Primate Cognitive Neuroscience (LPCNS) of Kunming Primate Research Center
1 Principal Investigator: Ma Yuanye, Prof.
1982.6 --1986.9 Research fellow in KIZ, Kunming Yunnan, China
1987.5 --1988.5 Post-doctor in Section of Neurobiology, Yale University, School of Medicine, New Haven, CT, USA.
1988.10--1995.2 Assistant Professor in KIZ
1995.3 --1996.3 Visiting Scientist in Dept of Experimental Psychology, Oxford University, Oxford, UK
1996.4 --1999.4 Visiting Scientist in Dept of Psychology, University of Arizona, Tucson, Arizona, USA
1999.5 -- Professor & Director of Lab of Primate Neuroscience, KIZ
2 Staff and Students
1 professor, 1 vice professor, 5 assistant professors and technicians, 17 graduate students.
3 Research Interests
The long-term purpose for this lab is to study the prefrontal mechanisms on the cognitive process. The long term study will provide insights into the neural mechanisms that underlie the cognitive functions of the prefrontal cortex that are common to human and non-human primates.
In the coming 10 years, we will focus on the ventral part of this cortex. The ventral prefrontal cortex in people is thought to mediate complex cognitive processes such as planning，decision-making, rewarding etc. Our present proposes to study the VPFC is because that this part of brain may be involved specifically in drug addiction, impairment of selective attention and mental illness. It is possible that research in monkeys would lead to a conclusion similar to that in people
The proposal will undertake experiments that are based on research on the functions of the ventral prefrontal cortex in people; the present proposal is designed to evaluate the position that the prefrontal function in monkeys is part of a more fundamental set of processes that enable both monkeys and people to make decisions and predictions about future actions, a prerequisite for planning. Some experiments are described in which recordings of brain activity were made in monkeys performing tasks requiring learning, memory, and attention; these experiments build on recent neurophysiological findings at our lab. The results of these studies should clarify the nature of mechanisms in monkeys that contribute to the drug addiction, selection and planning of behavioral choices for rewarding.
This proposal is designed to evaluate two competing hypotheses about the nature of prefrontal control mechanisms. These hypotheses arose from research showing that subregions of the ventral prefrontal cortex (VPFC) had different functions, which included self-control, value discrimination, analysis of complex rewarding based information, and which had implications for the role of this cortical expanse in cognition. Two mutually exclusive hypotheses resulted from the research: One, that VPFC neural mechanisms reflected the value properties of rewarding and has feed-forward information process. Two, that VPFC mechanisms were important for controlling the action based on value and has feedback information process in order for monkeys to make decisions about behavioral choices. During the funded series of neurophysiological investigations, it became apparent that the results strongly favor the feed-back/behavioral decision hypothesis. Specifically, we find evidence for prefrontal feed-back control; on the contrary, it appears that the appearance of the rewarding is only important in so far as it enables monkeys to identify the value and thus make intelligent decisions about how to respond to these rewarding.
4 Major Research Findings
(1) Reinforcement-related neurons in the primate basal forebrain respond to the learned significance of task events rather than to the hedonic attributes of reward
The objective of this study was to determine if the responses of basal forebrain neurons are related to the cognitive processes necessary for the performance of behavioral tasks, or to the hedonic attributes of the reinforces delivered to the monkey as a consequence of task performance. In all cases, it was found that the primary neuronal responses were to visual stimuli that (through learning were associated with reinforcement) required analysis important for the selection of a behavioral response, and not to delivery of reinforcement per se. Indeed, reinforcement-related neurons that responded only to the delivery of juice or of saline were never encountered. In additional experiments it was found that abstract visual cues - specific gestures of the experimenter - that signaled the impending delivery of reinforcement were able to activate these neurons. These data are consistent with the view that reinforcement-related basal forebrain neurons influence sensory and motor processes in the cerebral cortex, providing control signals that optimize the processing of complex sensory stimuli and/or the generation of appropriate behavioral responses.
(2) Dissociation of egocentric and allocentric spatial processing in prefrontal cortex
Monkeys with lesions of areas 9 and 46 performed three variants of the spatial delayed response (SDR) task. There were no impairments in allocentric spatial memory in which geometrical relationships between environmental cues were used to identify spatial location; thus, memory of a 3D environmental map is intact. In contrast, there were severe impairments in egocentric spatial memory guided by visual or tactile cues that monkeys can relate to their viewing perspective during testing. These results strongly suggest that dorsolateral prefrontal cortex selectively mediates spatial memory tasks that are solved by referencing the location of objects to the body’s orientation.
