprague–Dawley rats were housed for six weeks in either EE, Colony Nesting (CN), or Standard Housing (SD) conditions. We show that adolescent exposure to environmental complexity changed the dynamics of social interactions, sensory processing, and underlying basal stress neuro-circuitry, in a sex-and enrichment-type-dependent manner. Specifically, EE and CN increased prosocial engagement and the social saliency of male and female rats while the profile of hippocampal Crhr2 expression was affected only in EE males. Hippocampal Crh was associated with anxiety-like behavior in SD males – this did not extend to EE or CN groups, nor to females. Observations such as these are an important consideration for the validity of translational research investigating the neurocircuitry of stress resiliency, and for understanding the mechanisms of psychiatric disorders. Future work must focus on characterizing how individual environmental enhancements (e.g. novelty, social enrichment, physical activity) shape phenotypic differences, how they vary as a function of species, strain and sex, and (if warranted) how to meaningfully implement this knowledge into biomedical research designs.

Epidemiological evidence suggests that exposure to infection during early development increases the risk for neurodevelopmental disorders associated with symptoms such as a decreased desire to engage in social interactions. In animals, disruptions in social behavior can be modelled by administering bacterial mimetics such as liposaccharide (LPS). However, when evaluating social interactions in the laboratory, attention is rarely directed on the reciprocal relationship as a whole, which is important as peers may drive social withdrawal. Previously, we have shown that male adolescent rats treated neonatally (n) with LPS receive less contact from their con-specifics in a social interaction test, and that this effect is mediated through olfactory communication. In the present study, we reconfirmed this effect using a more direct social test and evaluated the hypothesis that changes in the microbiome underlie the olfactory induced social aversion. Male and female Sprague-Dawley rats were administered nLPS (50 μg/kg, i.p) or nSaline on postnatal days (P)3 and 5. On P40, adolescent nLPS treated males received less contact in a social preference test compared to nSaline treated controls, an effect not observed in females. To confirm that nLPS led male rats to elicit a scent cue, resulting in social aversion, a subset of neurotypical conspecifics underwent an anosmia procedure that disrupted their olfactory processing via olfac-tory neuroepithelium degeneration. This normalized the contact that they directed towards nLPS and nSaline male rats. Although 16 s rRNA sequencing failed to detect significant differences in bacterial phyla across either sex or neonatal treatment, treating male nLPS rats with an antibiotic cocktail, which induced clear changes in microbial communities, diminished the social rejection effect. Therefore, manipulation of the microbiome appears to affect social communication where there exists an underlying deficit. Moreover, our data reaffirm that social engagement is a reciprocal process and the behavior of all individuals within a dynamic interaction should be evaluated.

Given that both men and women experience cardiovascular disease (CVD), a common misconception is that they have similar risk factors and clinical presentation, receive comparable treatment, and have equivalent clinical outcomes; in reality differences are observed between men and women for each of these endpoints. Moreover, these differences occur as a function of both gender and sex. A review of the literature reveals widespread bias in the selection of research subjects based on these factors, in addition to implicit patient and provider biases that impede the access of women to recommended primary and secondary CVD management. In this perspective, we identify strategies to eliminate such biases and improve women's access to CVD treatments to ensure their care is consistent with current guidelines.

