Reduced physical activity and increased intake of calorically-dense diets are the main risk facto... more Reduced physical activity and increased intake of calorically-dense diets are the main risk factors for obesity, glucose intolerance, and type 2 diabetes. Chronic overnutrition and hyperglycemia can alter gene expression, contributing to long-term obesity complications. While caloric restriction can reduce obesity and glucose intolerance, it is currently unknown whether it can effectively reprogram transcriptome to a pre-obesity level. The present study addressed this question by the preliminary examination of the transcriptional dynamics in skeletal muscle after exposure to overnutrition and following caloric restriction. Six male rhesus macaques of 12-13 years of age consumed a high-fat western-style diet for 6 months and then were calorically restricted for 4 months without exercise. Skeletal muscle biopsies were subjected to longitudinal gene expression analysis using next-generation whole-genome RNA sequencing. In spite of significant weight loss and normalized insulin sensitiv...
Early parental loss is associated with social-emotional dysregulation and amygdala physiologic ch... more Early parental loss is associated with social-emotional dysregulation and amygdala physiologic changes. Previously, we examined whole amygdala gene expression in infant monkeys exposed to early maternal deprivation. Here, we focus on an amygdala region with immature neurons at birth: the paralaminar nucleus (PL). We hypothesized that 1) the normal infant PL is enriched in a subset of neural maturation (NM) genes compared to a nearby amygdala subregion; and 2) maternal deprivation would downregulate expression of NM transcripts (mRNA). mRNAs for bcl2, doublecortin, neuroD1, and tbr1-genes expressed in post-mitotic neurons-were enriched in the normal PL. Maternal deprivation at either 1 week or 1 month of age resulted in PL-specific downregulation of tbr1-a transcription factor necessary for directing neuroblasts to a glutamatergic phenotype. tbr1 expression also correlated with typical social behaviors. We conclude that maternal deprivation influences glutamatergic neuronal developme...
Children exposed to early parental loss from death or separation carry a greater risk for develop... more Children exposed to early parental loss from death or separation carry a greater risk for developing future psychiatric illnesses, such as major depression and anxiety. Monkeys experiencing maternal separation at 1 week of age show fewer social behaviors and an increase in self-comforting behaviors (e.g., thumb sucking) over development, whereas in contrast, monkeys experiencing maternal separation at 1 month of age show increased seeking of social comfort later in life. We sought to identify neural systems that may underlie these stress-induced behavioral changes by examining changes in mRNA content in amygdala tissue collected from 1 week separated, 1 month separated, and maternally reared infants at 3 months of age. mRNA from the right medial temporal lobe, primarily the amygdala, was analyzed using Affymetrix U133A 2.0 arrays. One gene, guanylate cyclase 1 α 3 (GUCY1A3), showed differential expression between the 1 week and maternally reared groups and the 1 week and 1 month gro...
Proceedings of the National Academy of Sciences, 2011
We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis... more We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis in the dentate gyrus of the hippocampus. In the first group, six adult monkeys ( Macaca mulatta ) received a single injection of the thymidine analog BrdU (75 mg/kg), which is incorporated into replicating DNA and serves as a marker for new cell birth. Brain tissue was collected 48 h, 2 wk, and 6 wk after BrdU injection to examine the initial stages of neurogenesis. Because mature neurons were not evident at 6 wk, we examined tissue collected over a longer time course in a second study. In this study, eight monkeys ( Macaca fascicularis ) who were subjects in a separate exercise study received 10 weekly injections of BrdU (75 mg/kg), and brain tissue was collected at 16 and 28 wk from the first injection. Based on the timing of expression of neuronal cell markers (βIII-tubulin, doublecortin, NeuN), the extent of dendritic arborization, and acquisition of mature cell body morphology, we ...
