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1.  Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates 
Psychiatry research  2011;192(1):37-44.
Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants, MRI scans were completed an average of four years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. Animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
PMCID: PMC4090111  PMID: 21377844
stress; monkeys; corpus callosum; hippocampus; brain abnormalities; 5-HTTLPR
Physiology & behavior  2011;103(5):535-539.
Obesity is associated with the insulin resistance metabolic syndrome, postulated to be mediated by stress-induced alterations within the hypothalamic-pituitary-adrenal (HPA) axis. In adult bonnet macaques we examined relationships between components of the metabolic syndrome, hippocampal neurometabolic asymmetry, an indicator of negative affect, and juvenile cerebrospinal fluid (csf) corticotropin-releasing factor (CRF) levels obtained after stress exposure associated with maternal food insecurity and in controls.
Eleven adult male monkeys (seven with early life stress) who had undergone csf-CRF analyses as juveniles had magnetic resonance spectroscopic imaging (MRSI) of bilateral hippocampus, morphometry (body mass index, BMI; sagittal abdominal diameter, SAD) and determination of fasting plasma glucose and insulin as adults. Neurometabolite ratios included N-acetyl-aspartate as numerator (NAA; a marker of neuronal integrity) and choline (Cho; cell turnover) and creatine (Cr; reference analyte) as denominators.
Elevated juvenile csf-CRF levels positively predicted adult BMI and SAD and were associated with right > left shift of NAA ratio within the hippocampus. Adult visceral obesity and insulin level correlated with right > left shift in hippocampal NAA concentrations, controlling for age and denominator.
Juvenile csf-CRF levels, a neuropeptide associated with early life stress, predict adult visceral obesity and hippocampal asymmetry supporting the hypothesis that metabolic syndrome in adults may be related to early life stress. Furthermore, this study demonstrates asymmetrical hippocampal alterations related to obesity.
PMCID: PMC3107881  PMID: 21459102
Corticotropin releasing factor; hippocampus; stress; metabolic syndrome; food insecurity; obesity
3.  Early-life Stress, Corticotropin-Releasing Factor, and Serotonin Transporter Gene: A Pilot Study 
Psychoneuroendocrinology  2010;36(2):289-293.
Recent studies have indicated a gene by environment interaction between serotonin transporter gene (5-HTTLPR) polymorphism and childhood abuse on depressive symptoms. In addition, persistent elevation of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) concentrations following early-life adversity has been posited to underlie the subsequent development of major depression. This pilot study tested the hypothesis that elevations of juvenile CSF CRF concentrations are, in part, determined by an interaction between polymorphisms of the 5-HTTLPR and early-life stress. Nine juvenile male bonnet macaques (Macaca radiata) had been raised under variable foraging demand (VFD) conditions, a nonhuman primate model of early-life stress, whereas nine subjects were normatively raised under LFD (low foraging demand) conditions. Genotyping revealed that four (44.4%) of the VFD-reared monkeys possessed at least one “s” allele whereas five VFD monkeys were of the l/l genotype. Of the nine LFD subjects, two (22%) had the s/l genotype and seven had the l/l genotype. A “juvenile” CSF sample was obtained at approximately three years of age. CSF CRF concentrations were elevated specifically in the VFD “s/s” and “s/l” allele group in comparison to each of the remaining three groups, indicating a gene by environment (GxE) interaction.
PMCID: PMC3017732  PMID: 20692103
Nonhuman primates; corticotropin-releasing hormone; early-life stress; serotonin transporter gene; major depression; anxiety disorders; gene by environment interaction
4.  Early-Life Stress and Neurometabolites of the Hippocampus 
Brain research  2010;1358:191-199.
We tested the hypothesis that early life stress would persistently compromise neuronal viability of the hippocampus of the grown nonhuman primate. Neuronal viability was assessed through ascertainment of N-acetyl aspartate (NAA) – an amino acid considered reflective of neuronal density/functional integrity – using in vivo proton magnetic resonance spectroscopic imaging (MRSI). The subjects reported herein represent a re-analysis of a sample of nineteen adult male bonnet macaques that had been reared in infancy under induced stress by maternal variable foraging demand (VFD) (N = 10) or control rearing conditions (N = 9). The MRSI spectral readings were recorded using a GE 1.5 Tesla machine under anesthesia. Relative NAA values were derived using NAA as numerator and both choline (Cho) or creatine (Cr) as denominators. Left medial temporal lobe (MTL) NAA/Cho but not NAA/Cr was decreased in VFD subjects versus controls. An MTL NAA/Cho ratio deficit remained significant when controlling for multiple confounding variables. Regression analyses suggested that the NAA/Choline finding was due to independently low left NAA and high left choline. Right MTL showed no rearing effects for NAA, but right NAA was positively related to body mass, irrespective of denominator. The current data indicate that decreased left MTL NAA/Cho may reflect low neuronal viability of the hippocampus following early life stress in VFD-reared versus normally-reared subjects. Given the importance of the hippocampus in stress-mediated toxicity, validation of these data using absolute quantification is suggested and correlative neurohistological studies of hippocampus are warranted.