Exposure to painful procedures and/or stressors during the early neonatal period can reprogram the underlying neurocircuitry involved in nociception and neuropathic pain perception. The reprogramming of these systems can result in an enduring elevation in sensitivity towards mechanical and thermal stimuli. Recent evidence suggests that exposure to mild inflammatory mediators during the neonatal period can induce similar pain responses in both adolescent and adult rats. Therefore, we sought to profile changes in the expression of several genes across brain areas involved in the active modulation of noci-ception and neuropathic pain using a well-recognized model of neonatal inflammation. In the present study male and female Sprague-Dawley rats were administered either the inflammatory endotoxin lipopolysaccharide (LPS; 0.05 mg/kg, i.p.) or saline (equivolume) on postnatal days (PND) 3 and 5. During adolescence, hind paw mechanical withdrawal thresholds were evaluated using an electronic von Frey anesthesiometer. Animals challenged neonatally with LPS (nLPS) had increased pain sensitivity on this measure which was associated with decreased Oprm1 expression in the prefrontal cortex (PFC) and periaqueductal gray (PAG) of both male and female rats. Although a 'second hit' with LPS in adolescence (aLPS) did not confer protection or reveal additional vulnerabilities, aLPS given to animals treated neonatally with saline was associated with increased pain sensitivity, but only in females. Interestingly, adolescent inflammatory challenge decreased Hcrt2 mRNA in the PAG and elevated Trpv1 in the PAG and PFC of both sexes. There was no effect of inflammatory treatment on either anxiety or depressive-like behavior suggesting that affective functioning did not account for differences in mechanical pain sensitivity. Finally, a preliminary investigation demonstrated that administration of a broad spectrum antibiotic cocktail attenuated the mechanical sensitivity that followed nLPS. Together, these data extend upon evidence that inflammation imparts long term changes in quality of life and pain responses via interference within the descending pain network. Moreover, they highlight a potential window of opportunity to target the microbiota-gut-brain axis and reverse pain processing disturbances following perinatal inflammation.

Environmental enrichment (EE) has been successful at rescuing the brain from a variety of early-life psy-chogenic stressors. However, its ability to reverse the behavioral and neural alterations induced by a pre-natal maternal infection model of schizophrenia is less clear. Moreover, the specific interactions between the components (i.e. social enhancement, novelty, physical activity) of EE that lead to its success as a supportive intervention have not been adequately identified. In the current study, standard housed female Sprague-Dawley rats were administered either the inflammatory endotoxin lipopolysaccharide (LPS; 100 lg/kg) or pyrogen-free saline (equivolume) on gestational day 15. On postnatal day 50, offspring were randomized into one of three conditions: EE (group housed in a large multi-level cage with novel toys, tubes and ramps), Colony Nesting (CN; socially-housed in a larger style cage), or Standard Care (SC; pair-housed in standard cages). Six weeks later we scored social engagement and performance in the object-in-place task. Afterwards hippocampus and prefrontal cortex (n = 7–9) were collected and evaluated for excitatory amino acid transporter (EAAT) 1-3, brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor type 2 (TrkB) gene expression (normalized to GAPDH) using qPCR methods. Overall, we show that gestational inflammation downregulates genes critical to synaptic transmission and plasticity, which may underlie the pathogenesis of neurodevelopmental disorders such as schizophrenia and autism. Additionally, we observed disruptions in both social engagement and spatial discrimination. Importantly, behavioral and neurophysiological effects were rescued in an experience dependent manner. Given the evidence that schizophrenia and autism may be associated with infection during pregnancy, these data have compelling implications for the prevention and reversibility of the consequences that follow immune activation in early in life.

Environmental enrichment (EE) mimics positive life experiences by providing enhanced social and physical stimulation. Placement into EE following weaning, or in later life, confers beneficial outcomes on both emotional and cognitive processes. However, anxiety-like behavior is also reported, particularly in rats exposed to enhanced housing during early development. Notably, the quality of maternal behavior affects stress regulation and emotional stability in offspring, yet the impact of environmental context on maternal care has not been thoroughly evaluated, nor are the influences of EE on their offspring understood. To investigate the role of EE on these factors we analyzed the details of mother-neonate interactions, and juvenile offspring performance on several anxiety measures. Additionally, we evaluated neurochemical differences (i.e. serotonin, corticosterone, GABA, glutamate) in prefrontal cortex and hippocampus as a function of EE, Communal Nesting (CN) and Standard Care (SC). Although EE dams spent significantly less time on the nest and had lower nursing frequencies compared to SC dams, there were no differences in maternal licking/grooming. In offspring, EE increased GLUR1 level and GABA concentrations in the prefrontal cortex of both juvenile male and female rats. A similar pattern for glutamate was only observed in males. Although EE offspring spent less time on the open arms of the elevated plus maze and had faster escape latencies in a light-dark test, there were no other indications of anxiety-like behavior on these measures or when engaged in social interaction with a conspecific. In the wild, rats live in complicated and variable environments. Consequently dams must leave their nest to defend and forage, limiting their duration of direct contact. EE exposure in early development may mimic this naturalistic maternal separation, shaping parental behavior and offspring resiliency to stressors.

