%0 Journal Article %J Neuroimage %D 2009 %T Serotonin transporter binding and genotype in the nonhuman primate brain using [C-11]DASB PET. %A Christian, B T %A Fox, A S %A Oler, J A %A Vandehey, N T %A Murali, D %A Rogers, J %A Oakes, T R %A Shelton, S E %A Davidson, R J %A Kalin, N H %K Aniline Compounds %K Animals %K Brain %K Carbon Radioisotopes %K Female %K Genotype %K Humans %K Macaca mulatta %K Male %K Positron-Emission Tomography %K Protein Binding %K Radiopharmaceuticals %K Serotonin Plasma Membrane Transport Proteins %K Sulfides %K Tissue Distribution %X

UNLABELLED: The length polymorphism of the serotonin (5-HT) transporter gene promoter region has been implicated in altered 5-HT function and, in turn, neuropsychiatric illnesses, such as anxiety and depression. The nonhuman primate has been used as a model to study anxiety-related mechanisms in humans based upon similarities in behavior and the presence of a similar 5-HT transporter gene polymorphism. Stressful and threatening contexts in the nonhuman primate model have revealed 5-HT transporter genotype dependent differences in regional glucose metabolism. Using the rhesus monkey, we examined the extent to which serotonin transporter genotype is associated with 5-HT transporter binding in brain regions implicated in emotion-related pathology.

METHODS: Genotype data and high resolution PET scans were acquired in 29 rhesus (Macaca mulatta) monkeys. [C-11]DASB dynamic PET scans were acquired for 90 min in the anesthetized animals and images of distribution volume ratio (DVR) were created to serve as a metric of 5-HT transporter binding for group comparison based on a reference region method of analysis. Regional and voxelwise statistical analysis were performed with corrections for anatomical differences in gray matter probability, sex, age and radioligand mass.

RESULTS: There were no significant differences when comparing l/l homozygotes with s-carriers in the regions of the brain implicated in anxiety and mood related illnesses (amygdala, striatum, thalamus, raphe nuclei, temporal and prefrontal cortex). There was a significant sex difference in 5-HT transporter binding in all regions with females having 18%-28% higher DVR than males.

CONCLUSIONS: Because these findings are consistent with similar genotype findings in humans, this further strengthens the use of the rhesus model for studying anxiety-related neuropathologies.

%B Neuroimage %V 47 %P 1230-6 %8 2009 Oct 01 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/19505582?dopt=Abstract %R 10.1016/j.neuroimage.2009.05.090 %0 Journal Article %J Genes Brain Behav %D 2008 %T Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. %A Rogers, J %A Shelton, S E %A Shelledy, W %A Garcia, R %A Kalin, N H %K Animals %K Anxiety Disorders %K Behavior, Animal %K Brain %K Brain Chemistry %K Disease Models, Animal %K Fear %K Female %K Gene Expression Regulation, Developmental %K Genetic Predisposition to Disease %K Genetic Variation %K Inhibition, Psychological %K Macaca mulatta %K Male %K Neural Inhibition %K Polymorphism, Single Nucleotide %K Serotonin %K Serotonin Plasma Membrane Transport Proteins %K Social Behavior %X

In humans and other animals, behavioral responses to threatening stimuli are an important component of temperament. Among children, extreme behavioral inhibition elicited by novel situations or strangers predicts the subsequent development of anxiety disorders and depression. Genetic differences among children are known to affect risk of developing behavioral inhibition and anxiety, but a more detailed understanding of genetic influences on susceptibility is needed. Nonhuman primates provide valuable models for studying the mechanisms underlying human behavior. Individual differences in threat-induced behavioral inhibition (freezing behavior) in young rhesus monkeys are stable over time and reflect individual levels of anxiety. This study used the well-established human intruder paradigm to elicit threat-induced freezing behavior and other behavioral responses in 285 young pedigreed rhesus monkeys. We examined the overall influence of quantitative genetic variation and tested the specific effect of the serotonin transporter promoter repeat polymorphism. Quantitative genetic analyses indicated that the residual heritability of freezing duration (behavioral inhibition) is h(2) = 0.384 (P = 0.012) and of 'orienting to the intruder' (vigilance) is h(2) = 0.908 (P = 0.00001). Duration of locomotion and hostility and frequency of cooing were not significantly heritable. The serotonin transporter polymorphism showed no significant effect on either freezing or orienting to the intruder. Our results suggest that this species could be used for detailed studies of genetic mechanisms influencing extreme behavioral inhibition, including the identification of specific genes that are involved in predisposing individuals to such behavior.

%B Genes Brain Behav %V 7 %P 463-9 %8 2008 Jun %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/18045243?dopt=Abstract %R 10.1111/j.1601-183X.2007.00381.x %0 Journal Article %J Mol Psychiatry %D 2008 %T The serotonin transporter genotype is associated with intermediate brain phenotypes that depend on the context of eliciting stressor. %A Kalin, N H %A Shelton, S E %A Fox, A S %A Rogers, J %A Oakes, T R %A Davidson, R J %K Animals %K Behavior, Animal %K Brain %K Brain Mapping %K Disease Models, Animal %K Female %K Fluorodeoxyglucose F18 %K Genotype %K Macaca mulatta %K Male %K Phenotype %K Polymorphism, Genetic %K Positron-Emission Tomography %K Serotonin Plasma Membrane Transport Proteins %K Stress, Psychological %X

A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [18F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.

%B Mol Psychiatry %V 13 %P 1021-7 %8 2008 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/18414408?dopt=Abstract %R 10.1038/mp.2008.37