Neurons In Non-human Primates Research Articles

Role of the parietal cortex in predicting incoming actions

Animal and human studies have shown that the parietal and the ventral premotor cortices constitute the neural substrate of the so-called mirror system. The word "mirror" originally referred to the discovery of neurons in non-human primates whose visual response echoes their motor response. This account proposes that action understanding and imitation depend on a mechanism which activates directly our own motor system as we observe the actions of other agents (Rizzolatti and Sinigaglia, 2010). Single unit recording experiments have also demonstrated that parietal neurons have predictive activity and discharge well ahead of a planned movement. Interestingly, patients with parietal damage can show impairments in their ability to imitate or understand an observed action, but they have also difficulties in monitoring early phases of their own movement planning, be it simple reaching movements or more complex object-directed actions. The fact that both deficits may co-occur after a parietal lesion raises the question whether this reflects the impairment of a common mechanism. To address this question we examined EEG activity in patients with selective lesions in the inferior parietal lobe (N=6) who were requested to watch passively a video showing an actor grasping a colored object. The object's color cued the subject that the actor was about to move. We recorded the Readiness Potential (RP), a marker of motor preparation which also arises when preparing to observe an action (Kilner et al., 2004). Parietal patients' performance was compared to that of neurologically normal subjects (n=9) and patients with a ventral premotor cortex lesion (N=4). We show that neurologically normal subjects and premotor patients exhibit a significant RP prior to the observed action, whereas no such RP is observed in parietal patients. Our results indicate that parietal cortex injury alters the ability to monitor the early planning phases not only of one's own actions but those of other agents as well. We speculate that parietal activity during action observation does not only or essentially reflect a mirroring process, as recently proposed by mirror neurons' account, but involve instead an anticipatory process which arises through prior learning and predictive mechanisms.

Monkey and humans exhibit similar motion-processing mechanisms

Single cell recording studies have resulted in a detailed understanding of motion-sensitive neurons in non-human primate visual cortex. However, it is not known to what extent response properties of motion-sensitive neurons in the non-human primate brain mirror response characteristics of motion-sensitive neurons in the human brain. Using a motion adaptation paradigm, the direction aftereffect, we show that changes in the activity of human motion-sensitive neurons to moving dot patterns that differ in dot density bear a strong resemblance to data from macaque monkey. We also show a division-like inhibition between neural populations tuned to opposite directions, which also mirrors neural-inhibitory behaviour in macaque. These findings strongly suggest that motion-sensitive neurons in human and non-human primates share common response and inhibitory characteristics.

Regular exercise training protects against MPTP-damage to nigrostriatal dopamine neurons in nonhuman primates

Regular exercise training protects against MPTP-damage to nigrostriatal dopamine neurons in nonhuman primates

Decoding the direction of auditory motion in blind humans

Accurate processing of nonvisual stimuli is fundamental to humans with visual impairments. In this population, moving sounds activate an occipito-temporal region thought to encompass the equivalent of monkey area MT+, but it remains unclear whether the signal carries information beyond the mere presence of motion. To address this important question, we tested whether the processing in this region retains functional properties that are critical for accurate motion processing and that are well established in the visual modality. Specifically, we focussed on the property of ‘directional selectivity’, because MT+ neurons in non-human primates fire preferentially to specific directions of visual motion. Recent neuroimaging studies have revealed similar properties in sighted humans by successfully decoding different directions of visual motion from fMRI activation patterns.Here we used fMRI and multivariate pattern classification to demonstrate that the direction in which a sound is moving can be reliably decoded from dorsal occipito-temporal activation in the blind. We also show that classification performance is at chance (i) in a control region in posterior parietal cortex and (ii) when motion information is removed and subjects only hear a sequence of static sounds presented at the same start and end positions. These findings reveal that information about the direction of auditory motion is present in dorsal occipito-temporal responses of blind humans. As such, this area, which appears consistent with the hMT+ complex in the sighted, provides crucial information for the generation of a veridical percept of moving non-visual stimuli.

