Behavior In Nonhuman Primates Research Articles

59. Effects of Ketamine on Anxiety-Like Behavior in Non-Human Primates

59. Effects of Ketamine on Anxiety-Like Behavior in Non-Human Primates

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.

The Use of Guanfacine to Mediate Anxiety-related Reactivity and Reduce Associated Agonistic Behavior in Two Pigtail Macaques (Macaca nemestrina).

Guanfacine, an α₂ adrenoceptor agonist, has been used to successfully treat self-injurious behavior in nonhuman primates, including macaques (Macaca mulatta) and baboons (Papio anubis). It does so by facilitating a correction to the dopaminergic system that mediates a reduction in impulsivity and reactivity. Given this, we assessed the potential efficacy of guanfacine to treat socially directed agonistic behavior in primates with an apparent reactive behavioral phenotype. We present data from 2 pigtail macaques (Macaca nemestrina): an intact adult male housed in a breeding group, and an experimentally naive adult female living in a research setting with her social partner. Baseline behavioral assessments suggested that both macaques showed extreme responses to external stressors that triggered them to aggress social partners often leading to wounding that required veterinary intervention. Both animals were tracked during the course of 1 y. Once treated regularly with guanfacine, both animals showed significant reduction in their agonistic behavior and the rate at which they wounded other animals. Indeed, in the year since the female has been treated with guanfacine she has never wounded her cagemate. By collecting regular and detailed behavioral observations on the male in the breeding colony, we were able to identify triggers for his aggression and to track the behavioral changes evidenced after guanfacine treatment. These data supported our hypothesis that his aggression reflected extreme reactivity to external stressors, rather than general anxiety. Importantly, we saw only a limited and short-lived reduction in the male's affiliative behavioral rates, and thus guanfacine had no sedative effect, but did successfully reduce his reactivity and resultant agonism and wounding.

Open plains are not a level playing field for hominid consonant-like versus vowel-like calls

Africa’s paleo-climate change represents an “ecological black-box” along the evolutionary timeline of spoken language; a vocal hominid went in and, millions of years later, out came a verbal human. It is unknown whether or how a shift from forested, dense habitats towards drier, open ones affected hominid vocal communication, potentially setting stage for speech evolution. To recreate how arboreal proto-vowels and proto-consonants would have interacted with a new ecology at ground level, we assessed how a series of orangutan voiceless consonant-like and voiced vowel-like calls travelled across the savannah. Vowel-like calls performed poorly in comparison to their counterparts. Only consonant-like calls afforded effective perceptibility beyond 100 m distance without requiring repetition, as is characteristic of loud calling behaviour in nonhuman primates, typically composed by vowel-like calls. Results show that proto-consonants in human ancestors may have enhanced reliability of distance vocal communication across a canopy-to-ground ecotone. The ecological settings and soundscapes experienced by human ancestors may have had a more profound impact on the emergence and shape of spoken language than previously recognized.

Frontal cortex activity during the production of diverse social communication calls in marmoset monkeys

Vocal communication is essential for social behaviors in humans and non-human primates. While the frontal cortex is crucial to human speech production, its role in vocal production in non-human primates has long been questioned. It is unclear whether activities in the frontal cortex represent diverse vocal signals used in non-human primate communication. Here we studied single neuron activities and local field potentials (LFP) in the frontal cortex of male marmoset monkeys while the animal engaged in vocal exchanges with conspecifics in a social environment. We found that both single neuron activities and LFP were modulated by the production of each of the four major call types. Moreover, neural activities showed distinct patterns for different call types and theta-band LFP oscillations showed phase-locking to the phrases of twitter calls, suggesting a neural representation of vocalization features. Our results suggest important functions of the marmoset frontal cortex in supporting the production of diverse vocalizations in communication.

Rhesus monkeys exhibiting spontaneous ritualistic behaviors resembling obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric disorder that affects ∼2%-3% of the population globally. Studying spontaneous OCD-like behaviors in non-human primates may improve our understanding of the disorder. In large rhesus monkey colonies, we found 10 monkeys spontaneously exhibiting persistent sequential motor behaviors (SMBs) in individual-specific sequences that were repetitive, time-consuming and stable over prolonged periods. Genetic analysis revealed severely damaging mutations in genes associated with OCD risk in humans. Brain imaging showed that monkeys with SMBs had larger gray matter (GM) volumes in the left caudate nucleus and lower fractional anisotropy of the corpus callosum. The GM volume of the left caudate nucleus correlated positively with the daily duration of SMBs. Notably, exposure to a stressor (human presence) significantly increased SMBs. In addition, fluoxetine, a serotonergic medication commonly used for OCD, decreased SMBs in these monkeys. These findings provide a novel foundation for developing better understanding and treatment of OCD.

