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This case study describes how one county health department in Alabama used the best available evidence to address the needs of its citizens during the first 6 months of the COVID-19 pandemic. The authors explore issues of scope of authority by government officials, individual freedom versus population health, and challenges of health communication during a disease outbreak. Despite the availability of vaccines, boosters, and access to vaccines by children as young as 5 years, COVID-19 cases are on the rise across the United States more than 2 years after the official news broke out of Wuhan, China. Health officials have expressed concerns that backlash against governmental public health during the pandemic will limit public health authorities from responding to the traditional challenges that were present pre-COVID-19 and will remain in a post-COVID-19 world.

Adverse social experience during childhood and adolescence leads to developmental alterations in emotional and stress regulation and underlying neurocircuits. We examined the consequences of social subordination (low social rank) in juvenile female rhesus monkeys, as an ethologically valid model of chronic social stressor exposure, on brain structural and behavioral development through the pubertal transition. Adolescence is a developmental period of extensive brain remodeling and increased emotional and stress reactivity. Puberty-induced increases in gonadal hormones, particularly estradiol (E2), are likely involved due to its organizational effects on the brain and behavior. Thus, we also examined how experimentally delaying pubertal onset with Lupron (gonadotropin releasing hormone -GnRH- agonist used clinically to delay early puberty) interacted with social rank (dominant vs. subordinate) to affect brain and behavioral outcomes. Using a longitudinal experimental design, structural MRI (sMRI) scans were collected on socially housed juvenile female rhesus monkeys living in indoor-outdoor enclosures prior to the onset of puberty (18-25 months), defined as menarche or the initial occurrence of perineal swelling and coloration, and again at 29-36 months, when all control animals had reached puberty but none of the Lupron-treated had. We examined the effects of both social rank and pubertal delay on overall structural brain volume (i.e. intracranial, grey matter (GM) and white matter (WM) volumes), as well as on cortico-limbic regions involved in emotion and stress regulation: amygdala (AMYG), hippocampus (HC), and prefrontal cortex (PFC). Measures of stress physiology, social behavior, and emotional reactivity were collected to examine functional correlates of the brain structural effects. Apart from expected developmental effects, subordinates had bigger AMYG volumes than dominant animals, most notably in the right hemisphere, but pubertal delay with Lupron-treatment abolished those differences, suggesting a role of gonadal hormones potentiating the brain structural impact of social stress. Subordinates also had elevated baseline cortisol, indicating activation of stress systems. In general, Lupron-treated subjects had smaller AMYG and HC volume than controls, but larger total PFC (driven by bigger GM volumes), and different, region-specific, developmental patterns dependent on age and social rank. These findings highlight a region-specific effect of E2 on structural development during female adolescence, independent of those due to chronological age. Pubertal delay and AMYG volume, in turn, predicted differences in emotional reactivity and social behavior. These findings suggest that exposure to developmental increases in E2 modifies the consequences of adverse social experience on the volume of cortico-limbic regions involved in emotional and stress regulation during maturation. But, even more importantly, they indicate different brain structural effects of chronological age and pubertal developmental stage in females, which are very difficult to disentangle in human studies. These findings have additional relevance for young girls who experience prolonged pubertal delays or for those whose puberty is clinically arrested by pharmacological administration of Lupron.

Research findings for supplementing boar stud diets with fish oils are inconsistent. This study was designed to address three possible causes of performance variation of boars to fish oil supplementation: stability of the fatty acid source, level of inclusion and breed of boars tested. Three groups of 87 boars each, from two genetic lines (PIC 337 and PIC 800), were assigned to treatment based on age, mean sperm production (previous 12 weeks), and body condition score. All boars received a corn-soybean meal diet with a commercial fish oil supplement providing 1.83 g/boar/day of docosahexaenoic acid (DHA) as a preconditioning diet. On 10-Aug., 2020, the DHA source was changed to a stabilized starch imbedded source of refined fish oil (Salmate&reg), providing 1.83 g/b/d for the test diet. Two additional levels providing 2.38 and 2.94 g/b/d of DHA were fed for a 9 week pretreatment period and during the test period. Salmate&reg fed at 2.38 g/b/d of DHA resulted in a reduction in the number of rejected ejaculates (P 0.045) by 7.5% and 6.4% compared to the lowest and highest inclusion rates, respectively. There were no treatments by genetic line interactions. A retrospective study of semen production and quality of 77 boars on the Salmate&reg diet containing 1.83 g/b/d DHA was done to compare to the original source of DHA at the same inclusion level. There were no differences in semen quality parameters between the 2 lipid sources. Ejaculate volume increased from 177.9 ml to 233.4 ml (P 0.001) and total sperm cells per ejaculate increased from 69.7 × 109 to 82.0 × 109 (P 0.001) due to substitution of Salmate&reg. Adding Salmate&reg at 2.38 g/b/d resulted in a lower number of rejected ejaculates per boar by 7.5% and 6.4% vs. 1.83 and 2.94 g/b/d, respectively, and boars fed Salmate&reg at 1.83 g/b/d produced 17% more doses than the competing product.

The objective of this study was to determine the effect of dietary manganese (ProPath Mn, Zinpro Corporation) on the reproductive performance of sows. Sows (N = 39; 231 ± 8 kg) were randomly assigned to 1 of three dietary levels of Mn (CON: 0 ppm Mn; PRO20: 20 ppm Mn; PRO40: 40 ppm Mn). Experimental treatments were initiated at breeding and continued through 2 parities. Sows were blocked by parity within each farrowing group and dietary treatments were represented within each block. Data were analyzed as a randomized complete block design using the MIXED procedure of SAS with diet as a fixed effect and block as a random effect. Dietary treatment did not affect sow body weights (P > 0.10). Lactation feed intake was increased in PRO20 sows compared with CON and PRO40 sows (P < 0.05). PRO20 and PRO40 sows farrowed heavier piglets (CON 1.23 kg; PRO20 1.57 kg; PRO40 1.40 kg; P = 0.001) with improved average daily gain to weaning (CON 213 g/day; PRO20 237 g/day; 220 g/day; P < 0.05), compared with CON sows. Milk fat content (average from d 7 and 14 of lactation) was reduced in PRO20 (5.5%) and PRO40 sows (6.1%; P < 0.05) compared with CON sows (7.8%), possibly due to increased milk demand from the piglets. There were no significant differences in milk mineral concentrations during lactation or piglet tissue Mn-superoxide dismutase (MnSOD) activity at weaning (P > 0.10). On day 3 of lactation, prolactin concentrations were similar across treatments (P > 0.10), whereas progesterone concentrations tended to differ in response to Mn level (CON 23.70 ng/mL; PRO20 26.15 ng/mL; PRO40 22.10 ng/ml; P = 0.09). Supplementary dietary Mn throughout 2 gestation and lactation cycles led to increased birth weights and pre-weaning growth of piglets.