(3) Differential amplitude modulation of auditory evoked cortical potentials associated with brain state in the freely moving rhesus monkey
We simultaneously recorded auditory evoked potentials (AEP) from the temporal cortex (TCx), the dorsolateral prefrontal cortex (dPFCx) and the parietal cortex (PCx) in the freely moving rhesus monkey to investigate state-dependent changes of the AEP. AEPs obtained during passive wakefulness, active wakefulness (AW), slow wave sleep and rapid-eye-movement sleep (REM) were compared. Results showed that AEP from all three cerebral areas were modulated by brain states. However, the amplitude of AEP from dPFCx and PCx significantly appeared greater attenuation than that from the TCx during AW and REM. These results indicate that the modulation of brain state on AEP from all three cerebral areas investigated is not uniform, which suggests that different cerebral areas have differential functional contributions during sleep–wake cycle. q 2002 Elsevier Science Ireland Ltd. All rights reserved.
(4) GABA and Its Agonists Improved Visual Cortical Function in Senescent Monkeys
Human cerebral cortical function degrades during old age. Much of this change may result from a degradation of intracortical inhibition during senescence. We used multibarreled microelectrodes to study the effects of electrophoretic application of _-aminobutyric acid (GABA), the GABA type a (GABAa) receptor agonist muscimol, and the GABAa receptor antagonist bicuculline, respectively, on the properties of individual V1 cells in old monkeys. Bicuculline exerted a much weaker effect on neuronal responses in old than in young animals, confirming a degradation of GABA-mediated inhibition. On the other hand, the administration of GABA and muscimol resulted in improved visual function. Many treated cells in area V1 of old animals displayed responses typical of young cells. The present results have important implications for the treatment of the sensory, motor, and cognitive declines that accompany old age.
(5) Age-related effects of bilateral frontal eye fields’ lesions on rapid eye movements during REM sleep in rhesus monkeys
Rapid eye movement (REM) is one of the most characteristic features of REM sleep, but the mechanisms underlying its regulation remain unclear. The present study aims to investigate whether the frontal eye field (FEF) is involved in the regulation of the rapid eye movements during REM sleep. To address this question, we ablated the FEF in four rhesus monkeys and observed the effects of the lesions on sleep architecture. After lesions, two adult monkeys did not show any lesion effect. However, in the other two adolescent monkeys, both the total duration and percentage of the rapid eye movements during REM sleep were decreased moderately. The result suggests that the relation between the FEF and the regulation of the rapid eye movements during REM sleep may be affected by age factor, also indicating that both the functions of the FEF and the mechanisms underlying the control of rapid eye movements during REM sleep might not be the same throughout the whole life span of an animal.
(6) Telemetric recordings of single neuron activity and visual scenes in monkeys walking in an open field
This paper describes a portable recording system and methods for obtaining chronic recordings of single units and tracking rhesus monkey behavior in an open field. The integrated system consists of four major components: (1) microelectrode assembly; (2) head-stage; (3) recording station; and (4) data storage station, the first three of which are carried by the monkey and weigh 800 g. Our system provides synchronized video and electrophysiological signals, which are transmitted by a wireless system to a distance of 50 m. Its major advantages are that neuronal recordings are made in freely moving monkeys, and well-separated action potentials with amplitude five times higher than the background noise are usually recorded and readily kept for many hours. Using this system, we were able to study “place cells” in non-human primate brains. The described methods provide a new way to examine correlations between single neuron activity and primate behaviors, and can also be used to study the cellular basis of social behaviors in non-human primates.
(7) A microelectrode drive for long-term recording of neurons in freely moving and chaired monkeys
An electrode drive is described for recordings of neurons in freely moving and chaired monkeys during the performance of behavioral tasks. The electrode drives are implanted for periods of up to 6 months, and can advance up to 42 electrodes using 14 independent drive mechanisms. The drive samples 288 points within a 12 mm_/12 mm region, with 15 mm of electrode travel. Major advantages are that recordings are made in freely moving monkeys, and these recordings can be compared with those in chaired experiments; waveforms of single neurons are stable, enabling prolonged recordings of the same neurons across periods of days; recordings can be made throughout the brain, including the dorsolateral prefrontal cortex and hippocampus; the drive accommodates both sharp microelectrodes and fine wire assemblies such as tetrodes.