THU122 Effects Of A GLP-1 Agonist On Consumption Of Alcohol In Patients Treated For Smoking Cessation

Abstract Disclosure: L.S. Probst: None. S. Monnerat: None. S. Lengsfeld: None. C. Bathelt: None. A. Meienberg: None. T. Burkard: None. M. Christ-crain: None. B.F. Winzeler: None. Introduction: Alcohol use disorder causes high socio-economic costs and has a detrimental impact on health globally, being considered a key factor contributing to non-communicable diseases. In Switzerland four substances are currently approved for treatment of alcohol use disorder with only limited to moderate effects. Thus, the need for new treatment options in alcohol and substance use disorder is evident. Recent research has shed light on a new potential target for treatment of addiction: a body of preclinical studies provide evidence for the attenuating effects of GLP-1 agonists on addictive behavior in rodents and non-human primates. A few studies have shown a link between GLP-1 receptors and reward related processes in humans, and a trial from denmark examined the effect of exenatide in patients treated for alcohol use disorder, however clinical data are scarce and results remain inconclusive. Methods: This is a secondary analysis of the SKIP study, a double-blind, randomized, placebo-controlled trial to evaluate treatment with the GLP-1 agonist dulaglutide (Trulicy®) as a new therapy for smoking cessation. In the present analysis, the primary objective was to assess differences in alcohol consumption after 12 weeks of treatment with dulaglutide compared to placebo in alcohol-consuming smokers willing to quit smoking. We selected patients out of the cohort (n=255) who consumed alcohol at baseline and completed 12 weeks of treatment (n= 151). The independent effect of dulaglutide on alcohol consumption was analysed by fitting a multivariate generalized linear regression model with quasipoisson distribution and adjustment for baseline alcohol consumption. Preliminary Results: One hundred and fifty-one patients (placebo n=75, dulaglutide n=76) were included in the primary analysis. Baseline patient characteristics were well balanced between groups. The median age was 42 [IQR 33, 53] years with 61% (n=92) females. At baseline, patients in both treatment groups consumed 3 [IQR 2, 7] standard glasses of alcohol per week on average. At week 12, patients in the dulaglutide group drank an estimated 29% (IRR = 0.71; 95% CI 0.52, 0.97; p=0.04) less compared to the placebo group. For each additional glass consumed at baseline, alcohol consumption at week 12 increased by 6% (95% CI 5, 7; p<0.001). Conclusion: These preliminary findings suggest that in patients who drink, alcohol intake tends to increase during smoking cessation. In the present analysis we were able to show that this increase was attenuated by the addition of a 12-week treatment with dulaglutide to standard smoking cessation therapy. Presentation: Thursday, June 15, 2023

Behavioral and Cognitive Outcomes of Rhesus Macaques Following Neonatal Exposure to Antiseizure Medications.

Exposure of neonatal macaques to the antiseizure medications phenobarbital and midazolam (PbM) causes widespread apoptotic death of neurons and oligodendrocytes. We studied behavior and neurocognitive performance in 12 to 24 month-old macaques treated as neonates with PbM. A total of 14 monkeys received phenobarbital and midazolam over 24 hours under normothermia (n = 8) or mild hypothermia (n = 6). Controls (n = 8) received no treatment. Animals underwent testing in the human intruder paradigm at ages 12 and 18 months, and a 3-step stimulus discrimination task at ages 12, 18, and 24 months. Animals treated with PbM displayed lower scores for environmental exploration, and higher scores for locomotion and vocalizations compared with controls. Combined PbM and hypothermia resulted in lower scores for aggression and vigilance at 12 months compared with controls and normothermic PbM animals. A mixed-effects generalized linear model was used to test for differences in neurocognitive performance between the control and PbM groups in the first step of the stimulus discrimination task battery (shape center baited to shape center non-baited). The odds of passing this step differed by group (p = 0.044). At any given age, the odds of passing for a control animal were 9.53-fold (95% CI 1.06-85) the odds for a PbM animal. There was also evidence suggesting a higher learning rate in the shape center non-baited for the control relative to the PbM group (Cox model HR 2.13, 95% CI 1.02-4.43; p = 0.044). These findings demonstrate that a 24-hour-long neonatal treatment with a clinically relevant combination of antiseizure medications can have long-lasting effects on behavior and cognition in nonhuman primates. ANN NEUROL 2023.

Primate archaeology 3.0.