Social neuroscience is a new, interdisciplinary field devoted to understanding how biological sys... more Social neuroscience is a new, interdisciplinary field devoted to understanding how biological systems implement social processes and behavior. Social neuroscience capitalizes on biological concepts and methods to inform and refine theories of social behavior, and it uses social and behavioral constructs and data to inform and refine theories of neural organization and function. We focus here on the progress and potential of social neuroscience in the area of mental health. Research in social neuroscience has grown dramatically in recent years. Among the most active areas of research we found are brain-imaging studies in normal children and adults; animal models of social behavior; studies of stroke patients; imaging studies of psychiatric patients; and research on social determinants of peripheral neural, neuroendocrine, and immunological processes. We also found that these areas of research are proceeding along largely independent trajectories. Our goals in this article are to revi...
It has been established that weight gain and weight loss are heavily influenced by activity level... more It has been established that weight gain and weight loss are heavily influenced by activity level. In this study, we hypothesized that the motor cortex exhibits a distinct physical activity‐associated gene expression profile, which may underlie changes in weight associated with movement. Using DNA microarrays we profiled gene expression in the motor cortex of a group of 14 female rhesus monkeys (Macaca mulatta) with a wide range of stable physical activity levels. We found that neuronal growth factor signaling and nutrient sensing transcripts in the brain were highly correlated with physical activity. A follow‐up of AKT3 expression changes (a gene at the apex of neuronal survival and nutrient sensing) revealed increased protein levels of total AKT, phosphorylated AKT, and forkhead box O3 (FOXO3), one of AKT's main downstream effectors. In addition, we successfully validated three other genes via quantitative polymerase chain reaction (qPCR) (cereblon (CRBN), origin recognition c...
A body of knowledge implicates an increase in output from the locus ceruleus (LC) during stress. ... more A body of knowledge implicates an increase in output from the locus ceruleus (LC) during stress. We questioned the innervation and function of the LC in our macaque model of Functional Hypothalamic Amenorrhea, also known as Stress-Induced Amenorrhea. Cohorts of macaques were initially characterized as highly stress resilient (HSR) or stress-sensitive (SS) based upon the presence or absence of ovulation during a protocol involving 2 menstrual cycles with psychosocial and metabolic stress. Afterwards, the animals were rested until normal menstrual cycles resumed and then euthanized on day 5 of a new menstrual cycle [a] in the absence of further stress; or [b] after 5 days of resumed psychosocial and metabolic stress. In this study, parameters of the LC were examined in HSR and SS animals in the presence and absence of stress (2 x 2 block design) using ICC and image analysis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the synthesis of catecholamines; and the TH level was used to assess by inference, NE output. The pixel area of TH-positive dendrites extending outside the medial border of the LC was significantly increased by stress to a similar degree in both HSR and SS animals (p<0.0001). There is a significant CRF innervation of the LC. The positive pixel area of CRF boutons, lateral to the LC, was higher in SS than HSR animals in the absence of stress. Five days of moderate stress significantly increased the CRF-positive bouton pixel area in the HSR group (p<0.02), but not in the SS group. There is also a significant serotonin innervation of the LC. A marked increase in medial serotonin dendrite swelling and beading was observed in the SS + stress group, which may be a consequence of excitotoxicity. The dendrite beading interfered with analysis of axonal boutons. However, at one anatomical level, the serotonin-positive bouton area was obtained between the LC and the superior cerebellar peduncle. Serotonin-positive bouton pixel area was significantly higher in HSR than SS animals (p<0.04). There was no change in either group after 5 days of moderate stress. The ratio of serotonin/TH correlates with ovarian estrogen production
Immunocytochemical localization of immediate early gene proteins, such as Fos, provides a powerfu... more Immunocytochemical localization of immediate early gene proteins, such as Fos, provides a powerful tool with which to demonstrate activated neuronal populations in response to specific stimuli. In contrast to studies using rat brain tissue that consistently show good Fos detection with a variety of antisera, studies using brain tissue from other species yield variable Fos detection. This may be partly due to differences in Fos protein sequences among species or to perfusion and fixation methods. To determine the ability of various Fos antisera to detect neuronal activation in nonhuman primate tissue, we tested nine Fos antisera and compared these antibodies under conditions of intense or physiological stimulation. Monkey brain tissue was either perfused and postfixed with 4% paraformaldehyde or perfused with 4% paraformaldehyde and postfixed with 2.5% acrolein in 4% paraformaldehyde. In rat tissue, stained for comparison, several antisera resulted in good to excellent Fos detection....
