Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

Departments of Psychology and Psychiatry and HealthEmotions Research Institute, University of Wisconsin, Madison, WI 53719.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2012; 109(44). DOI: 10.1073/pnas.1206723109
Source: PubMed


Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.


Available from: Patrick H Roseboom
  • Source
    • "The aim of the present study is to examine enduring BI-related alterations in amygdala iFC in a sample of young adults who were initially assessed as infants. Based on work in animal models of BI (Birn et al., 2014; Fox et al., 2012; Shackman et al., 2013) and human studies (Hardee et al., 2013), we predict that adults with a childhood history of BI will show alterations in amygdala iFC with insula and dlPFC. To examine the unique impact of BI on amygdala circuitry, independent of anxious pathology, we only included participants without current or lifetime anxiety diagnoses in our analyses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Behavioral inhibition (BI) is a temperament identified early in life that is associated with increased risk for anxiety disorders. Amygdala hyperresponsivity, found both in behaviorally inhibited and anxious individuals, suggests that amygdala dysfunction may represent a marker of anxiety risk. However, broader amygdala networks have not been examined in individuals with a history of childhood BI. This study uses resting state fMRI to assess amygdala intrinsic functional connectivity (iFC) in 38 healthy young adults (19 with a history of BI, 19 with no history of BI) selected from a longitudinal study. Centromedial, basolateral, and superficial amygdala iFCs were compared between groups and examined in relation to self-report measures of anxiety. Group differences were observed in amygdala iFC with prefrontal cortex, striatum, anterior insula, and cerebellum. Adults characterized with BI in childhood endorsed greater state anxiety prior to entering the scanner, which was associated with several of the group differences. Findings support enduring effects of BI on amygdala circuitry, even in the absence of current psychopathology.
    Biological Psychology 09/2014; 103. DOI:10.1016/j.biopsycho.2014.09.007 · 3.40 Impact Factor
  • Source
    • "EEG (Kagan et al., 1998; Fox et al., 2005a). Furthermore, both inhibited humans and non-human primates consistently show altered amygdala function (Pérez-Edgar et al., 2007; Beaton et al., 2008; Fox et al., 2008; Oler et al., 2010; Blackford et al., 2011; Schwartz et al., 65 2012; Shackman et al., 2013), which may reflect differences in gene expression within the amygdala (Fox et al., 2012). Given prior work that demonstrates that brain structure is associated with brain function (Kalin et al., 2004; Machado et al., 2008; Bliss-Moreau et al., 2010), we propose that these differences in behavior and brain function may be 70 related to variation in brain structure. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Children born with an inhibited temperament are at heightened risk for developing anxiety, depression, and substance use. Inhibited temperament is believed to have a biological basis; however little is known about the structural brain basis of this vulnerability trait. Structural MRI scans were obtained from eighty-four (44 inhibited, 40 uninhibited) young adults. Given previous findings of amygdala hyperactivity in inhibited individuals, groups were compared on three measures of amygdala structure. To identify novel substrates of inhibited temperament, a whole brain analysis was performed. Functional activation and connectivity were examined across both groups. Inhibited adults had larger amygdala and caudate volume and larger volume predicted greater activation to neutral faces. In addition, larger amygdala volume predicted greater connectivity with subcortical and higher order visual structures.Larger caudate volume predicted greater connectivity with the basal ganglia, and less connectivity with primary visual and auditory cortex. We propose that larger volume in these salience detection regions may result in increased activation and enhanced connectivity in response to social stimuli. Given the strong link between inhibited temperament and risk for psychiatric illness, novel therapeutics that target these brain regions and related neural circuits have the potential to reduce rates of illness in vulnerable individuals.
    Social Cognitive and Affective Neuroscience 02/2014; 9(12). DOI:10.1093/scan/nsu019 · 7.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Children with an anxious temperament (AT) are at risk for developing psychiatric disorders along the internalizing spectrum, including anxiety and depression. Like these disorders, AT is a multidimensional phenotype and children with extreme anxiety show varying mixtures of physiological, behavioral, and other symptoms. Using a well-validated juvenile monkey model of AT, we addressed the degree to which this phenotypic heterogeneity reflects fundamental differences or similarities in the underlying neurobiology. The rhesus macaque is optimal for studying AT because children and young monkeys express the anxious phenotype in similar ways and have similar neurobiology. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) in 238 freely behaving monkeys identified brain regions where metabolism predicted variation in three dimensions of the AT phenotype: hypothalamic-pituitary-adrenal (HPA) activity, freezing behavior, and expressive vocalizations. We distinguished brain regions that predicted all three dimensions of the phenotype from those that selectively predicted a single dimension. Elevated activity in the central nucleus of the amygdala and the anterior hippocampus was consistently found across individuals with different presentations of AT. In contrast, elevated activity in the lateral anterior hippocampus was selective to individuals with high levels of HPA activity, and decreased activity in the motor cortex (M1) was selective to those with high levels of freezing behavior. Furthermore, activity in these phenotype-selective regions mediated relations between amygdala metabolism and different expressions of anxiety. These findings provide a framework for understanding the mechanisms that lead to heterogeneity in the clinical presentation of internalizing disorders and set the stage for developing improved interventions.
    Proceedings of the National Academy of Sciences 03/2013; 110(15). DOI:10.1073/pnas.1214364110 · 9.67 Impact Factor
Show more