The new field of primate archaeology investigates the technological behavior and material record of nonhuman primates, providing valuable comparative data on our understanding of human technological evolution. Yet, paralleling hominin archaeology, the field is largely biased toward the analysis of lithic artifacts. While valuable comparative data have been gained through an examination of extant nonhuman primate tool use and its archaeological record, focusing on this one single aspect provides limited insights. It is therefore necessary to explore to what extent other non-technological activities, such as non-tool aided feeding, traveling, social behaviors or ritual displays, leave traces that could be detected in the archaeological record. Here we propose four new areas of investigation which we believe have been largely overlooked by primate archaeology and that are crucial to uncovering the full archaeological potential of the primate behavioral repertoire, including that of our own: (1) Plant technology; (2) Archaeology beyond technology; (3) Landscape archaeology; and (4) Primate cultural heritage. We discuss each theme in the context of the latest developments and challenges, as well as propose future directions. Developing a more "inclusive" primate archaeology will not only benefit the study of primate evolution in its own right but will aid conservation efforts by increasing our understanding of changes in primate-environment interactions over time.

Simultaneous changes in acetylcholine (ACh) levels and neural activity during goal-directed behavior in non-human primates.

Simultaneous changes in acetylcholine (ACh) levels and neural activity during goal-directed behavior in non-human primates.

Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors.

Major depressive disorder represents a serious public health challenge worldwide; however, the underlying cellular and molecular mechanisms are mostly unknown. Here, we profile the dorsolateral prefrontal cortex of female cynomolgus macaques with social stress-associated depressive-like behaviors using single-nucleus RNA-sequencing and spatial transcriptomics. We find gene expression changes associated with depressive-like behaviors mostly in microglia, and we report a pro-inflammatory microglia subpopulation enriched in the depressive-like condition. Single-nucleus RNA-sequencing data result in the identification of six enriched gene modules associated with depressive-like behaviors, and these modules are further resolved by spatial transcriptomics. Gene modules associated with huddle and sit alone behaviors are expressed in neurons and oligodendrocytes of the superficial cortical layer, while gene modules associated with locomotion and amicable behaviors are enriched in microglia and astrocytes in mid-to-deep cortical layers. The depressive-like behavior associated microglia subpopulation is enriched in deep cortical layers. In summary, our findings show cell-type and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behaviors in female non-human primates.

Alteration of functional connectivity in the cortex and major brain networks of non-human primates following focused ultrasound exposure in the dorsal striatum

BackgroundFocused ultrasound (FUS) is a non-invasive neuromodulation technology that is being investigated for potential treatment of neurological and psychiatric disorders. FUS combined with microbubbles can temporarily open the intact blood-brain barrier (BBB) of animals and humans, and facilitate drug delivery. FUS exposure, either with or without microbubbles, has been demonstrated to alter the behavior of non-human primates (NHP), and previous studies have demonstrated the transient and long-term effects of FUS neuromodulation on functional connectivity using resting state functional MRI. The behavioral effects of FUS vary depending on whether or not it is applied in conjunction with microbubbles to open the BBB, but it is unknown whether opening the BBB affects functional connectivity differently than FUS alone. ObjectiveTo compare the effects of applying FUS alone (FUS neuromodulation) and FUS with microbubbles (FUS-BBB opening) on changes of resting state functional connectivity in NHP. MethodsWe applied 2 min FUS exposure without (neuromodulation) and with microbubbles (BBB opening) in the dorsal striatum of lightly anesthetized non-human primates, and acquired resting state functional MRI 40 min respectively after FUS exposure. The functional connectivity (FC) in the cortex and major brain networks between the two approaches were measured and compared. ResultsWhen applying FUS exposure to the caudate nucleus of NHP, we found that both FUS neuromodulation can activate FC between caudate and insular cortex, while inhibiting the FC between caudate and motor cortex. FUS-BBB opening can activate FC between the caudate and medial prefrontal cortex, and within the frontotemporal network (FTN). We also found both FUS and FUS-BBB opening can significantly activate FC within the default mode network (DMN). ConclusionThe results suggest applying FUS to a deep brain structure can alter functional connectivity in the DMN and FTN, and that FUS neuromodulation and FUS-mediated BBB opening can have different effects on patterns of functional connectivity.

Tool mastering today - an interdisciplinary perspective.