The Journal of Clinical Endocrinology & Metabolism, 1992
Administration of the dopamine receptor agonist apomorphine causes a dose-dependent increase in p... more Administration of the dopamine receptor agonist apomorphine causes a dose-dependent increase in plasma oxytocin concentrations and dose-specific behavioral changes in rodents. To investigate
The Journal of Clinical Endocrinology & Metabolism, 1996
Fasting male subjects received each of four treatments on different days: a large oral dose of mo... more Fasting male subjects received each of four treatments on different days: a large oral dose of monosodium L-glutamate (MSG; 12.7 g), the MSG vehicle, an iv injection of TRH, or a high protein meal. Blood samples were drawn via an indwelling venous line before and at 20-min intervals after each treatment for 4 h. Plasma glutamate levels rose 11-fold within 1 h of MSG ingestion, but did not change appreciably with any of the other treatments. Plasma PRL levels rose lo-fold after TRH infusion and a-fold after the protein meal, but did not rise significantly after MSG ingestion. No effects resulted from any of the treatments on plasma LH, FSH, testosterone, GH, or cortisol concentrations. Plasma levels of TSH, T,, and T, showed minimal changes after any of the treatments except TRH; TRH elevated plasma TSH and T, levels. Self-rating instruments of mood and side-effects revealed no treatment-related effects on mood or physical state for up to 48 h after each treatment. Together, these results suggest that acute pharmacological elevations of plasma glutamate levels in adult men produce minimal, if any, effects on hypothalamic or pituitary function.
Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical ... more Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical research. To create new opportunities for genetic and genomic studies using rhesus monkeys, we constructed a genetic linkage map of the rhesus genome. This map consists of 241 microsatellite loci, all previously mapped in the human genome. These polymorphisms were genotyped in five pedigrees of rhesus monkeys totaling 865 animals. The resulting linkage map covers 2048 cM including all 20 rhesus autosomes, with average spacing between markers of 9.3 cM. Average heterozygosity among those markers is 0.73. This linkage map provides new comparative information concerning locus order and interlocus distances in humans and rhesus monkeys. The map will facilitate whole-genome linkage screens to locate quantitative trait loci (QTLs) that influence individual variation in phenotypic traits related to basic primate anatomy, physiology, and behavior, as well as QTLs relevant to risk factors for human disease.
Obesity affects over 500 million people worldwide, and has far reaching negative health effects. ... more Obesity affects over 500 million people worldwide, and has far reaching negative health effects. Given that high body mass index (BMI) and insulin resistance are associated with alterations in many regions of brain and that physical activity can decrease obesity, we hypothesized that in Rhesus monkeys (Macaca mulatta) fed a high fat diet and who subsequently received reduced calories BMI would be associated with a unique gene expression signature in motor regions of the brain implicated in neurodegenerative disorders. In the motor cortex with increased BMI we saw the upregulation of genes involved in apoptosis, altered gene expression in metabolic pathways, and the downregulation of pERK1/2 (MAPK1), a protein involved in cellular survival. In the caudate nucleus with increased BMI we saw the upregulation of known obesity related genes (the insulin receptor (INSR) and the glucagon-like peptide-2 receptor (GLP2R)), apoptosis related genes, and altered expression of genes involved in various metabolic processes. These studies suggest that the effects of high BMI on the brain transcriptome persist regardless of two months of calorie restriction. We hypothesize that active lifestyles with low BMIs together create a brain homeostasis more conducive to brain resiliency and neuronal survival.
