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Fox AS, Oler JA, Shelton SE, Nanda SA, Davidson RJ, Roseboom PH, Kalin NH. Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates. Proc Natl Acad Sci U S A. 2012 Oct 30 ; 109(44):18108-13. Pubmed Abstract

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

Comment by:  Jacqueline A. ClaussJenni Blackford
Submitted 20 December 2012
Posted 20 December 2012

Genetic Differences in Neuroplasticity May Underlie Risk for Developing Psychopathology
Kalin and colleagues have a unique resource that promises to elucidate both the genetic and neural underpinnings of vulnerability for psychopathology: a cohort of several hundred rhesus monkeys. Their group studies individual differences in "anxious temperament" characterized by freezing, decreased cooing, and increased cortisol in the presence of a stranger. This trait is the analogue of behavioral inhibition in humans, one of the best established risk factors for developing psychopathology, including anxiety (Clauss and Blackford, 2012), depression (Caspi et al., 1996), and substance abuse (Williams et al., 2010). In both rhesus monkeys and humans, this trait is heritable (Rogers et al., 2008; Robinson et al., 1992), stable over time (Fox et al., 2008; Fox et al., 2001), and mediated by multiple brain regions, including the amygdala (Kalin et al., 2004; Schwartz et al., 2003; Blackford et al., 2009), orbitofrontal cortex (Kalin et al., 2007), and hippocampus (Oler et al., 2010; Blackford et al., 2012).

In a recent study of this cohort of rhesus monkeys, Fox et al. (Fox et al., 2012) linked individual differences in anxious temperament to gene expression differences in the central nucleus of the amygdala, providing specific evidence for a genetic basis of anxious temperament. Using a microarray analysis and quantitative real-time PCR, they identified that anxious temperament was negatively associated with the expression of the neurotrophic tyrosine kinase receptor, type 3 (NTRK3, also known as TrkC) gene. NTRK3 is activated by neurotrophin-3, a member of the BDNF family of neurotrophins (Hohn et al., 1990), and activates signaling pathways involved in neuronal survival, differentiation, and synaptic plasticity (Martínez et al., 1998; Kang and Schuman, 1995). Neurotrophin-3 and NTRK3 have diverse effects in development and adult neuroplasticity, and have been implicated in anxiety disorders (Dierssen et al., 2006). These findings provide preliminary evidence that neuroplasticity plays a role in anxious temperament, and may underlie vulnerability for psychopathology.

These initial findings are exciting, and suggest several future directions. First, future studies should examine gene expression in female rhesus monkeys; the present study only included males. Second, it will be important to examine gene expression in other brain regions, such as the hippocampus, which has been associated with anxious temperament in the rhesus (Oler et al., 2010) and in humans (Blackford et al., 2011). NTRK3 is highly expressed in both the developing (Ernfors et al., 1992) and mature hippocampus (Ernfors et al., 1990), and knockout of NTRK3 reduces axonal arborization and synaptic densities in the hippocampus (Martínez et al., 1998), suggesting that NTRK3 expression in the hippocampus may be important. Finally, future studies should investigate the time course and developmental effects of NTRK3 expression in anxious temperament. Better understanding of this signaling pathway could inspire novel strategies for preventing psychopathology in high-risk children.


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Fox AS, Oler JA, Shelton SE, Nanda SA, Davidson RJ, Roseboom PH, Kalin NH. (2012) Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates. Proceedings of the National Academy of Sciences doi:10.1073/pnas.1206723109. Abstract

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