PMCID: PMC2988576  PMID: 20713023
Early-Life Stress; Nonhuman Primate; Magnetic Resonance Spectroscopy; Hippocampus; N-Acetyl-Aspartate; Brain laterality
5.  The role of early life stress in development of the anterior limb of the internal capsule in non-human primates 
Neuroscience letters  2010;480(2):93-96.
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
PMCID: PMC2951885  PMID: 20541590
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
6.  Correlations between Hippocampal Neurogenesis and Metabolic Indices in Adult Nonhuman Primates 
Neural Plasticity  2011;2011:875307.
Increased neurogenesis in feeding centers of the murine hypothalamus is associated with weight loss in diet-induced obese rodents (Kokoeva et al., 2005 and Matrisciano et al., 2010), but this relationship has not been examined in other species. Postmortem hippocampal neurogenesis rates and premortem metabolic parameters were statistically analyzed in 8 chow-fed colony-reared adult bonnet macaques. Dentate gyrus neurogenesis, reflected by the immature neuronal marker, doublecortin (DCX), and expression of the antiapoptotic gene factor, B-cell lymphoma 2 (BCL-2), but not the precursor proliferation mitotic marker, Ki67, was inversely correlated with body weight and crown-rump length. DCX and BCL-2 each correlated positively with blood glucose level and lipid ratio (total cholesterol/high-density lipoprotein). This study demonstrates that markers of dentate gyrus neuroplasticity correlate with metabolic parameters in primates.
PMCID: PMC3151518  PMID: 21837282
7.  Characterization of Arterial Wave Reflection in Healthy Bonnet Macaques: Feasibility of Applanation Tonometry 
Nonhuman primates are commonly used in cardiovascular research. Increased arterial stiffness is a marker of subclinical atherosclerosis and higher CV risk. We determined the augmentation index (AI) using applanation tonometry in 61 healthy monkeys (59% female, age 1–25 years). Technically adequate studies were obtained in all subjects and required 1.5 ± 1.3 minutes. The brachial artery provided the highest yield (95%). AI was correlated with heart rate (HR) (r = −0.65, P < .001), crown rump length (CRL) (r = 0.42, P = .001), and left ventricular (LV) mass determined using echocardiography (r = 0.52, P < .001). On multivariate analysis, HR (P < .001) and CRL (P = .005) were independent predictors of AI (R2 = 0.46, P < .001). Body Mass Index (BMI) and AI were independent predictors of higher LV mass on multivariate analysis (P < .001 and P = .03). In conclusion, applanation tonometry is feasible for determining AI. Reference values are provided for AI in bonnet macaques, in whom higher AI is related to HR and CRL, and in turn contributes to higher LV mass.
PMCID: PMC2654075  PMID: 19283078
8.  Energy expenditure in chow-fed female non-human primates of various weights 
Until now no technology has been available to study energy metabolism in monkeys. The objective of this study was to determine daily energy expenditures (EE) and respiratory quotients (RQ) in female monkeys of various body weights and ages.
16 socially reared Bonnet Macaque female monkeys [5.5 ± 1.4 kg body weight, modified BMI (length measurement from head to base of the tail) = 28.8 ± 6.7 kg/crown-rump length, m2 and 11.7 ± 4.6 years] were placed in the primate Enhanced Metabolic Testing Activity Chamber (Model 3000a, EMTAC Inc. Santa Barbara, CA) for 22-hour measurements of EE (kcal/kg) and RQ (VCO2/VO2). All were fed monkey chow (4.03 kcal/g) ad-libitum under a 12/12 hour light/dark cycle. Metabolic data were corrected for differences in body weight. Results were divided into day (8-hours), dark (12 hours) and morning (2-hours) periods. Data analysis was conducted utilizing SPSS (Version 13).
Modified BMI negatively correlated with 22-hour energy expenditure in all monkeys (r = -0.80, p < 0.01). The large variability of daily energy intake (4.5 to 102.0 kcal/kg) necessitated division into two groups, non-eaters (< 13 kcal/kg) and eaters (> 23 kcal/kg). There were reductions (p < 0.05) in both 22-hour and dark period RQs in the "non-eaters" in comparison to those who were "eaters". Monkeys were also classified as "lean" (modified BMI < 25) or "obese" (modified BMI > 30). The obese group had lower EE (p < 0.05) during each time period and over the entire 22-hours (p < 0.05), in comparison to their lean counterparts.
The EMTAC proved to be a valuable tool for metabolic measurements in monkeys. The accuracy and sensitivity of the instrument allowed detection of subtle metabolic changes in relation to energy intake. Moreover, there is an association between a reduction of energy expenditure and a gain in body weight.
PMCID: PMC2621221  PMID: 19014676

Results 1-8 (8)