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Intended amygdala damage is shown in gray on coronal sections through the amygdala of an infant macaque brain atlas in the left column. Location of hypersignals shown on FLAIR MR coronal images is given at several matched anterior-posterior levels through the amygdala in case Neo-Aibo-1 (middle column). Edema caused by cell death appears white within and around the amygdala. The estimated reconstructed lesion extent is shown in the right column. Arrows point to areas of unintended damage or sparing. Abbreviations: Is – lateral sulcus; sts – superior temporal sulcus; ots – occipital temporal sulcus; ERh – entorhinal cortex; PRh – perirhinal cotex; TE, temporal cortical area and TH/TF – cytoarchitectonic fields of the parahippocampal gyrus.
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The amygdala is known to be a key neural structure in many neuropsychiatric disorders. Primarily known for its involvement in fear regulation, the amygdala also plays a critical role in appetitive flexible decision-making. Yet, its contribution to the development of flexible goal-directed behavior has not been thoroughly examined.
The current study...
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... Following selective satiation, monkeys typically shift their preference away from objects associated with the devaluated (sated) food and toward objects associated with a contrasting (e.g., salty vs. sweet) food reinforcer. This shift in behavior demonstrates that the satiated reinforcer has been transiently and selectively devalued and that the change in value is transferred to the objects associated with that food (Baxter et al., 2000(Baxter et al., , 2009Browning et al., 2015;Burke et al., 2014;Chakraborty et al., 2019;Chudasama et al., 2008Chudasama et al., , 2013Croxson et al., 2011;Kazama & Bachevalier, 2013;Kazama et al., 2014;Machado & Bachevalier, 2007;Málková et al., 1997;Mitchell et al., 2007;Murray et al., 2015;Rudebeck et al., 2013;Thornton et al., 1998;Waguespack et al., 2018;Wellman et al., 2005;West, DesJardin, et al., 2011;Wicker et al., 2018). Here, we aimed to determine whether extended training affects this behavior. ...
... In these cases, the cumulative number of exposures to each set is indicated, including discrimination trials performed in baseline sessions between devaluation testing days. Some studies did not report (NR) the number of sessions or trials performed before devaluation testing (Baxter et al., 2000;Burke et al., 2014;Croxson et al., 2011;Izquierdo & Murray, 2007;Kazama & Bachevalier, 2013;Machado & Bachevalier, 2007;Murray et al., 2015;Waguespack et al., 2018;Wicker et al., 2018). a Excluded one outlier requiring 66 sessions to reach criterion. ...
... The circuitry underlying reinforcer devaluation in humans, nonhuman primates, and rodents is highly conserved. Key structures, including the amygdala (monkeys, Kazama & Bachevalier, 2013;Machado & Bachevalier, 2007;Málková et al., 1997;Thornton et al., 1998;Wellman et al., 2005;rodents, (Balleine et al., 2003;Hatfield et al., 1996;West et al., 2012), mediodorsal thalamus (monkeys, Chakraborty et al., 2019;Mitchell et al., 2007;Wicker et al., 2018;rodents, Corbit & Balleine, 2005;Corbit et al., 2003), and orbitofrontal cortex (monkeys, Kazama et al., 2014;Machado & Bachevalier, 2007;Murray et al., 2015;Rudebeck et al., 2013;West, Forcelli, et al., 2011;rodents, (Gallagher et al., 1999;Pickens et al., 2003;West et al., 2013) have been implicated in both primate and rodent models. Given the conservation of circuitry, variations in the tasks both between-and within-species likely drive the differences in outcomes regarding "habit" formation (see above). ...
