Schizophrenia Research Forum - A Catalyst for Creative Thinking


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

Comments on News and Primary Papers


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.

References:

Clauss JA, Blackford JU. (2012) Behavioral inhibition and risk for developing social anxiety disorder: a meta-analytic study. Journal of the American Academy of Child and Adolescent Psychiatry 51, 1066-1075. Abstract

Caspi A, Moffitt TE, Newman DL, Silva PA. (1996) Behavioral observations at age 3 years predict adult psychiatric disorders. Longitudinal evidence from a birth cohort. Archives of General Psychiatry 53, 1033-1039. Abstract

Williams LR, Fox NA, Lejuez CW, Reynolds EK, Henderson HA, Perez-Edgar KE, Steinberg L, Pine DS. (2010) Early temperament, propensity for risk-taking and adolescent substance-related problems: A prospective multi-method investigation. Addictive Behaviors 35, 1148-1151. Abstract

Rogers J, Shelton SE, Shelledy W, Garcia R, Kalin NH. (2008) Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques. Genes, Brain and Behavior 7, 463-469. Abstract

Robinson, J.L., Reznick, J.S., Kagan, J. & Corley, R. (1992) The heritability of inhibited and uninhibited behavior: a twin study. Developmental Psychology 28, 1030-1037.

Fox, A.S., Shelton, S.E., Oakes, T.R., Davidson, R.J. & Kalin, N.H. (2008) Trait-like brain activity during adolescence predicts anxious temperament in primates. PLoS ONE 3, e2570. Abstract

Fox AS, Shelton SE, Oakes TR, Davidson RJ, Kalin NH. (2001) Continuity and discontinuity of behavioral inhibition and exuberance: Psychophysiological and behavioral influences across the first four years of life. Child Development 72, 1-21. Abstract

Kalin NH, Shelton SE, Davidson RJ. (2004) The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate. Journal of Neuroscience 24, 5506-5515. Abstract

Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL. (2003) Inhibited and uninhibited infants “grown up”: adult amygdalar response to novelty. Science 300, 1952-1953. Abstract

Blackford JU, Avery SN, Shelton RC, Zald DH. (2009) Amygdala temporal dynamics: temperamental differences in the timing of amygdala response to familiar and novel faces. BMC Neuroscience 10:145. Abstract

Kalin NH, Shelton SE, Davidson RJ. (2007) Role of the primate orbitofrontal cortex in mediating anxious temperament. Biological Psychiatry 62, 1134-1139. Abstract

Oler JA, Fox AS, Shelton SE, Rogers J, Dyer TD, Davidson RJ, Shelledy W, Oakes TR, Blangero J, Kalin NH. (2010) Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature 466, 864-868. Abstract

Blackford JU, Allen AH, Cowan RL, Avery SN. (2012) Amygdala and hippocampus fail to habituate to faces in individuals with an inhibited temperament. Social Cognitive and Affective Neuroscience doi:10.109. Abstract

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

Hohn A, Leibrock J, Bailey K, Barde YA. (1990) Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family. Nature 344, 339-341. Abstract

Martínez A, Alcántara S, Borrell V, Del Río JA, Blasi J, Otal R, Campos N, Boronat A, Barbacid M, Silos-Santiago I, Soriano E. (1998) TrkB and TrkC signaling are required for maturation and synaptogenesis of hippocampal connections. The Journal of Neuroscience 18, 7336-7350. Abstract

Kang HJ, Schuman EM. (1995) Neurotrophin-induced modulation of synaptic transmission in the adult hippocampus. Journal of Physiology 89, 11-22. Abstract

Dierssen M, Gratacòs M, Sahún I, Martín M, Gallego X, Amador-Arjona A, Martínez de Lagrán M, Murtra P, Martí E, Pujana MA, Ferrer I, Dalfó E, Martínez-Cué C, Flórez J, Torres-Peraza JF, Alberch J, Maldonado R, Fillat C, Estivill X. (2006) Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction. Neurobiology of Disease 24, 403-418. Abstract

Blackford JU, Avery SN, Cowan RL, Shelton RC, Zald DH. (2011) Sustained amygdala response to both novel and newly familiar faces characterizes inhibited temperament. Social Cognitive and Affective Neuroscience 6, 621-629. Abstract

Ernfors P, Merlio JP, Persson H. (1992) Cells expressing mRNA for neurotrophins and their receptors during embryonic rat development. European Journal of Neuroscience 4, 1140-1158. Abstract

Ernfors P, Wetmore C, Olson L, Persson H. (1990) Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family. Neuron 5, 511-26. Abstract

View all comments by Jacqueline A. Clauss
View all comments by Jenni Blackford