Social subordination increases risk for psychiatric disorders, while dominance increases resilience to these disorders. Fluoxetine, a selective serotonin (5HT) reuptake inhibitor whose actions are mediated in part by the 5HT1A receptor (5HT1AR), has sex- and social status-specific effects on socioemotional behavior and aggressive behavior. However, the impact of social status on these sex-specific effects remains unclear. The current study evaluated the impact of acute fluoxetine treatment and social status on dominance-related behaviors in female and male hamsters, and the impact of chronic fluoxetine treatment on socioemotional behavior and 5HT1AR binding potential (5HT1AR(BP)) in female rhesus macaques. We hypothesized that sex differences in the effects of fluoxetine on aggression in hamsters would be diminished in dominant and enhanced in subordinate males and that aggression in female hamsters would be enhanced in dominants and diminished in subordinates. In female rhesus macaques, we hypothesized that chronic fluoxetine would alter socioemotional behaviors and site-specific 5HT1AR(BP) in a status-dependent manner. Male (n=46) and female (n=56) hamsters were paired with conspecifics for three days to establish social rank. Hamsters received a single dose of 20mg/kg fluoxetine or vehicle two-hours prior to a test with a non-aggressive intruder. Female rhesus monkeys (n=14) housed were administered fluoxetine (2.8mg/kg/day) or vehicle injections chronically for 14-days, separated by a three-week washout period. On Day 15, positron emission tomography neuroimaging for 5HT1AR(BP) was conducted. Fluoxetine treatment decreased aggression in subordinate female monkeys and subordinate female hamsters but not in dominant females of either species. Fluoxetine decreased aggression in dominant but not in subordinate male hamsters. Fluoxetine also reduced and increased prefrontal 5HT1AR(BP) in dominant and subordinate females, respectively. Taken together, these results provide cross-species evidence that social status and sex impact how increased 5HT modulates agonistic behavior.

This manuscript describes one nursing school's innovative community-based partnership with community organizations and Nurse-Family Partnership (NFP), an established nurse home visiting program for first-time, low income mothers and infants. The aim of this academic nursing endeavor with the community and NFP is to improve the health and well-being of low-income, first time mothers and their children while also providing comprehensive, population-based nursing experiences for students and service leadership and scholarship opportunities for faculty. The academic-practice community partnership described here makes a case for utilizing the expertise and capacity of a nursing school to implement and administer an NFP program and serves as an exemplar for the recommendations described in the New Era for Academic Nursing report (AACN, 2016). The value of forming partnerships between a public health department, the philanthropic community and an academic nursing institution is highlighted. In this case, the three organizations partnering together around a common purpose of improving birth outcomes enabled the partnership to accomplish more than any individual organization could have accomplished alone.

Porcine pregnancy establishment and maintenance are dependent on the formation of functional corpora lutea (CL). Manganese (Mn) is critical for CL function as it is a cofactor for Mn superoxide dismutase and enzymes involved in cholesterol synthesis. Previously, we have shown that luteal Mn content increased and luteal progesterone (P4) concentration decreased in the CL of gilts fed diets supplemented with an Mn–amino acid complex (Availa-Mn; Zinpro Corporation) compared with controls fed Mn sulfate. Importantly, serum P4 increased from 0 (estrus onset) to 12 d post estrus (dpe), as expected, but P4 abundance in circulation was not affected by dietary Mn source (P = 0.15). We hypothesized that a more bioavailable Mn source (which results in increased luteal Mn content) would alter the luteal proteome and abundance of mRNA associated with steroid biogenesis during the mid-luteal phase of the estrous cycle. Postpubertal gilts (n = 32) were assigned to one of the four gestation diets. The control diet (CON) contained 20 ppm of supplemental Mn in the form of Mn sulfate. Three additional diets included 20 (TRT1), 40 (TRT2), or 60 (TRT3) ppm of supplemental Mn in the form of a Mn–amino acid complex instead of Mn sulfate. Dietary treatment began at estrus synchronization (approximately 20 d before estrus) and continued through 12 dpe when gilts were euthanized and tissues were collected. Protein and total RNA extracts from the CL were used for proteomic analysis via label-free liquid chromatography with tandem mass spectrometry to assess global protein abundance and quantitative real-time polymerase chain reaction (qRT-PCR) to assess specific mRNA abundance, respectively. Compared with CON, 188, 382, and 401 proteins were differentially abundant (P < 0.10) in TRT1, TRT2, and TRT3, respectively. Gene Ontology enrichment software revealed that proteins involved in P4 signaling and cholesterol synthesis were downregulated in CL of gilts fed Mn–amino acid complex compared with controls. Quantitative RT-PCR showed that relative transcript abundance of genes encoding steroidogenic enzymes (CYP11A1 and StAR) in CL tissue was decreased in gilts from TRT2 compared with CON (P = 0.02), but TRT1 and TRT3 were not affected (P ≥ 0.30). Collectively, these data support our hypothesis that a more bioavailable dietary Mn source may influence luteal function by altering the abundance of protein and mRNA involved in steroidogenesis.

Functional corpora lutea (CL) are required for pregnancy establishment and gestational maintenance in swine, and CL function is susceptible to environmental influences. Manganese (Mn) could be critical in regulating CL function since it is a component of the antioxidant enzyme Mn superoxide dismutase (MnSOD) as well as enzymes involved in cholesterol and steroid hormone synthesis. We hypothesized that a more bioavailable dietary Mn source would increase Mn content in the CL thereby influencing luteal function during the mid-luteal phase of the estrous cycle. Postpubertal gilts (n = 32) were assigned to one of four gestation diets. The control diet (CON) met or exceeded National Research Council (2012) requirements and was formulated to contain 20 parts per million (ppm) of added Mn in the form of Mn sulfate. Three additional diets included 20 (treatment [TRT]1), 40 (TRT2), or 60 (TRT3) ppm of added Mn from a Mn–amino acid complex (Availa-Mn; Zinpro Corporation) instead of Mn sulfate. Dietary treatment began at estrus synchronization onset and continued through 12 days post estrus (dpe) of the ensuing estrous cycle. Blood samples were collected at estrus onset, which was assigned as 0 dpe, as well as 4, 8, and 12 dpe. Gilts were euthanized and tissues were collected at 12 dpe. Serum progesterone (P4) increased (P < 0.01) from 0 to 12 dpe but was unaffected by dietary treatment (P = 0.15) and there was no effect of the interaction between day and treatment (P = 0.85). Luteal Mn content increased (P ≤ 0.05) by 19%, 21%, and 24% in gilts fed TRT1, TRT2, and TRT3, respectively, compared to CON. Luteal P4 concentrations decreased (P = 0.03) 25%, 26%, and 32% in gilts fed TRT1, TRT2, and TRT3, respectively, compared to CON. Relative to CON gilts, CL calcium content decreased (P = 0.02) by 36%, 24%, and 34% for TRT1, TRT2, and TRT3 gilts, respectively. Collectively, these data support the hypothesis that feeding a more bioavailable Mn source increases Mn accumulation in CL tissue. If and how this influences CL function may be related to altered luteal P4 concentrations.

Boars are a source of genetic improvement and influence farrowing rate and litter size. Overfeeding boars increases incidence of feet and leg problems and reduces libido, whereas underfeeding boars may decrease semen output and libido. To help boar stud personnel estimate the energy requirements and base feeding levels, an interactive web application named PIC Optimum Boar Feeding Tool has been developed. The application encompasses three components, including an input interface using dynamic models to estimate energy requirement, an output interface displaying recommended feeding program, and functional modules facilitating the ease of use. The input interface requests users to provide the start and final weight of boars in isolation, isolation length, boar stud room temperature, number of collections per week, and dietary energy level. The daily energy requirement (Mcal of ME/day) is calculated using the following energy-demanding factors: 1) maintenance, 0.1823 × (body weight, kg)0.665; 2) weight gain, 0.00489 × (average daily gain, kg/d); 3) each degree below 17°C for individually penned boars on slatted floors, 0.00382 × (body weight, kg)0.75; 4) mating activity, 0.0043 × (body weight, kg)0.75; and 5) sperm production, 0.1. These factors and the user-defined inputs including dietary energy, are used to calculate a daily feeding amount. The users also have the option to calculate the recommended feeding level for boars of specified body weight. Other functional modules include a flank-to-flank measurement tool that estimates boar body weight and customized downloadable nutrient specifications. This web application incorporates a spectrum of biological, nutritional, and management aspects to allow boar stud personnel to easily make boar feeding decisions.

