Pharmacological Inhibition of the Nucleus Accumbens Increases Dyadic Social Interaction in Macaques.

The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties of social stimuli have a vital role in guiding behavior (both in humans and nonhuman animals), the NAc is likely to contribute to the brain circuitry controlling social behavior. In rodents, prior studies have found that focal pharmacological inhibition of NAc and/or elevation of dopamine in NAc increases social interactions. However, the role of the NAc in social behavior in nonhuman primates remains unknown. We measured the social behavior of eight dyads of male macaques following (1) pharmacological inhibition of the NAc using the GABAA agonist muscimol and (2) focal application of quinpirole, an agonist at the D2 family of dopamine receptors. Transient inhibition of the NAc with muscimol increased social behavior when drug was infused in submissive, but not dominant partners of the dyad. Focal application of quinpirole was without effect on social behavior when infused into the NAc of either dominant or submissive subjects. Our data demonstrate that the NAc contributes to social interactions in nonhuman primates.

Hippocampal lesions impair non-navigational spatial memory in macaques.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks-which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.

Quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition of the acoustic startle in rhesus macaques.

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABAA agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition.

Pharmacological Inactivation of the Bed Nucleus of the Stria Terminalis Increases Affiliative Social Behavior in Rhesus Macaques.

The bed nucleus of the stria terminalis (BNST) has been implicated in a variety of social behaviors, including aggression, maternal care, mating behavior, and social interaction. Limited evidence from rodent studies suggests that activation of the BNST results in a decrease in social interaction between unfamiliar animals. The role of the BNST in social interaction in primates remains wholly unexamined. Nonhuman primates provide a valuable model for studying social behavior because of both their rich social repertoire and neural substrates of behavior with high translational relevance to humans. To test the hypothesis that the primate BNST is a critical modulator of social behavior, we performed intracerebral microinfusions of the GABAA agonist muscimol to transiently inactivate the BNST in male macaque monkeys. We measured changes in social interaction with a familiar same-sex conspecific. Inactivation of the BNST resulted in significant increase in total social contact. This effect was associated with an increase in passive contact and a significant decrease in locomotion. Other nonsocial behaviors (sitting passively alone, self-directed behaviors, and manipulation) were not impacted by BNST inactivation. As part of the "extended amygdala," the BNST is highly interconnected with the basolateral (BLA) and central (CeA) nuclei of the amygdala, both of which also play critical roles in regulating social interaction. The precise pattern of behavioral changes we observed following inactivation of the BNST partially overlaps with our prior reports in the BLA and CeA. Together, these data demonstrate that the BNST is part of a network regulating social behavior in primates.SIGNIFICANCE STATEMENT The bed nucleus of the stria terminalis (BNST) has a well-established role in anxiety behaviors, but its role in social behavior is poorly understood. No prior studies have evaluated the impact of BNST manipulations on social behavior in primates. We found that transient pharmacological inactivation of the BNST increased social behavior in pairs of macaque monkeys. These data suggest the BNST contributes to the brain networks regulating sociability.

Macaques fail to develop habit responses during extended training on a reinforcer devaluation task.

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).

Intrahippocampal blockade of nicotinic or muscarinic receptors fails to impair nonnavigational spatial memory in macaques.

Cholinergic neurotransmission within the hippocampus has long been suggested to play a pivotal role in memory processing, based partly on the assumption that the well-established amnestic effects of systemic cholinergic receptor blockade are mediated by the hippocampus. However, experimental evidence suggests that this may not be the case; a growing number of studies employing selective lesion or pharmacological approaches to disrupt cholinergic transmission within the hippocampus have failed to find robust deficits in either learning or memory, primarily in rodent models. Here, we evaluated the contribution of nicotinic acetylcholine receptor (nAChR)- and muscarinic acetylcholine receptor (mAChR)-mediated neurotransmission in the hippocampus of rhesus macaques for performance in a hippocampal-dependent spatial memory task, the Hamilton Search Task. We infused the nAChR antagonist, mecamylamine, or the mAChR antagonist, scopolamine, and evaluated performance on a within-subject basis. Neither treatment impaired performance under any task conditions. These data demonstrate that the hippocampus is not the critical site for the mnemonic actions of cholinergic neurotransmission, at least in the context of spatial memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The Parahippocampal Cortex and its Functional Connection with the Hippocampus are Critical for Nonnavigational Spatial Memory in Macaques.