The impact of stressors upon some metabolic and endocrine parameters differs when the gonad is pr... more The impact of stressors upon some metabolic and endocrine parameters differs when the gonad is present and in the follicular vs. luteal phase. However, a high vs. low sex steroid milieu did not alter the metabolic response, as assessed by leptin levels, in response to the stressor of fasting.
Cross-sectional studies of exercise-induced reproductive dysfunction have documented a high propo... more Cross-sectional studies of exercise-induced reproductive dysfunction have documented a high proportion of menstrual cycle disturbances in women involved in strenuous exercise training. However, longitudinal studies have been needed to examine individual susceptibility to exercise-induced reproductive dysfunction and to elucidate the progression of changes in reproductive function that occur with strenuous exercise training. Using the female cynomolgus monkey (Macaca fascicularis), we documented changes in menstrual cyclicity and patterns of LH, FSH, estradiol, and progesterone secretion as the animals developed exercise-induced amenorrhea. As monkeys gradually increased running to 12.3 Ϯ 0.9 km/day, body weight did not change significantly although food intake remained constant. The time spent training until amenorrhea developed varied widely among animals (7-24 months; mean ϭ 14.3 Ϯ 2.2 months) and was not correlated with initial body weight, training distance, or food intake. Consistent changes in function of the reproductive axis occurred abruptly, one to two menstrual cycles before the development of amenorrhea. These included significant declines in plasma reproductive hormone concentrations, an increase in follicular phase length, and a decrease in luteal phase progesterone secretion. These data document a high level of interindividual variability in the development of exercise-induced reproductive dysfunction, delineate the progression of changes in reproductive hormone secretion that occur with exercise training, and illustrate an abrupt transition from normal cyclicity to an amenorrheic state in exercising individuals, that is not necessarily associated with weight loss.
Agouti-related protein (AGRP) is a recently described homolog of the skin agouti protein. AGRP is... more Agouti-related protein (AGRP) is a recently described homolog of the skin agouti protein. AGRP is transcribed primarily in the adrenal and hypothalamus and is a high affinity antagonist of the neural melanocortin-3 and melanocortin-4 receptors. The perikarya expressing AGRP messenger RNA are found in the arcuate nucleus of the rat and rhesus monkey. Using a polyclonal antibody against the pharmacologically active domain of AGRP (amino acids 83-132), we have also characterized the distribution of AGRP-immunoreactive neurons in both species. The major fiber tracts are conserved in both species, with dense projections originating in the arcuate nucleus and proceeding along the third ventricle. Dense fiber bundles are also visible
In rodents, stimulation of melanocortin-3 and-4 receptor subtypes (MC3-R and MC4-R) causes a redu... more In rodents, stimulation of melanocortin-3 and-4 receptor subtypes (MC3-R and MC4-R) causes a reduction in food intake, whereas antagonism of MC3-R and MC4-R increases food intake. This report describes the effects of the stable ␣MSH analog, NDP-MSH ([Nle 4 , D-Phe 7 ]␣MSH), and the endogenous ␣MSH receptor antagonist, agouti-related protein, on feeding behavior in adult male rhesus macaques. Infusion of NDP-MSH into the lateral cerebral ventricle dose dependently suppressed intake of a normally scheduled meal without affecting nonfeeding behaviors. Conversely, infusion of agouti-related protein stimulated food intake during the scheduled afternoon meal. In addition to these physiological experiments, the effect of fasting on hypothalamic POMC gene expression was assessed by in situ hybridization. Missing a single meal or fasting for 48 h caused a similar reduction in POMC gene expression in the arcuate nucleus. These results demonstrate that in the primate, central melanocortin receptors can acutely regulate food intake and suggest that the central melanocortinergic system is a physiological regulator of energy balance in primate species.