Goal-directed behavior and habit are parallel and, at times, competing processes. The relative balance of flexible, goal-directed responding as compared to inflexible habitual responding is highly dependent on experience (e.g., training history in a task) and conditions under which the behavior was formed. Reinforcer devaluation tasks have been used widely across species to study the neurobiology of goal-directed behavior. In rodents, under some conditions, extended training in reinforcer devaluation tasks transforms goal-directed responses into habits, rendering the animals insensitive to devaluation. In nonhuman primates, no studies have previously evaluated the impact of extended training. Here we trained four macaques in a variant of the standard reinforcer devaluation task (Málková et al., 1997), in which we presented objects with either a standard number of exposures (i.e., up to 55) or with a high number of exposures (i.e., up to 454). We tested for goal-directed behavior at three time points during the course of this extended training with different combinations of high- and low-repetition objects and stratified results based on whether the preferred or nonpreferred reinforcer was devalued. We found robust devaluation effects across all three cycles of training; however, the magnitude of the effect was modulated by reinforcer preference and by the relative training history of the objects. These data argue against habit formation after overtraining in the reinforcer devaluation task in macaques, a finding that is consistent with reports in humans and with tasks in rodents that employ multiple stimuli, reinforcers, and instrumental actions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
... All subjects were fed a diet of nonhuman primate chow (Purina, St. Louis, MO, USA), given fruit and vegetables daily, and water ad libitum. All animals were trained for behavioral testing for related experiments (Kazama and Bachevalier, 2013), but were naïve to the procedures and stimuli presented in this experiment. Subjects were pseudorandomly assigned into one of four groups: lesions of OFC area 12 (Group OFC12, n = 4; one female), lesions of OFC area 13 (Group OFC13, n = 4, one female), lesions of OFC area 14 (Group OFC14, n = 5, four females), and sham-operations (Group C, n = 4, three females). ...
An earlier study in monkeys indicated that lesions to the mid-portion of the ventral orbitofrontal cortex (OFC), including Walker’s areas 11 and 13 (OFC11/13), altered the spontaneous scanning of still pictures of primate faces (neutral and emotional) and the modulation of arousal. Yet, these conclusions were limited by several shortcomings, including the lesion approach, use of static rather than dynamic stimuli, and manual data analyses. To confirm and extend these earlier findings, we compared attention and arousal to social and nonsocial scenes in three groups of rhesus macaques with restricted lesions to one of three OFC areas (OFC12, OFC13, or OFC14) and a sham-operated control group using eye-tracking to capture scanning patterns, focal attention and pupil size. Animals with damage to the lateral OFC areas (OFC12 and OFC13) showed decreased attention specifically to the eyes of negative (threatening) social stimuli and increased arousal (increased pupil diameter) to positive social scenes. In contrast, animals with damage to the ventromedial OFC area (OFC14) displayed no differences in attention or arousal in the presence of social stimuli compared to controls. These findings support the notion that areas of the lateral OFC are critical for directing attention and modulating arousal to emotional social cues. Together with the existence of face-selective neurons in these lateral OFC areas, the data suggest that the lateral OFC may set the stage for multidimensional information processing related to faces and emotion and may be involved in social judgments.
... Only the center well was used for this experiment. All animals had equal and extensive prior experience with the WGTA because of previous cognitive testing Kazama & Bachevalier, 2013). ...
The amygdala plays an essential role in evaluating social information, threat detection, and learning fear associations. Yet, most of that knowledge comes from studies in adult humans and animals with a fully developed amygdala. Given the considerable protracted postnatal development of the amygdala, it is important to understand how early damage to this structure may impact the long-term development of behavior. The current study examined behavioral responses toward social, innate, or learned aversive stimuli among neonatal amygdala lesion (Neo-Aibo; males = 3, females = 3) or sham-operated control (Neo-C; males = 3, females = 4) rhesus macaques. Compared with controls, Neo-Aibo animals exhibited less emotional reactivity toward aversive objects, including faster retrieval of food reward, fewer fearful responses, and more manipulation of objects. This lower reactivity was only seen in response to social and innate aversive stimuli, whereas Neo-Aibo animals had similar responses to controls for learned aversive stimuli. The current study also detected sex differences in behavioral response to aversive stimuli, such that, as compared with males, females took longer to retrieve the food reward across all aversive stimuli types, but only expressed more hostility and more coo vocalizations during learned aversive trials. Early amygdala damage impacted the expression of some, but not all, sex differences. For example, neonatal amygdala damage eliminated the sex difference in object manipulation. These findings add important information that broaden our understanding of the role of the amygdala in the expression of sexually dimorphic behaviors, as well as its role in learning fear associations and threat detection. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
... Studies from our laboratory have shown that selective neonatal lesions of the amygdala yielded significant changes in emotional and stress reactivity as well as in the ability to flexibly alter behavioral responses when context changed (Kazama & Bachevalier, 2013;Raper, Kazama, & Bachevalier, 2009;Raper, Wallen, et al., 2013;Raper, Wilson, Sanchez, Machado, & Bachevalier, 2013). These behavioral and cognitive changes not only persisted when the animals reached adulthood but also were as severe as the behavioral changes reported in monkeys that had received similar amygdala lesions in adulthood (Bachevalier, Machado, & Kazama, 2011). ...
