Ludise Malkova

Effects of aspiration versus neurotoxic lesions of the amygdala on emotional responses in monkeys

All previous reports describing alterations in emotional reactivity after amygdala damage in monkeys were based on aspiration or radiofrequency lesions which likely disrupted fibres of passage coursing to and from adjacent ventral and medial temporal cortical areas. To determine whether this associated indirect damage was responsible for some or all of the changes described earlier, we compared the changes induced by aspiration of the amygdala with those induced by fibre‐sparing neurotoxic lesions. Four different stimuli, two with and two without a social component, were used to evaluate the expression of defence, aggression, submission and approach responses. In unoperated controls, defence and approach behaviours were elicited by all four stimuli, ‘social’ and inanimate alike, whereas aggression and submission responses occurred only in the presence of the two ‘social’ stimuli. Furthermore, all defence reactions were reduced with an attractive inanimate item, while freezing was selectively increased with an aversive one. Relative to controls, monkeys with neurotoxic amygdala lesions showed the same array of behavioural changes as those with aspiration lesions, i.e. reduced fear and aggression, increased submission, and excessive manual and oral exploration. Even partial neurotoxic lesions involving less than two‐thirds of the amygdala significantly altered fear and manual exploration. These findings convincingly demonstrate that the amygdala is crucial for the normal regulation of emotions in monkeys. Nevertheless, because some of the symptoms observed after neurotoxic lesions were less marked than those seen after aspiration lesions, the emotional disorders described earlier after amygdalectomy in monkeys were likely exacerbated by the attendant fibre damage.

GABAA-Mediated Inhibition of Basolateral Amygdala Blocks Reward Devaluation in Macaques

Amygdala ablation disrupts reinforcer “devaluation” in monkeys (Malkova et al., 1997). Here, we tested the hypothesis that transient inactivation of amygdala by the GABAA agonist muscimol (MUS), specifically during the period of reward satiation, would have a similar effect. Six pigtail macaques were trained on a visual object discrimination task in which 60 objects were associated with one of two specific food rewards. Subsequently, we evaluated the selective satiation-induced change (devaluation) in object preference in probe sessions. We also examined the effect of the amygdala inactivation during the probe sessions to determine whether the inactivation limited to the testing period (and not during the satiation period) is sufficient to impair the expression of reinforcer devaluation. MUS infusions were aimed at basolateral amygdala (BLA) in a pseudorandomized design; each monkey received MUS or saline either before or after selective satiation with each of the two food rewards (six infusions total). Under the control (saline) condition, the monkeys significantly shifted their preference from objects representing the sated food rewards to those representing the nonsated rewards (30% change). When BLA was inactivated during selective satiation (i.e., MUS infused before satiation), this devaluation effect was blocked. In contrast, MUS infusion after satiation, so that it was present just during the testing period, did not impair the shift in object preference (27% change). Thus, BLA is necessary for the appropriate registration of the change in the reinforcer value but not for the subsequent expression of the devaluation involving its transfer to secondary reinforcers.

Transient Inactivation of Orbitofrontal Cortex Blocks Reinforcer Devaluation in Macaques

The orbitofrontal cortex (OFC) and its interactions with the basolateral amygdala (BLA) are critical for goal-directed behavior, especially for adapting to changes in reward value. Here we used a reinforcer devaluation paradigm to investigate the contribution of OFC to this behavior in four macaques. Subjects that had formed associations between objects and two different primary reinforcers (foods) were presented with choices of objects overlying the two different foods. When one of the two foods was devalued by selective satiation, the subjects shifted their choices toward the objects that represented the nonsated food reward (devaluation effect). Transient inactivation of OFC by infusions of the GABAA receptor agonist muscimol into area 13 blocked the devaluation effect: the monkeys did not reduce their selection of objects associated with the devalued food. This effect was observed when OFC was inactivated during both satiation and the choice test, and during the choice test only. This supports our hypothesis that OFC activity is required during the postsatiety object choice period to guide the selection of objects. This finding sharply contrasts with the role of BLA in the same devaluation process (Wellman et al., 2005). Whereas activity in BLA was required during the selective satiation procedure, it was not necessary for guiding the subsequent object choice. Our results are the first to demonstrate that transient inactivation of OFC is sufficient to disrupt the devaluation effect, and to document a role for OFC distinct from that of BLA for the conditioned reinforcer devaluation process in monkeys.