Reduced physical activity and increased intake of calorically-dense diets are the main risk facto... more Reduced physical activity and increased intake of calorically-dense diets are the main risk factors for obesity, glucose intolerance, and type 2 diabetes. Chronic overnutrition and hyperglycemia can alter gene expression, contributing to long-term obesity complications. While caloric restriction can reduce obesity and glucose intolerance, it is currently unknown whether it can effectively reprogram transcriptome to a pre-obesity level. The present study addressed this question by the preliminary examination of the transcriptional dynamics in skeletal muscle after exposure to overnutrition and following caloric restriction. Six male rhesus macaques of 12-13 years of age consumed a high-fat western-style diet for 6 months and then were calorically restricted for 4 months without exercise. Skeletal muscle biopsies were subjected to longitudinal gene expression analysis using next-generation whole-genome RNA sequencing. In spite of significant weight loss and normalized insulin sensitiv...
Early parental loss is associated with social-emotional dysregulation and amygdala physiologic ch... more Early parental loss is associated with social-emotional dysregulation and amygdala physiologic changes. Previously, we examined whole amygdala gene expression in infant monkeys exposed to early maternal deprivation. Here, we focus on an amygdala region with immature neurons at birth: the paralaminar nucleus (PL). We hypothesized that 1) the normal infant PL is enriched in a subset of neural maturation (NM) genes compared to a nearby amygdala subregion; and 2) maternal deprivation would downregulate expression of NM transcripts (mRNA). mRNAs for bcl2, doublecortin, neuroD1, and tbr1-genes expressed in post-mitotic neurons-were enriched in the normal PL. Maternal deprivation at either 1 week or 1 month of age resulted in PL-specific downregulation of tbr1-a transcription factor necessary for directing neuroblasts to a glutamatergic phenotype. tbr1 expression also correlated with typical social behaviors. We conclude that maternal deprivation influences glutamatergic neuronal developme...
Children exposed to early parental loss from death or separation carry a greater risk for develop... more Children exposed to early parental loss from death or separation carry a greater risk for developing future psychiatric illnesses, such as major depression and anxiety. Monkeys experiencing maternal separation at 1 week of age show fewer social behaviors and an increase in self-comforting behaviors (e.g., thumb sucking) over development, whereas in contrast, monkeys experiencing maternal separation at 1 month of age show increased seeking of social comfort later in life. We sought to identify neural systems that may underlie these stress-induced behavioral changes by examining changes in mRNA content in amygdala tissue collected from 1 week separated, 1 month separated, and maternally reared infants at 3 months of age. mRNA from the right medial temporal lobe, primarily the amygdala, was analyzed using Affymetrix U133A 2.0 arrays. One gene, guanylate cyclase 1 α 3 (GUCY1A3), showed differential expression between the 1 week and maternally reared groups and the 1 week and 1 month gro...
Proceedings of the National Academy of Sciences, 2011
We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis... more We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis in the dentate gyrus of the hippocampus. In the first group, six adult monkeys ( Macaca mulatta ) received a single injection of the thymidine analog BrdU (75 mg/kg), which is incorporated into replicating DNA and serves as a marker for new cell birth. Brain tissue was collected 48 h, 2 wk, and 6 wk after BrdU injection to examine the initial stages of neurogenesis. Because mature neurons were not evident at 6 wk, we examined tissue collected over a longer time course in a second study. In this study, eight monkeys ( Macaca fascicularis ) who were subjects in a separate exercise study received 10 weekly injections of BrdU (75 mg/kg), and brain tissue was collected at 16 and 28 wk from the first injection. Based on the timing of expression of neuronal cell markers (βIII-tubulin, doublecortin, NeuN), the extent of dendritic arborization, and acquisition of mature cell body morphology, we ...