The Hamilton Search Task (HST) is a test of nonnavigational spatial memory that is dependent on the hippocampus. The parahippocampal cortex (PHC) is a major route for spatial information to reach the hippocampus, but the extent to which the PHC and hippocampus function independently of one another in the context of nonnavigational spatial memory is unclear. Here, we tested the hypotheses that (1) bilateral pharmacological inactivation of the PHC would impair HST performance, and (2) that functional disconnection of the PHC and hippocampus by contralateral (crossed) inactivation would likewise impair performance. Transient inactivation of the PHC impaired HST performance most robustly with 30 s intertrial delays, but not when color cues were introduced. Functional disconnection of the PHC and hippocampus, but not separate unilateral inactivation of either region, also selectively impaired long-term spatial memory. These findings indicate a critical role for the PHC and its interactions with the hippocampus in nonnavigational spatial memory.

Dysregulation of behavioral and autonomic responses to emotional and social stimuli following bidirectional pharmacological manipulation of the basolateral amygdala in macaques.

The amygdala is a key component of the neural circuits mediating the processing and response to emotionally salient stimuli. Amygdala lesions dysregulate social interactions, responses to fearful stimuli, and autonomic functions. In rodents, the basolateral and central nuclei of the amygdala have divergent roles in behavioral control. However, few studies have selectively examined these nuclei in the primate brain. Moreover, the majority of non-human primate studies have employed lesions, which only allow for unidirectional manipulation of amygdala activity. Thus, the effects of amygdala disinhibition on behavior in the primate are unknown. To address this gap, we pharmacologically inhibited by muscimol or disinhibited by bicuculline methiodide the basolateral complex of the amygdala (BLA; lateral, basal, and accessory basal) in nine awake, behaving male rhesus macaques (Macaca mulatta). We examined the effects of amygdala manipulation on: (1) behavioral responses to taxidermy snakes and social stimuli, (2) food competition and social interaction in dyads, (3) autonomic arousal as measured by cardiovascular response, and (4) prepulse inhibition of the acoustic startle (PPI) response. All modalities were impacted by pharmacological inhibition and/or disinhibition. Amygdala inhibition decreased fear responses to snake stimuli, increased examination of social stimuli, reduced competitive reward-seeking in dominant animals, decreased heart rate, and increased PPI response. Amygdala disinhibition restored fearful response after habituation to snakes, reduced competitive reward-seeking behavior in dominant animals, and lowered heart rate. Thus, both hypoactivity and hyperactivity of the basolateral amygdala can lead to dysregulated behavior, suggesting that a narrow range of activity is necessary for normal functions.

Inhibition of the Deep and Intermediate Layers of the Superior Colliculus Disrupts Sensorimotor Gating in Monkeys.

The deep and intermediate layers of the superior colliculus (DLSC) respond to visual, auditory, and tactile inputs and act as a multimodal sensory association area. In turn, activity in the DLSC can drive orienting and avoidance responses-such as saccades and head and body movements-across species, including in rats, cats, and non-human primates. As shown in rodents, DLSC also plays a role in regulating pre-pulse inhibition (PPI) of the acoustic startle response (ASR), a form of sensorimotor gating. DLSC lesions attenuate PPI and electrical stimulation of DLSC inhibits the startle response. While the circuitry mediating PPI is well-characterized in rodents, less is known about PPI regulation in primates. Two recent studies from our labs reported a species difference in the effects of pharmacological inhibition of the basolateral amygdala and substantia nigra pars reticulata (SNpr) on PPI between rats and macaques: in rats, inhibition of these structures decreased PPI, while in macaques, it increased PPI. Given that the SNpr sends direct inhibitory projections to DLSC, we next sought to determine if this species difference was similarly evident at the level of DLSC. Here, we transiently inactivated DLSC in four rhesus macaques by focal microinfusion of the GABAA receptor agonist muscimol. Similar to findings reported in rodents, we observed that bilateral inhibition of the DLSC in macaques significantly disrupted PPI. The impairment was specific to the PPI as the ASR itself was not affected. These results indicate that our previously reported species divergence at the level of the SNpr is not due to downstream differences at the level of the DLSC. Species differences at the level of the SNpr and basolateral amygdala emphasize the importance of studying the underlying circuitry in non-human primates, as impairment in PPI has been reported in several disorders in humans, including schizophrenia, autism, and PTSD.