Monkey and humans exhibit similar motion-processing mechanisms

Single cell recording studies have resulted in a detailed understanding of motion-sensitive neurons in non-human primate visual cortex. However, it is not known to what extent response properties of motion-sensitive neurons in the non-human primate brain mirror response characteristics of motion-sensitive neurons in the human brain. Using a motion adaptation paradigm, the direction aftereffect, we show that changes in the activity of human motion-sensitive neurons to moving dot patterns that differ in dot density bear a strong resemblance to data from macaque monkey. We also show a division-like inhibition between neural populations tuned to opposite directions, which also mirrors neural-inhibitory behaviour in macaque. These findings strongly suggest that motion-sensitive neurons in human and non-human primates share common response and inhibitory characteristics.

A contemporary view of MDMA

Several years of pre-clinical and clinical research specify that MDMA (a principal ingredient in the drug known as “ecstasy”) is neurotoxic to serotonergic nerve terminals, and these neurobiological changes have been predicted to account for neurocognitive deficits, depression, and anxiety seen in human users. In 2002, a high-profile scientific report presented evidence that acute MDMA exposure caused significant damage to dopamine neurons in nonhuman primates (Ricaurte et al. 2002). The finding received considerable media attention, and gave the public the impression that MDMA was far more hazardous than originally thought. Less than a year later, the authors conceded that they were unable to replicate or extend their findings, and this was attributed to the fact that methamphetamine, not MDMA, was used in the earlier experiment (Ricaurte et al. 2003). Critics heralded the mix-up as the tip of an iceberg of a larger scientific/government coalition with an agenda to push forward the War on Drugs. The battle cry went out that “the US research agency that supports research on drug abuse needs to ensure its independence from intense political pressure to prove that recreational drugs are harmful” (Nature 2003), and a claim was made that NIDA favors “studies that are liable to prove the toxicity of recreational drugs” (Knight 2003). As expected, this issue provided fodder for individuals and organizations that would like a major revamping of MDMA research efforts. As a result, a debate on the actual harms of MDMA use was ignited with questions on whether MDMA is neurotoxic at all (Morris 2003). In the following year, Rich De La Garza and Ron Cowan organized a mini-symposium for the annual meeting of the Society for Neuroscience with the intent of providing the essential facts of neurotoxicity and neurocognitive changes that result from MDMA exposure in humans and animals. The current special issue is one outcome of that presentation and the contributions include original investigations as well as reviews that provide a critical analysis of published data pointing out strengths and weaknesses of established findings and frequently used methodologies. The special issue begins with the elegant and comprehensive work of Baumann and colleagues who show that typical doses of MDMA causing long-term serotonin (5-HT) depletion in rats do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA administration induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. A review article by De La Garza and colleagues reveals that MDMA serves as a reinforcer in rats (as measured in intravenous self-administration assays), though the responses are not of similar frequency relative to those previously reported for other psychostimulants (e.g., cocaine). Kuhn and colleagues report sex-specific differences in locomotor effects produced by MDMA. Female rats exhibit greater behavioral activation than males after MDMA treatment initially and upon challenge after a 2-week recovery period. The mechanism by which MDMA increases locomotor activity more in females is attributed to Psychopharmacology (2007) 189:403–405 DOI 10.1007/s00213-006-0636-4

Response to O'Shea and Colado: the MDMA neurotoxicity profile might provide clues to mechanisms

Response to O'Shea and Colado: the MDMA neurotoxicity profile might provide clues to mechanisms