Social neuroscience is a new, interdisciplinary field devoted to understanding how biological sys... more Social neuroscience is a new, interdisciplinary field devoted to understanding how biological systems implement social processes and behavior. Social neuroscience capitalizes on biological concepts and methods to inform and refine theories of social behavior, and it uses social and behavioral constructs and data to inform and refine theories of neural organization and function. We focus here on the progress and potential of social neuroscience in the area of mental health. Research in social neuroscience has grown dramatically in recent years. Among the most active areas of research we found are brain-imaging studies in normal children and adults; animal models of social behavior; studies of stroke patients; imaging studies of psychiatric patients; and research on social determinants of peripheral neural, neuroendocrine, and immunological processes. We also found that these areas of research are proceeding along largely independent trajectories. Our goals in this article are to revi...
It has been established that weight gain and weight loss are heavily influenced by activity level... more It has been established that weight gain and weight loss are heavily influenced by activity level. In this study, we hypothesized that the motor cortex exhibits a distinct physical activity‐associated gene expression profile, which may underlie changes in weight associated with movement. Using DNA microarrays we profiled gene expression in the motor cortex of a group of 14 female rhesus monkeys (Macaca mulatta) with a wide range of stable physical activity levels. We found that neuronal growth factor signaling and nutrient sensing transcripts in the brain were highly correlated with physical activity. A follow‐up of AKT3 expression changes (a gene at the apex of neuronal survival and nutrient sensing) revealed increased protein levels of total AKT, phosphorylated AKT, and forkhead box O3 (FOXO3), one of AKT's main downstream effectors. In addition, we successfully validated three other genes via quantitative polymerase chain reaction (qPCR) (cereblon (CRBN), origin recognition c...
A body of knowledge implicates an increase in output from the locus ceruleus (LC) during stress. ... more A body of knowledge implicates an increase in output from the locus ceruleus (LC) during stress. We questioned the innervation and function of the LC in our macaque model of Functional Hypothalamic Amenorrhea, also known as Stress-Induced Amenorrhea. Cohorts of macaques were initially characterized as highly stress resilient (HSR) or stress-sensitive (SS) based upon the presence or absence of ovulation during a protocol involving 2 menstrual cycles with psychosocial and metabolic stress. Afterwards, the animals were rested until normal menstrual cycles resumed and then euthanized on day 5 of a new menstrual cycle [a] in the absence of further stress; or [b] after 5 days of resumed psychosocial and metabolic stress. In this study, parameters of the LC were examined in HSR and SS animals in the presence and absence of stress (2 x 2 block design) using ICC and image analysis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the synthesis of catecholamines; and the TH level was used to assess by inference, NE output. The pixel area of TH-positive dendrites extending outside the medial border of the LC was significantly increased by stress to a similar degree in both HSR and SS animals (p<0.0001). There is a significant CRF innervation of the LC. The positive pixel area of CRF boutons, lateral to the LC, was higher in SS than HSR animals in the absence of stress. Five days of moderate stress significantly increased the CRF-positive bouton pixel area in the HSR group (p<0.02), but not in the SS group. There is also a significant serotonin innervation of the LC. A marked increase in medial serotonin dendrite swelling and beading was observed in the SS + stress group, which may be a consequence of excitotoxicity. The dendrite beading interfered with analysis of axonal boutons. However, at one anatomical level, the serotonin-positive bouton area was obtained between the LC and the superior cerebellar peduncle. Serotonin-positive bouton pixel area was significantly higher in HSR than SS animals (p<0.04). There was no change in either group after 5 days of moderate stress. The ratio of serotonin/TH correlates with ovarian estrogen production
Immunocytochemical localization of immediate early gene proteins, such as Fos, provides a powerfu... more Immunocytochemical localization of immediate early gene proteins, such as Fos, provides a powerful tool with which to demonstrate activated neuronal populations in response to specific stimuli. In contrast to studies using rat brain tissue that consistently show good Fos detection with a variety of antisera, studies using brain tissue from other species yield variable Fos detection. This may be partly due to differences in Fos protein sequences among species or to perfusion and fixation methods. To determine the ability of various Fos antisera to detect neuronal activation in nonhuman primate tissue, we tested nine Fos antisera and compared these antibodies under conditions of intense or physiological stimulation. Monkey brain tissue was either perfused and postfixed with 4% paraformaldehyde or perfused with 4% paraformaldehyde and postfixed with 2.5% acrolein in 4% paraformaldehyde. In rat tissue, stained for comparison, several antisera resulted in good to excellent Fos detection....