Abstract

Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100μg/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.

Exposure to early-life inflammation results in time-of-challenge dependent changes in both brain and behavior.  The consequences of this neural and behavioral reprogramming are most often reported in adulthood.  However, the trajectory for the expression of  these various changes are not well delineated, particularly between the juvenile and adult phases of development.  Moreover, interventions to protect against these neurodevelopmental disruptions are rarely evaluated.  Here, female Sprague-Dawley rats were housed in either environmental enrichment (EE) or standard care (SC) and their male and female offspring were administered 50 ug/kg i.p of lipopolysaccharide (LPS) or pyrogen-free saline in a dual-administration neonatal protocol.  All animals maintained their respective housing assignments from breeding until the end of the study.  LPS exposure on postnatal days (P) 3 and 5 of life resulted in differential expression of emotional and cognitive disruptions and evidence of oxidative stress across development. Specifically, social behavior was reduced in neonatal treated (n)LPS animals at adolescence (P40), but not adulthood (P70).  In contrast, male nLPS rats exhibited intact spatial memory as adolescents which was impaired in later life.  Moreover, these males had decreased prefrontal cortex levels of glutathione at P40, which was normalized in adult animals.  Notably, EE appeared to offer some protection against the consequences of inflammation on juvenile social behavior and fully prevented reduced glutathione levels in juvenile prefrontal cortex. Combined, these time dependent effects provide evidence that early-life inflammation interacts with other developmental variables, specifically puberty and EE, in the expression (and prevention) of select behavioral and molecular programs.

Early-life exposure to inflammation has been associated with several behavioral and cognitive deficits detected in adulthood. However, early behavioral changes have not been well described in rodent models of infection, specifically with respect to social behavior. In the present work we show that lipopolysaccharide (LPS) challenge at 3 and 5days of age reduced overall social contact time in male juvenile rats, primarily mediated by the amount of contact they received from a novel conspecific. Given that there are important sensory, motor, and motivational components that underlie social interaction we sought to uncover the mechanism(s) responsible for the reduced social contact directed towards neonatal (n)LPS treated animals. Using an intranasal perfusion procedure, we induced a ZnSO4 lesion in a subset of novel conspecifics, effectively disrupting their olfactory processing via olfactory neuroepithelium degeneration. Overall, this procedure equalized the amount of social contact directed towards nLPS animals compared to nsaline rats. To determine whether nLPS disrupted auditory communication we evaluated ultrasonic vocalizations (USVs) for the total number and duration of calls, and the average duration and frequency from each vocalization recording. There were no differences in USVs across treatment groups. Treating nLPS rats with diazepam maintained the level of social contact they initiated, compared to the stress-induced decrease observed in their saline treated counterparts. However, diazepam did not stabilize the amount of contact directed towards them. Together, this indicates that neither vocalized motor pathways nor anxiety cues, mediated by auditory/motor communication, are involved in the social deficits following nLPS. Instead, our data suggest that olfactory indicators, likely mediated through microbiota/immunomodulatory scent signals underlie the reductions in social contact that follow neonatal inflammation.