(8)Effects of morphine on hippocampal sensory gating during morphine- dependence development and withdrawal in rats
Sensory gating is an important tool for evaluating mammalian cognition and is measured by the double-click auditory evoked potential suppression paradigm. Gating changes are correlated with mesolimbic dopamine activity and may provide an index of the state of the brain in morphine addiction. We investigated the effects of morphine on hippocampal sensory gating (N40 component) in Sprague-Dawley rats during the development of morphine dependence and during withdrawal. The morphine-treated group exhibited significantly reduced hippocampal gating compared with controls during the development of morphine dependence, indicating the acute effects of morphine on hippocampal gating. Haloperidol pretreatment partially reversed this attenuated gating. After three days of morphine injections, hippocampal gating was disrupted, suggesting a long-term effect of morphine on hippocampal suppression. In contrast, there was significantly enhanced hippocampal gating on the fifth and sixth days of withdrawal. The alternately disrupted and enhanced hippocampal gating, observed during the development of morphine dependence and withdrawal, was probably associated with dopaminergic transmission in the hippocampus. The results are consistent with documented changes in dopaminergic neurotransmission during drug addiction and with the role of dopaminergic regulation in sensory gating.
(9) Potentiation of orbitofrontal gamma activity during opiate withdrawal
Incentive–sensitization model of addiction suggests that sensitization of a neural system that attributes incentive salience causes compulsive motivation or “wanting” to take addictive drugs and there is no electrophysiological marker to address this view. We show here that repeated opiate administration increases the orbitofrontal gamma activity during withdrawal. Furthermore, environmental stimuli associated with opiate administration induce stronger orbitofrontal gamma activity during withdrawal than that during conditioning periods.
(10) Functional dissociation of dorsal and ventral prefrontal cortex in the process of morphine addiction
The purpose of the present research was to compare the activities of the OFC and DLPFC to determine the function of the OFC and DLPFC in the process of addiction. We recorded spontaneous EEG in the bilateral OFC and R-DLPFC at 25 minutes and 2 hours after injection to respectively evaluate the acute and chronic effects of morphine. A main finding in this study was that the acute effects of morphine on the activities in the L-OFC, R-OFC and R-DLPFC were different during the development of morphine dependence. In contrast with those in the R-DLPFC, the activities in the OFC were more modified at 25 minutes after injection during the development of morphine dependence (from day 1 to day 6). In the OFC, the changes of EEG activities occurred on all components. However, in the R-DLPFC, only Alpha components were affected. These results suggest that the OFC is a probable direct target for the effects of drugs of abuse but not the DLPFC. Our study provided direct evidence that the OFC is a probable direct target for the effects of drugs of abuse but not the DLPFC, that is, the OFC play a more important role than DLPFC in drug addiction. Our results indicated that the activities of the OFC and DLPFC were all influence by drug addiction.
Since 2001, 12 papers have been published in international journals including Science and a technology to record neuron activities in totally free moving monkeys have been developed by LPCNS. This technology enables us to study the relationship of brain functions and some kinds of behaviours such as social behaviour, sexual behaviour etc that requires subjects in a natural condition while the recording is in processing. So far LPCNS is the unique lab, which has such technique around the world.
5 Selected Publications (2000-2004)
[1] Wang YC, Zhou YF, Ma Y-Y and Leventhal A, Degradation of signal timing in cortical areas V1 and V2 of senescent monkeys", Cerebral Cortex.2004 ( in Press) .
[2] Shan Yu, Ning Liu, Tao Zeng, Shaohua Tian, Nanhui Chen, Yifeng Zhou, Yuanye Ma, Age-related effects of bilateral frontal eye fields lesions on rapid eye movements during REM sleep in rhesus monkeys Neuroscience Letters 2004 (in Press).
[3] Wang JH, Cai JX, Ma Y-Y.Effect of stress on memory process in a passive avoidance paradigm. Neurology, Psychiatry and Brain Research, 2004 (in Press).
[4] Ingram N, Martin S, Wang JH, Laan S, Loiacono R, Buuse ven den M. Interaction of corticosterone and nicotine in regulation of prepulse inhibition in mice. Neuropharmacology, 2004, ( in press).