... Thus, the early timing of the lesions in our study (approximately 2 weeks of age) allows for the possibility of functional compensation by other brain regions. However, this putative compensation of amygdala functions seems unlikely given that these same monkeys with neonatal amygdala lesions have long-lasting impairments in emotional, social and cognitive domains, as well as aberrant stressrelated hormonal responses (Kazama & Bachevalier, 2013;Raper et al., 2009;Raper, Wilson, et al., 2013). ...
Perceiving, integrating, and interpreting multimodal signals are essential for social success, but the neural substrates mediating these functions are not fully understood. This study examined the role of the amygdala in processing bimodal species-specific vocalizations using eye tracking in rhesus macaques. Looking behavior of 6 adult rhesus monkeys with neonatal amygdala lesions (Neo-Aibo; 3M, 3F) was compared with that of 6 sham-operated controls (Neo-C; 3M, 3F). Two side-by-side videos of unknown male conspecifics emitting different vocalizations were presented with the audio signal matching one video. The percentage of time spent looking at each video was used to assess crossmodal integration ability and the percentages of time spent looking at a priori regions of interest (ROIs; eyes, mouth, and rest of each video) were used to characterize scanning patterns. Both groups looked more to one video, indicating that early amygdalar damage did not impair crossmodal integration of complex social signals. However, scanning patterns differed across groups as a function of sex and stimulus parameter. Whereas Neo-C males exhibited differential viewing to the eye and mouth regions as a function of the relative identity of the stimulus animals and Neo-C females made similar distinctions as a function of the relative valence of the vocalizations in females, Neo-Aibo males and females scanned these regions similarly across all trial types. The results suggest that neonatal amygdala damage alters the ability to perceive the social relevance of stimulus features, and are consistent with a role of the amygdala in the recognition of the social salience of complex cues.
... The ability to alter behavioral strategies in the face of shifts in reward value is thus a key survival mechanism. One family of tasks that has been particularly well characterized in this context in nonhuman primates are reinforcer devaluation tasks [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. ...
The capacity to adjust actions based on new information is a vital cognitive function. An animal's ability to adapt behavioral responses according to changes in reward value can be measured using a reinforcer devaluation task, wherein the desirability of a given object is reduced by decreasing the value of the associated food reinforcement. Elements of the neural circuits serving this ability have been studied in both rodents and nonhuman primates. Specifically, the basolateral amygdala, orbitofrontal cortex, nucleus accumbens, and mediodorsal thalamus have each been shown to play a critical role in the process of value updating, required for adaptive goal selection. As these regions receive dense cholinergic input, we investigated whether systemic injections of non-selective nicotinic or muscarinic acetylcholine receptor antagonists, mecamylamine and scopolamine, respectively, would impair performance on a reinforcer devaluation task. Here we demonstrate that in the presence of either a nicotinic or muscarinic antagonist, animals are able to shift their behavioral responses in an appropriate manner, suggesting that disruption of cholinergic neuromodulation is not sufficient to disrupt value updating, and subsequent goal selection, in rhesus macaques.
... In addition, amygdala lesions affect perception of personal space in humans (Kennedy, Gläscher, Tyszka, & Adolphs, 2009) and decrease interest towards infants typical of juvenile females (Toscano et al., 2009). Evidence for a failure to assess the reward value of stimuli has also been shown in monkeys with neonatal amygdala lesions while performing a discrimination devaluation task in which they demonstrate an inability to inhibit selection of objects associated with a devalued food (Kazama & Bachevalier, 2013). ...
Attachment to the caregiver, typically the biological mother, is crucial to young mammals' socio-emotional development. Although studies in nonprimate species suggest that the amygdala regulates social preference and attachment development, its role in primate filial attachment development has been little investigated and has produced mixed results. This study assessed the effects of neonatal amygdala- (Neo-A, N = 16) and sham- (Neo-C, N = 12) lesions on mother recognition and discrimination in macaques raised in species-typical social groups. Neonatal amygdalectomy did not affect social discriminative abilities and mother preference at 3 and 6 months of age, strongly suggesting that the amygdala is not involved in the cognitive processes underlying the development of filial attachment at least when the amygdala damage occurred after the third to fourth weeks of age. Nevertheless, as compared to sham-operated controls, amygdalectomized infants initiated physical contact with their mothers less frequently. The findings are discussed in relation to the known contribution of the amygdala to filial attachment in both rodents and humans. © 2014 Wiley Periodicals, Inc. Dev Psychobiol
... These neonatal lesions also alter the magnitude of the expression of emotional and neuroendocrine reactivity to stressors (Raper et al., 2013a,b). Finally, neonatal amygdala lesions also altered the ability to flexibly adjust choices when reward value has changed (Kazama & Bachevalier, 2013). However, the few studies examining the effects of early amygdala damage on mother-infant interactions have produced mixed results. ...
