Experiments In Non-human Primates Research Articles

Unique and shared roles of the posterior parietal and dorsolateral prefrontal cortex in cognitive functions

The dorsolateral prefrontal cortex (PFC) and posterior parietal cortex (PPC) are two parts of a broader brain network involved in the control of cognitive functions such as working-memory, spatial attention, and decision-making. The two areas share many functional properties and exhibit similar patterns of activation during the execution of mental operations. However, neurophysiological experiments in non-human primates have also documented subtle differences, revealing functional specialization within the fronto-parietal network. These differences include the ability of the PFC to influence memory performance, attention allocation, and motor responses to a greater extent, and to resist interference by distracting stimuli. In recent years, distinct cellular and anatomical differences have been identified, offering insights into how functional specialization is achieved. This article reviews the common functions and functional differences between the PFC and PPC, and their underlying mechanisms.

CS06-02 - Genetic underpinning of resilience

Experiences and stressful encounters during early development profoundly influence development of the brain to convey either risk for or resilience to later psychopathology. Whereas a considerable proportion of the population will develop stress-related conditions such as anxiety disorders or depression in later life, the majority are resilient, cope with stress and escape such outcomes. The biology for this heterogeneity is multi-factorial, involving a complex interplay between genetic and environmental factors. Although substantial heritability is predicted, recent genome-wide approaches have reliably linked only a few genes to resilience, indicating that also the environment is of critical importance when it comes to developmental processes. It therefore appears that subtle differences in either of these may be responsible for altering developmental trajectories that confer vulnerability or resilience. Current research is providing compelling data that epigenetic processes translating environmental stimuli into changes in expression of established and novel candidate genes play a pivotal role in establishing long-lasting changes in brain function related to resilience. Experiments in rodents and non-human primates reveal that experiences during sensitive periods of development influence DNA methylation patterns of numerous genes. These experience-induced DNA methylation patterns represent stable epigenetic modifications that alter gene transcription throughout the lifespan and promote specific behavioural outcomes. Recent clinical and pre-clinical data suggest that epigenetic differences in various regions of the brain are associated with a range of stress-related psychiatric disorders. Here, an overview is provided of how these epigenetic differences, and hence susceptibility to neuropsychiatric disorders, might arise through exposure to stress during critical periods of development.

Contribution of the central thalamus to the generation of volitional saccades

Lesions in the motor thalamus can cause deficits in somatic movements. However, the involvement of the thalamus in the generation of eye movements has only recently been elucidated. In this article, we review recent advances into the role of the thalamus in eye movements. Anatomically, the anterior group of the intralaminar nuclei and paralaminar portion of the ventrolateral, ventroanterior and mediodorsal nuclei of the thalamus send massive projections to the frontal eye field and supplementary eye field. In addition, these parts of the thalamus, collectively known as the 'oculomotor thalamus', receive inputs from the cerebellum, the basal ganglia and virtually all stages of the saccade-generating pathways in the brainstem. In their pioneering work in the 1980s, Schlag and Schlag-Rey found a variety of eye movement-related neurons in the oculomotor thalamus, and proposed that this region might constitute a 'central controller' playing a role in monitoring eye movements and generating self-paced saccades. This hypothesis has been evaluated by recent experiments in non-human primates and by clinical observations of subjects with thalamic lesions. In addition, several recent studies have also addressed the involvement of the oculomotor thalamus in the generation of anti-saccades and the selection of targets for saccades. These studies have revealed the impact of subcortical signals on the higher-order cortical processing underlying saccades, and suggest the possibility of future studies using the oculomotor system as a model to explore the neural mechanisms of global cortico-subcortical loops and the neural basis of a local network between the thalamus and cortex.

A new synaptic player leading to autism risk: Met receptor tyrosine kinase

The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD.

