Facilities housing non-human primates are required to make provisions for their psychological wellbeing, which may include monitoring animals for signs of decreased wellbeing such as the presence of abnormal behaviors or alopecia. By analyzing archival behavioral data collected by the Behavior Management Unit at the Yerkes National Primate Research Center (YNPRC), I aimed to identify behavioral predictors of self-wounding and alopecia and to evaluate the effectiveness of current treatments in reducing abnormal behavior and alopecia in rhesus macaques (Macaca mulatta). The behaviors of self-biting and hair plucking (conditional logistic regression, p < .05) as well as floating limb and self-oral behaviors (Mantel-Haenszel chi-square tests, p < .05) were identified as behavioral predictors of self-wounding. Fear behaviors were associated with an increased risk of developing alopecia (Mantel-Haenszel chi square, p < .05). An inverse relationship was found between alopecia and stereotypic locomotor behaviors such as pacing, with animals who displayed these behaviors being less likely to develop significant hair loss (conditional logistic regression, p < .05). Overall, the type of treatment provided (e.g., additional foraging opportunities, the provision of toys, or the provision of visual barriers) did not predict improvement in levels of abnormal behavior or alopecia (logistic regression, p > .05). The results of these analyses add to the literature on self-wounding and alopecia and will allow refinement of the quantitative behavioral monitoring system at YNPRC such that more at-risk animals can be identified and treated prior to the development of abnormal or harmful behaviors.

The corticospinal tract (CST), which carries commands from the cerebral cortex to the spinal cord, is vital to fine motor control. Spinal cord injury (SCI) often damages CST axons, causing loss of motor function, most notably in the hands and legs. Our preliminary work in rats suggests that CST circuitry is complex: neurons whose axons project to the lower cervical spinal cord, which directly controls hand function, also send axon collaterals to other locations in the nervous system and may engage parallel motor systems. To inform research into repair of SCI, we therefore aimed to map the entire projection pattern, or “connectome,” of such cervically-projecting CST axons. In this study, we mapped the corticospinal connectome of the Rhesus macaque - an animal model more similar to humans, and therefore more clinically relevant for examining SCI. Comparison of the Rhesus macaque and rat CST connectome, and extrapolation to the human CST connectome, may improve targeting of treatments and rehabilitation after human SCI. To selectively trace cervically-projecting CST motor axons, a virus encoding a Cre-recombinase-dependent tracer (AAV-DIO-gCOMET) was injected into the hand motor cortex, and a virus encoding Cre-recombinase (AAV-Cre) was injected into the C8 level of the spinal cord. In this intersectional approach, the gCOMET virus infects many neurons in the cortex, but gCOMET expression is not turned on unless the nucleus also contains Cre-recombinase, which must be retrogradely transported from axon terminals in the C8 spinal cord. Thus, gCOMET is only expressed in neurons that project to the C8 spinal cord, and it proceeds to fill the entire neuron, including all axon collaterals. Any gCOMET-labeled axon segments observed in other regions of the nervous system are therefore collaterals of cervically-projecting axons. gCOMET-positive axons were immunohistochemically labeled, and axon density was quantified using a fluorescence microscope and Fiji/ImageJ software. Specific regions of interest were chosen for analysis because of their known relevance in motor function in humans, and for comparison to results of a similar study in rats. Results in the first monkey have revealed both similarities and differences between the monkey and rodent CST connectome. Analyses of additional monkeys are ongoing. The final results will provide detailed information about differences between rodent and primate CST, will serve as a baseline for examining changes in the CST connectome after SCI, and will provide guidance for studies targeting treatment and functional recovery after SCI.