... Alternatively, Neo-A infants may not have found physical contact with the mother as rewarding as did controls. Support for this latter idea comes from the amygdala's role in reward processing such that damage reduced the rewarding properties of stimuli (Kazama & Bachevalier, 2013;Murray, 2007). ...
The current study examined the effects of neonatal amygdala lesions on mother-infant interactions in rhesus monkeys reared in large species-typical social groups. Focal observations of mother-infant interactions were collected in their social group for the first 12 months postpartum on infants that had received amygdala lesions (Neo-A) at 24-25 days of age and control infants. Early amygdala lesions resulted in subtle behavioral alterations. Neo-A females exhibited earlier emergence of independence from the mother than did control females, spending more time away from their mother, whereas Neo-A males did not. Also, a set of behaviors, including coo vocalizations, time in contact, and time away from the mother, accurately discriminated Neo-A females from control females, but not Neo-A and control males. Data suggest that neonatal amygdalectomy either reduced fear, therefore increasing exploration in females, or reduced the positive reward value of maternal contact. Unlike females, neonatal amygdala lesions had little measurable effects on male mother-infant interactions. The source of this sex difference is unknown. © 2014 Wiley Periodicals, Inc. Dev Psychobiol.
... These results suggest that these areas play a critical role in the development of behavioral adaptation during goal-directed behaviors, but not or less so, in the development of the ability to process emotionally salient stimuli and to modulate emotional reactivity using environmental contexts, which could be supported by other OFC subfields, such as the most ventromedial subfields (i.e., areas 14/25). Given similar impaired decision-making abilities and spared modulation of fear after both neonatal lesions of either OFC areas 11 and 13 or amygdala Kazama and Bachevalier, 2013), the present results suggest that interactions between these two neural structures play a critical role in the development of behavioral adaptation; an ability essential for the self-regulation of emotion and behavior that assures the maintenance of successful social relationships. Keywords: orbitofrontal cortex (OFC), flexible decision-making, safety-signal processing, non-human primate development, areas 11 and 13 www.frontiersin.org ...
... In recent publications, we showed that neonatal amygdala lesions impaired the ability to modulate animals' defensive responses toward different social signals depicted by a human intruder's gaze direction and this deficit emerged in infancy and persisted throughout adulthood (Raper et al., 2012). These same animals with neonatal amygdala lesions failed to update choice preferences when the rewarding value of stimuli was changed (Kazama and Bachevalier, 2013). Yet, despite a slight retardation in fear conditioning, animals with neonatal amygdala lesions discriminated normally between cues signaling fear and cues signaling safety and, more remarkably, were able to use safety cues to regulate their reactivity to the fear cues as did the control animals . ...
... Yet, despite a slight retardation in fear conditioning, animals with neonatal amygdala lesions discriminated normally between cues signaling fear and cues signaling safety and, more remarkably, were able to use safety cues to regulate their reactivity to the fear cues as did the control animals . As discussed in an earlier report (Kazama and Bachevalier, 2013), these differential effects of neonatal amygdala lesions on social and rewarding cues vs. fear conditioning suggest that the amygdala may rely on the rapid updating (on the span of a single exposure) of the valence of external or internal cues to guide optimal decision making and emotional reactivity; a function that may likely be realized by the functional interactions between the amygdala and orbital frontal cortex. If this proposal is correct, it is likely that a similar dichotomy may be found when the neonatal lesions are restricted to the orbital frontal cortex. ...
