Matthew J. Jorgensen

Social Impulsivity Inversely Associated with CSF 5-HIAA and Fluoxetine Exposure in Vervet Monkeys

Animal and human research suggests that the central serotonin system is involved in the inhibition of impulsive behavior. Two studies were designed to assess this relationship in male vervet monkeys (Cercopithecus aethiops sabaeus) using a standardized test of impulsivity in a social context: the Intruder Challenge. In the first study, an index of impulsivity in response to an unfamiliar adult male intruder (including latency to approach and aggressive and assertive interactions) was inversely correlated with levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (r = −0.33, p < .01, n = 138). The approach, but not aggressive, component of the Impulsivity Index was the primary contributor to this relationship (partial r = −0.27, p < .01). The second experiment compared responses to the Intruder Challenge after 9 weeks of daily treatment with fluoxetine (2 mg/kg, i.m.) or vehicle. Fluoxetine-treated subjects (n = 6) had significantly lower Impulsivity Index scores than controls (n = 12). The results from these two investigations provide evidence for serotonergic influences on social impulsivity.

Genetic contributions to social impulsivity and aggressiveness in vervet monkeys

BACKGROUND Impulsivity contributes to multiple psychiatric disorders and sociobehavioral problems, and the more serious consequences of impulsivity are typically manifest in social situations. This study assessed the genetic contribution to impulsivity and aggressiveness in a social context using a nonhuman primate model. METHODS Subjects were 352 adolescent and adult vervet monkeys from an extended multigenerational pedigree. Behavior was assessed in the Intruder Challenge Test, a standardized test that measures impulsivity and aggressiveness toward a stranger. Genetic and maternal contributions to variation in the Social Impulsivity Index and its two subscales, impulsive approach and aggression, were estimated using variance components analyses. RESULTS The results found significant genetic contributions to social impulsivity (h2 =.35 +/-.11) and to each of the subscales, with no significant influence of maternal environment. There was a high genetic correlation between the impulsive approach and aggression subscales (rho =.78 +/-.12). CONCLUSIONS This is the first study to demonstrate heritability of social impulsivity in adolescents and adults for any nonhuman primate species. The high genetic correlation suggests the same genes may influence variation in both impulsive approach and aggression. These results provide a promising basis for identification of susceptibility loci for impulsivity and aggressiveness.

Canaries in the coal mine: a cross-species analysis of the plurality of obesity epidemics

A dramatic rise in obesity has occurred among humans within the last several decades. Little is known about whether similar increases in obesity have occurred in animals inhabiting human-influenced environments. We examined samples collectively consisting of over 20 000 animals from 24 populations (12 divided separately into males and females) of animals representing eight species living with or around humans in industrialized societies. In all populations, the estimated coefficient for the trend of body weight over time was positive (i.e. increasing). The probability of all trends being in the same direction by chance is 1.2 × 10−7. Surprisingly, we find that over the past several decades, average mid-life body weights have risen among primates and rodents living in research colonies, as well as among feral rodents and domestic dogs and cats. The consistency of these findings among animals living in varying environments, suggests the intriguing possibility that the aetiology of increasing body weight may involve several as-of-yet unidentified and/or poorly understood factors (e.g. viral pathogens, epigenetic factors). This finding may eventually enhance the discovery and fuller elucidation of other factors that have contributed to the recent rise in obesity rates.

Heritability and genetic correlation of hair cortisol in vervet monkeys in low and higher stress environments

Chronic activation of the hypothalamic-pituitary adrenal (HPA) system is a risk factor for a variety of physical and mental disorders, and yet the complexity of the system has made it difficult to define the role of genetic and environmental factors in producing long-term individual differences in HPA activity. Cortisol levels in hair have been suggested as a marker of total HPA activation over a period of several months. This study takes advantage of a pedigreed nonhuman primate colony to investigate genetic and environmental influences on hair cortisol levels before and after an environmental change. A sample of 226 adult female vervet monkeys (age 3-18) living in multigenerational, matrilineal social groups at the Vervet Research Colony were sampled in a stable low stress baseline environment and 6 months after the entire colony was moved to a new facility with more frequent handling and group disturbances (higher stress environment). Variance components analysis using the extended colony pedigree was applied to determine heritability of hair cortisol levels in the two environments. Bivariate genetic correlation assessed degree of overlap in genes influencing hair cortisol levels in the low and higher stress environments. The results showed that levels of cortisol in hair of female vervets increased significantly from the baseline to the post-move environment. Hair cortisol levels were heritable in both environments (h(2)=0.31), and there was a high genetic correlation across environments (rhoG=0.79), indicating substantial overlap in the genes affecting HPA activity in low and higher stress environments. This is the first study to demonstrate that the level of cortisol in hair is a heritable trait. It shows the utility of hair cortisol as a marker for HPA activation, and a useful tool for identifying genetic influences on long term individual differences in HPA activity. The results provide support for an additive model of the effects of genes and environment on this measure of long term HPA activity.

Characterization and Heritability of Obesity and Associated Risk Factors in Vervet Monkeys

Objective: The objective was to determine the prevalence and heritability of obesity and risk factors associated with metabolic syndrome (MS) in a pedigreed colony of vervet monkeys.