Diverse Actions of Ovarian Steroids in the Serotonin Neural System

All of the serotonin-producing neurons of the mammalian brain are located in 10 nuclei in the mid- and hindbrain regions. The cells of the rostal nuclei project to almost every area of the forebrain and regulate diverse neural processes from higher order functions in the prefrontal cortex such as integrative cognition and memory, to limbic system control of arousal and mood, to diencephalic functions such as pituitary hormone secretion, satiety, and sexual behavior. The more caudal serotonin neurons project to the spinal cord and interact with numerous autonomic and sensory systems. All of these neural functions are sensitive to the presence or absence of the ovarian hormones, estrogen and progesterone. We have shown that serotonin neurons in nonhuman primates contain estrogen receptor β and progestin receptors. Thus, they are targets for ovarian steroids which in turn modify gene expression. Any change in serotoninergic neural function could be manifested by a change in any of the projection target systems and in this manner, serotonin neurons integrate steroid hormone information and partially transduce their action in the CNS. This article reviews the work conducted in this laboratory on the actions of estrogens and progestins in the serotonin neural system of nonhuman primates. Comparisons to results obtained in other laboratory animal models are made when available and limited clinical data are referenced. The ability of estrogens and progestins to alter the function of the serotonin neural system at various levels provides a cellular mechanism whereby ovarian hormones can impact cognition, mood or arousal, hormone secretion, pain, and other neural circuits.

Bimodal (auditory and visual) left frontoparietal circuitry for sensorimotor integration and sensorimotor learning.

We used PET to test whether human premotor and posterior parietal areas can subserve basic sensorimotor integration and sensorimotor learning equivalently in response to auditory and visual stimuli, as has been shown in frontoparietal neurons in non-human primates. Normal subjects were studied while they performed a spatial compatibility task. They were instructed to respond to lateralized auditory and visual stimuli with the ipsilateral hand (compatible condition) or with the contralateral hand (incompatible condition). Reaction times were faster in the compatible than in the incompatible condition, for both auditory and visual stimuli. Left rostral dorsal premotor and posterior parietal blood-flow increases were observed in the incompatible condition, compared with the compatible condition, for both auditory and visual modalities. Blood-flow increases, which were correlated with the reaction-time learning curves, were observed in both auditory and visual modalities in the left caudal dorsal premotor cortex. These data suggest that, as in non-human primates, human frontoparietal areas can subserve basic sensorimotor transformations equivalently in the auditory and visual modality. Further, they reveal a functional rostrocaudal fractionation of human dorsal premotor cortex that resembles the rostrocaudal anatomical and physiological fractionation observed in non-human primates.

Widespread origin of the primate mesofrontal dopamine system.

The dopaminergic innervation of the frontal cortex, commonly implicated in psychiatric and neurological disorders, has traditionally been associated with a circumscribed midline group of ventral tegmental area (VTA) neurons. We have employed a combination of retrograde tracing, using fluorescent dyes, and tyrosine hydroxylase (TH) immunohistochemistry to amplify knowledge of frontal cortex-projecting dopamine (DA) neurons in non-human primates. Injections of retrograde fluorochromes were made in areas 46, 8B/6M, 12, 4, 24, and the prelimbic (PL) and infralimbic areas (IL) of the rhesus monkey. The mesencephalic distribution of neurons exhibiting both retrograde labeling and TH immunoreactivity or retrograde labeling alone was examined from the level of the mammillary bodies to the locus coeruleus. DA afferents innervating the macaque frontal cortex as a whole originate from an unexpectedly widespread continuum of neurons distributed in the dorsal aspects of all three of the mesencephalic DA cell groups [A9, A10 and A8; generally corresponding to the DA cells of the substantia nigra (SN), VTA, and the retrorubral area (RRA) respectively]. A large number of these retrogradely labeled neurons are non-dopaminergic. The dorsal frontal cortex (areas 46, BB/6M and 4) receive DA projections primarily from the full medial-lateral extent of A9 cells dorsal to the SN pars compacta (i.e. A9 dorsalis), the RRA and to a lesser extent from the A10 parabrachial pigmented nucleus (PBPG) and linear nuclei, the latter of which have been associated with the mesocortical DA system. In contrast, the ventromedial PL and IL exhibit a significantly more robust input from the PBPG and midline linear VTA nuclei than from the lateral groups. The anterior cingulate cortex (area 24) is innervated by a group of DA neurons primarily located between these laterally and medially concentrated populations. These findings demonstrate a degree of compartmentalization of the mesofrontal DA system in primates, and suggest that this projection should no longer be viewed as a unitary midline system.