Motivation and movement: the effect of monetary incentive on performance speed

From observation of human behavior, we know that speed of movement initiation and execution can be influenced by motivational factors, for example we walk faster when in a hurry (sense of urgency) or write faster during an exam (potential reward of good results). However, there is scant experimental evidence for the motivational modulation of movement in man. Experiments in non-human primates have demonstrated shortening of reaction times in response to reward. However, it is not clear how reward might affect performance of reaction time (RT) tasks in humans, and specifically whether warned and unwarned simple and uncued and precued choice RTs are similarly or differentially affected by reward. The effect of monetary incentive on total time (TT, (RT + MT)) was assessed in 16 healthy participants using four paradigms: warned simple RT (wSRT), unwarned simple RT (uSRT), uncued choice RT (uCRT), and precued choice RT (pCRT). wSRT, uSRT, and pCRT tasks all allow advance preparation and preprogramming of the movement, whereas uCRT does not. We found a significant effect of monetary incentive in shortening TTs in wSRT, uSRT, and pCRT tasks, but no effect on the uCRT task. These results demonstrate that monetary incentive can speed up movement initiation and execution in human participants, but only in tasks where preprogramming of the response is possible. This suggests that in reaction time tasks such as these, monetary incentive is having its effect by enhancing preparation of preprogrammed movement, but has little effect when movements cannot be specified in advance. These "RT and reward" tasks provide a useful paradigm for investigation into the effects of monetary incentive on reaction times in man and to study motivational modulation of movement speed in health and disease.

“Counting” serially presented stimuli by human and nonhuman primates and pigeons

Much of Stewart Hulse's career was spent analyzing how animals can extract patterned information from sequences of stimuli. Yet an additional form of information contained in a sequence may be the number of times different elements occurred. Experiments that required numerical discrimination between different stimulus items presented in sequence are analyzed for primates and pigeons. It is shown that a model based on magnitude discrimination can account well for data from human and nonhuman primate experiments. Similar experiments carried out with pigeons showed a strong recency effect not found with primates. The pigeon data are modeled successfully, however, by assuming that representations of events decay as other events are presented.

Update on mucosal HIV vaccine vectors

HIV's primary site of infection is at mucosal surfaces. To successfully defend against sexually transmitted diseases (STDs), including HIV, protection may need to be specifically elicited at the mucosal interface, where the organism enters the host. Recent advances in measuring adaptive responses at mucosal sites and optimization of techniques for low-dose repeated mucosal challenge in nonhuman primate animal models allow more in depth studies of mucosal vaccine vectors. Although parenterally administered vaccines can elicit responses at mucosal sites, vaccination of mucosal sites is being explored in an attempt to increase the frequency, strength and distribution of the adaptive mucosal response. Recent studies in nonhuman primates involve vaccination of the gastrointestinal tract and rectum, as well as the nose, oropharynx or respiratory tree in an attempt to elicit responses at the distal mucosal sites where HIV transmission occurs, the rectum and genital tract. Recent experiments in nonhuman primates indicate that vaccination at mucosal sites can elicit robust responses in the periphery and at mucosal sites, although the response pattern varies widely by route and regimen used. For most regimens, disease course after challenge did not differ by route of vaccination.

Integration of EEG source imaging and fMRI during continuous viewing of natural movies

