Innate fear responses are reflected in the blood epigenome of rhesus macaques

AbstractFear and anxiety are complex physiological states aimed at promoting adaptive behaviors. They are also core symptoms of many neuropsychiatric disorders; yet, our knowledge of the underlying biological correlates remains fragmented. Non-human primate models are critical for our understanding of mechanisms associated with complex higher-order behavioral phenotypes. Here we investigated individual variations in innate fear responses to a snake stimulus in free-ranging rhesus macaques and discovered an unusual bimodal distribution of fearful and fearless behavior, likely as a result of an environmental insult by a hurricane. In a translational approach, we discovered a DNA methylation profile associated with fear behavior in these monkeys. We also found evidence that this epigenetic signature is associated with innate fear responses in humans in the form of acoustic startle. Our data highlight the importance and translational utility of non-human primate models for neuropsychiatric research and provide a potential epigenetic signature of innate fear.

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Rhesus monkeys show human-like changes in gaze following across the lifespan

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2016.0376 ◽

2016 ◽

Vol 283 (1830) ◽

pp. 20160376 ◽

Cited By ~ 24

Author(s):

Alexandra G. Rosati ◽

Alyssa M. Arre ◽

Michael L. Platt ◽

Laurie R. Santos

Keyword(s):

Rhesus Monkeys ◽

Sexual Maturity ◽

Rhesus Macaques ◽

Gaze Following ◽

Cognitive Mechanisms ◽

Juvenile Period ◽

Free Ranging ◽

Human Social Behaviour ◽

Human Primate ◽

Human Specific

Gaze following, or co-orienting with others, is a foundational skill for human social behaviour. The emergence of this capacity scaffolds critical human-specific abilities such as theory of mind and language. Non-human primates also follow others' gaze, but less is known about how the cognitive mechanisms supporting this behaviour develop over the lifespan. Here we experimentally tested gaze following in 481 semi-free-ranging rhesus macaques ( Macaca mulatta ) ranging from infancy to old age. We found that monkeys began to follow gaze in infancy and this response peaked in the juvenile period—suggesting that younger monkeys were especially attuned to gaze information, like humans. After sexual maturity, monkeys exhibited human-like sex differences in gaze following, with adult females showing more gaze following than males. Finally, older monkeys showed reduced propensity to follow gaze, just as older humans do. In a second study ( n = 80), we confirmed that macaques exhibit similar baseline rates of looking upwards in a control condition, regardless of age. Our findings indicate that—despite important differences in human and non-human primate life-history characteristics and typical social experiences—monkeys undergo robust ontogenetic shifts in gaze following across early development, adulthood and ageing that are strikingly similar to those of humans.

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Reproductive Performance, Population Dynamics and Anthropometrics of the Free‐Ranging Cayo Santiago Rhesus Macaques

Journal of Medical Primatology ◽

10.1111/j.1600-0684.1984.tb00145.x ◽

1984 ◽

Vol 13 (5) ◽

pp. 247-259 ◽

Cited By ~ 10

Author(s):

Richard G. Rawlins ◽

Matt J. Kessler ◽

Jean E. Turnquist

Keyword(s):

Population Dynamics ◽

Reproductive Performance ◽

Rhesus Macaques ◽

Cayo Santiago ◽

Free Ranging

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Urinary suPAR: a non-invasive biomarker of infection and tissue inflammation for use in studies of large free-ranging mammals

Royal Society Open Science ◽

10.1098/rsos.191825 ◽

2020 ◽

Vol 7 (2) ◽

pp. 191825 ◽

Cited By ~ 1

Author(s):

James P. Higham ◽

Christiane Stahl-Hennig ◽

Michael Heistermann

Keyword(s):

Immune Activation ◽

Rhesus Macaques ◽

Soluble Form ◽

Surgical Trauma ◽

Large Mammals ◽

Urokinase Plasminogen Activator Receptor ◽

Different Temperatures ◽

Processing And Storage ◽

Cellular Immune ◽

Free Ranging

Studies of large free-ranging mammals incorporating physiological measurements typically require the collection of urine or faecal samples, due to ethical and practical concerns over trapping or darting animals. However, there is a dearth of validated biomarkers of immune activation and inflammation that can be measured non-invasively. We here evaluate the utility of urinary measurements of the soluble form of the urokinase plasminogen activator receptor (suPAR), for use as a health marker in studies of wild large mammals. We investigate how urinary suPAR concentrations change in response to viral infection and surgical trauma (inflammation), comparing it to the measurement of a marker of cellular immune activation, urinary neopterin (uNEO), in captive rhesus macaques. We then test the field utility of urinary suPAR, assessing the effects of soil and faecal contamination, sunlight, storage at different temperatures, freeze–thaw cycles, and lyophilization. We find that suPAR concentrations rise markedly in response to both infection and surgery-associated inflammation, unlike uNEO concentrations, which only rise in response to the former. Our field validation demonstrates that urinary suPAR is reasonably robust to many of the issues associated with field collection, sample processing, and storage, as long as samples can be stored in a freezer. Urinary suPAR is thus a promising biomarker applicable for monitoring various aspects of health in wild primates and potentially also other large mammals.