[5] Wilson FA，Ma Y-Y.Reinforcement-related neurons in the primate basal forebrain respond to the learned significance of task events rather than to the hedonic attributes of reward. Cognitive Brain Research, 2004 19 (1): 74-81.
[6] Lei YL, et al.，Ma Y-Y.Telemetric recordings of single neuron activity and visual scenes in monkeys walking in an open field. Journal of Neuroscience Methods，2004，135/1-2：35-41.
[7] Buuse ven den M, Chavez C., Martin S., Wang JH. Effect of adrenalectomy and corticosterone replacement on prepulse inhibition and locomotor activity in mice. British J. of Pharmacology. 2004, Jun; 142 (3): 543-50.
[8] Ma Y-Y, Tian BP, Wilson FA. Dissociation of egocentric and allocentric spatial processing in prefrontal cortex. Neuroreport, 2003: 14 (13) 1737-1741.
[9] Audie G. Leventhal, Yongchang Wang, Mingliang Pu, Yifeng Zhou, Ma Y-Y. GABA and Its Agonists Improved Visual Cortical Function in Senescent Monkey, Science, 2003, 2 May Vol 300, 812-815.
[10] Wilson FA, Ma Y-Y, Greenberg PA, Ryou JW, Kim BH. A microelectrode drive for long term recording of neurons in freely moving and chaired monkeys. J Neurosci Methods. 2003, 15;127 (1): 49-61.
[11] Wang JH et al, Ma Y-Y. Effect of paradoxical sleep deprivation and stress on passive avoidance. behavior.Physiology and Behavior, 2003，79: 516-519.
[12] Wang JH, Short J, Ledent C, Lawrence AJ, Buuse M. Reduced startle habituation and prepulse inhibition in mice lacking the adenosine A2A receptor. Behav Brain Res. 2003 14;143 (2): 201-7.
[13] Tian SW et al，Ma Y-Y.Differential amplitude modulation of auditory evoked cortical potentials associated with brain state in the freely moving rhesus monkey. Neurosci Lett, 2002, 18;331 (3): 159-62.
[14] Chen NH, White IM, Wise SP. Neuronal activity in dorsomedial frontal cortex and prefrontal cortex reflecting irrelevant stimulus dimensions. Exp Brain Res. 200l;139 (1): 116-9.
Books and chapters
[1] Ma Y-Y，Ryou JW, Kim BH and Wilson FA. Spatially-directed movement and neuronal activity in freely moving monkeys. In: Mori S, Stuart DG, Wiesendanger M, editors. Brain Mechanisms for the Integration of Posture and Movement, Progress in Brain Research, chapter 48. Amsterdam: Elsevier, 2003：505-512。
[2] Ma Y-Y. The function of prefrontal cortex in self-consciousness. In: Wang YJ and Yang YF editors. Consciousness and Brain. Ren Ming Publish House, 2003：98-114。
[3] Ma YY and Wang JH. The Principle and Technique of Cognitive Neuroscience. (600, 000words) Chongqin Publish House. China. 2003.
Patents
Authorized: 2.
6 Honors and Awards
“The receptor mechanisms of catecholamine on working memory in rhesus monkeys” won the first-class prize for natural sciences of Yunnan province in 2001. (As the second winner)
Yunnan Science and Technique Leadership. (The First Grade).
7 Research Grants
Brain and Mind. (A project from CAS)
The brain mechanisms of addiction. (A project from CAS)
Reward circuits and memory in drug addiction. (A national project)
8 International Cooperation
We encourage international exchange of scientific information and the scientists who wish to share our interest in brain research.
Following the signing of the agreement in 2002 between LPCN and the University of Utah, an agreement was reached that in the next three years, the two labs have been carried out a program of collaborative research supported by the NIH RO1 grant. Under this agreement, we have set up a joint lab in KIZ to study the functional brain degeneration in aged monkeys and received one associate professor, Dr YC Wang from Utah and doing research in our lab.
After the official contact and correspondence in 2002 between KIZ and MPI, we have sent a postdoctoral student to do the training in MPI Brain Institute and will have some cooperation with Prof. W Singer and his brain institute.
We have also a pleasure to have Dr. Fraser Wilson who was an assistant professor of University of Arizona to work in our lab for next 3 years.
Out visiting: Dr. Cheng NH visited Max-Planck Institute, German, during 2003-2005. Wang JH (PhD student) visited Mental Health Research Institute of Victoria, Australia during 2002-2003.