With the prevalence of obesity among women the United States surpassing 40%, it is critical to understand how environmental factors influence appetite, body fat accumulation, and the ability to lose weight and maintain weight loss. Psychosocial stress exposure is a risk factor for increased consumption of calorically dense diets (CDD), which are high in fat and sugars and promote both increased food intake and weight gain. However, it remains unclear how appetite is affected by psychosocial factors when people striving to lose weight restrict intake of unhealthy, calorically dense foods. Using a translational non-human primate model of chronic psychosocial stressor exposure in females (n = 16), mediated by social subordination, we examined ad libitum food intake, weight change, and social behavior during three consecutive, 15-week dietary conditions: 1) obesogenic, dietary choice; 2) chow-only; and 3) a switch back to dietary choice. Data showed that a choice dietary environment that includes both chow and CDD promotes increased calorie consumption of CDD in subordinate female rhesus monkeys during the baseline choice and back-to-choice phases (p = 0.016). Removal of the CDD during the chow-only phase resulted in mild inappetence (p = 0.005) and a loss in body weight (p 0.001) in subordinate females. Reintroduction of the CDD to subordinate, but not dominant, females was associated with increased calorie intake that surpassed baseline intake (p 0.001), and greater body weight gain (p = 0.026). There were no effects of diet cycling on total food intake and body weight change in dominant females (p's 0.05). Overall, our results suggest that adverse psychosocial experience is associated with increased preference for highly palatable, calorically dense food in a choice dietary environment.

We present the status of ongoing work at NASA-Goddard Space Flight Center (GSFC) to build a low-cost flexible ground terminal for optical communication. Previous laser communication missions at NASA have been supported by one-of-akind ground terminals built specifically for each mission. If NASA is to build a global network of optical terminals to enable widespread use of optical communications, then a blueprint for an economical ground terminal able to support a variety of missions is needed. With this goal in mind, NASA is constructing a ground terminal in Greenbelt, Maryland to enable testing of new ground terminal technologies from industry to academia.

Functional corpora lutea (CL) are required for pregnancy establishment and gestational maintenance in swine. Manganese (Mn) could be critical in regulating CL function since it is a cofactor for the enzyme Mn superoxide dismutase (Mn-SOD) as well as enzymes involved in progesterone (P4) synthesis. We hypothesized a more bioavailable dietary Mn source would increase CL Mn content thereby influencing luteal function during the mid-luteal phase of the estrous cycle. Post-pubertal gilts (n = 32) were assigned to one of four gestation diets. The control diet (CON) met or exceeded NRC requirements and was formulated to contain 20 ppm added Mn in the form of Mn sulfate. Three additional diets included 20 (TRT1), 40 (TRT2) or 60 (TRT3) ppm Mn from a Mn-amino acid complex (Availa-Mn; Zinpro Corporation) in place of Mn sulfate. Dietary treatment began at estrus synchronization onset and continued through D12 of the ensuing estrous cycle when gilts were euthanized. Mn content increased (P ≤ 0.06) 19, 21 and 24% in CLs of gilts fed TRT1, TRT2, and TRT3, respectively, and luteal P4 concentration decreased (P ≤ 0.03) 25, 26, and 32% in gilts fed TRT1, TRT2, and TRT3, respectively, compared to CON. Total CL protein was extracted and liquid chromatography with tandem mass spectrometry (LC-MS/MS) was performed to assess global protein abundance. Compared to CON, 29, 105, and 118 proteins were differentially abundant (P < 0.01) in TRT1, TRT2, and TRT3, respectively. KEGG pathway analysis revealed proteins involved in P4 signaling (membrane-associated P4 receptor component 2) and cholesterol synthesis and transport (mevalonate kinase, diphosphomevalonate decarboxylase, low density lipoprotein receptor) were downregulated in response to Availa-Mn. Collectively, these data support the posit that dietary Mn source affects Mn accumulation and P4 concentration in CL tissue and influences protein abundance which may affect CL function.

In females, pubertal onset appears to signal the opening of a window of increased vulnerability to the effects of stress on neurobehavioral development. What is the impact of pubertal timing on this process? We assessed the effects of pubertal timing and stress on behavior and amygdala functional connectivity (FC) in adolescent female macaques, whose social hierarchy provides an ethologically valid model of chronic psychosocial stress. Monkeys experienced puberty spontaneously (n=34) or pubertal delay via Lupron treatment from age 16-33 months (n=36). We examined the effects of stress (continuous dimension spanning dominant/low-stress to subordinate/high-stress) and experimental pubertal delay (Lupron-treated vs. Control) on socioemotional behavior and FC at 43-46 months, after all animals had begun puberty. Regardless of treatment, subordinate monkeys were more submissive and less affiliative, and exhibited weaker FC between amygdala and dorsolateral prefrontal cortex and stronger FC between amygdala and temporal pole. Regardless of social rank, Lupron-treated monkeys were also more submissive, less affiliative, and explored less in a “Human Intruder” task but were less anxious than untreated monkeys; they exhibited stronger FC between amygdala and orbitofrontal cortex. No interactions between rank and Lupron treatment were observed. These data suggest that some of the effects of chronic subordination stress and delayed puberty overlap behaviorally, such that late-onset puberty-linked exposure to female hormones mimics chronic stress. In the brain, however, delayed puberty and subordination stress had separable effects, suggesting that the overlapping socioemotional outcomes may be mediated by distinct neuroplastic mechanisms. To gain further insights, additional longitudinal studies are required.

The Laser Interferometer Space Antenna (LISA) mission is a space-based gravitational wave detector consisting of three spacecraft with two transceiver telescopes per spacecraft. In addition to tight wavefront error control as expected for an interferometric system, there are tight pupil imaging and optical path length specifications. We use concepts gleaned from pupil aberration theory to understand these latter two constraints and show how these concepts led to a successful design for the LISA transceiver.

Early lesions of osteochondrosis (OC) are exhibited by regions of cartilage retention along the growth plate and articular cartilage. Progression of OC lesions may impair locomotion and necessitate euthanasia in adherence to animal welfare guides. Little is known about the role of nutrition in the initiation and early stages of OC. However, dietary components are commonly implicated as predisposing factors. In this study, diets were altered as an attempt to induce early stage OC lesions under controlled conditions. At 8 wk of age, 96 crossbred gilts (body weight [BW] = 17.4 ± 0.18 kg) were randomly assigned to one of four corn-soybean meal-based diets (four pens per diet, six pigs per pen) to assess diet effects on the number and volume of OC lesions in the distal femur. Diets included a non-pelleted control diet (Ctl); Ctl plus 20% glucose (Glc); the Ctl with increased concentrations of lysine, Ca, and P (+CaP); and the +CaP diet in a pelleted form (PEL). Femurs were collected from pigs euthanized at either 14-wk (Wk 14) or 24-wk (Wk 14) of age for assessments of OC lesions. Based on a mixed model analysis with pen as the experimental unit, dietary treatments did not affect final BW (129.3 ± 3.8 kg) or average daily gain (ADG) (1.00 ± 0.03 kg/d) over the trial. As expected, pigs fed PEL and Glc diets were more efficient (P < 0.05) in feed conversion compared with Ctl and +CaP. Using femurs as the experimental unit at Wk 14 (collected from two of the six pigs per pen), bone mineral content, determined by dual-energy x-ray absorptiometry scans, was greater (P < 0.05) in pigs fed +CaP and PEL than Ctl or Glc diets; however, only +CaP group differed (P < 0.05) at Wk 24 (collected from four pigs per pen). Computed tomography (CT) scans of femurs were reconstructed as three-dimensional images to allow detection of the number, volume, and surface area of lesions in distal growth plates. At Wk 14, pigs fed Ctl had fewer number of lesions (P < 0.05); however, no differences were detected among dietary treatments in lesion volume or lesion surface area. Pigs had fewer lesions at Wk 24 than Wk 14; however, differences were not detected among dietary treatments. At Wk 24, pigs fed Ctl diets had the greatest lesion volume among dietary treatments (P < 0.05). In conclusion, none of the pigs exhibited symptoms of lameness regardless of dietary treatment or OC lesion traits. Diet modifications due to pelleting or inclusion of rapidly digestible ingredients, such as glucose, did not increase prevalence or size of OC lesions. Image analysis of CT scans was a reliable method to quantify the number, size, and location of OC lesions.

