Neonatal lesions of orbital frontal areas 11/13 in monkeys alter goal-directed behavior but spare fear conditioning and safety signal learning.

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.

Development of memory for spatial locations and object/place associations in infant rhesus macaques with and without neonatal hippocampal lesions.

This study traces the development of spatial memory abilities in monkeys and reports the effects of selective neonatal hippocampal lesions on performance across development. Two different versions of the visual paired-comparison (VPC) task were used. The VPC-Spatial-Location task tested memory for object-locations that could be solved using an egocentric spatial frame of reference and the VPC-Object-In-Place task taxed memory for spatial relations using an allocentric reference frame. Eleven rhesus macaques (6 neonatal sham-operated controls and 5 with neonatal neurotoxic hippocampal lesions) were tested on both tasks as infants (8 months), juveniles (18 months), and adults (5-6 years). Memory for spatial locations was present by 18 months of age, whereas memory for object-place relations was present only in adulthood. Also, neonatal hippocampal lesions delayed the emergence of memory for spatial locations and abolished memory for object-place associations, particularly in animals that had sustained extensive and bilateral hippocampal lesions. The differential developmental time course of spatial memory functions and of the effects of neonatal hippocampal lesions on these functions are discussed in relation to morphological maturation of the medial temporal lobe structures in monkeys. Implications of the findings for the neural basis of spatial memory development in humans are also considered.

A novel AX+/BX- paradigm to assess fear learning and safety-signal processing with repeated-measure designs.

One of the core symptoms of anxiety disorders, such as post-traumatic stress disorder, is the failure to overcome feelings of danger despite being in a safe environment. This deficit likely stems from an inability to fully process safety signals, which are cues in the environment that enable healthy individuals to over-ride fear in aversive situations. Studies examining safety signal learning in rodents, humans, and non-human primates currently rely on between-groups designs. Because repeated-measure designs reduce the number of subjects required, and facilitate a broader range of safety signal studies, the current project sought to develop a repeated-measures safety-signal learning paradigm in non-human primates. Twelve healthy rhesus macaques of both sexes received three rounds of auditory fear-potentiated startle training and testing using an AX+/BX- design with all visual cues. Cue AX was paired with an aversive blast of air, whereas the same X cue in compound with another B cue (BX) signaled the absence of an air blast. Hence, cue B served as a safety signal. Once animals consistently discriminated between the aversive (AX+) and safe (BX-) cues, measured by greater startle amplitude in the presence of AX vs. BX, they were tested for conditioned inhibition by eliciting startle in the presence of a novel ambiguous combined cue (AB). Similar to previous AX+/BX- studies, healthy animals rapidly learned to discriminate between the AX+ and BX- cues as well as demonstrate conditioned inhibition in the presence of the combined AB cue (i.e. lower startle amplitude in the presence of AB vs. AX). Additionally, animals performed consistently across three rounds of testing using three new cues each time. The results validate this novel method that will serve as a useful tool for better understanding the mechanisms for the regulation of fear and anxiety.

Inhibition of fear by learned safety signals: a mini-symposium review.

Safety signals are learned cues that predict the nonoccurrence of an aversive event. As such, safety signals are potent inhibitors of fear and stress responses. Investigations of safety signal learning have increased over the last few years due in part to the finding that traumatized persons are unable to use safety cues to inhibit fear, making it a clinically relevant phenotype. The goal of this review is to present recent advances relating to the neural and behavioral mechanisms of safety learning, and expression in rodents, nonhuman primates, and humans.

Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques.

Fear conditioning studies have demonstrated the critical role played by the amygdala in emotion processing. Although all lesion studies until now investigated the effect of adult-onset damage on fear conditioning, the current study assessed fear-learning abilities, as measured by fear-potentiated startle, in adult monkeys that had received neonatal neurotoxic amygdala damage or sham-operations. After fear acquisition, their abilities to learn and use a safety cue to modulate their fear to the conditioned cue, and, finally, to extinguish their response to the fear conditioned cue were measured with the AX+/BX- Paradigm. Neonatal amygdala damage retarded, but did not completely abolish, the acquisition of a learned fear. After acquisition of the fear signal, four of the six animals with neonatal amygdala lesions discriminated between the fear and safety cues and were also able to use the safety signal to reduce the potentiated-startle response and to extinguish the fear response when the air-blast was absent. In conclusion, the present results support the critical contribution of the amygdala during the early phases of fear conditioning that leads to quick, robust responses to potentially threatening stimuli, a highly adaptive process across all species and likely to be present in early infancy. The neonatal amygdala lesions also indicated the presence of amygdala-independent alternate pathways that are capable to support fear learning in the absence of a functional amygdala. This parallel processing of fear responses within these alternate pathways was also sufficient to support the ability to flexibly modulate the magnitude of the fear responses.

Preserved stimulus-reward and reversal learning after selective neonatal orbital frontal areas 11/13 or amygdala lesions in monkeys.