Detecting and interpreting sensory events, and remembering those events in in the service of future actions, forms the foundation of all behavior. Each of these pillars of the so-called "perception-action cycle" have been topics of extensive inquiry throughout recorded history, with philosophical foundations provided by early BCE and CE periods (especially during the Classic and Renaissance eras) leading to intensive empirical study in the twentieth and twenty-first centuries. Such experiments have described detailed (but incomplete) behavioral functions reflecting perception and memory, and have begun to unravel the extraordinarily complex substrates of these functions in the nervous system. The current dissertation was motivated by these findings, with the goal of meaningfully extending our understanding of such processes through a multi-experiment approach spanning the behavioral and neurophysiological levels. The focus of these experiments is on short-term memory (STM), though as we shall see, STM is ultimately inseparable from sensory perception and is directly or indirectly associated with guidance of motor responses. It thus provides a nexus between the sensory inputs and motor outputs that describe interactions between the organism and environment. In Chapter 2, previous findings from nonhuman primate literature describing relatively poor performance for auditory compared to visual or tactile STM inspired similar comparisons among modalities in humans. In both STM and recognition memory paradigms, accuracy is shown to be lowest for the auditory modality, suggesting commonalities among primate species. Chapters 3-5 examined STM processing in nonhuman primates at the behavioral and neurophysiological levels. In Chapter 3, a systematic investigation of memory errors produced by recycling memoranda across trials (proactive interference) is provided for the understudied auditory modality in monkeys. Such errors were ameliorated (but not completely eliminated) by increasing the proportions of unique memoranda presented within a session, and by separating successive trials by greater time intervals. In Chapter 4, previous results revealing a human memory advantage for audiovisual events (compared to unimodal auditory or visual events) inspired a similar comparison in monkeys using a concurrent auditory, visual, and audiovisual STM task. Here, the primary results conformed to a priori expectations, with superior performance observed on audiovisual trials compared to either unimodal trial type. Surprisingly, two of three subjects exhibited superior unimodal performance on auditory trials. This result contrasts with previous results in nonhuman primates, but can be interpreted in light of these subjects' extensive prior experience with unimodal auditory STM tasks. In Chapter 5, the same subjects performed the concurrent audiovisual STM task while activity of single cells and local cell populations was recorded within prefrontal cortex (PFC), a region known to exhibit multisensory integrative and memory functions. The results indicate that both of these functions converge within PFC, down to the level of individual cells, as evidenced by audiovisual integrative responses within mnemonic processes such as delay-related changes in activity and detection of repeated versus different sensory cues. Further, a disproportionate number of the recorded units exhibited such mnemonic processes on audiovisual trials, a finding that corresponds to the superior behavioral performance on these trials. Taken together, these findings reinforce the important role of PFC in STM and multisensory integration. They further strengthen the evidence that "memory" is not a unitary phenomenon, but can be seen as the outcome of processing within and among multiple subsystems, with substantial areas of overlap and separation across modalities. Finally, cross-species comparisons reveal substantial similarities in memory processing between humans and nonhuman primates, suggesting shared evolutionary heritage of systems underlying the perception-action cycle.

<p>Brain-machine interfaces (BMIs) use neuronal activity to control external actuators. As such, they show great promise for restoring motor and communication abilities in persons with paralysis or debilitating neurological disorders.</p><p>While BMIs aim to enact normal sensorimotor functions, so far they have lacked afferent feedback in the form of somatic sensation. This deficiency limits the utility of current BMI designs and may hinder the translation of future clinical BMIs, which will need a means of delivering sensory signals from prosthetic devices back to the user. </p><p>This dissertation describes the development of brain-machine-brain interfaces (BMBIs) capable of bidirectional communication with the brain. The interfaces consisted of efferent and afferent modules. The efferent modules decoded motor intentions from the activity of populations of cortical neurons recorded with chronic multielectrode recording arrays. The activity of these ensembles was used to drive the movements of a computer cursor and a realistic upper-limb avatar. The afferent modules encoded tactile feedback about the interactions of the avatar with virtual objects through patterns of intracortical microstimulation (ICMS).</p><p>I first show that a direct intracortical signal can be used to instruct rhesus monkeys about the direction of a reach to make with a BMI. Rhesus monkeys placed an actuator over an instruction target and obtained, from the target's artificial texture, information about the correct reach path. Initially these somatosensory instructions took the form of vibrotactile stimulation of the hands. Next, ICMS of primary somatosensory cortex (S1) in one monkey and posterior parietal cortex (PPC) in another was substituted for this peripheral somatosensory signal. Finally, the monkeys made direct brain-controlled reaches using the activity of ensembles of primary motor cortex (M1) cells, conditional on the ICMS cues. The monkey receiving ICMS of S1 was able to achieve the same level of proficiency with ICMS as with the stimulus delivered to the skin of the hand. The monkey receiving ICMS of PPC was unable to perform the task above chance. This experiment indicates that ICMS of S1 can form the basis of an afferent prosthetic input to the brain for guiding brain-controlled prostheses.</p><p>I next show that ICMS of S1 can provide feedback about the interactions of a virtual-reality upper-limb avatar and virtual objects, enabling active touch. Rhesus monkeys initially controlled the avatar with the movements of their arms and used it to search through sets of up to three objects. Feedback in the form of temporal patterns of ICMS occurred whenever the avatar touched a virtual object. Monkeys learned to use this feedback to find the objects with particular artificial textures, as encoded by the ICMS patterns, and select those associated with reward while avoiding selecting the non-rewarded objects. Next, the control of the avatar was switched to direct brain-control and the monkeys continued to move the avatar with motor commands derived from the extracellular neuronal activity of M1 cells. The afferent and efferent modules of this BMBI were temporally interleaved, and as such did not interfere with each other, yet allowed effectively concurrent operation. Cortical motor neurons were measured while the monkey passively observed the movements of the avatar and were found to be modulated, a result that suggests that concurrent visual and artificial somatosensory feedback lead to the incorporation of the avatar into the monkey's internal brain representation.</p><p>Finally, I probed the sensitivity of S1 to precise temporal patterns of ICMS. Monkeys were trained to discriminate between periodic and aperiodic ICMS pulse trains. The periodic pulse-trains consisted of 200 Hz bursts at a 10 Hz secondary frequency. The aperiodic pulse trains had a distorted periodicity and consisted of 200 Hz bursts at a variable instantaneous secondary frequency. The statistics of the aperiodic pulse trains were drawn from a gamma distribution with equal mean inter-burst intervals to the periodic pulse trains. The monkeys were able to distinguish periodic pulse trains from aperiodic pulse trains with coefficients of variation of 0.25 or greater. This places an upper-bounds on the communication bandwidth that can be achieved with a single channel of temporal ICMS in S1.</p><p>In summary, rhesus monkeys were augmented with a bidirectional neural interface that allowed them to make reaches to objects and discriminate them by their textures--all without making actual movements and without relying on somatic sensation from their real bodies. Both action and perception were mediated by the brain-machine-brain interface. I probed the sensitivity of the afferent leg of the interface to precise temporal patterns of ICMS. Moreover, I describe evidence that the BMBI controlled avatar was incorporated into the monkey's internal brain representation. These results suggest that future clinical neuroprostheses could implement realistic feedback about object-actuator interactions through patterns of ICMS, and that these artificial somatic sensations could lead to the incorporation of the prostheses into the user's body schema.</p> / Dissertation