Colocalization of Tectal Inputs With Amygdala-Projecting Neurons in the Macaque Pulvinar.

Neuropsychological and neuroimaging studies have suggested the presence of a fast, subcortical route for the processing of emotionally-salient visual information in the primate brain. This putative pathway consists of the superior colliculus (SC), pulvinar and amygdala. While the presence of such a pathway has been confirmed in sub-primate species, it has yet to be documented in the primate brain using conventional anatomical methods. We injected retrograde tracers into the amygdala and anterograde tracers into the colliculus, and examined regions of colocalization of these signals within the pulvinar of the macaque. Anterograde tracers injected into the SC labeled axonal projections within the pulvinar, primarily within the oral, lateral and medial subdivisions. These axonal projections from the colliculus colocalized with cell bodies within the pulvinar that were labeled by retrograde tracer injected into the lateral amygdala. This zone of overlap was most notable in the medial portions of the medial (PM), oral (PO) and inferior pulvinar (PI), and was often densely concentrated in the vicinity of the brachium of the SC. These data provide an anatomical basis for the previously suggested pathway mediating fast processing of emotionally salient information.

Genetically Epilepsy-Prone Rats Display Anxiety-Like Behaviors and Neuropsychiatric Comorbidities of Epilepsy.

Epilepsy is associated with a variety of neuropsychiatric comorbidities, including both anxiety and depression. Despite high occurrences of depression and anxiety seen in human epilepsy populations, little is known about the etiology of these comorbidities. Experimental models of epilepsy provide a platform to disentangle the contribution of acute seizures, genetic predisposition, and underlying circuit pathologies to anxious and depressive phenotypes. Most studies to date have focused on comorbidities in acquired epilepsies; genetic models, however, allow for the assessment of affective phenotypes that occur prior to onset of recurrent seizures. Here, we tested male and female genetically epilepsy-prone rats (GEPR-3s) and Sprague-Dawley controls in a battery of tests sensitive to anxiety-like and depressive-like phenotypes. GEPR-3s showed increased anxiety-like behavior in the open field test, elevated plus maze, light-dark transition test, and looming threat test. Moreover, GEPR-3s showed impaired prepulse inhibition of the acoustic startle reflex, decreased sucrose preference index, and impaired novel object recognition memory. We also characterized defense behaviors in response to stimulation thresholds of deep and intermediate layers of the superior colliculus (DLSC), but found no difference between strains. In sum, GEPR-3s showed inherited anxiety, an effect that did not differ significantly between sexes. The anxiety phenotype in adult GEPR-3s suggests strong genetic influences that may underlie both the seizure disorder and the comorbidities seen in epilepsy.

Inhibition of the substantia nigra pars reticulata produces divergent effects on sensorimotor gating in rats and monkeys.

The basal ganglia are an evolutionarily old group of structures, with gross organization conserved across species. Despite this conservation, there is evidence suggesting that anatomical organization of a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNpr), diverges across species. Nevertheless, there are relatively few comparative studies examining the impact of manipulations of SNpr across species. Here, we evaluated the role of SNpr in a highly conserved behavior: prepulse inhibition of the acoustic startle response (PPI). We performed parallel experiments in both rats and rhesus macaques using intracranial microinfusions of GABAA agonist muscimol to investigate the role of SNpr in PPI. SNpr inactivation significantly disrupted PPI in rats, congruent with prior studies; however, in macaques, SNpr inactivation resulted in facilitation of PPI. We suggest that this difference in circuit function results from a divergence in anatomical connectivity, underscoring the importance of circuit dissection studies across species.

Mediodorsal thalamus is required for discrete phases of goal-directed behavior in macaques.

Reward contingencies are dynamic: outcomes that were valued at one point may subsequently lose value. Action selection in the face of dynamic reward associations requires several cognitive processes: registering a change in value of the primary reinforcer, adjusting the value of secondary reinforcers to reflect the new value of the primary reinforcer, and guiding action selection to optimal choices. Flexible responding has been evaluated extensively using reinforcer devaluation tasks. Performance on this task relies upon amygdala, Areas 11 and 13 of orbitofrontal cortex (OFC), and mediodorsal thalamus (MD). Differential contributions of amygdala and Areas 11 and 13 of OFC to specific sub-processes have been established, but the role of MD in these sub-processes is unknown. Pharmacological inactivation of the macaque MD during specific phases of this task revealed that MD is required for reward valuation and action selection. This profile is unique, differing from both amygdala and subregions of the OFC.