Neither lesions of orbital frontal (OFC) areas 11/13 nor selective amygdala lesions alter the ability to learn stimulus-reinforcer association and reversal discriminations in adult monkeys. Here, we investigated whether the same conclusion will hold true when the same lesions occur in infancy. Infant rhesus monkeys received sham-operations, neurotoxic amygdala lesions, or aspiration OFC 11/13 lesions at 8-15 days of age and were trained on object discrimination reversal (ODR) tasks. Performance on a single pair (1-Pair) ODR was assessed at the age of 3 months and 3 years, and then animals were tested in a 5-Pair ODR task in which they had to concurrently learn and reverse five discrimination problems. The results indicated that the ability to solve a single-pair discrimination problem followed by six reversals appears to be late maturing in monkeys but is spared following selective lesions of either OFC areas 11/13 or amygdala, even with the use of the more challenging 5-object ODR task. Finally, performance in the 1 and 5-Pair ODR at 3 years was comparable to that following adult-onset lesions, indicating that neither OFC areas 11/13 nor amygdala are critical for the development of reversal learning.

Behavioral outcomes of late-onset or early-onset orbital frontal cortex (areas 11/13) lesions in rhesus monkeys.

The orbital frontal cortex (OFC) has been implicated in a number of psychiatric disorders, including depression, anxiety, phobia, and obsessive-compulsive disorder. Thus, a better understanding of its functions will likely provide critical information to understand the specific behavioral and cognitive processes affected in these human disorders. In recent years, a growing number of studies have provided evidence for anatomical and functional differentiation within the OFC. Here we discuss the effects of selective OFC (areas 11/13) lesions on social behavior, emotional regulation, and behavioral adaptation. Damage to these specific OFC subfields in adult monkeys resulted in profound changes in the flexible modulation of responses guided by reward value that could explain the poor fear regulation and disturbed social interactions observed in the same animals. A similar pattern of results was found when the OFC lesions were done in infancy. Thus, in monkeys, self-regulation abilities mediated by OFC areas 11/13 emerge from midinfancy through adolescence.

The effects of selective hippocampal damage on tests of oddity in rhesus macaques.

The oddity task (e.g., A-, A-, B+) is classified as a conjunctive or relational task in which accurate performance depends upon learning to attend to stimulus relationships, not stimulus identity, and has no retention component as stimuli are presented simultaneously. It has been suggested that the hippocampus may play a particular role in learning this type of task in humans and animals. To test this, we trained adult rhesus macaques with selective neurotoxic damage to the hippocampal formation on their ability to learn and apply an oddity rule. The results suggest that the monkeys were able to adapt simple strategies to solve variations of the oddity task, however as the opportunity for such strategies was reduced, monkeys with hippocampal damage were increasingly impaired.

Impact of amygdala, orbital frontal, or hippocampal lesions on threat avoidance and emotional reactivity in nonhuman primates.

The authors measured the effects of bilateral amygdaloid, orbital frontal, or hippocampal lesions on emotional reactivity and passive avoidance in rhesus monkeys (Macaca mulatta). Animals were presented with 8 neutral or 8 aversive objects, each paired with a highly preferred food reward. Sham-operated control animals displayed heightened defensive behaviors and typically would not approach or retrieve the food when paired with a potential predator (coiled rubber snake), 2 conditioned aversive stimuli for laboratory-housed monkeys (a capture net and leather handling gloves), and 1 object displaying a threatening social signal (direct eye contact from a human-like doll). Animals with amygdala lesions, but not hippocampal or orbital frontal lesions, showed less tension-related behaviors and diminished passive avoidance of the rubber snake and its matched neutral item (a coiled piece of hose) relative to control animals. All operated groups displayed normal patterns of behavior toward conditioned and socially aversive objects. These results expand our understanding of how the primate brain evaluates reward and threat, and indicate a highly specialized role for the amygdala in mediating passive avoidance and emotional reactivity to potentially life-threatening stimuli.

Selective aspiration or neurotoxic lesions of orbital frontal areas 11 and 13 spared monkeys' performance on the object discrimination reversal task.

Damage to the orbital frontal cortex (OFC) has long been associated with reversal learning deficits in several species. In monkeys, this impairment follows lesions that include several OFC subfields. However, the different connectional patterns of OFC subfields together with neuroimaging data in humans have suggested that specific OFC areas play distinctive roles in processing information necessary to guide behavior (Kringelbach and Rolls, 2004; Barbas, 2007; Price, 2007). More specifically, areas 11 and 13 contribute to a sensory network, whereas medial areas 10, 14, and 25 are heavily connected to a visceromotor network. To examine the contribution of areas 11 and 13 to reversal learning, we tested monkeys with selective damage to these two OFC areas on two versions of the ODR task using either one or five discrimination problems. We compared their performance with that of sham-operated controls and of animals with neurotoxic amygdala lesions, which served as operated controls. Neither damage to areas 11 and 13 nor damage to the amygdala affected performance on the ODR tasks. The results indicate that areas 11 and 13 do not critically contribute to reversal learning and that adjacent damage to OFC subfields (10, 12, 14, and 25) could account for the ODR deficits found in earlier lesion studies. This sparing of reversal learning will be discussed in relation to deficits found in the same animals on tasks that measure behavioral modulation when relative value of affective (positive and negative) stimuli was manipulated.