R, 2008). In contrast to behavioral effects of adult lesions, recent studies have shown that neonatal amygdala lesions in monkeys result in increased freezing during threat (NEC condition; Raper et al., 2013b, 2013c). Typically, monkeys display a modulation of fearful, hostile, and defensive behavior across the human intruder paradigm; however, monkeys with neonatal amygdala lesions displayed similar levels of fearful, hostile, and defensive behavior across the conditions (ALN, NEC, and ST) of the human intruder paradigm at two to four months of age (Raper et al., 2013b, 2013c). Neonatal amygdala lesions also resulted in a flattened diurnal order Valsartan/sacubitril cortisol rhythm in monkeys at 5 months of age (Raper et al., 2013a) and blunted cortisol response to stress in young adult monkeys (Raper et al., 2013c). Finally, neonatal amygdala lesions resulted in significantly less freezing in adulthood (Raper et al., 2013c). Together, these mixed findings support the notion that developmental processes continue to influence the amygdala throughout childhood and into adolescence. The amygdala undergoes extensive postnatal development in macaques (Chareyron et al., 2012; Payne et al., 2010), and plays a critical role in the development of normative fear, such as fear of strangers, heights, and other dangerous situations (Blackford and Pine, 2012). Therefore, opposing findings may depend on the age at which the amygdala was lesioned may be the result of developmental differences. Early amygdala lesion findings may also have been influenced by heterogeneity in the extent of the amygdala subnuclei that were lesioned. The amygdala has a complex neurocircuitry. Input from sensory and prefrontal regions enters through the basolateral regions and flows both directly to the CeA and through inhibitory intercalated cells to the CeA (Par?and Smith, 1993; Sah et al., 2003; Tye et al., 2011). Initial amygdala lesion studies used large, nonspecific lesions; however, the amygdala is a heterogeneous structure and is composed of multiple subnuclei, including the CeA, basal nucleus, and lateral nucleus. Of these, the CeA has been proposed to be critical for anxious temperament. The CeA provides the mainProg Neurobiol. Author manuscript; available in PMC 2016 April 01.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptClauss et al.Pageamygdala output and projects to descending sympathetic, hypothalamic, and brainstem pathways; the CeA may mediate the behavioral effects of amygdala activation and increased sympathetic response (LeDoux et al., 1988; Sah et al., 2003). To examine the role of the CeA specifically in anxious temperament, Kalin and Ornipressin site colleagues (2004) performed CeA lesions in early adolescent monkeys. CeA lesions resulted in a reduction of several components of anxious temperament, including reduced freezing and increased cooing across all three conditions (ALN, NEC, and ST) of the human intruder paradigm. CeA lesions also resulted in less fear of snakes, and less activity of the hypothalamic-pituitary axis, including less cortisol, CRF, and ACTH release. These findings suggest that the CeA is critical for the expression of all three components of anxious temperament and bring up an important question: why do CeA specific lesions ameliorate almost all of the anxious temperament phenotype, but entire amygdala lesions only affect freezing and cortisol response? One answer may be that the entire amygdala lesions were incomplete in many monkeys and may not.R, 2008). In contrast to behavioral effects of adult lesions, recent studies have shown that neonatal amygdala lesions in monkeys result in increased freezing during threat (NEC condition; Raper et al., 2013b, 2013c). Typically, monkeys display a modulation of fearful, hostile, and defensive behavior across the human intruder paradigm; however, monkeys with neonatal amygdala lesions displayed similar levels of fearful, hostile, and defensive behavior across the conditions (ALN, NEC, and ST) of the human intruder paradigm at two to four months of age (Raper et al., 2013b, 2013c). Neonatal amygdala lesions also resulted in a flattened diurnal cortisol rhythm in monkeys at 5 months of age (Raper et al., 2013a) and blunted cortisol response to stress in young adult monkeys (Raper et al., 2013c). Finally, neonatal amygdala lesions resulted in significantly less freezing in adulthood (Raper et al., 2013c). Together, these mixed findings support the notion that developmental processes continue to influence the amygdala throughout childhood and into adolescence. The amygdala undergoes extensive postnatal development in macaques (Chareyron et al., 2012; Payne et al., 2010), and plays a critical role in the development of normative fear, such as fear of strangers, heights, and other dangerous situations (Blackford and Pine, 2012). Therefore, opposing findings may depend on the age at which the amygdala was lesioned may be the result of developmental differences. Early amygdala lesion findings may also have been influenced by heterogeneity in the extent of the amygdala subnuclei that were lesioned. The amygdala has a complex neurocircuitry. Input from sensory and prefrontal regions enters through the basolateral regions and flows both directly to the CeA and through inhibitory intercalated cells to the CeA (Par?and Smith, 1993; Sah et al., 2003; Tye et al., 2011). Initial amygdala lesion studies used large, nonspecific lesions; however, the amygdala is a heterogeneous structure and is composed of multiple subnuclei, including the CeA, basal nucleus, and lateral nucleus. Of these, the CeA has been proposed to be critical for anxious temperament. The CeA provides the mainProg Neurobiol. Author manuscript; available in PMC 2016 April 01.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptClauss et al.Pageamygdala output and projects to descending sympathetic, hypothalamic, and brainstem pathways; the CeA may mediate the behavioral effects of amygdala activation and increased sympathetic response (LeDoux et al., 1988; Sah et al., 2003). To examine the role of the CeA specifically in anxious temperament, Kalin and colleagues (2004) performed CeA lesions in early adolescent monkeys. CeA lesions resulted in a reduction of several components of anxious temperament, including reduced freezing and increased cooing across all three conditions (ALN, NEC, and ST) of the human intruder paradigm. CeA lesions also resulted in less fear of snakes, and less activity of the hypothalamic-pituitary axis, including less cortisol, CRF, and ACTH release. These findings suggest that the CeA is critical for the expression of all three components of anxious temperament and bring up an important question: why do CeA specific lesions ameliorate almost all of the anxious temperament phenotype, but entire amygdala lesions only affect freezing and cortisol response? One answer may be that the entire amygdala lesions were incomplete in many monkeys and may not.
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