Effects of systemic cholinergic antagonism on reinforcer devaluation in macaques.

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.

MRI Overestimates Excitotoxic Amygdala Lesion Damage in Rhesus Monkeys.

Selective, fiber-sparing excitotoxic lesions are a state-of-the-art tool for determining the causal contributions of different brain areas to behavior. For nonhuman primates especially, it is advantageous to keep subjects with high-quality lesions alive and contributing to science for many years. However, this requires the ability to estimate lesion extent accurately. Previous research has shown that in vivo T2-weighted magnetic resonance imaging (MRI) accurately estimates damage following selective ibotenic acid lesions of the hippocampus. Here, we show that the same does not apply to lesions of the amygdala. Across 19 hemispheres from 13 rhesus monkeys, MRI assessment consistently overestimated amygdala damage as assessed by microscopic examination of Nissl-stained histological material. Two outliers suggested a linear relation for lower damage levels, and values of unintended amygdala damage from a previous study fell directly on that regression line, demonstrating that T2 hypersignal accurately predicts damage levels below 50%. For unintended damage, MRI estimates correlated with histological assessment for entorhinal cortex, perirhinal cortex and hippocampus, though MRI significantly overestimated the extent of that damage in all structures. Nevertheless, ibotenic acid injections routinely produced extensive intentional amygdala damage with minimal unintended damage to surrounding structures, validating the general success of the technique. The field will benefit from more research into in vivo lesion assessment techniques, and additional evaluation of the accuracy of MRI assessment in different brain areas. For now, in vivo MRI assessment of ibotenic acid lesions of the amygdala can be used to confirm successful injections, but MRI estimates of lesion extent should be interpreted with caution.

Defensive Vocalizations and Motor Asymmetry Triggered by Disinhibition of the Periaqueductal Gray in Non-human Primates.

Rapid and reflexive responses to threats are present across phylogeny. The neural circuitry mediating reflexive defense reactions has been well-characterized in a variety of species, for example, in rodents and cats, the detection of and species-typical response to threats is mediated by a network of structures including the midbrain tectum (deep and intermediate layers of the superior colliculus [DLSC]), periaqueductal gray (PAG), and forebrain structures such as the amygdala and hypothalamus. However, relatively little is known about the functional architecture of defense circuitry in primates. We have previously reported that pharmacological activation of the DLSC evokes locomotor asymmetry, defense-associated vocalizations, cowering behavior, escape responses, and attack of inanimate objects (Holmes et al., 2012; DesJardin et al., 2013; Forcelli et al., 2016). Here, we sought to determine if pharmacological activation of the PAG would induce a similar profile of responses. We activated the PAG in three awake, behaving macaques by microinfusion of GABA-A receptor antagonist, bicuculline methiodide. Activation of PAG evoked defense-associated vocalizations and postural/locomotor asymmetry, but not motor defense responses (e.g., cowering, escape behavior). These data suggest a partial dissociation between the role of the PAG and the DLSC in the defense network of macaques, but a general conservation of the role of PAG in defense responses across species.

Blockade of glutamatergic transmission in the primate basolateral amygdala suppresses active behavior without altering social interaction.

The amygdala is an integrator of affective processing, and a key component of a network regulating social behavior. While decades of lesion studies in nonhuman primates have shown alterations in social interactions after amygdala damage, acute manipulations of the amygdala in primates have been underexplored. We recently reported (Wellman, Forcelli, Aguilar, & Malkova, 2016) that acute pharmacological inhibition of the basolateral complex of the amygdala (BLA) or the central nucleus of the amygdala increased affiliative social interactions in experimental dyads of macaques; this was achieved through microinjection of a GABA-A receptor agonist. Prior studies in rodents have shown similar effects achieved by blocking NMDA receptors or AMPA receptors within the BLA. Here, we sought to determine the role of these receptor systems in the primate BLA in the context of social behavior. In familiar dyads, we microinjected the NMDA receptor antagonist 2-amino-7-phosphonoheptanoic acid (AP7) or the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) and observed behaviors and social interactions in the immediate postinjection period. In striking contrast with our prior report using GABA agonists, and in contrast with prior reports in rodents using glutamate antagonists, we found that neither NMDA nor AMPA blockade increase social interaction. Both treatments, however, were associated with decreases in locomotion and manipulation and increases in passive behavior. These data suggest that local blockade of glutamatergic neurotransmission in BLA is not the functional equivalent of local activation of GABAergic signaling, and raise interesting questions regarding the functional microcircuitry of the nonhuman primate amygdala in the context of social behavior. (PsycINFO Database Record

Development of relational memory processes in monkeys.