Tools have coined human life, living conditions, and culture. Recognizing the cognitive architecture underlying tool use would allow us to comprehend its evolution, development, and physiological basis. However, the cognitive underpinnings of tool mastering remain little understood in spite of long-time research in neuroscientific, psychological, behavioral and technological fields. Moreover, the recent transition of tool use to the digital domain poses new challenges for explaining the underlying processes. In this interdisciplinary review, we propose three building blocks of tool mastering: (A) perceptual and motor abilities integrate to tool manipulation knowledge, (B) perceptual and cognitive abilities to functional tool knowledge, and (C) motor and cognitive abilities to means-end knowledge about tool use. This framework allows for integrating and structuring research findings and theoretical assumptions regarding the functional architecture of tool mastering via behavior in humans and non-human primates, brain networks, as well as computational and robotic models. An interdisciplinary perspective also helps to identify open questions and to inspire innovative research approaches. The framework can be applied to studies on the transition from classical to modern, non-mechanical tools and from analogue to digital user-tool interactions in virtual reality, which come with increased functional opacity and sensorimotor decoupling between tool user, tool, and target. By working towards an integrative theory on the cognitive architecture of the use of tools and technological assistants, this review aims at stimulating future interdisciplinary research avenues.

Sustained modulation of primate deep brain circuits with focused ultrasonic waves

BackgroundTranscranial focused ultrasound has the potential to noninvasively modulate deep brain circuits and impart sustained, neuroplastic effects. ObjectiveBring the approach closer to translations by demonstrating sustained modulation of deep brain circuits and choice behavior in task-performing non-human primates. MethodsLow-intensity transcranial ultrasound of 30 s in duration was delivered in a controlled manner into deep brain targets (left or right lateral geniculate nucleus; LGN) of non-human primates while the subjects decided whether a left or a right visual target appeared first. While the animals performed the task, we recorded intracranial EEG from occipital screws. The ultrasound was delivered into the deep brain targets daily for a period of more than 6 months. ResultsThe brief stimulation induced effects on choice behavior that persisted up to 15 minutes and were specific to the sonicated target. Stimulation of the left/right LGN increased the proportion of rightward/leftward choices. These effects were accompanied by an increase in gamma activity over visual cortex. The contralateral effect on choice behavior and the increase in gamma, compared to sham stimulation, suggest that the stimulation excited the target neural circuits. There were no detrimental effects on the animals' discrimination performance over the months-long course of the stimulation. ConclusionThis study demonstrates that brief, 30-s ultrasonic stimulation induces neuroplastic effects specifically in the target deep brain circuits, and that the stimulation can be applied daily without detrimental effects. These findings encourage repeated applications of transcranial ultrasound to malfunctioning deep brain circuits in humans with the goal of providing a durable therapeutic reset.

Evaluating depression- and anxiety-like behaviors in non-human primates.

Depression and anxiety are some of the most prevalent and debilitating mental health conditions in humans. They can present on their own or as co-morbidities with other disorders. Like humans, non-human primates (NHPs) can develop depression- and anxiety-like signs. Here, we first define human depression and anxiety, examine equivalent species-specific behaviors in NHPs, and consider models and current methods to identify and evaluate these behaviors. We also discuss knowledge gaps, as well as the importance of evaluating the co-occurrence of depression- and anxiety-like behaviors in animal models of human disease. Lastly, we consider ethical challenges in depression and anxiety research on NHPs in order to ultimately advance the understanding and the personalized treatment of these disorders.

A statistical mechanics approach to cultural evolution of structured behavior in non-human primates: From disorder to tetris-like structures

This paper explores a statistical mechanics approach to cultural evolution of structured behavior in non-human primates. Previous works on cultural evolution have proposed Iterated Learning procedures, in which the behavioral output of one individual becomes the target behavior for the next individual in the chain. Within this line of research, previous work has suggested that even in non-human primates this paradigm shows that cultural transmission can lead to the progressive emergence of tetris-like structures. Our simulations are based on several interrelated statistical mechanics measurements, which quantify the way structures become closer to each other and the tendency to put activated cells together (understood by means of a number of measures and an energy-like function). With these tools, we suggested the hypothesis that the appearance of tetris-like structures might be an indirect consequence of the energy-like minimization. From this, it is plausible to think that the preference of the participants for tetris-like structures is strongly related to some kind of minimization towards simplicity in cognition.