B virus diagnosis presents a challenge largely complicated by the asymptomatic infection of rhesus macaques, and extremely pathogenic fatal infections in humans. Humoral detection of antibodies is generally performed using whole virus antigen for which preparation requires strict biosafety measures and specialized BSL-4 facilities. As an alternative to utilizing B virus antigen, we describe the production of a truncated form of B virus envelope glycoprotein D, gD 287, in a baculovirus expression system, and evaluate its diagnostic potential as an antigen in recombinant ELISA. After purification and characterization, gD 287 was tested using 22 negative and 72 positive macaque sera samples previously classified using the traditional method. We find that sensitivity and specificity of the recombinant ELISA are dependent on antibody titer of tested serum and gD 287 shows good to excellent predictive potential for identification of positive sera with titers higher than 500.

In the present study, electrophysiological and behavioral effects of compromised Gama-Aminobutyric Acid (GABAergic) transmission were investigated in adult Rhesus macaque monkeys (N=2). GABAergic transmission was perturbed in the putamen by administration of a GABAa receptor antagonist, gabazine (10 and 500 μM), via a microdialysis-local field potential (MD-LFP) probe. Resultant changes in striatal local field potentials (LFPs) were measured as an assay of synchrony. Gabazine perfusion evoked discrete large amplitude spikes in LFPs in all subjects, and the frequency and shape of individual spikes were concentration-dependent. Pre-treatment with the GABAa receptor agonist, muscimol (100 μM) blocked the gabazine-induced events, confirming a role for GABAa receptors in the effects. Behavioral manifestations of gabazine treatment were observed only at the maximum concentration. Unusual facial movements suggested aberrant electrical activity was propagated from striatum to motor cortex, perhaps via reentrant circuits. These results support a role for GABAergic transmission in segregation of striatal circuits.

Natural killer (NK) cells can kill virus-infected cells without prior antigenic exposure, and are therefore important for controlling viral replication prior to the onset of adaptive immune responses. Primate NK cells express activating and inhibitory killer-cell immunoglobulin-like receptors (KIRs) that bind to specific major histocompatibility complex (MHC) class I molecules. The importance of KIR interactions with MHC class I in human immunodeficiency virus (HIV) pathogenesis is demonstrated by the association of select KIR and MHC class I genotypes with delayed progression to acquired immunodeficiency syndrome (AIDS).