The Journal of Clinical Endocrinology & Metabolism, 1992
Administration of the dopamine receptor agonist apomorphine causes a dose-dependent increase in p... more Administration of the dopamine receptor agonist apomorphine causes a dose-dependent increase in plasma oxytocin concentrations and dose-specific behavioral changes in rodents. To investigate
The Journal of Clinical Endocrinology & Metabolism, 1996
Fasting male subjects received each of four treatments on different days: a large oral dose of mo... more Fasting male subjects received each of four treatments on different days: a large oral dose of monosodium L-glutamate (MSG; 12.7 g), the MSG vehicle, an iv injection of TRH, or a high protein meal. Blood samples were drawn via an indwelling venous line before and at 20-min intervals after each treatment for 4 h. Plasma glutamate levels rose 11-fold within 1 h of MSG ingestion, but did not change appreciably with any of the other treatments. Plasma PRL levels rose lo-fold after TRH infusion and a-fold after the protein meal, but did not rise significantly after MSG ingestion. No effects resulted from any of the treatments on plasma LH, FSH, testosterone, GH, or cortisol concentrations. Plasma levels of TSH, T,, and T, showed minimal changes after any of the treatments except TRH; TRH elevated plasma TSH and T, levels. Self-rating instruments of mood and side-effects revealed no treatment-related effects on mood or physical state for up to 48 h after each treatment. Together, these results suggest that acute pharmacological elevations of plasma glutamate levels in adult men produce minimal, if any, effects on hypothalamic or pituitary function.
Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical ... more Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical research. To create new opportunities for genetic and genomic studies using rhesus monkeys, we constructed a genetic linkage map of the rhesus genome. This map consists of 241 microsatellite loci, all previously mapped in the human genome. These polymorphisms were genotyped in five pedigrees of rhesus monkeys totaling 865 animals. The resulting linkage map covers 2048 cM including all 20 rhesus autosomes, with average spacing between markers of 9.3 cM. Average heterozygosity among those markers is 0.73. This linkage map provides new comparative information concerning locus order and interlocus distances in humans and rhesus monkeys. The map will facilitate whole-genome linkage screens to locate quantitative trait loci (QTLs) that influence individual variation in phenotypic traits related to basic primate anatomy, physiology, and behavior, as well as QTLs relevant to risk factors for human disease.
Obesity affects over 500 million people worldwide, and has far reaching negative health effects. ... more Obesity affects over 500 million people worldwide, and has far reaching negative health effects. Given that high body mass index (BMI) and insulin resistance are associated with alterations in many regions of brain and that physical activity can decrease obesity, we hypothesized that in Rhesus monkeys (Macaca mulatta) fed a high fat diet and who subsequently received reduced calories BMI would be associated with a unique gene expression signature in motor regions of the brain implicated in neurodegenerative disorders. In the motor cortex with increased BMI we saw the upregulation of genes involved in apoptosis, altered gene expression in metabolic pathways, and the downregulation of pERK1/2 (MAPK1), a protein involved in cellular survival. In the caudate nucleus with increased BMI we saw the upregulation of known obesity related genes (the insulin receptor (INSR) and the glucagon-like peptide-2 receptor (GLP2R)), apoptosis related genes, and altered expression of genes involved in various metabolic processes. These studies suggest that the effects of high BMI on the brain transcriptome persist regardless of two months of calorie restriction. We hypothesize that active lifestyles with low BMIs together create a brain homeostasis more conducive to brain resiliency and neuronal survival.