The present study tested whether relational memory processes, as measured by the transverse patterning problem, are late-developing in nonhuman primates as they are in humans. Eighteen macaques ranging from 3 to 36 months of age, were trained to solve a set of visual discriminations that formed the transverse patterning problem. Subjects were trained at 3, 4-6, 12, 15-24 or 36 months of age to solve three discriminations as follows: 1) A+ vs. B-; 2) B+ vs. C-; 3) C+ vs. A. When trained concurrently, subjects must adopt a relational strategy to perform accurately on all three problems. All 36 month old monkeys reached the criterion of 90% correct, but only one 24-month-old and one 15-month-old did, initially. Three-month-old infants performed at chance on all problems. Six and 12-month-olds performed at 75-80% correct but used a 'linear' or elemental solution (e.g. A>B>C), which only yields correct performance on two problems. Retraining the younger subjects at 12, 24 or 36 months yielded a quantitative improvement on speed of learning, and a qualitative improvement in 24-36 month old monkeys for learning strategy. The results suggest that nonspatial relational memory develops late in macaques (as in humans), maturing between 15 and 24 months of age.

Amygdala selectively modulates defensive responses evoked from the superior colliculus in non-human primates.

Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g. the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models, little is known about this system in the primate brain. Employing focal pharmacological manipulations, we have previously shown that activation of the DLSC triggers reflexive defensive responses, including cowering, escape behaviors and defensive vocalizations. Here, we show that activation of the DLSC also disrupts normal dyadic social interactions between familiar pairs of monkeys. When the basolateral complex of the amygdala (BLA) was inhibited concurrent with DLSC activation, cowering behavior was attenuated, whereas escape behaviors and defensive vocalizations were not. Moreover, inhibition of the BLA, previously shown to produce a profound increase in dyadic social interactions, was unable to normalize the decrease in social behavior resulting from DLSC activation. Together these data provide an understanding of forebrain-midbrain interactions in a species and circuit with translational relevance for the psychiatry of anxiety and post-traumatic stress disorders.

Bidirectional Control of Social Behavior by Activity within Basolateral and Central Amygdala of Primates.

UNLABELLED: Both hypoactivity and hyperactivity in the amygdala are associated with perturbations in social behavior. While >60 years of experimental manipulations of the amygdala in animal models have shown that amygdala is critical for social behavior, many of these studies contradict one another. Moreover, several questions remain unaddressed. (1) What effect does activation of amygdala have on social behavior? (2) What is the effect of transient silencing, rather than permanent damage? (3) Is there a dissociation between the roles of the central (CeA) and basolateral amygdala (BLA) in regulating social behavior? (4) Can the prosocial effects of amygdala manipulations be explained by anxiolytic effects? We focally manipulated activity within the CeA or BLA in macaques by intracerebral microinjection of muscimol (to inactivate) or bicuculline (to activate) to these amygdaloid subregions. Social interactions were observed in pairs of highly familiar monkeys. We compared these effects to those achieved with systemic diazepam. Activation of the BLA but not CeA suppressed social behavior. Inhibition of either structure increased social behavior, although the effect was greater following inhibition of the BLA. Systemic diazepam was without effect. These studies, which are the first to bidirectionally manipulate the primate amygdala for effects on social behavior, revealed that (1) the amygdala, as a critical regulator of the social network, is bidirectionally sensitive to perturbations in activity, and (2) increased sociability after amygdala inactivation cannot be solely explained by decreased fear. SIGNIFICANCE STATEMENT: Many previous studies reported loss of social interactions following permanent damage to the amygdala in nonhuman primates. In contrast, we report that transient inhibition of the basolateral amygdala triggered a profound increase in social interactions in dyads of monkeys highly familiar with each other. We compared these effects to those of systemic diazepam, which failed to increase social behavior. While it has been suggested that suppression of "fear" could underlie the prosocial effects of amygdala manipulations, our data strongly suggest that impairment in fear processing per se cannot account for the prosocial effects of amygdala inhibition. Furthermore, our studies are the first to examine activation of the amygdala and to assess the separate roles of the amygdaloid nuclei in social behavior in primates.