Neurotoxic lesions of perirhinal cortex impair visual recognition memory in rhesus monkeys

Recent excitotoxic lesion studies in monkeys have shown that the recognition memory deficits originally attributed to amygdalo-hippocampal damage were due in whole or in part to the accompanying damage to surrounding tissue, including fibers of passage. Here we show that the same conclusion does not apply to the visual recognition impairment produced by aspiration lesions of perirhinal cortex inasmuch as equally severe impairment was found after excitotoxic lesions of this cortex. The finding demonstrates that damage limited to perirhinal neurons is sufficient to impair visual memory and that damage to fibers of passage neither caused nor exacerbated the effect described initially.

Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood

The present study reviews the long-term effects of neonatal hippocampal damage in monkeys on the development of memory functions and socioemotional behavior. The results showed that neonatal damage to the hippocampal formation impairs specific memory processes, such as those subserving automatic (as opposed to effortful) recognition memory and relational learning, while sparing the abilities to acquire skills, such as object discriminations. Furthermore, the neonatal hippocampectomy led to a progressive loss of social affiliation and a protracted emergence of locomotor stereotypies. While the memory losses following neonatal hippocampal lesions resemble those found after similar lesions acquired in adulthood, only the neonatal lesions resulted in a protracted emergence of abnormal behaviors. These later findings suggested that, presumably, the neonatal lesions impacted on neural systems remote from the site of damage. This was confirmed by our more recent neurobiological studies, demonstrating that neonatal, but not late, lesions of the medial temporal lobe region, disrupt the normal behavioral and cognitive processes subserved by the prefrontal cortex and the caudate nucleus. All together the data support the neurodevelopmental hypothesis viewing early insult to the medial temporal region as the origin of developmental psychosis in humans, such as schizophrenia.

Longitudinal magnetic resonance imaging study of rhesus monkey brain development.

To examine early brain development, T1‐weighted structural MRI scans of seven rhesus monkeys (Macaca mulatta) were obtained longitudinally between the ages of 1 week and 4 years at 12 age points. Total brain volume, calculated at each age point, increased significantly, by 56%, between 1 week and 4 years. The greatest increase of 22% occurred between 1 week and 1 month, followed by further significant increases between 1 and 2 months, and 3 and 4 months. Gradually smaller increases continued up to 3 years with no further significant changes thereafter. A robust maturation of white matter occurred between 1 week, at which the only easily identifiable fibre tracts were internal capsule and optic radiations, and 3 months, at which most large fibre tracts were visible; only at this age reproducible measurements were possible for all cases. White matter volume increased by 126% between 3 months and 4 years, with the biggest increase between 3 and 4 months (32%) followed by smaller but significant increases up to 4 years. The macaque brain development parallels that of humans by reaching the maximum in total brain volume around the age of sexual maturity (in macaques 3–4 years) and by the increases in white matter continuing beyond this age. The most rapid growth in both total brain volume and white matter from birth to approximately 4 months is consistent with the emergence of various cognitive abilities in macaques at that age.

Effects of selective neonatal temporal lobe lesions on socioemotional behavior in infant rhesus monkeys (Macaca mulatta).

