Sex-dependent role of the amygdala in the development of emotional and neuroendocrine reactivity to threatening stimuli in infant and juvenile rhesus monkeys

Abstract

Amygdala dysfunction and abnormal fear and stress reactivity are common features of several developmental neuropsychiatric disorders. Yet, little is known about the exact role the amygdala plays in the development of threat detection and emotional modulation. The current study examined the effects of neonatal amygdala lesions on defensive, emotional, and neuroendocrine reactivity of infant rhesus monkeys reared with their mothers in large species-typical social groups. Monkeys received either bilateral MRI-guided ibotenic acid amygdala (Neo-A; n = 16) or sham (Neo-C; n = 12) lesions at 24.8 ± 1.2 days of age, or served as behavioral control (Neo-BC; n = 3). Defensive and emotional responses were assessed using the Human Intruder Paradigm as infants and as juveniles (2.5 and 12 months of age, respectively), whereas neuroendocrine reactivity was only examined during the juvenile period. As infants, Neo-A animals expressed similar levels of freezing and hostile behaviors as compared to controls, whereas during the juvenile period Neo-A animals expressed significantly less freezing compared to controls. Interestingly, the sex of the infant modulated the behavioral effects of neonatal amygdalectomy, leading to different patterns of behavior depending on the sex and lesion status of the infant. Unlike controls, Neo-A infants did not modulate their behavioral responses based on the salience of the threat. The impact of neonatal amygdalectomy increased with age, such that Neo-A juveniles exhibited fewer emotional behaviors and increased cortisol response to the stressor as compared to controls. These data indicate that the amygdala plays a critical role in the development of both emotional and neuroendocrine reactivity as well as the expression of sexually dimorphic emotional expression.

Neonatal perirhinal cortex lesions impair monkeys’ ability to modulate their emotional responses.

“…The HI task is designed to assess emotional reactivity to a social stressor (Kalin, 1993), and the modulation of emotional behavior to different levels of social threat based on the gaze direction of an unfamiliar human [reviewed in (Coleman & Pierre, 2014)]. In addition, the HI task has been shown to rapidly activate the HPA axis and stimulate the release of glucocorticoids (Jahn et al, 2010; Kalin, Larson, Shelton, & Davidson, 1998; Kalin, Shelton, Davidson, & Kelley, 2001; Raper et al, 2013a; Raper et al, 2013b). As such, the HI task enables the measurement of both behavioral and physiological reactivity to emotionally charged stimuli.…”

“…Finally, the intruder left the room leaving the animal alone for another 10 minutes (Alone 2). A different rubber masks was worn by the intruder at each age of testing, so that the same intruder was seen at each age across all subjects in our laboratory (Raper et al, 2013a; Raper et al, 2013b; Raper et al, 2017). The intruder wore a rubber mask to provide a uniform stimulus to each subject.…”

The nature of individual differences in inhibited temperament and risk for psychiatric disease: A review and meta-analysis

“…Similarly, in a study by another lab, amygdala lesions in young adult monkeys reduced the duration of freezing and reduced cortisol levels in response to a new environment (Machado and Bachevalier, 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).…”

“…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).…”

“… Note: data from (Fox et al, 2010; Izquierdo and Murray, 2004; Kalin et al, 2007, 2004, 2001; Machado et al, 2009; Machado and Bachevalier, 2008; Raper et al, 2013a, 2013b, 2013c). HPA = hypothalamic-pituitary-adrenal axis; ACTH = adrenocorticotropic hormone; CRF = corticotropin-releasing hormone; ↑ = one study showing a significant increase; - = one study showing no effect; ↓ = one study showing a significant decrease…”