Long-Term Methamphetamine Administration in the Vervet Monkey Models Aspects of a Human Exposure: Brain Neurotoxicity and Behavioral Profiles

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1–3 μM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on ‘injection’ days. Anxiety increased on ‘no injection’ days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.

Techniques for collecting saliva from awake, unrestrained, adult monkeys for cortisol assay

Cortisol levels serve as an index of pituitary‐adrenal activity in nonhuman primates. In adult monkeys, cortisol is normally measured in blood (typically requiring restraint or sedation) or urine (reflecting a state rather than point estimate). In contrast, saliva collection is less invasive than drawing blood and allows for repeated sampling within a short period of time. Although protocols exist for collecting saliva from young monkeys, these procedures are inadequate for awake, unrestrained adult animals. Our laboratory has developed two methods for collecting saliva from adult rhesus monkeys: a “screen” method, which involves licking screen‐covered gauze, and a “pole” method, which involves sucking and chewing on an attached rope. Twenty‐three adult male rhesus monkeys were used to evaluate these two methods. After a period of adaptation, saliva samples were collected from 21 of 23 subjects. Saliva collection was faster with the pole than with the screen method (P < 0.01), but the pole method was not suitable for some animals because of their tendency to bite off the attached rope. An analysis of 19 saliva samples revealed a mean cortisol concentration of 0.84 μg/dl (range 0.27–1.77 μg/dl). There was no statistically significant difference in cortisol value between methods used (P > 0.22). The influence of the flavoring on the cortisol assay was tested, and was found to have no significant effect (P > 0.28). Our results indicate that either technique can be used to safely collect saliva from unrestrained adult monkeys. Choice of technique will depend on the proclivities of individual monkeys. Am. J. Primatol. 52:93–99, 2000.

Physiological correlates of self-injurious behavior in captive, socially-reared rhesus monkeys.

This study examined the relationship between self-injurious behavior (SIB) in rhesus monkeys and several biological variables, including monoamine metabolites in cerebrospinal fluid (CSF) and circulating levels of ACTH, cortisol, and testosterone. Cisternal CSF and blood plasma samples were obtained from 23 individually housed male rhesus macaques, 14 of which had a veterinary record of self-inflicted wounding. CSF samples were analyzed for 5-hydroxyindole-3-acetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) using isocratic high-performance liquid chromatography with electrochemical detection (HPLC-EC). Plasma samples were analyzed for ACTH, cortisol, and testosterone using commercially available radioimmunoassays (RIAs). Rates of self-directed biting were determined by systematic observation of all monkeys. Monkeys with SIB did not differ from controls in their basal monoamine or gonadal activity. However, the SIB group showed consistently lower mean plasma cortisol levels than the control group. Plasma cortisol was negatively correlated with rates of self-directed biting. These results suggest a persistent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in monkeys with SIB. It is not yet clear whether this phenomenon of low cortisol represents chronically reduced adrenocortical secretion under basal conditions or a difference in response to the mild stress of capture and chemical restraint. The implications of these findings will be discussed with respect to SIB in humans as well as post-traumatic stress disorder (PTSD), a condition characterized by pituitary-adrenocortical hypoactivity.

Identifying Heritable Brain Phenotypes in an Extended Pedigree of Vervet Monkeys

The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes. The estimated heritabilities (h2) for these measures in the VRC are higher than those reported previously for such features in humans or in other nonhuman primates: total brain volume (h2 = 0.99, SE = 0.06), cerebral volume (h2 = 0.98, SE = 0.06), cerebellar volume (h2 = 0.86, SE = 0.09), hippocampal volume (h2 = 0.95, SE = 0.07) and corpus callosum cross-sectional areas (h2 = 0.87, SE = 0.07). These findings indicate that, in the controlled environment and with the inbreeding structure of the VRC, additive genetic factors account for almost all of the observed variance in brain structure, and suggest the potential of the VRC for genetic mapping of quantitative trait loci underlying such variance.

Dimensions of Impulsivity Are Associated with Poor Spatial Working Memory Performance in Monkeys

Impulsive behavior and novelty seeking are dimensions of temperament that are behavioral determinants of risk for attention deficit/hyperactivity disorder and its neurocognitive endophenotypes, and variation in the dopamine D4 receptor gene (DRD4) explains at least a portion of the variance in the traits. To further characterize the dimensional phenotype associated with impulsiveness, adolescent male monkeys were evaluated using ecologically valid tests of impulsive approach and aggression in response to social or nonsocial stimuli; subsequently, a delayed response task was implemented to assess spatial working memory performance. Subjects were selected into this study based on their response to the social challenge task or by DRD4 genotype, resulting in three groups: low-impulsivity/common DRD4 allele, high-impulsivity/common DRD4 allele, or rare DRD4 allele. All animals acquired the delayed response task and could perform at near ceiling levels when a ∼0 s delay version was imposed, but as delays were lengthened, high-impulsive animals, regardless of DRD4 genotype, made fewer correct responses than did low-impulsive subjects; an inverse relationship existed for working memory and impulsivity. Notably, impulsive behavior evoked by social and nonsocial stimuli explained overlapping and independent portions of the variance in working memory performance. CSF levels of monoamine metabolites did not significantly differentiate the high- and low-impulsive animals, although monkeys carrying the DRD4 rare allele tended to exhibit higher monoamine turnover. These data indicate that dimensions of impulsivity may impact on working memory performance in qualitatively similar ways but through different mechanisms.