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are noninvasive neuroimaging tools which can be used to measure brain activity with excellent temporal and spatial resolution, respectively. By combining the neural and hemodynamic recordings from these modalities, we can gain better insight into how and where the brain processes complex stimuli, which may be especially useful in patients with different neural diseases. However, due to their vastly different spatial and temporal resolutions, the integration of EEG and fMRI recordings is not always straightforward. One fundamental obstacle has been that paradigms used for EEG experiments usually rely on event-related paradigms, while fMRI is not limited in this regard. Therefore, here we ask whether one can reliably localize stimulus-driven EEG activity using the continuously varying feature intensities occurring in natural movie stimuli presented over relatively long periods of time. Specifically, we asked whether stimulus-driven aspects in the EEG signal would be co-localized with the corresponding stimulus-driven BOLD signal during free viewing of a movie. Secondly, we wanted to integrate the EEG signal directly with the BOLD signal, by estimating the underlying impulse response function (IRF) that relates the BOLD signal to the underlying current density in the primary visual area (V1). We made sequential fMRI and 64-channel EEG recordings in seven subjects who passively watched 2-min-long segments of a James Bond movie. To analyze EEG data in this natural setting, we developed a method based on independent component analysis (ICA) to reject EEG artifacts due to blinks, subject movement, etc., in a way unbiased by human judgment. We then calculated the EEG source strength of this artifact-free data at each time point of the movie within the entire brain volume using low-resolution electromagnetic tomography (LORETA). This provided for every voxel in the brain (i.e., in 3D space) an estimate of the current density at every time point. We then carried out a correlation between the time series of visual contrast changes in the movie with that of EEG voxels. We found the most significant correlations in visual area V1, just as seen in previous fMRI studies (Bartels A, Zeki, S, Logothetis NK. Natural vision reveals regional specialization to local motion and to contrast-invariant, global flow in the human brain. Cereb Cortex 2008;18(3):705–717), but on the time scale of milliseconds rather than of seconds. To obtain an estimate of how the EEG signal relates to the BOLD signal, we calculated the IRF between the BOLD signal and the estimated current density in area V1. We found that this IRF was very similar to that observed using combined intracortical recordings and fMRI experiments in nonhuman primates. Taken together, these findings open a new approach to noninvasive mapping of the brain. It allows, firstly, the localization of feature-selective brain areas during natural viewing conditions with the temporal resolution of EEG. Secondly, it provides a tool to assess EEG/BOLD transfer functions during processing of more natural stimuli. This is especially useful in combined EEG/fMRI experiments, where one can now potentially study neural-hemodynamic relationships across the whole brain volume in a noninvasive manner.

RATIONALE AND RECOMMENDATIONS FOR TREATMENT OF RADIATION INJURY WITH CYTOKINES

Treatment of the hematopoietic syndrome includes replacement with blood products, stem cell transplantation, and the use of hematopoietic cytokines. Cytokines have predictable effects based upon their mechanism of action. Those acting on early hematopoietic stem/progenitor cells have multilineage effects, while those acting upon more differentiated progenitor cells have lineage restricted activity. The selection of cytokines for treatment of acute hematopoietic toxicity in man is largely based upon results of experiments in non-human primates and canines. Since randomized controlled trials are unable to be performed in man after accidental radiation exposure, recommendations for therapy are largely based upon expert opinion. There is general agreement that granulocyte colony-stimulating factor (G-CSF) is an acceptable choice for treatment of individuals receiving a whole-body dose of 3 Gy or more, or 2 Gy or more in the presence of mechanical trauma and/or burns (i.e., combined injury). G-CSF is available in radiation stockpiles that have been developed in the U.S. and by the World Health Organization.

The brain's router: a cortical network model of serial processing in the primate brain.

The human brain efficiently solves certain operations such as object recognition and categorization through a massively parallel network of dedicated processors. However, human cognition also relies on the ability to perform an arbitrarily large set of tasks by flexibly recombining different processors into a novel chain. This flexibility comes at the cost of a severe slowing down and a seriality of operations (100–500 ms per step). A limit on parallel processing is demonstrated in experimental setups such as the psychological refractory period (PRP) and the attentional blink (AB) in which the processing of an element either significantly delays (PRP) or impedes conscious access (AB) of a second, rapidly presented element. Here we present a spiking-neuron implementation of a cognitive architecture where a large number of local parallel processors assemble together to produce goal-driven behavior. The precise mapping of incoming sensory stimuli onto motor representations relies on a “router” network capable of flexibly interconnecting processors and rapidly changing its configuration from one task to another. Simulations show that, when presented with dual-task stimuli, the network exhibits parallel processing at peripheral sensory levels, a memory buffer capable of keeping the result of sensory processing on hold, and a slow serial performance at the router stage, resulting in a performance bottleneck. The network captures the detailed dynamics of human behavior during dual-task-performance, including both mean RTs and RT distributions, and establishes concrete predictions on neuronal dynamics during dual-task experiments in humans and non-human primates.