Normal infant monkeys and infant monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal visual area were assessed in dyadic social interactions at 2 and 6 months of age. Unlike the normal infant monkeys, which developed strong affiliative bonds and little or no behavioral disturbances, the lesioned monkeys (each of which was observed with an unoperated control) exhibited socioemotional abnormalities and aberrant behaviors. The socioemotional changes predominated at 6 months of age and were particularly severe in monkeys with medial temporal lesions. In both the pattern and time course, the socioemotional deficits produced by the neonatal medial temporal lesions bear a striking resemblance to the behavioral syndrome in children with autism. Further analysis of these lesion-induced abnormalities in nonhuman primates may therefore provide insight into this debilitating human developmental disorder.

Stereotypies and loss of social affiliation after early hippocampectomy in primates

THE present study was aimed at determining whether early hippocampal damage alters the development of normal social interactions. Results showed that, at 2 months of age, animals with neonatal hippocampal lesions presented minor disturbances in initiation of social interactions. These subtle changes in behavior were less evident at 6 months, although at this age, the operated animals displayed more withdrawals in response to an increase in aggressive responses from their unoperated peers. Finally, in adulthood, the amount of time spent by the operated monkeys in social contacts with their normal peers was markedly less than that in normal dyads. Only in adulthood did the operated animals exhibit more locomotor Stereotypies than normal controls. This finding suggest that the hippocampal formation may directly or indirectly affect the maintenance of social bounds in primates.

Defense-Like Behaviors Evoked by Pharmacological Disinhibition of the Superior Colliculus in the Primate

Stimulation of the intermediate and deep layers of superior colliculus (DLSC) in rodents evokes both orienting/pursuit (approach) and avoidance/flight (defense) responses (Dean et al., 1989). These two classes of response are subserved by distinct output projections associated with lateral (approach) and medial (defense) DLSC (Comoli et al., 2012). In non-human primates, DLSC has been examined only with respect to orienting/approach behaviors, especially eye movements, and defense-like behaviors have not been reported. Here we examined the profile of behavioral responses evoked by activation of DLSC by unilateral intracerebral infusions of the GABAA receptor antagonist, bicuculline methiodide (BIC), in nine freely moving macaques. Across animals, the most consistently evoked behavior was cowering (all animals), followed by increased vocalization and escape-like behaviors (seven animals), and attack of objects (three animals). The effects of BIC were dose-dependent within the range 2.5–14 nmol (threshold dose of 4.6 nmol). The behaviors and their latencies to onset did not vary across different infusion sites within DLSC. Cowering and escape-like behaviors resembled the defense-like responses reported after DLSC stimulation in rats, but in the macaques these responses were evoked from both medial and lateral sites within DLSC. Our findings are unexpected in the context of an earlier theoretical perspective (Dean et al., 1989) that emphasized a preferential role of the primate DLSC for approach rather than defensive responses. Our data provide the first evidence for induction of defense-like behaviors by activation of DLSC in monkeys, suggesting that the role of DLSC in responding to threats is conserved across species.

Developmental patterns of chimpanzee cerebral tissues provide important clues for understanding the remarkable enlargement of the human brain.

Developmental prolongation is thought to contribute to the remarkable brain enlargement observed in modern humans (Homo sapiens). However, the developmental trajectories of cerebral tissues have not been explored in chimpanzees (Pan troglodytes), even though they are our closest living relatives. To address this lack of information, the development of cerebral tissues was tracked in growing chimpanzees during infancy and the juvenile stage, using three-dimensional magnetic resonance imaging and compared with that of humans and rhesus macaques (Macaca mulatta). Overall, cerebral development in chimpanzees demonstrated less maturity and a more protracted course during prepuberty, as observed in humans but not in macaques. However, the rapid increase in cerebral total volume and proportional dynamic change in the cerebral tissue in humans during early infancy, when white matter volume increases dramatically, did not occur in chimpanzees. A dynamic reorganization of cerebral tissues of the brain during early infancy, driven mainly by enhancement of neuronal connectivity, is likely to have emerged in the human lineage after the split between humans and chimpanzees and to have promoted the increase in brain volume in humans. Our findings may lead to powerful insights into the ontogenetic mechanism underlying human brain enlargement.