L’hallux de l’humain (plus couramment appelé gros orteil) est aujourd’hui aligné avec les autres orteils ce qui rend son opposition aux autres orteils impossible. Il a été proposé que la perte de l’opposabilité de l’hallux, chez les premiers hominines, aurait mené à une augmentation des coûts liés à la maternité, due à l’obligation de transporter activement les juvéniles lors de longs trajets (Tanner & Zihlman 1976 ; Wall-Sheffler 2007 ; Watson et al. 2008). Cela suggère que l’Australopithecus afarensis devait transporter activement son juvénile car il ne pouvait pas se maintenir par lui-même lors des transports. Mon étude propose de vérifier cette hypothèse en déterminant si un primate juvénile a besoin de son hallux pour s’accrocher au poil de sa mère. Les deux hypothèses de ce travail sont donc les suivantes : L’abduction de l’hallux est nécessaire à la préhension du poil d’un porteur (généralement la mère) par les jeunes macaques et l’abduction de l’hallux n’est pas nécessaire à la préhension du poil d’un porteur (généralement la mère) par les jeunes macaques lors des transports. L’observation de vidéos de dyades mère/enfant de macaques rhésus vivant en liberté à Cayo Santiago (Costa Rica) filmées sur une période de cinq mois, tend à supporter mon hypothèse. En effet, les résultats de mon étude montrent que les macaques rhésus sont capables de s’accrocher, et se maintenir, par eux-mêmes à leur mère durant les transports sans se servir de leur hallux. Il serait cependant nécessaire de compléter cette étude par des recherches supplémentaires pour inférer avec plus de confiance ce type de comportement à l’A. afarensis. / The human hallux (more commonly called big toe) is now aligned with the other toes, which makes its opposition to other toes impossible. It has been proposed that the loss of opposability of the hallux in early hominins would have led to increase the energetic costs related to maternity, due to the obligation to carry juveniles actively (Tanner & Zihlman 1976; Wall-Sheffler 2007, Watson et al. 2008). This implies that Australopithecus afarensis juveniles had to be actively transported instead of grasping their mother's hair. My study proposes to test whether a juvenile primate needs its hallux to cling to the hair of its mother. The two hypotheses of this work are as follows: The abduction of the hallux is essential for the grasping of the hair of a carrier (usually the mother) by the young macaques and the abduction of the hallux is not necessary for the grasp of the hair of a carrier (usually the mother) by young macaques during transport. Videos of mother/child dyads of rhesus macaques are used in this study to evaluate the use of the hallux in juveniles being carried. The macaques are from a free-range colony in Cayo Santiago, Costa Rica, and they were filmed over a 5-month period. Results tend to support my hypothesis. Indeed, rhesus macaques are able to cling and maintain themselves on their mother during transport without using their hallux. It would, however, be necessary to supplement this study with further research in order to infer this type of behavior in A. afarensis.

Mu-opioid receptor (MOR) agonists are effective agents for pain management, but are also limited by a number of undesirable effects. One approach to enhance the therapeutic effects and minimize the undesirable effects of MOR agonists may be to combine MOR agonists with an adjunct targeting a different receptor system. This targeted medical approach, known as “combination therapy”, aims to augment the desired effects of the MOR agonist (i.e. antinociception) and/or diminish the undesirable deleterious side effects of the MOR agonist. This dissertation investigated the utility of this approach in an assay of thermal nociception and schedule-controlled responding in male rhesus monkeys with three aims. One aim determined the utility of N-methyl D-aspartate (NMDA) receptor antagonists to selectively enhance MOR agonist antinociception. A second identified the pharmacological determinants of antinociceptive interactions between a nociceptin opioid peptide (NOP) receptor agonist and MOR agonists. A third aim investigated the potential for fixed-proportion mixtures of a competitive MOR antagonist and MOR agonist to manipulate antinociceptive efficacy. Experimental results did not support the utility of NMDA antagonists as adjuncts to selectively enhance MOR agonist antinociception. Furthermore, the antinociceptive interactions between a NOP agonist and MOR agonists were modest and occurred under a narrow range of conditions. Finally, fixed proportion MOR antagonist-agonist mixtures were effective in manipulating antinociceptive in vivo efficacy. In conclusion, this dissertation does not provide strong empirical evidence that a combination therapy approach will result in clinically effective and selective enhancement of MOR agonist analgesia. The dissertation concludes with proposed strategies and novel preclinical methods to enhance preclinical-to-clinical translation of effective candidate analgesics.

Colors and color-perception may play an important role in animal ethology (foraging, intra or inter-species communication). However, trichromatic color vision is quite rare among mammals and occurs only in some primate species. Humans, apes, and most of the Old World primates are trichromats, whereas color vision among New World primate species varies strikingly. The pigment gene perciving longer wavelenghts (red) have appeared most recently. Moreover, the pigment genes for the perception of red color have appear independently in these two primates lines (Old and New World) (Kainz et al, 1998). Although the genetic mechanism of trichromacy is quite understood, the question remains, what was the adaptive advantage responsible for the spreading of the above mentioned genes. The basic functions of trichromatic vision may be better detection of food (folivory and frugivory hypothesis), signaling or warning functions. The main goals of the thesis is to study spontaneous preference for color in children (pre- school and school age) and non-human Old World primates who have routine trichromic vision. Moreover, the thesis will focus on preference of red color to understand what was an adaptive function of red color perception. We assume that the spontaneous preference for color may reflect an adaptive...