A Human Anti-CD40 Monoclonal Antibody, 4D11, for Kidney Transplantation in Cynomolgus Monkeys: Induction and Maintenance Therapy

Blockade of CD40-CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higher-dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.

Chapter 4: Pre‐clinical efficacy and complication data required to justify a clinical trial

Abstract: Pre‐clinical efficacy and complication data required to justify a porcine islet transplantation clinical trial have been considered. To be relevant to clinical islet transplantation, pre‐clinical data should be obtained in a pig‐to‐diabetic non‐human primate (NHP) model. In view of the difficulties of maintaining immunosuppressed NHPs for long periods of time, flexibility must be allowed with regard to the following recommendations. A pre‐clinical trial would be deemed a success if five of eight consecutive experiments in NHPs with proven diabetes meet the following guidelines.1. The fasting and non‐fasting blood glucose levels have been maintained in the NHP at approximately <150 mg/dl (>8.3 mmol/l) and <200 mg/dl (11.1 mmol/l), respectively, throughout a 6‐month follow‐up period (preferably with observations in one or two NHPs extending to 12 months).2. After the transplantation of adult or fetal/neonatal pig islets, no or greatly reduced exogenous insulin has been required after the development of a state of normoglycemia (that may take approximately the first 4 weeks for adult and 12 weeks for fetal/neonatal islets, respectively), except under exceptional, temporary circumstances.3. Sequential intravenous glucose tolerance tests [at 1, 3, 6 (and 12) months post‐transplantation] or arginine stimulation tests have indicated a significant response to glucose in the form of porcine C‐peptide in the absence of a significant response of NHP C‐peptide.4. Histologic study of the native pancreas (if present) after necropsy indicates no or minimal insulin‐positive β cells, and histologic examination of the liver or other site of islet transplantation indicates multiple viable insulin‐positive cells.5. Numerous or serious life‐threatening complications have not been associated with the transplantation procedure, immunosuppressive regimen, tolerance‐inducing regimen, or encapsulation of the islets.Pre‐clinical trials in which the recipient NHPs do not require continuing immunosuppressive therapy (e.g., when encapsulated islets have been transplanted) may possibly be considered acceptable as a basis for a clinical trial with slightly less stringent requirements with regard to points (1) and (2), but would be expected to provide evidence that points (3), (4), and (5) had been achieved.Table of Contents Introduction Induction of diabetes in the non‐human primate potential recipient Porcine islet transplantation Immunotherapeutic protocol Determination of success of islet transplantation Conclusions

Neural correlates of learning and working memory in the primate posterior parietal cortex

The posterior parietal cortex has been traditionally associated with coordinate transformations necessary for interaction with the environment and with visual-spatial attention. More recently, involvement of posterior parietal cortex in other cognitive functions such as working memory and task learning has become evident. Neurophysiological experiments in non-human primates and human imaging studies have revealed neural correlates of memory and learning at the single neuron and at the brain network level. During working memory, posterior parietal neurons continue to discharge and to represent stimuli that are no longer present. This activation resembles the responses of prefrontal neurons, although important differences have been identified in terms of the ability to resist stimulation by distracting stimuli, which is more evident in the prefrontal than the posterior parietal cortex. Posterior parietal neurons also become active during tasks that require the organization of information into larger structured elements and their activity is modulated according to learned context-dependent rules. Neural correlates of learning can be observed in the mean discharge rate and spectral power of neuronal spike trains after training to perform new task sets or rules. These findings demonstrate the importance of posterior parietal cortex in brain networks mediating working memory and learning.