Alterations in dopamine (DA) signaling and reductions in functional connectivity (FC; a measure of temporal correlations of activity between different brain regions) within dopaminergic reward pathways are implicated in the etiology of psychopathology and have been associated with increased concentrations of inflammatory markers, including C-reactive protein. Peripheral and central inflammatory cytokines that have been shown to disrupt DA signaling and corticostriatal FC are associated with C-reactive protein, an acute phase reactant that is used translationally as a marker of systemic inflammation. One factor that can significantly increase systemic inflammation to produce neuroadaptations in reward pathways is a diet that results in fat mass accumulation (e.g. obesogenic diet). The current study in female rhesus monkeys maintained in a standard laboratory chow (n = 18) or on obesogenic diet (n = 16) for 12-months tested the hypothesis that an obesogenic diet would alter central DA and homovanillic acid (HVA) concentrations, and be associated with increased CRP concentrations and decreased FC between corticostriatal regions at 12-months following dietary intervention. We specifically assessed FC between the nucleus accumbens (NAcc) and two sub-regions of the prefrontal cortex (PFC) previously associated with CRP concentrations, the ventromedial PFC (vmPFC) and the orbitofrontal cortex (OFC), which are also involved in emotional and motivational salience assessment, and in goal-directed behavior, impulse control and the salience/value of food, respectively. Results showed that CSF DA concentrations were decreased (p = 0.002), HVA:DA ratios were increased (p = 0.016), and body mass index was increased (p = 0.047) over the 12-months of consuming an obesogenic diet. At 12-months, females maintained in the obesogenic diet exhibited higher CRP concentrations than females consuming chow-only (p = 0.008). Linear regression analyses revealed significant CRP by dietary condition interactions on DA concentrations (β = -5.10; p = 0.017) and HVA:DA ratios (β = 5.14; p = 0.029). Higher CRP concentrations were associated with lower CSF DA concentrations (r = -0.69; p = 0.004) and greater HVA:DA ratios only in females maintained in the obesogenic dietary condition (r = 0.58; p = 0.024). Resting-state magnetic resonance neuroimaging (rs-fMRI) in a subset of females from each diet condition (n = 8) at 12-months showed that higher CRP concentrations were associated decreased FC between the NAcc and subregions of the prefrontal cortex (PFC; p's 0.05). Decreased FC between the NAcc and PFC subregions were also associated with lower concentrations of DA and greater HVA:DA ratios (p's 0.05). Overall, these data suggest that increased inflammatory signaling driving heightened CRP levels may mediate the adverse consequences of obesogenic diets on DA neurochemistry and corticostriatal connectivity.

Preclinical studies demonstrate that chronic stress modulates the effects of oestradiol (E2) on behaviour through the modification of the amygdala and the medial prefrontal cortex (mPFC) neuronal structure. Clinical studies suggest that alterations in amygdala functional connectivity (FC) with the mPFC may be associated with stress-related phenotypes, including mood and anxiety disorders. Thus, identifying the effects of stress and E2 on amygdala-mPFC circuits is critical for understanding the neurobiology underpinning the vulnerability to stress-related disorders in women. In the present study, we used a well-validated rhesus monkey model of chronic psychosocial stress (subordinate social rank) to examine effects of E2 on subordinate (SUB) (i.e. high stress) and dominant (DOM) (i.e. low stress) female resting-state amygdala FC with the mPFC and with the whole-brain. In the non-E2 treatment control condition, SUB was associated with stronger left amygdala FC to subgenual cingulate (Brodmann area [BA] 25: BA25), a region implicated in several psychopathologies in people. In SUB females, E2 treatment strengthened right amygdala-BA25 FC, induced a net positive amygdala-visual cortex FC that was positively associated with frequency of submissive behaviours, and weakened positive amygdala-para/hippocampus FC. Our findings show that subordinate social rank alters amygdala FC and the impact of E2 on amygdala FC with BA25 and with regions involved in visual processing and memory encoding.

Social experiences are an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a pro-inflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here, we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent pro-inflammatory pathways and lower expression of genes involved in the antiviral response and type I interferon (IFN) signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are not only linked to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history – in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

Study objectives were to determine the effects of zinc (Zn) amino acid complex (Availa Zn, Zinpro Corporation, Eden Prairie, MN) on metabolism, biomarkers of leaky gut, and inflammation during and following heat stress (HS) and nutrient restriction. Crossbred gilts (n = 50; 50 ± 2 kg BW) were blocked by initial BW and randomly assigned to one of five treatments: 1) thermoneutral (TN) and ad libitum fed a control diet (TNCtl), 2) TN and pair-fed a control diet (PFCtl), 3) TN and pair-fed a Zn-supplemented diet (PFZn), 4) HS and ad libitum fed a control diet (HSCtl), and 5) HS and ad libitum fed a Zn-supplemented diet (HSZn). The study consisted of 3 experimental periods (P): during P1 (7 d), all pigs were fed their respective diets ad libitum and housed in TN conditions (20.84 ± 0.03 °C, 47.11 ± 0.42% relative humidity). During P2 (7 d), HSCtl and HSZn pigs were exposed to progressive cyclical HS conditions (27 to 30 °C, 41.9 ± 0.5% relative humidity), while TNCtl, PFCtl, and PFZn pigs remained in TN conditions and were fed ad libitum or pair-fed to their respective HSCtl and HSZn counterparts. During P3 (5 d; "recovery phase"), all pigs were housed in TN conditions and fed ad libitum. Pigs exposed to HS had overall increased rectal temperature, skin temperature, and respiration rate (0.33 °C, 3.76 °C, and 27 bpm, respectively; P 0.10). In summary, Zn reduced TNFα (regardless of HS), and the stimulatory effect of HS on insulin secretion is amplified during HS recovery.

Exposure to psychosocial stressors increases consumption of palatable, calorically dense diets (CDD) and the risk for obesity, especially in females. While consumption of an obesogenic diet and chronic stress have both been shown to decrease dopamine 2 receptor (D2R) binding and alter functional connectivity (FC) within the prefrontal cortex (PFC) and the nucleus accumbens (NAcc), it remains uncertain how social experience and dietary environment interact to affect reward pathways critical for the regulation of motivated behavior. Using positron emission tomography (PET) and resting state functional connectivity magnetic resonance neuroimaging (rs-fMRI), in female rhesus monkeys maintained in a low calorie chow (n = 18) or a dietary choice condition (chow and a CDD; n = 16) for 12 months, the current study tested the overarching hypothesis that the adverse social experience resulting from subordinate social status would interact with consumption of an obesogenic diet to increase caloric intake that would be predicted by greater cortisol, lower prefrontal D2R binding potential (D2R-BP) and lower PFC-NAcc FC. Results showed that the consequences of adverse social experience imposed by chronic social subordination vary significantly depending on the dietary environment and are associated with alterations in prefrontal D2R-BP and FC in NAcc-PFC sub-regions that predict differences in caloric intake, body weight gain, and fat accumulation. Higher levels of cortisol in the chow-only condition were associated with mild inappetence, as well as increased orbitofrontal (OFC) D2R-BP and greater FC between the NAcc and the dorsolateral PFC (dlPFC) and ventromedial PFC (vmPFC). However, increased cortisol release in females in the dietary choice condition was associated with reduced prefrontal D2R-BP, and opposite FC between the NAcc and the vmPFC and dlPFC observed in the chow-only females. Importantly, the degree of these glucocorticoid-related neuroadaptations predicted significantly more total calorie intake as well as more consumption of the CDD for females having a dietary choice, but had no relation to calorie intake in the chow-only condition. Overall, the current findings suggest that dietary environment modifies the consequences of adverse social experience on reward pathways and appetite regulation and, in an obesogenic dietary environment, may reflect impaired cognitive control of food intake.