The impact of stressors upon some metabolic and endocrine parameters differs when the gonad is pr... more The impact of stressors upon some metabolic and endocrine parameters differs when the gonad is present and in the follicular vs. luteal phase. However, a high vs. low sex steroid milieu did not alter the metabolic response, as assessed by leptin levels, in response to the stressor of fasting.
Cross-sectional studies of exercise-induced reproductive dysfunction have documented a high propo... more Cross-sectional studies of exercise-induced reproductive dysfunction have documented a high proportion of menstrual cycle disturbances in women involved in strenuous exercise training. However, longitudinal studies have been needed to examine individual susceptibility to exercise-induced reproductive dysfunction and to elucidate the progression of changes in reproductive function that occur with strenuous exercise training. Using the female cynomolgus monkey (Macaca fascicularis), we documented changes in menstrual cyclicity and patterns of LH, FSH, estradiol, and progesterone secretion as the animals developed exercise-induced amenorrhea. As monkeys gradually increased running to 12.3 Ϯ 0.9 km/day, body weight did not change significantly although food intake remained constant. The time spent training until amenorrhea developed varied widely among animals (7-24 months; mean ϭ 14.3 Ϯ 2.2 months) and was not correlated with initial body weight, training distance, or food intake. Consistent changes in function of the reproductive axis occurred abruptly, one to two menstrual cycles before the development of amenorrhea. These included significant declines in plasma reproductive hormone concentrations, an increase in follicular phase length, and a decrease in luteal phase progesterone secretion. These data document a high level of interindividual variability in the development of exercise-induced reproductive dysfunction, delineate the progression of changes in reproductive hormone secretion that occur with exercise training, and illustrate an abrupt transition from normal cyclicity to an amenorrheic state in exercising individuals, that is not necessarily associated with weight loss.
Agouti-related protein (AGRP) is a recently described homolog of the skin agouti protein. AGRP is... more Agouti-related protein (AGRP) is a recently described homolog of the skin agouti protein. AGRP is transcribed primarily in the adrenal and hypothalamus and is a high affinity antagonist of the neural melanocortin-3 and melanocortin-4 receptors. The perikarya expressing AGRP messenger RNA are found in the arcuate nucleus of the rat and rhesus monkey. Using a polyclonal antibody against the pharmacologically active domain of AGRP (amino acids 83-132), we have also characterized the distribution of AGRP-immunoreactive neurons in both species. The major fiber tracts are conserved in both species, with dense projections originating in the arcuate nucleus and proceeding along the third ventricle. Dense fiber bundles are also visible
In rodents, stimulation of melanocortin-3 and-4 receptor subtypes (MC3-R and MC4-R) causes a redu... more In rodents, stimulation of melanocortin-3 and-4 receptor subtypes (MC3-R and MC4-R) causes a reduction in food intake, whereas antagonism of MC3-R and MC4-R increases food intake. This report describes the effects of the stable ␣MSH analog, NDP-MSH ([Nle 4 , D-Phe 7 ]␣MSH), and the endogenous ␣MSH receptor antagonist, agouti-related protein, on feeding behavior in adult male rhesus macaques. Infusion of NDP-MSH into the lateral cerebral ventricle dose dependently suppressed intake of a normally scheduled meal without affecting nonfeeding behaviors. Conversely, infusion of agouti-related protein stimulated food intake during the scheduled afternoon meal. In addition to these physiological experiments, the effect of fasting on hypothalamic POMC gene expression was assessed by in situ hybridization. Missing a single meal or fasting for 48 h caused a similar reduction in POMC gene expression in the arcuate nucleus. These results demonstrate that in the primate, central melanocortin receptors can acutely regulate food intake and suggest that the central melanocortinergic system is a physiological regulator of energy balance in primate species.
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Papers by Judy Cameron