Inflammatory molecules, such as cyclooxygenase (COX), a prostaglandin synthetic enzyme, have been identified as a marker of depressive symptomology. Previously, we have observed elevated basal COX-2 expression in the hypothalamus of adult male rats treated neonatally with lipopolysaccharide (LPS), which might suggest a phenotype for disrupted hedonic behavior, a symptom of depression. However, COX-2 and its contribution to the expression of anhedonic behavior has not been investigated in these males or in female rats across the estrous cycle, which is the purpose of the current work. Here, we examine the effects of a neonatal LPS challenge or saline on the sucrose preference test as a measure of anhedonia, and hypothalamic COX-2 expression, in adult male and freely cycling female rats. Our data indicate a sex difference in that neonatal LPS at postnatal d 14 causes elevated basal expression of hypothalamic COX-2 in male, but not in female, rats. Additionally, baseline sucrose preference in male and female rats was unaltered as a function of neonatal LPS treatment or estrous cycle stage. In both male and female animals, 50 microg/kg LPS in adulthood caused elevated plasma IL-6 and hypothalamic COX-2 expression in neonatally saline-treated rats but significantly less so in neonatally LPS-treated rats of both sexes; this neonatal programming was not evident for sucrose preference or for total fluid intake (even after much higher doses of LPS). Our data are suggestive of a dissociation between inflammation and anhedonic behavior and a differential effect of neonatal inflammation in males and females.

Responding for rewarding brain stimulation has been used to track hedonic status in animals. In addition to neurochemical alterations, stimulation of the lateral hypothalamus or ventral tegmentum has been shown to influence immunological processes, including elevation of peripheral natural killer cell activity. In the present study, we examined whether ventral tegmental area (VTA) stimulation or environmental enrichment altered the severity of lipopolysaccharide (LPS)-induced sickness behaviors and the provocation of cytokine expression induced by the endotoxin. Accordingly, rats received either trials of brain stimulation reward or exposure to an enriched environment and subsequently challenged with 150 ug/kg i.p. of LPS. Groups receiving LPS and saline injections without further manipulation were also included. Using the real-time RT-PCR and a multiplex bead assay, mRNA and protein levels for several cytokines and their receptors were determined to evaluate how these may vary as a consequence of reward. Both brain stimulation and environmental enrichment similarly diminished sickness behaviors associated with the endotoxin. Receptor gene levels were generally stable across groups. Levels of IL-6 within the VTA were increased in the group receiving LPS challenge alone and environmental enrichment was associated with modestly reduced IL-6 levels within this brain region. Taken together, these data suggest that rewarding brain stimulation and environmental enrichment buffer against malaise provoked by endotoxin challenge. Moreover, IL-6 expression within the VTA may influence the development of sickness behavior following inflammatory stimuli.

Acute inflammation results in alterations in both peripheral and central nervous system cytokine levels that together can exert transient but profound alterations in neuroendocrine function. This has been particularly well studied with respect to the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonadal axes. There is now evidence, particularly in rodents, that an inflammation in the neonatal period can have long-term, sex-specific effects on these neuroendocrine axes that persist into adulthood. There are critical time periods for the establishment of these long-term programming effects, and in adulthood they may be revealed either as alterations in basal functioning or in altered responses to a subsequent inflammatory challenge. These studies highlight the importance of early environmental exposure to pathogens in sculpting adult physiology and behavior.

The behavioral, biochemical, and physiologic consequences of 6 wk of environmental enrichment were evaluated in male Long Evans and Sprague-Dawley rats and compared with those of rats in standard single-housing conditions. Standard housing provided little or no social or physical stimulation whereas environmental enrichment comprised group housing for 8 h daily in a 3-story cage equipped with novel stimuli. Dependent measures included performance in the forced swim test, thresholds for brain-stimulation reward, sucrose intake and preference, determination of corticosterone levels before and after brief restraint stress, and rate of weight gain. In forced swimming tests, active behaviors (diving, swimming with struggling, and climbing) tended to dominate over passive behaviors (sinking, floating) in both groups and outbred rat stocks (especially in enriched groups) on the first day. These behaviors were replaced with maintenance behaviors such as grooming and swimming without struggling on the second exposure, with enriched Long Evans rats showing the largest decline in activity. Baseline plasma corticosterone levels were elevated in both rat stocks after 6 wk of enrichment. After restraint stress, hormone levels in enriched animals tended to peak earlier and approach or exceed baseline values more quickly than was observed in the comparable control groups. Rate of body weight gain was greater in enriched Long Evans rats than Sprague-Dawley or control rats. Our observations indicate that stock- and group-associated differences in several indices occur in association with enrichment. The data support the claim that environmental enrichment may render animals more resilient to challenges.

Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6-trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation-induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral-induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor α in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients.

Anhedonia, a core symptom of clinical depression, refers to the loss of interest in normally rewarding stimuli; the chronic mild stress paradigm, an animal model of depression, was designed with this as an underlying feature. The procedure consists of the administration ...

The chronic mild stress (CMS) procedure was developed in rodents to target anhedonia, the core symptom of depressive melancholia. Stress exposure has been shown to induce a variety of physiological, biochemical and behavioral alterations associated with depression, although its anhedonic consequences as indexed by either sucrose intake and preference or thresholds for brain stimulation reward are less reliably observed. In the present study, we assessed the effects of six weeks of CMS on the latter measure in two strains of male and female rats subsequently challenged with an acute psychophysical stressor, forced swimming; their behavior in the swimming cylinder was evaluated on two consecutive days. While brain stimulation reward thresholds and response rates were unchanged by CMS exposure, significant differences in forced swim behaviors were observed between male control and CMS groups. In particular, male Long Evans rats with a history of CMS showed the largest decrease in the duration of active behaviors on the second test day, a pattern less evident in the Sprague-Dawley strain of rats, or in any of the female groups. The results suggest that the effects of depressogenic manipulations are strain and gender dependent, with male Long Evans rats most susceptible, as demonstrated by the selective reduction of struggling behaviors. Inclusion of multiple measures, including the forced swim test, would provide a better understanding of the psychopathological profile engendered by chronic exposure to mild stressors and its genetic specificity.

UMI, ProQuest ® Dissertations & Theses. The world's most comprehensive collection of dissertations and theses. Learn more... ProQuest, Exploring the influence of reward mechanisms on the interaction between sickness and immunity: Reasons to 'press-on'. ...

BACKGROUND / PURPOSE: The benefits of prescribing cardiac rehabilitation (CR) for patients following heart surgery is well documented; however, physicians continue to underuse CR programs, and disparities in the referral of women are common. Previous research into the causes of these problems has relied on self-report methods, which presume that physicians have insight into their referral behavior and can describe it accurately. In contrast, the research presented here used clinical judgment analysis (CJA) to discover the tacit judgment and referral policies of individual physicians. The specific aims were to determine 1) what these policies were, 2) the degree of self-insight that individual physicians had into their own policies, 3) the amount of agreement among physicians, and 4) the extent to which judgments were related to attitudes toward CR.
METHODS:Thirty-six Canadian physicians made judgments and decisions regarding 32 hypothetical cardiac patients, each described on 5 characteristics (gender, age, type of cardiovascular procedure, presence/absence of musculoskeletal pain, and degree of motivation) and then completed the 19 items of the Attitude towards Cardiac Rehabilitation Referral scale.
RESULTS:Consistent with previous studies, there was wide variation among physicians in their tacit and stated judgment policies, and self-insight was modest. On the whole, physicians showed evidence of systematic gender bias as they judged women as less likely than men to benefit from CR. Insight data suggest that 1 in 3 physicians were unaware of their own bias. There was greater agreement among physicians in how they described their judgments (stated policies) than in how they actually made them (tacit policies). Correlations between attitude statements and CJA measures were modest. CONCLUSIONS:These findings offer some explanation for the slow progress of efforts to improve CR referrals and for gender disparities in referral rates.