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Infant handling enhances social bonds in free-ranging rhesus macaques (Macaca mulatta)

Behaviour ◽

10.1163/1568539x-00003448 ◽

2017 ◽

Vol 154 (7-8) ◽

pp. 875-907 ◽

Cited By ~ 3

Author(s):

Erica S. Dunayer ◽

Carol M. Berman

Keyword(s):

Macaca Mulatta ◽

Social Bonds ◽

Rhesus Macaques ◽

Social Characteristics ◽

Future Research ◽

Fitness Effects ◽

Early Handling ◽

Infant Handling ◽

Free Ranging ◽

The Relationship

Throughout the primate order, individuals are highly motivated to handle infants that are not their own. Given the differing and often conflicting interests of the various participants in handling interactions (handler, infant, and mother), most functional hypotheses are specific to particular handling roles. Here we explore one hypothesis that may apply to all participants, but that has received relatively little attention: that handling may facilitate the formation and maintenance of social bonds. Using free-ranging rhesus macaques (Macaca mulatta) on Cayo Santiago, we examine the relationship between infant handling in the early weeks and the strength and diversity of infant social bonds months later, when infant relationships were more independent from those of their mothers. Our results largely confirm the influence of several social characteristics (kinship, rank, sex, and age) in governing handling interactions. They also provide the first evidence that early handling is associated with later social bonds that are stronger than expected based on these social characteristics. However, the enhancement of bonds is largely confined to related handlers; frequent unrelated handlers did not generally go on to form strong bonds with infants. This suggests that kinship may be a sort of prerequisite to the enhancement of social bonds via handling. Given the adaptive benefits of strong social bonds among adult primates, future research should investigate whether early infant handling may have longer term fitness effects.

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Aspects of fight interference in free-ranging and compound-dwelling rhesus macaques (Macaca mulatta)

American Journal of Primatology ◽

10.1002/ajp.1350120306 ◽

1987 ◽

Vol 12 (3) ◽

pp. 287-298 ◽

Cited By ~ 9

Author(s):

Jay R. Kaplan ◽

Dennis K. Chikazawa ◽

Stephen B. Manuck

Keyword(s):

Macaca Mulatta ◽

Rhesus Macaques ◽

Free Ranging

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

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2020.610702 ◽

2020 ◽

Vol 14 ◽

Author(s):

Hannah F. Waguespack ◽

Brittany L. Aguilar ◽

Ludise Malkova ◽

Patrick A. Forcelli

Keyword(s):

Superior Colliculus ◽

Startle Response ◽

Basolateral Amygdala ◽

Rhesus Macaques ◽

Species Difference ◽

Acoustic Startle ◽

Acoustic Startle Response ◽

Sensorimotor Gating ◽

Intermediate Layers ◽

Association Area

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.

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Selective intra-arterial brain cooling improves long-term outcomes in a non-human primate model of embolic stroke: Efficacy depending on reperfusion status

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20903697 ◽

2020 ◽

Vol 40 (7) ◽

pp. 1415-1426 ◽

Cited By ~ 3

Author(s):

Di Wu ◽

Jian Chen ◽

Mohammed Hussain ◽

Longfei Wu ◽

Jingfei Shi ◽

...

Keyword(s):

Rhesus Macaques ◽

Motor Dysfunction ◽

Neurological Deficits ◽

Brain Cooling ◽

Long Term Outcomes ◽

Primate Model ◽

Tissue Plasminogen ◽

Human Primate ◽

Arterial Thrombolysis

Nearly all stroke neuroprotection modalities, including selective intra-arterial cooling (SI-AC), have failed to be translated from bench to bed side. Potentially overlooked reasons may be biological gaps, inadequate attention to reperfusion states and mismatched attention to neurological benefits. To advance stroke translation, we describe a novel thrombus-based stroke model in adult rhesus macaques. Intra-arterial thrombolysis with tissue plasminogen activator leads to three clinically relevant outcomes – complete, partial, and no recanalization based on digital subtraction angiography. We also find reperfusion as a prerequisite for SI-AC-induced benefits, in which models with complete or partial reperfusion exhibit significantly reduced infarct volumes, mitigated neurological deficits, improved upper limb motor dysfunction in both acute and chronic stages; however, no further neuroprotection is observed in those without reperfusion. In summary, we discover reperfusion as a crucial regulator of SI-AC-induced neuroprotection and provide insights of long-term functional benefits in behavior and imaging levels. Our findings could be important not only for the translational prerequisite and potential molecular targets, but also for this thrombus-thrombolysis model in monkeys as a powerful tool for further translational stroke studies.

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