Measles studies in the macaque model.

Much of our current understanding of measles has come from experiments in non-human primates. In 1911, Goldberger and Anderson showed that macaques inoculated with filtered secretions from measles patients developed measles, thus demonstrating that the causative agent of this disease was a virus. Since then, different monkey species have been used for experimental measles virus infections. Moreover, infection studies in macaques demonstrated that serial passage of the virus in vivo and in vitro resulted in virus attenuation, providing the basis for all current live-attenuated measles vaccines. This chapter will review the macaque model for measles, with a focus on vaccination and immunopathogenesis studies conducted over the last 15 years. In addition, recent data are highlighted demonstrating that the application of a recombinant measles virus strain expressing enhanced green fluorescent protein dramatically increased the sensitivity of virus detection, both in living and sacrificed animals, allowing new approaches to old questions on measles vaccination and pathogenesis.

The Miiller-Lyer Illusion as a Tool for Schizophrenia Screening

The perceptual deficit hypothesis for schizophrenia is based on more general models of normal human visual perception, which have traditionally postulated that objects must compete for attention and processing space in the visual system. Recent evidence suggests that susceptibility of schizophrenics to the Müller-Lyer (ML) illusion may be a marker of vulnerability, detectable in prodromic patients, but disappearing with the progression of the illness. This illusion consists of overestimating the length of a straight line with converging arrowheads at the ends, while underestimating those with diverging arrowheads. Although the ML illusion has been shown to occur in touch as well as vision, it is not known whether abnormal contextual suppression extends to other sensory modalities in schizophrenics. Another challenge consists in verifying whether different visual parameters of the illusion which favor the magnocellular and parvocellular systems would have diverse ML illusion effects in schizophrenia. In this review we present data showing the degree of illusion in capuchin monkeys (Cebus spp.), a possible animal model for schizophrenia. To this end, a computer program was developed to conduct experiments in humans and non-human primates, allowing the display of illusory figures, manipulation of the stimuli's exposure time, interval between stimuli and number of trials. In the non-primate experiments, the visual illusion test based on achromatic ML illusion figures indicated the presence of the ML illusory effect in 10 capuchin monkeys. These results suggest that Cebus might be a good model for the experimental study of schizophrenia.

Markedly enhanced immunogenicity of a Pfs25 DNA-based malaria transmission-blocking vaccine by in vivo electroporation

Pfs25 is a promising target antigen for the development of a malaria transmission-blocking vaccine and prior research has demonstrated induction of high and functionally effective antibodies in mice with IM injection of Pfs25 encoding DNA plasmid. Likewise, Pfs25 DNA vaccine was immunogenic in rhesus macaques but required a protein boost to elicit significant transmission-blocking antibodies. The translation of these encouraging findings to human clinical trials has been impeded largely by the relatively poor immunogenicity of DNA plasmids in larger animals. In vivo electroporation (EP) has revealed significant enhancement of the potency of DNA plasmids. The results reported here compared the immunogenicity and functional transmission-blocking effects of immunization with DNA plasmid (25 microg) by the traditional IM route compared to coupling the IM injection (0.25, 2.5 and 25 microg doses) with in vivo EP. Significantly, a 0.25 microg dose of DNA plasmid, when administered with EP, induced antibody titers (1:160,000) and functional transmission-blocking effects that were equivalent to those achieved by a one hundred fold higher (25 microg) dose of DNA plasmid given without EP. At a 25.0 microg DNA dose with or without EP there was sufficient antigenic stimulation to result in effective antibody titers; however EP method yielded antibody titer of 1:1,280,000 as compared to only 1:160,000 titer without EP. This observed two log reduction in the amount of DNA plasmid required to induce significant transmission-blocking effects makes a compelling argument in favor of further evaluation of DNA vaccines by in vivo EP method in larger animals. Further experiments in non-human primates and eventually in phase I human trials will determine if the use of EP will induce effective and sustained malaria transmission-blocking effects at acceptable doses of plasmid DNA.