The hippocampus is most notably known for its role in cognition and spatial memory; however it also plays an essential role in emotional behaviors and neuroendocrine responses. The current study investigated the long-term effects of neonatal hippocampal lesions (Neo-Hibo) on emotional and hypothalamic-pituitary-adrenal (HPA) axis functioning. During infancy, unlike controls, Neo-Hibo monkeys exhibited enhanced expression of emotional behaviors (e.g. freezing, anxiety-like, and self-directed behaviors) when exposed to a human intruder (HI task). Upon reaching adulthood, they exhibited reduced freezing and hostility, but increased anxiety-like and self-directed behaviors during the HI task. Neo-Hibo monkeys behaved as if they systematically over-rated the risk inherent in the HI task, which supports Gray and McNaughton's septo-hippocampal theory of anxiety. Also, in adulthood, the increased levels of anxiety-like behaviors in Neo-Hibo monkeys were associated with a blunted cortisol response to the HI task. Examination of basal HPA axis function revealed that Neo-Hibo monkeys exhibited the typical diurnal cortisol decline throughout the day, but had lower cortisol concentrations in the morning as compared to controls. Taken together these data suggest that an intact hippocampus during development plays a larger role beyond that of inhibitory/negative feedback regulation of the HPA axis stress-activation, and may be critical for HPA axis basal functioning as well as for the stress response. The behavioral and neuroendocrine changes demonstrated in the current study are reminiscent of those seen in human or nonhuman primates with adult-onset hippocampal damage, demonstrating little functional compensation following early hippocampal damage.

Status alters immune function in macaques Rhesus macaques experience variable levels of stress on the basis of their position in the social hierarchy. To examine how stress affects immune function, Snyder-Mackler et al. manipulated the social status of individual macaques (see the Perspective by Sapolsky). Social status influenced the immune system at multiple levels, from immune cell numbers to gene expression, and altered signaling pathways in a model of response to infection. Macaques possess a plastic and adaptive immune response wherein social subordination promotes antibacterial responses, whereas high social status promotes antiviral responses. Science , this issue p. 1041 ; see also p. 967

In many social mammals, social adversity predicts compromised health and reduced fitness. These effects are thought to be driven in part by chronic social stress, but their molecular underpinnings are not well understood. Recent work suggests that chronic stress can affect mitochondrial copy number, heteroplasmy rates and function. Here, we tested the first two possibilities for the first time in non-human primates. We manipulated dominance rank in captive female rhesus macaques ( n = 45), where low rank induces chronic social stress, and measured mitochondrial DNA (mtDNA) copy number and heteroplasmy in five peripheral blood mononuclear cell types from each study subject. We found no effect of dominance rank on either mtDNA copy number or heteroplasmy rates. However, grooming rate, a measure of affiliative social behaviour predicted by high social status, was positively associated with mtDNA copy number in B cells, cytotoxic T cells and monocytes. Our results suggest that social interactions can influence mtDNA regulation in immune cells. Further, they indicate the importance of considering both affiliative and competitive interactions in investigating this relationship.

Significance Chronic, low social status-induced stress predicts disease susceptibility, but the molecular basis for this relationship is not well understood. We manipulated social status in female rhesus macaques to investigate how status differences alter the gene expression and chromatin accessibility response to glucocorticoids (hormones involved in stress regulation). We found that social status changes immune cell gene expression and chromatin accessibility, that glucocorticoid treatment attenuates these effects, and that the DNA of low-status animals may be less accessible to glucocorticoid response-associated transcription factors. Our results thus show that social status affects multiple aspects of immune cell gene regulation, including the 3D structure of DNA. Further, they emphasize the importance of the cellular environment in determining the strength of this relationship., Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro GC challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression after GC exposure. Regions that were more accessible in high-status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the GC receptor cofactor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.

Oxytocin (OXT) and its receptor (OXTR) are encoded by OXT and OXTR, respectively. Variable methylation of these genes has been linked to variability in sociability and neuroendophenotypes. Here we examine whether OXTR or OXT methylation in blood predicts concentrations of OXT in cerebrospinal fluid (CSF) (n = 166) and social behavior (n = 207) in socially-housed female rhesus macaques. We report a similarity between human and rhesus CpG sites for OXT and OXTR and a putative negative association between methylation of two OXTR CpG units with aggressive behavior (both P = 0.003), though this finding does not survive the most stringent correction for multiple comparison testing. We did not detect a statistically significant association between methylation of any CpG sites and CSF OXT concentrations, either. Because none of the tested associations survived statistical corrections, if there is any relationship between blood-derived methylation of these genes and the behavioral and physiological outcomes measured here, the effect size is too small to be detected reliably with this sample size. These results do not support the hypothesis that blood methylation of OXT or OXTR is robustly associated with CSF OXT concentration or social behavior in rhesus. It is possible, though, that methylation of these loci in the brain or in cheek epithelia may be associated with central OXT release and behavior. Finally, we consider the limitations of this exploratory study in the context of statistical power.

Maternal and progeny diets supplemented with 2 sources of trace mineral (TM) were evaluated for effects on the size and severity of osteochondrosis (OC) lesions in progeny produced by 64 Landrace × Large White sows. At breeding, sows were randomly assigned to maternal diets (gestation and lactation) consisting 1 of 2 TM treatments. One treatment consisted of inorganic TM (ITM) with ZnO, MnSO, and CuSO at concentrations to provide 150, 50, and 16.5 mg/kg diet of Zn, Mn, and Cu, respectively. The other treatment consisted of the same ITM concentrations plus an additional 50, 20, and 10 mg/kg diet of Zn, Mn, and Cu, respectively, supplied by a blend of AA-complexed TM (CTM) using Availa Sow. Within maternal dietary treatment groups, selected progeny ( = 280) were fed either ITM- or CTM-supplemented diets. The humerus and femur (1 each) from progeny euthanized at 12 ( = 80) or 24 wk ( = 200) were collected for microscopic (12 wk) or gross (24 wk) assessment of OC lesions. Microscopic OC lesions were present in all pigs at 12 wk. Dietary treatments had limited effects on OC prevalence or severity. A maternal × progeny diet interaction ( = 0.044) revealed femoral OC latens lesions that were approximately twice the size in progeny fed CTM that were produced by sows fed CTM compared with those found in pigs in the other 3 dietary treatment groups. At 24 wk, the sum of gross OC scores at predilection sites of the thoracic (elbow joint) and pelvic (stifle and hock joints) limbs remained similar among treatments, despite greater ( = 0.004) gross OC scores of the medial femoral condyle in progeny from sows fed CTM diets than in progeny from sows fed ITM diets, regardless of progeny diet. Progeny produced by sows fed CTM vs. ITM had increased ADG (0.71 vs. 0.68 ± 0.01 kg/d), regardless of the diet fed to progeny during the growth phases. Covariant analysis using ADG did not alter inferences about maternal or progeny diet effects on OC responses. Although 100% of progeny at 12 wk had histologically apparent OC lesions, only 3 of the 200 pigs examined at 24 wk had gross lesions of sufficient severity to potentially result in clinically apparent disease. Therefore, although some results imply that maternal and progeny CTM diets increased the size (12 wk) and severity (24 wk) of OC in 1 site (the femur), on the whole animal level, no evidence of lameness was noted.