Recent studies in monkeys have demonstrated that damage to the lateral subfields of orbital frontal cortex (OFC areas 11/13) yields profound changes in flexible modulation of goal-directed behaviors and deficits in fear regulation. Yet, little consideration has been placed on its role in emotional and social development throughout life. The current study investigated the effects of neonatal lesions of the OFC on the flexible modulation of goal-directed behaviors and fear responses in monkeys. Infant monkeys received neonatal lesions of OFC areas 11/13 or sham-lesions during the first post-natal week. Modulation of goal-directed behaviors was measured with a devaluation task at 3–4 and 6–7 years. Modulation of fear reactivity by safety signals was assessed with the AX+/BX− fear-potentiated-startle paradigm at 6–7 years. Similar to adult-onset OFC lesions, selective neonatal lesions of OFC areas 11/13 yielded a failure to modulate behavioral responses guided by changes in reward value, but spared the ability to modulate fear responses in the presence of safety signals. These results suggest that these areas play a critical role in the development of behavioral adaptation during goal-directed behaviors, but not or less so, in the development of the ability to process emotionally salient stimuli and to modulate emotional reactivity using environmental contexts, which could be supported by other OFC subfields, such as the most ventromedial subfields (i.e., areas 14/25). Given similar impaired decision-making abilities and spared modulation of fear after both neonatal lesions of either OFC areas 11 and 13 or amygdala (Kazama et al., 2012; Kazama and Bachevalier, 2013), the present results suggest that interactions between these two neural structures play a critical role in the development of behavioral adaptation; an ability essential for the self-regulation of emotion and behavior that assures the maintenance of successful social relationships.
Sensory-motor gating, the process of filtering sensory stimuli to modulate motor responses, is impaired in many psychiatric diseases but especially schizophrenia. Sensory-motor gating assessed with the prepulse inhibition paradigm (PPI) measures startle in response to preceding acoustic stimuli. PPI studies in rodents have consistently found that neonatal hippocampal lesions impair sensory-motor gating in adult animals, but its applicability to primates has yet to be tested. The study examined acoustic startle responses and PPI in adult rhesus monkeys with neonatal lesions of the hippocampus (Neo-Hibo), amygdala (Neo-Aibo), and orbital frontal cortex areas 11 and 13 (Neo-Oasp) and with sham-operations (Neo-C). All monkeys were initially habituated to the startle apparatus and assayed for acoustic startle response curves. Subsequently, PPI was measured with the prepulse occurring at 60, 120, 240, 480, 1000 and 5000 msec prior to the pulse onset. No significant group differences in baseline startle were found. Compared to Neo-C monkeys, Neo-Hibo monkeys showed normal startle curves as well as normal PPI at short prepulse delays but prepulse facilitation (PPF) at longer prepulse intervals. Neo-Aibo monkeys displayed enhanced startle responses with only minor changes in PPI, whereas Neo-Oasp monkeys had severe dampening of startle responses and impaired PPI at shorter prepulse intervals. These results support prior evidence from rodent literature of the involvement of each of these areas in the development of the complex cortico-limbic circuit modulating sensory-motor gating and may shade light on the specific neural structures associated with deficits in PPI reported in neuropsychiatric disorders, such as schizophrenia, autism spectrum disorders, and post-traumatic disorders.
KeyWords
PPI, Schizophrenia, Sensory-motor gating, Animal Models
The hippocampus is important for long-term memory storage, but also plays a role in regulating the hypothalamic-pituitary-adrenal (HPA) axis and emotional behaviors. We previously reported that early hippocampal damage in monkeys result in increased anxious expression and blunted HPA responses to an acute stressor. Here, we further probe their responses toward aversive stimuli (conditioned and unconditioned) and evaluate HPA axis dysfunction. Responses toward social, innate, and learned aversive stimuli, fear potentiated acoustic startle, and pituitary-adrenal function were investigated in 13 adult rhesus monkeys with neonatal hippocampal lesions (Neo-Hibo=6) and controls (Neo-C=7). Neo-Hibo monkeys' responses depend on the type of unconditioned stimulus, with increased anxiety behaviors toward social and learned, but decreased reactivity toward innate stimuli. Neo-C and Neo-Hibo monkeys exhibited similar performance learning conditioned cues and safety signals. Neo-Hibo monkeys were less sensitive to HPA axis stimulation, potentially suggesting adrenal fatigue. Current findings suggest that the hippocampus plays a large role in regulating not only anxiety behaviors, but also the HPA-axis, a neural system crucial to regulate how we respond to the world around us. These data have important clinical significance considering that many developmental neuropsychiatric disorders exhibit altered hippocampal structure and function, emotional and HPA axis dysregulation.
