Neuroplasticity, Neurogenesis, and Social Dominance
The explosion of research in neurodevelopment has afforded the opportunity of taking a specific animal model of anxiety, such as one concerned with dominance or subordination stress, and investigating its neurobiological correlates by means of in vivo neuroimaging or postmortem tissue sampling. One of the more important findings in human neurobiology in the past decade is accumulating evidence for the remarkable plasticity of the brain and the development of neurogenesis in diverse brain regions, such as the cortex, hippocampus, cerebellum, and olfactory bulb (33). Gould et al. (34) demonstrated altered neuroplasticity in tree shrews in an enduring dominant-subordinate relationship derived from a social dominance paradigm (35). Specifically, her group showed a rapid decrease in the number of new cells produced in the dentate gyrus of subordinate tree shrews compared to those who remained unexposed to a stressful experience (34). This finding was more recently replicated in marmoset monkeys by using a resident intruder paradigm, a psychosocial stress model similar to that of the dominant-subordinate model for the tree shrews (36). At this time, we do not know the nature of neuroplastic changes in the brains of human infants with early signs and symptoms of social anxiety; thus, the translational implications of stress-induced decreases in granule cell production in animal models is unknown. However, a recent study has shown that granule neurons are potentially involved in hippocampal-dependent learning tasks (37) and that consequent decreases in the number of granule neurons are likely to alter adult hippocampal formation (37). Stressful experiences, which increase levels of circulating glucocorticoids and stimulate hippocampal glutamate release (38), might thus inhibit granule cell neurogenesis. In adult social anxiety, we hypothesize that excessive glutamatergic transmission in hippocampal and cortical regions might be a key component of the dysfunctional circuitry, and successful treatments might serve to prevent the inhibition of neurogenesis while modifying glutamatergic neurotransmission.
Although most animal studies have focused on hippoampal formation, there is evidence that stressors affect cortical neurons as well (39). Neuroplastic changes are also dependent on levels of neurotrophins, such as nerve growth factor, which is known to be differentially modulated by experience (40). In fact, drugs such as the selective serotonin reuptake inhibitors (SSRIs), useful in treating social anxiety, are known to increase expression of brain-derived neurotrophic factor in the hippocampus (41, 42).
Course and Neural Circuitry of Precursors
Given the remarkable developmental plasticity of key neural structures, there is considerable interest in delineating the fear and anxiety circuitry across the stages of development (43, 44). Longitudinally, recent work has confirmed that a significant number of children classified as "inhibited" will develop generalized social anxiety by young adulthood (45, 46). Kagan (47) noted that 4-month-old infants who had a low threshold for becoming distressed and motorically aroused to unfamiliar stimuli were likely to become fearful and subdued in early childhood. Similarly, children identified as behaviorally inhibited at 21 months who remained inhibited at subsequent follow-up visits at ages 4, 5.5, and 7.5 years, showed higher rates of anxiety disorders than children who were not behaviorally inhibited (48), although the findings were not specific for social anxiety. However, a more recent prospective study by Pine et al. (43) has suggested a more specific association between childhood and adult social phobia, a finding consistent with those of family studies among adults (49).
The identification of neurobiological correlates to adult social anxiety disorder in children helps validate clinical and epidemiological observations linking behaviorally inhibited children with adult patients (50). The most notable neurobiological correlates of clinical observations have been the brain laterality studies performed in high-reactive and inhibited children (51, 52) and in animals (53). Davidson (52, 54) demonstrated in infants and adults that withdrawal-related emotions, such as anxiety, were associated with activation of the right frontal region, whereas left prefrontal cortex activation was related to approach-related emotions. Adult patients with social anxiety disorder showed a large increase in activations in right anterior temporal and lateral prefrontal scalp regions when anticipating making a speech in relation to comparison subjects (52, 55). In related preclinical work, EEG recordings in fearful rhesus macaques demonstrated relatively higher right frontal lobe activity, elevated cortisol and CSF CRF concentrations, and more intense defensive responses (53, 56). Although these findings are interesting, they might be relatively disorder nonspecific, in that Rauch et al. (57) demonstrated increased activation in the right inferior frontal cortex, among other regions, across three anxiety diagnoses (obsessive-compulsive disorder [OCD], PTSD, and simple phobia) in a PET symptom-provocation paradigm. Thus, although the epidemiological links between behavioral inhibition and adult social anxiety disorder appear to be validated by common regional alterations in brain activity, the biological associations might be disorder nonspecific.
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