Strong social relationships confer health and fitness benefits in a number of species, motivating the need to understand the processes through which they arise. In female cercopithecine primates, both kinship and dominance rank are thought to influence rates of affiliative behaviour and social partner preference. Teasing apart the relative importance of these factors has been challenging, however, as female kin often occupy similar positions in the dominance hierarchy. Here, we isolated the specific effects of rank on social relationships in female rhesus macaques by analysing grooming patterns in 18 social groups that did not contain close relatives, and in which dominance ranks were experimentally randomized. We found that grooming was asymmetrically directed towards higher-ranking females and that grooming bouts temporarily decreased the likelihood of aggression between grooming partners, supporting the idea that grooming is associated with social tolerance. Even in the absence of kin, females formed the strongest grooming relationships with females adjacent to them in rank, a pattern that was strongest for the highest-ranking females. Using simulations, we show that three rules for allocating grooming based on dominance rank recapitulated most of the relationships we observed. Finally, we evaluated whether a female's tendency to engage in grooming behaviour was stable across time and social setting. We found that one measure, the rate of grooming females provided to others (but not the rate of grooming females received), exhibited modest stability after accounting for the primary effect of dominance rank. Together, our findings indicate that dominance rank has strong effects on social relationships in the absence of kin, suggesting the importance of considering social status and social connectedness jointly when investigating their health and fitness consequences.

Women have a higher risk of developing stress-related disorders compared to men and the experience of a stressful life event is a potent risk-factor. The rodent literature suggests that chronic exposure to stressors as well as 17β-estradiol (E2) can result in alterations in neuronal structure in corticolimbic brain regions, however the translation of these data to humans is limited by the nature of the stressor experienced and issues of brain homology. To address these limitations, we used a well-validated rhesus monkey model of social subordination to examine effects of E2 treatment on subordinate (high stress) and dominant (low stress) female brain structure, including regional gray matter and white matter volumes using structural magnetic resonance imaging. Our results show that one month of E2 treatment in ovariectomized females, compared to control (no) treatment, decreased frontal cortex gray matter volume regardless of social status. In contrast, in the cingulate cortex, an area associated with stress-induced emotional processing, E2 decreased grey matter volume in subordinates but increased it in dominant females. Together these data suggest that physiologically relevant levels of E2 alter cortical gray matter volumes in females after only one month of treatment and interact with chronic social stress to modulate these effects on brain structure.

Study objectives were to determine the effects of zinc (Zn) amino acid complex (Availa Zn, Zinpro Corporation, Eden Prairie, MN) on metabolism, biomarkers of leaky gut, and inflammation during and following heat stress (HS) and nutrient restriction. Crossbred gilts (n = 50; 50 ± 2 kg BW) were blocked by initial BW and randomly assigned to one of five treatments: 1) thermoneutral (TN) and ad libitum fed a control diet (TNCtl), 2) TN and pair-fed a control diet (PFCtl), 3) TN and pair-fed a Zn-supplemented diet (PFZn), 4) HS and ad libitum fed a control diet (HSCtl), and 5) HS and ad libitum fed a Zn-supplemented diet (HSZn). The study consisted of 3 experimental periods (P): during P1 (7 d), all pigs were fed their respective diets ad libitum and housed in TN conditions (20.84 ± 0.03 °C, 47.11 ± 0.42% relative humidity). During P2 (7 d), HSCtl and HSZn pigs were exposed to progressive cyclical HS conditions (27 to 30 °C, 41.9 ± 0.5% relative humidity), while TNCtl, PFCtl, and PFZn pigs remained in TN conditions and were fed ad libitum or pair-fed to their respective HSCtl and HSZn counterparts. During P3 (5 d; “recovery phase”), all pigs were housed in TN conditions and fed ad libitum. Pigs exposed to HS had overall increased rectal temperature, skin temperature, and respiration rate (0.33 °C, 3.76 °C, and 27 bpm, respectively; P < 0.01). Relative to TN controls, HS decreased ADFI and ADG (28 and 35%, respectively; P < 0.05), but these variables were unaffected by dietary treatment. Additionally, circulating insulin did not differ between HS and TN pigs (P = 0.41), but was decreased in PF relative to TN pigs (P < 0.01). During recovery, no differences were observed in rectal temperature or respiration rate across treatments, but HSZn pigs had decreased skin temperature relative to TN, PF, and HSCtl pigs (P < 0.01). During P3, no Zn effects were observed in production parameters; however, PF pigs had increased ADFI and ADG relative to TN and HS treatments (P < 0.01). During P3, circulating insulin was increased in pigs that were HS relative to TN and PF pigs (75%, P < 0.05). Interestingly, tumor necrosis factor alpha (TNFα) levels were decreased during P3 (P = 0.04) in Zn relative to Ctl-fed pigs. Circulating lipopolysaccharide-binding protein was not different among periods (P > 0.10). In summary, Zn reduced TNFα (regardless of HS), and the stimulatory effect of HS on insulin secretion is amplified during HS recovery.

Dietary zinc (inorganic and organic or zinc AA complex forms) is essential for normal intestinal barrier function and regeneration of intestinal epithelium. Given that heat stress (HS) exposure can negatively affect intestinal integrity and caloric intake, possible nutritional mitigation strategies are needed to improve health, performance, and well-being. Therefore, our objective was to evaluate 2 dietary zinc sources and reduced caloric intake on intestinal integrity in growing pigs subjected to 12 h of HS. A total of 36 pigs were fed 1 of 2 diets: 1) a control diet (CON; 120 mg/kg of zinc from zinc sulfate) or 2) 60 mg/kg from zinc sulfate and 60 mg/kg from zinc AA complex (ZnAA). After 17 d, the CON pigs were then exposed to thermal neutral (TN) conditions with ad libitum intake (TN-CON), HS (37°C) with ad libitum intake (HS-CON), or pair-fed to HS intake under TN conditions (PFTN); the ZnAA pigs were exposed to only HS (HS-ZnAA). All pigs were sacrificed after 12 h of environmental exposure, and blood and tissue bioenergetics stress markers and ex vivo ileum and colon integrity were assessed. Compared with TN-CON, HS significantly ( < 0.05) increased rectal temperatures and respiration rates. Ileum villus and crypt morphology was reduced by both pair-feeding and HS. Both PFTN and HS-CON pigs also had reduced ileum integrity (dextran flux and transepithelial resistance) compared with the TN-CON pigs. However, ZnAA tended to mitigate the HS-induced changes in ileum integrity. Ileum mucin 2 protein abundance was increased due to HS and pair-feeding. Colonic integrity did not differ due to HS or PFTN treatments. Compared with the HS-CON, HS-ZnAA pigs tended to have reduced blood endotoxin concentrations. In conclusion, HS and reduced feed intake compromised intestinal integrity in pigs, and zinc AA complex source mitigates some of these negative effects.