Intrastriatal Grafts From Multiple Donors Do Not Result in a Proportional Increase in Survival of Dopamine Neurons in Nonhuman Primates

We examined the potential for “double grafts,” i.e., grafts from two donors in each recipient, to enhance the total number of ventral mesencephalic dopamine neurons that survive grafting in adult African green monkeys. Because dopamine cell survival in grafts represents a small percentage of the total number of neurons grafted, several human clinical trials recently have employed grafts of tissue from multiple donors (e.g., from two to eight embryos per host recipient) in attempts to increase the total number of dopamine neurons that survive in grafts. Presumably, this is intended to elevate dopamine levels by providing more dopamine neurons to the damaged brain to alleviate the symptoms of parkinsonism. While well-developed grafts with several thousand dopamine neurons were found in most recipient animals, we observed a reduced total number of tyrosine hydroxylase positive neurons in the grafts in spite of the presence of some double grafts that were larger than normal. The overall growth of the grafts was impressive; some grafts were so large that they spanned the full dorsoventral extent of the caudate nucleus, probably reflecting the fact that twice as much tissue was implanted in each drop site in comparison to our standard protocol. However, some animals revealed atypical patterns of neurite outgrowth that appeared limited to the grafted tissue, and at least one monkey revealed “amorphous” grafts generally lacking in cellular structure, which suggests a possible rejection phenomenon. These findings raise questions about the use of multiple donors and suggest that the likelihood of rejection and/or cell death may be enhanced, which is of potential importance in the designof grafting strategies for clinical applications.

Intrastriatal grafts from multiple donors do not result in a proportional increase in survival of dopamine neurons in nonhuman primates.

We examined the potential for "double grafts," i.e., grafts from two donors in each recipient, to enhance the total number of ventral mesencephalic dopamine neurons that survive grafting in adult African green monkeys. Because dopamine cell survival in grafts represents a small percentage of the total number of neurons grafted, several human clinical trials recently have employed grafts of tissue from multiple donors (e.g., from two to eight embryos per host recipient) in attempts to increase the total number of dopamine neurons that survive in grafts. Presumably, this is intended to elevate dopamine levels by providing more dopamine neurons to the damaged brain to alleviate the symptoms of parkinsonism. While well-developed grafts with several thousand dopamine neurons were found in most recipient animals, we observed a reduced total number of tyrosine hydroxylase positive neurons in the grafts in spite of the presence of some double grafts that were larger than normal. The overall growth of the grafts was impressive; some grafts were so large that they spanned the full dorsoventral extent of the caudate nucleus, probably reflecting the fact that twice as much tissue was implanted in each drop site in comparison to our standard protocol. However, some animals revealed atypical patterns of neurite outgrowth that appeared limited to the grafted tissue, and at least one monkey revealed "amorphous" grafts generally lacking in cellular structure, which suggests a possible rejection phenomenon. These findings raise questions about the use of multiple donors and suggest that the likelihood of rejection and/or cell death may be enhanced, which is of potential importance in the design of grafting strategies for clinical applications.

The neural substrates of face processing models: A review

Abstract Prosopagnosia is an impairment of the ability to process visual information derived from faces. A number of models of face processing have been proposed, using methods and models developed in cognitive psychology, to explain the different forms of prosopagnosia. The proposed subcomponents of these models are based almost entirely on behavioural data from prosopagnosic human subjects. This paper reviews the physiological data on face processing, primarily obtained from single-cell recording from neurons in nonhuman primates, and relates this to a model of cognitive face processing. This allows localisation of the different processing modules in functional structures within the brain of higher primates, including man.

Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey

NGF, a trophic polypeptide, is necessary for the normal development and survival of certain populations of neurons in the CNS and PNS. In the CNS, cholinergic neurons of the basal forebrain magnocellular complex (BFMC) are prominent targets of NGF. During rat development, NGF increases the activity of ChAT in these neurons. In adult rats with experimental injury of axons in the fimbria-fornix, NGF prevents degenerative changes in axotomized cholinergic BFMC neurons in the medial septal nucleus (MSN). Because the amino acid sequences of NGF and its receptor (NGF-R) are highly conserved across species, we hypothesized that mouse NGF would also prevent degeneration of cholinergic BFMC neurons in nonhuman primates. Therefore, the present study was designed to test whether fimbria-fornix lesions result in retrograde degenerative changes in basal forebrain cholinergic neurons in macaques, whether these changes are prevented by mouse NGF, and whether the protective effect of NGF is selective for cholinergic neurons of the basal forebrain. Following unilateral complete transection of the fornix, animals were allowed to survive for 2 weeks, during which time half of the subjects received intraventricular NGF in vehicle and the other half received vehicle alone. In animals receiving vehicle alone, there was a 55% reduction in the number of ChAT-immunoreactive cell bodies within the MSN ipsilateral to the lesion; loss of immunoreactive somata was more severe in caudal planes of the MSN. Remaining immunoreactive neurons appeared smaller than those in control, unoperated animals. In Nissl stains, there was no apparent loss of basophilic profiles in the MSN, but cells showed reduced size and intensity of basophilia. Treatment with NGF almost completely prevented reductions in the number and size of cholinergic neurons and had a significant general effect in preventing atrophy in basophilic magnocellular neurons of the MSN, though some basophilic neurons in the MSN did not appear to respond to NGF. Adjacent 7-microns-thick sections stained with ChAT and NGF-R immunocytochemistry revealed that these markers are strictly colocalized in individual neurons in the MSN in controls and in both groups of experimental animals. Thus, mouse NGF profoundly influences the process of axotomy-induced retrograde degeneration in cholinergic BFMC neurons in primates. The in vivo effectiveness of mouse NGF on primate BFMC neurons suggests that mouse or human recombinant NGF may be useful in ameliorating the ACh-dependent, age-associated memory impairments that occur in nonhuman primates.(ABSTRACT TRUNCATED AT 400 WORDS)

(±3,4-Methylenedioxymethamphetamine Selectively Damages Central Serotonergic Neurons in Nonhuman Primates

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has been proposed to be useful as an adjunct to psychotherapy. This study assessed the neurotoxic potential of MDMA in nonhuman primates. Monkeys were repeatedly administered doses (2.50, 3.75, and 5.00 mg/kg) of MDMA subcutaneously and analyzed for regional brain content of serotonin and 5-hydroxyindoleacetic acid two weeks later. In all regions of the monkey brain examined, MDMA produced a selective dose-related depletion of serotonin and 5-hydroxyindoleacetic acid. These neurochemical deficits were associated with evidence of structural damage to serotonergic nerve fibers. In addition, MDMA produced pathological changes in nerve cell bodies in the dorsal, but not median, raphe nucleus. These results indicate that MDMA is a selective serotonergic neurotoxin in nonhuman primates and that humans using this drug may be at risk for incurring central serotonergic neuronal damage.

Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration

This study compared the toxic effects of oral versus subcutaneous and single versus multiple doses of 3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in non-human primates. Orally administered MDMA was approximately one-half as effective as subcutaneously administered drug. Multiple doses were more effective than single doses, but a single 5 mg/kg dose of MDMA given orally still produced a long-lasting depletion of serotonin in the monkey brain. These results indicate that when MDMA is given to monkeys in a manner similar to that employed by humans, it exerts toxic effects on central serotonergic neurons. This suggests that humans using MDMA may be at risk for incurring central serotonergic neuronal damage.