Possible roles of zinc nutriture in the fetal origins of disease

Risk of diseases of metabolism such as atherosclerosis and adult onset diabetes mellitus is increased by fetal malnutrition. Deficiencies of micronutrients essential for methylation are believed to contribute to the phenomenon in part through epigenetic abnormalities. Zinc is one of the nutrients essential for the epigenome. Because the worldwide prevalence of zinc deficiency is at least 20%, fetal zinc deficiency is common. We suggest fetal zinc deficiency contributes to the pathogenesis of metabolic diseases in adults. In support of our thesis, research in experimental models and humans established the essentiality of zinc at all stages of intrauterine and infant life. Experiments in rodents and/or non-human primates found that fetal and/or suckling zinc deficiency impairs neuropsychological functions of progeny and that the effects persist in spite of nutritional rehabilitation. In addition, maternal zinc deficiency in mice is reported to impair immunity of progeny; effects persist in spite of nutritional rehabilitation into the next generation. We suspect that zinc deficiency is a far greater human health problem than is generally recognized.

Localization of human intraparietal areas AIP, CIP, and LIP using surface orientation and saccadic eye movement tasks

In monkeys, areas in the intraparietal sulcus (IPS) play a crucial role in visuospatial information processing. Despite many human neuroimaging studies, the location of the human functional homologs of some IPS areas is still a matter of debate. The aim of the present functional magnetic resonance imaging (fMRI) study was to identify the distinct locations of specific human IPS areas based on their functional properties using stimuli adapted from nonhuman primate experiments, in particular, surface orientation discrimination and memory guided saccadic eye movements (SEM). Intersubject anatomical variability likely accounts for much of the debate. By applying subject by subject analysis, we can demonstrate that sufficient intersubject anatomical and functional commonalities exist. Both the lateral bank of the anterior part of IPS, the putative human homolog of the area AIP, and the caudal part of the IPS (putative CIP) showed activation related to spatial discrimination of surface orientation. Eye tracking conducted during fMRI data acquisition allowed us to show that both areas were separated by an area related to SEM. This area was located in the middle region of the IPS (most probably including LIP), i.e., similar to the location observed in nonhuman primates. In 10 of 11 subjects our putative CIP activation was located in a medial side branch of the posterior part of the IPS, on the opposite side as described in nonhuman primates, making this landmark a useful anatomical marker for the location of CIP.

Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans?

Can experiments in nonhuman primates expedite the translation of treatments for spinal cord injury in humans?

Narrative Review: Antiretroviral Therapy to Prevent the Sexual Transmission of HIV-1

Antiretroviral therapy (ART) has prolonged and improved the lives of persons infected with HIV. Theoretically, it can also be used to prevent the transmission of HIV. The pharmacology of ART in the male and female genital tract can be expected to affect the success of the intervention, and ART agents differ considerably in their ability to concentrate in genital tract secretions. Emergency ART is considered to be the standard of care after occupational exposures to fluids or tissues infected with HIV. More recently, ART for prophylaxis after nonoccupational HIV exposures has been widely used and most countries have developed specific guidelines for its implementation. However, developing clinical trials to prove the efficacy of ART postexposure prophylaxis has not been possible. Experiments with rhesus macaques suggest that therapy must be offered as soon as possible after exposure (within 72 hours) and must be continued for 28 days. Additional nonhuman primate experiments have demonstrated protection from HIV infection with ART preexposure prophylaxis, and several clinical trials are under way to evaluate the safety and efficacy of this approach. The degree to which ART offered to infected persons reduces infectiousness is of considerable public health importance, but the question has not been sufficiently answered. This article provides a review of the data on the use of ART to prevent the sexual transmission of HIV and identify challenges to improving and clarifying this approach.