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

Animal models have proven to be exceptionally informative in defining neuropeptide regulation of appetite and energy homeostasis (Gao and Horvath 2007, Berthoud 2012, Williams and Elmquist 2012). More recent studies using a range of animal models and molecular tools are elucidating how epigenetic changes resulting from specific prenatal and postnatal dietary environments or experiences affect metabolic processes and appetite regulation (Levin 2008, Zambrano and Nathanielsz 2013, Burdge and Lillycrop 2014). Taken together, these approaches are helping to define possible treatment interventions for eating disorders in people (Casper, Sullivan, and Tecott 2008, Foltin 2012, van Gestel et al. 2014, Lutter, Croghan, and Cui 2016). The choice of animal used is best dictated by the question being addressed. Because of similarities in physiology and neurobiology, studies of captive nonhuman primates have begun to contribute significantly to our understanding of appetite regulation (see Wilson et al. 2014 for a review). Importantly, the use of nonhuman primate models provides the unique opportunity to extend analyses beyond a focus on the homeostatic regulation of appetite. This is particularly relevant given the well-established notion that a number of psychosocial factors influence food intake in people (Bruce and Ricciardelli 2015), including chronic stressor exposure (Tsenkova, Boylan, and Ryff 2013), even in children (Nguyen-Rodriguez, Unger, and Spruijt-Metz 2009). While the importance of psychosocial factors can be modeled in nonprimate animals (Tamashiro, Hegeman, and Sakai 2006), socially housed nonhuman primates share many characteristics in addition to physiology and neurobiology, with humans increasing the translational value of these pre-clinical studies.

Chimpanzee (Pan troglodytes) and rhesus macaque (Macaca mulatta) and humans (Homo sapiens) share physiological and genetic characteristics, but have remarkably different life spans, with chimpanzees living 50–60 % and the rhesus living 35–40 % of maximum human survival. Since oxidative processes are associated with aging and longevity, we might expect to see species differences in age-related oxidative processes. Blood and extracellular fluid contain two major thiol redox nodes, glutathione (GSH)/glutathione-disulfide (GSSG) and cysteine (Cys)/cystine (CySS), which are subject to reversible oxidation–reduction reactions and are maintained in a dynamic non-equilibrium state. Disruption of these thiol redox nodes leads to oxidation of their redox potentials (EhGSSG and EhCySS) which affects cellular physiology and is associated with aging and the development of chronic diseases in humans. The purpose of this study was to measure age-related changes in these redox thiols and their corresponding redox potentials (Eh) in chimpanzees and rhesus monkeys. Our results show similar age-related decreases in the concentration of plasma GSH and Total GSH as well as oxidation of the EhGSSG in male and female chimpanzees. Female chimpanzees and female rhesus monkeys also were similar in several outcome measures. For example, similar age-related decreases in the concentration of plasma GSH and Total GSH, as well as age-related oxidation of the EhGSSG were observed. The data collected from chimpanzees and rhesus monkeys corroborates previous reports on oxidative changes in humans and confirms their value as a comparative reference for primate aging.

Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5-HTTLPR) in the regulatory region of the serotonin (5-HT) transporter (5-HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5-HTTLPR polymorphism. The present study determined the effects of social status and the 5-HTTLPR genotype on 5-HT1A receptor binding potential (5-HT1A BP(ND)) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol (E(2)) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p-[(18) F]MPPF was performed to determine the levels of 5-HT1A BP(ND) under a non-E(2) and a 3-week E(2) treatment condition. The short variant (s-variant) 5-HTTLPR genotype produced a significant reduction in 5-HT1A BP(ND) in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5-HT1A BP(ND) within the ACC. Both these effects of 5-HTTLPR were unaffected by E(2). Additionally, E(2) reduced 5-HT1A BP(ND) in the dorsal raphe of all females irrespective of psychosocial stress or 5-HTTLPR genotype. Hippocampal 5-HT1A BP(ND) was attenuated in subordinate females regardless of 5-HTTLPR genotype during the non-E(2) condition, an effect that was normalised with E(2). Similarly, 5-HT1A BP(ND) in the hypothalamus was significantly lower in subordinate females regardless of 5-HTTLPR genotype, an effect reversed with E(2). Taken together, the data indicate that the effect of E(2) on modulation of central 5HT1A BP(ND) may only occur in brain regions that show no 5-HTTLPR genotype-linked control of 5-HT1A binding.

We examined the relationship between social rank and brain white matter (WM) microstructure, and socioemotional behavior, and its modulation by serotonin (5HT) transporter (5HTT) polymorphisms in prepubertal female macaques. Using diffusion tensor imaging and tract-based spatial statistics, social status differences were found in medial prefrontal cortex (mPFC) WM and cortico-thalamic tracts, with subordinates showing higher WM structural integrity (measured as fractional anisotropy, FA) than dominant animals. 5HTT genotype-related differences were detected in the posterior limb of the internal capsule, where s-variants had higher FA than l/l animals. Status by 5HTT interaction effects were found in (1) external capsule (middle longitudinal fasciculus), (2) parietal WM, and (3) short-range PFC tracts, with opposite effects in dominant and subordinate animals. In most regions showing FA differences, opposite differences were detected in radial diffusivity, but none in axial diffusivity, suggesting that differences in tract integrity likely involve differences in myelin. These findings highlight that differences in social rank are associated with differences in WM structural integrity in juveniles, particularly in tracts connecting prefrontal, sensory processing, motor and association regions, sometimes modulated by 5HTT genotype. Differences in these tracts were associated with increased emotional reactivity in subordinates, particularly with higher submissive and fear behaviors.

In females, cyclical changes in the ovarian hormone oestradiol are known to modulate feeding behaviour. However, what is less clear is how these behavioural effects of oestradiol are modified by the macronutrient content of a diet. In the present study, we report data showing that oestradiol treatment results in both significantly smaller meals and a reduced total calorie intake in ovariectomised, socially-housed female rhesus macaques when only chow diet is available. Conversely, during a choice dietary condition where both palatable and chow options are available, oestradiol treatment had no observable, attenuating effect on calorie intake. During this choice dietary phase, all animals consumed more of the palatable diet than chow diet; however, oestradiol treatment appeared to further increase preference for the palatable diet. Finally, oestradiol treatment increased snacking behaviour (i.e. the consumption of calories outside of empirically defined meals), regardless of diet condition. These findings illustrate how oestradiol differentially influences feeding behaviour depending on the dietary environment and provides a framework in which we can begin to examine the mechanisms underlying these observed changes.

The complex, interacting influences on eating behavior and energy expenditure prevent elucidation of the causal role of any single factor in the current obesity epidemic. However, greater variety in the food supply, particularly in the form of highly palatable, energy-dense foods, has likely made a contribution. This study was undertaken to test the hypothesis that greater dietary variety is associated with greater caloric intake within individual meals consumed by free-feeding, socially-housed female rhesus monkeys. Meal patterns were assessed during two, two-week dietary phases. One phase consisted of a choice between a standard chow diet and a highly palatable diet (HPD). The other phase consisted of access to the chow only. Food intake for each subject was recorded continuously using previously validated, automated feeders, and a meal was defined based on a minimum kilocalorie requirement and a minimum inter-meal interval. During the choice condition, animals electively consumed mixed meals that incorporated both diets as well as other meals that consisted exclusively of a single diet – chow-only or HPD-only. Animals consumed the most calories per meal when the meal was comprised of both the chow and HPD, which differed in caloric density, flavor, and texture. Interestingly, however, there was no significant difference in the amount of calories consumed as HPD-only meals in the choice condition compared to meals in the chow-only, no choice condition, suggesting consumption of a single food during a meal, regardless of palatability, provides a constant sensory experience that may lead to more rapid habituation and subsequent meal cessation. Additionally, during the dietary choice condition, animals consumed fewer calories in the form of chow-only meals. Thus, the present results suggest that limiting dietary variety, regardless of palatability, may be a useful strategy for weight loss in overweight and obese individuals by reducing caloric intake within individual meals.

