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Oler JA, Fox AS, Shelton SE, Rogers J, Dyer TD, Davidson RJ, Shelledy W, Oakes TR, Blangero J, Kalin NH. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature. 2010 Aug 12 ; 466(7308):864-8. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Jenni BlackfordStephan Heckers (SRF Advisor)
Submitted 21 September 2010
Posted 21 September 2010
  I recommend the Primary Papers

Studies of the biological bases of temperament can provide critical insights into why certain individuals are at increased risk for psychiatric disease. The study by Oler and colleagues makes an important contribution to the field by assessing the heritability of temperament-related brain activity in a large colony of pre-adolescent rhesus monkeys. The authors used a standard human intruder paradigm to elicit the phenotypic behavior and concomitant brain activity associated with anxious temperament. Temperament-related brain activity was first identified by correlating anxious temperament with glucose metabolism, the measure of brain activity. Next, heritability estimates were calculated for each voxel in these brain regions. Activity in both the amygdala and hippocampus were correlated with anxious temperament. The amygdala finding confirms previous studies of increased amygdalar activity in both monkeys and humans with an anxious temperament; however, amygdalar activity was not heritable. Instead, the temperament-associated activation in the anterior hippocampus was heritable, providing initial evidence for the hippocampus as a genetically determined neural substrate of anxious temperament.

This hippocampal finding is intriguing and provides a potentially important link among anxious temperament, social anxiety, and schizophrenia. Anxious temperament is a significant risk factor for social anxiety, and social anxiety is very common in individuals with schizophrenia, but a direct link between anxious temperament and schizophrenia has yet to be established. Structural and functional hippocampal deficits are well established in schizophrenia (Heckers et al., 1998; Wright et al., 2000), but most research on anxious temperament and social anxiety has focused on the amygdala, given its role in fight-or-flight fear responses. However, a model of personality proposed by Gray (1982) specifically predicted the septohippocampal system as a neural substrate of the anxiety-related Behavioral Inhibition System—a “system that responds to novel stimuli or stimuli associated with punishment or non-reward by inhibiting ongoing behavior and increasing arousal and attention to the environment.” Kagan’s (1988) temperament trait of Behavioral Inhibition was defined as wary or avoidant responses to novel stimuli and is also associated with risk for social anxiety. Thus, individual differences in temperamental traits related to detection of and response to novelty may be associated with increased risk for social anxiety.

Novel stimuli activate both the hippocampus and amygdala (Blackford et al., 2010), and both regions are involved in emotional memory formation (Phelps, 2004). For individuals with temperament and personality traits associated with increased risk for social anxiety, novelty detection and facial memory may be especially important. Among healthy controls, repeated presentations of a novel face result in increased recognition memory for the face and an associated reduction in amygdala activation (Breiter et al., 1996). Individuals with an anxious temperament fail to show this reduction, but instead have a sustained amygdala response to even familiarized faces (Blackford et al., 2010). Interestingly, individuals with schizophrenia also demonstrate a sustained amygdala response across repeated presentations of faces (Holt et al., 2005). Sustained amygdala activation to even familiarized faces may reflect a deficit in the creation of facial memories, such that the amygdala continues to respond to the faces as though they are new. These empirical findings suggest that dysfunction in a hippocampal-dependent familiarity process may underlie a continuum of social dysfunction ranging from anxious temperament to social anxiety to schizophrenia. This deficit may result in the social anxiety characteristic of both anxious temperament and schizophrenia.

A logical next step is to identify the genes that underlie the temperament-associated hippocampal activation. While much of the discovery in psychiatric genetics has focused on specific disorders, a shift to examining the genes underlying a dimension of social dysfunction may be fruitful.

References:

Blackford JU, Avery SN, Cowan RL, Shelton RC, Zald DH. Sustained amygdala response to both novel and newly familiar faces characterizes inhibited temperament. Soc Cogn Affect Neurosci . 2010 Jul 26. Abstract

Blackford JU, Buckholtz JW, Avery SN, Zald DH. A unique role for the human amygdala in novelty detection. Neuroimage . 2010 Apr 15 ; 50(3):1188-93. Abstract

Breiter HC, Etcoff NL, Whalen PJ, Kennedy WA, Rauch SL, Buckner RL, Strauss MM, Hyman SE, Rosen BR. Response and habituation of the human amygdala during visual processing of facial expression. Neuron . 1996 Nov 1 ; 17(5):875-87. Abstract

Gray JA. The neuropsychology of anxiety. Issues Ment Health Nurs . 1985 Jan 1 ; 7(1-4):201-28.

Heckers S, Rauch SL, Goff D, Savage CR, Schacter DL, Fischman AJ, Alpert NM. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nat Neurosci . 1998 Aug 1 ; 1(4):318-23. Abstract

Holt DJ, Weiss AP, Rauch SL, Wright CI, Zalesak M, Goff DC, Ditman T, Welsh RC, Heckers S. Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol Psychiatry . 2005 May 1 ; 57(9):1011-9. Abstract

Kagan J, Reznick JS, Snidman N. Biological bases of childhood shyness. Science . 1988 Apr 8 ; 240(4849):167-71. Abstract

Phelps EA. Human emotion and memory: interactions of the amygdala and hippocampal complex. Curr Opin Neurobiol . 2004 Apr 1 ; 14(2):198-202. Abstract

Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry . 2000 Jan 1 ; 157(1):16-25. Abstract

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