The Ontogeny of Vocal Sequences: Insights from a Newborn Wild Chimpanzee (Pan troglodytes schweinfurthii)

Observations of early vocal behaviours in non-human primates (hereafter primates) are important for direct comparisons between human and primate vocal development. However, direct observations of births and perinatal behaviour in wild primates are rare, and the initial stages of behavioural ontogeny usually remain undocumented. Here, we report direct observations of the birth of a wild chimpanzee (Pan troglodytes schweinfurthii) in Budongo Forest, Uganda, including the behaviour of the mother and other group members. We monitored the newborn’s vocal behaviour for approximately 2 hours and recorded 70 calls. We categorised the vocalisations both qualitatively, using conventional call descriptions, and quantitatively, using cluster and discriminant acoustic analyses. We found evidence for acoustically distinct vocal units, produced both in isolation and in combination, including sequences akin to adult pant hoots, a vocal utterance regarded as the most complex vocal signal produced by this species. We concluded that chimpanzees possess the capacity to produce vocal sequences composed of different call types from birth, albeit in rudimentary forms. Our observations are in line with the idea that primate vocal repertoires are largely present from birth, with fine acoustic structures undergoing ontogenetic processes. Our study provides rare and valuable empirical data on perinatal behaviours in wild primates.

Maternal Western-style diet reduces social engagement and increases idiosyncratic behavior in Japanese macaque offspring

Recent evidence in humans and animals indicates an association between maternal obesity and offspring behavioral outcomes. In humans, increased maternal body mass index has been linked to an increased risk of children receiving a diagnosis of early-emerging neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and/or Autism Spectrum Disorder (ASD). However, a limited number of preclinical studies have examined associations between maternal Western-Style Diet (mWSD) exposure and offspring social behavior. To our knowledge, this is the first study to investigate relationships between mWSD exposure and social behavior in non-human primates. Since aberrant social behavior is a diagnostic criterion for several neurodevelopmental disorders, the current study focuses on examining the influence of maternal nutrition and metabolic state on offspring social behavior in Japanese macaques (Macaca fuscata). We found that mWSD offspring initiated less affiliative social behaviors as well as proximity to a peer. Using path analysis, we found that the association between mWSD consumption and reduced offspring social engagement was statistically mediated by increased maternal interleukin (IL)-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin in the third trimester. Together, these results suggest that NHP offspring exposed to mWSD exhibit behavioral phenotypes similar to what is described in some early-emerging neurodevelopmental disorders. These results provide evidence that mWSD exposure during gestation may be linked to increased risk of neurodevelopmental disorders and provides targets for prevention and intervention efforts.

Active vision during prey capture in wild marmoset monkeys

A foundational pressure in the evolution of all animals is the ability to travel through the world, inherently coupling the sensory and motor systems. While this relationship has been explored in several species,1-4 it has been largely overlooked in primates, which have typically relied on paradigms in which head-restrained subjects view stimuli on screens.5 Natural visual behaviors, by contrast, are typified by locomotion through the environment guided by active sensing as animals explore and interact with the world,4,6 a relationship well illustrated by prey capture.7-12 Here, we characterized prey capture in wild marmoset monkeys as they negotiated their dynamic, arboreal habitat to illustrate the inherent role of vision as an active process in natural nonhuman primate behavior. Not only do marmosets share the core properties of vision that typify the primate Order,13-18 but they are prolific hunters that prey on a diverse set of prey animals.19-22 Marmosets pursued prey using vision in several different contexts, but executed precise visually guided motor control that predominantly involved grasping with hands for successful capture of prey. Applying markerless tracking for the first time in wild primates yielded novel findings that precisely quantified how marmosets track insects prior to initiating an attack and the rapid visually guided corrections of the hands during capture. These findings offer the first detailed insight into the active nature of vision to guide multiple facets of a natural goal-directed behavior in wild primates and can inform future laboratory studies of natural primate visual behaviors and the supporting neural processes.

Performance-gated deliberation: A context-adapted strategy in which urgency is opportunity cost.

Finding the right amount of deliberation, between insufficient and excessive, is a hard decision making problem that depends on the value we place on our time. Average-reward, putatively encoded by tonic dopamine, serves in existing reinforcement learning theory as the opportunity cost of time, including deliberation time. Importantly, this cost can itself vary with the environmental context and is not trivial to estimate. Here, we propose how the opportunity cost of deliberation can be estimated adaptively on multiple timescales to account for non-stationary contextual factors. We use it in a simple decision-making heuristic based on average-reward reinforcement learning (AR-RL) that we call Performance-Gated Deliberation (PGD). We propose PGD as a strategy used by animals wherein deliberation cost is implemented directly as urgency, a previously characterized neural signal effectively controlling the speed of the decision-making process. We show PGD outperforms AR-RL solutions in explaining behaviour and urgency of non-human primates in a context-varying random walk prediction task and is consistent with relative performance and urgency in a context-varying random dot motion task. We make readily testable predictions for both neural activity and behaviour.