Psychosocial stress exposure is linked to the disruption of emotional regulation that can manifest as anxiety and depression. Women are more likely to suffer from such psychopathologies than men, indicating that sex-based differences in gonadal steroids may be a key factor in the aetiology of stress-induced adverse health outcomes. Oestradiol (E2 ) positively influences mood and cognition in females, an effect likely related to the ability of E2 to modulate the serotonin and dopamine neurotransmitter systems. Furthermore, genetic variation as a result of the polymorphism in the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5HTTLPR) also can influence the ability of E2 to modulate behaviour and physiology. However, it remains uncertain whether exposure to social stress interacts with the 5HTTLPR to influence E2 -induced changes in behaviour and physiology. The present study used ovariectomised adult female rhesus monkeys to investigate acute and chronic effects of E2 on central monoamine metabolite concentrations using cerobrospinal fluid sampling. We further assessed how E2 -induced changes in monoamine metabolite levels are modified by the unpredictable stress of social subordination and the 5HTTLPR polymorphism. Levels of the serotonin metabolite 5-hydroxyindoleacetic acid decreased significantly during chronic E2 treatment only in dominant females with the long promoter length of SLC6A4. Chronic administration of E2 decreased levels of the dopamine metabolite dihydrophenylacetic acid in a manner independent of the social status, 5HTTLPR genotype, or their interactions. Overall levels of dopamine and serotonin metabolites were increased in subordinate females, although this effect of social stress was not influenced by 5HTTLPR genotype. Together, these data emphasise how E2 can modulate central neurotransmitter systems and indicate that social subordination in female monkeys is a valid model for examining how chronic psychosocial stress alters sensitivity to E2 . Future studies are necessary to elaborate how changes in central neurotransmitter metabolism affect behaviour and physiology as a result of E2 and prolonged exposure to stress.

Mortality in swine herds is often associated with lameness, and trace minerals are implicated in maintaining integrity of skeletal tissues. The objectives of this study were to determine if prolific sows displayed evidence of trace mineral depletion with age and to determine the prevalence of osteochondrosis (OC) lesions. Reduced mineral concentrations with age would support recommendations for an increase in the amount of dietary minerals. Tissue samples were collected from 66 sows selected to represent a cross-sectional profile of a prolific herd fed diets with inorganic sources of trace minerals fortified at concentrations typically found in commercial diets. Females ranged from nulliparous (parity 0) to parity 7 with a lifetime average of 12.9 ± 0.5 pigs born alive per litter. Minerals were assessed in humerus, scapula, ovary, liver, and muscle (psoas major) tissues. Percent bone ash increased (P < 0.05) with parity from 64 to 66% but differed among bone sections. The Ca (39.0%) and P (18.9%) concentrations in bone ash were essentially constant in all sections and parities. Bone Cu, Fe, Mn, and Zn concentrations varied among sections, but differences due to parity (P < 0.05) were only detected in Fe. Bone Fe decreased from approximately 49 μg/g ash in parity 0 and 1 sows to approximately 29 μg/g ash in parity 7, likely reflecting loss of hemopoietic tissue with age. No evidence was detected in liver for depletion of trace minerals across parity; however, liver Cu and Zn concentrations tended to increase with age. Liver Mn concentrations varied with parity, but no consistent trend with parity was evident. Ovary Cu and Mn concentrations varied dramatically as a function of the reproductive status, but no evidence was detected for depletion with parity. Articular surfaces of the distal scapula and proximal and distal humerus were evaluated grossly for prevalence of OC; bones were then sectioned to evaluate lesions in subchondral bone and physis. Incidence of OC lesions on the articular-epiphyseal cartilage complex varied among bone sites, but differences across parities were not detected. In a subset of sows with subchondral bone lesions, the lesions appeared severe enough to contribute to clinical lameness, particularly in the distal humerus site. However, none of the sows exhibited lameness at slaughter. As no reductions in mineral concentrations with age were detected, recommendations to increase dietary mineral supplementation with age were not supported.

The goal of the present study was to examine how social subordination stress and 5HTT polymorphisms affect the development of brain serotonin (5HT) systems during the pubertal transition in female rhesus monkeys. We also examined associations with developmental changes in emotional reactivity in response to a standardized behavioral test, the Human Intruder (HI). Our findings provide the first longitudinal evidence of developmental increases in 5HT1A receptor and 5HTT binding in the brain of female primates from pre- to peripuberty. The increase in 5HT1A BP(ND) in these socially housed female rhesus monkeys is a robust finding, occurring across all groups, regardless of social status or 5HTT genotype, and occurring in the left and right hemispheres of all prefrontal regions studied, as well as the amygdala, hippocampus, hypothalamus, and raphe nuclei. 5HTT BP(ND) also showed an increase with age in raphe, anterior cingulate cortex, and dorsolateral prefrontal cortex. These changes in brain 5HT systems take place as females establish more adult-like patterns of social behavior, as well as during the HI paradigm. Indeed, the main developmental changes in behavior during the HI (increase in freezing and decrease in submission/appeasement) were related to neurodevelopmental increases in 5HT1A receptors and 5HTT, because the associations between these behaviors and 5HT endpoints emerge at peripuberty. We detected an effect of social status on 5HT1A BP(ND) in the hypothalamus and on 5HTT BP(ND) in the orbitofrontal cortex, with subordinates showing higher BP(ND) than dominants in both cases during the pubertal transition. No main effects of 5HTT genotype were observed for 5HT1A or 5HTT BP(ND). Our findings indicate that adolescence in female rhesus monkeys is a period of central 5HT reorganization, partly influenced by exposure to the social stress of subordination, that likely functions to integrate adrenal and gonadal systems and shape the behavioral response to emotionally challenging social situations.

Study question Do naturally occurring, hyperandrogenic (≥1 SD of population mean testosterone, T) female rhesus monkeys exhibit traits typical of women with polycystic ovary syndrome (PCOS)? Summary answer Hyperandrogenic female monkeys exhibited significantly increased serum levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), estradiol (E2), LH, antimullerian hormone (AMH), cortisol, 11-deoxycortisol and corticosterone, as well as increased uterine endometrial thickness and evidence of reduced fertility, all traits associated with PCOS. What is known already Progress in treating women with PCOS is limited by incomplete knowledge of its pathogenesis and the absence of naturally occurring PCOS in animal models. A female macaque monkey, however, with naturally occurring hyperandrogenism, anovulation and polyfollicular ovaries, accompanied by insulin resistance, increased adiposity and endometrial hyperplasia, suggests naturally occurring origins for PCOS in nonhuman primates. Study design, size, duration As part of a larger study, circulating serum concentrations of selected pituitary, ovarian and adrenal hormones, together with fasted insulin and glucose levels, were determined in a single, morning blood sample obtained from 120 apparently healthy, ovary-intact, adult female rhesus monkeys (Macaca mulatta) while not pregnant or nursing. The monkeys were then sedated for somatometric and ultrasonographic measurements. Participants/materials, setting, methods Female monkeys were of prime reproductive age (7.2 ± 0.1 years, mean ± SEM) and represented a typical spectrum of adult body weight (7.4 ± 0.2 kg; maximum 12.5, minimum 4.6 kg). Females were defined as having normal (n = 99) or high T levels (n = 21; ≥1 SD above the overall mean, 0.31 ng/ml). Electronic health records provided menstrual and fecundity histories. Steroid hormones were determined by tandem LC-MS-MS; AMH was measured by enzymeimmunoassay; LH, FSH and insulin were determined by radioimmunoassay; and glucose was read by glucose meter. Most analyses were limited to 80 females (60 normal T, 20 high T) in the follicular phase of a menstrual cycle or anovulatory period (serum progesterone