Nucleus Of Monkey Research Articles

Comparison of the distributions of urocortin‐containing and cholinergic neurons in the perioculomotor midbrain of the cat and macaque

Urocortin is a novel neurotransmitter that appears to play a role in eating and drinking behavior. Most urocortin-positive (urocortin(+)) neurons in rodents are found in the cytoarchitecturally defined Edinger-Westphal nucleus (EW). However, the EW is traditionally described as the source of the preganglionic parasympathetic outflow to the ciliary ganglion. We examined the distribution of urocortin(+) cells and motoneurons by use of immunohistochemical staining for this peptide and for choline acetyltransferase (ChAT) in macaque monkeys, in which most preganglionic motoneurons inhabit the EW, and in cats, in which most do not. In both species, lack of overt double labeling indicated that the ChAT(+) and urocortin(+) cells are separate populations. In the monkey, most nonoculomotor ChAT(+) neurons were found within the EW. In contrast, urocortin(+) cells were distributed mainly between the oculomotor nuclei and in the supraoculomotor area. In the cat, most nonoculomotor ChAT(+) cells were located in the supraoculomotor area and anteromedian nucleus. Few were present in the cat EW. Instead, this nucleus was filled with urocortin(+) cells. These results highlight the fact the term EW has come to indicate different nuclei in different species. Consequently, we have adopted the identifiers preganglionic (EW(PG)) and urocortin-containing (EW(U)) to designate the cytoarchitecturally defined EW nuclei in monkeys and cats, respectively. Furthermore, we propose a new open-ended nomenclature for the perioculomotor (pIII) cells groups that have distinctive projections and neurochemical signatures. This will allow more effective scientific discourse on the connections and function of groups such as the periculomotor urocortin (pIII(U)) and preganglionic (pIII(PG)) populations.

Striatal projections of the vagal‐responsive region of the thalamic parafascicular nucleus in macaque monkeys

We recently reported that the thalamic parafascicular nucleus (Pf) in monkeys is strongly activated by vagus nerve afferents. The main forebrain target of Pf is the striatum, but the specific striatal regions receiving visceral input via this pathway are unknown. We examined the projections of this region by injecting anterograde tracers into the vagus evoked potential (VEP) focus in Pf of macaque monkeys. The VEP was strongest lateral and anterior to the habenulointerpeduncular tract, but it was distributed across the entire horizontal extent of the ventral half of Pf. All injections produced labeled terminals in the caudate (Cd), especially the Cd tail and the adjacent ventral posterior Pu. Terminations occurred throughout the Cd head and body but spared the most anterior and dorsolateral parts. Injections in more anterior and lateral portions of Pf produced progressively more terminations in Pu, mainly in the precommissural region and the medial aspect of posterior Pu. Dual injections of different tracers revealed overlapping projections with interdigitated strands of striatal terminations from separate regions of Pf as well as the posteromedial to anterolateral topographic gradient of increasing Pf projections to Pu. An injection in the most anteromedial portion of Pf produced strong labeling in the ventral striatum. Thus, Pf transmits viscerosensory information to the "associative" and "limbic" territories of the striatum. These findings suggest the broad involvement of homeostatic afferent activity in striatal function and perhaps a role for the striatum in autonomic function.

Activation of Nigral and Pallidal Dopamine D1-Like Receptors Modulates Basal Ganglia Outflow in Monkeys

Studies of the effects of dopamine in the basal ganglia have focused on the striatum, whereas the functions of dopamine released in the internal pallidal segment (GPi) or in the substantia nigra pars reticulata (SNr) have received less attention. Anatomic and biochemical investigations have demonstrated the presence of dopamine D1-like receptors (D1LRs) in GPi and SNr, which are primarily located on axons and axon terminals of the GABAergic striatopallidal and striatonigral afferents. Our experiments assessed the effects of D1LR ligands in GPi and SNr on local gamma-aminobutyric acid (GABA) levels and neuronal activity in these nuclei in rhesus monkeys. Microinjections of the D1LR receptor agonist SKF82958 into GPi and SNr significantly reduced discharge rates in GPi and SNr, whereas injections of the D1LR antagonist SCH23390 increased firing in the majority of GPi neurons. D1LR activation also increased bursting and oscillations in neuronal discharge in the 3- to 15-Hz band in both structures, whereas D1LR blockade had the opposite effects in GPi. Microdialysis measurements of GABA concentrations in GPi and SNr showed that the D1LR agonist increased the level of the transmitter. Both findings are compatible with the hypothesis that D1LR activation leads to GABA release from striatopallidal or striatonigral afferents, which may secondarily reduce firing of basal ganglia output neurons. The antagonist experiments suggest that a dopaminergic "tone" exists in GPi. Our results support the finding that D1LR activation may have powerful effects on GPi and SNr neurons and may mediate some of the effects of dopamine replacement therapies in Parkinson's disease.

Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys

We have examined dopaminergic cell survival after alteration of the subthalamic nucleus (STN) in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The STN was lesioned with kainic acid (B series) or underwent deep brain stimulation (DBS) at high frequency (C series). In another series, MPTP-treated and non-MPTP-treated monkeys had no STN alteration (intact animals; A series). Animals were treated with MPTP either after (B1, C1) or before (B2, C2) STN alteration. We also explored the long-term ( approximately 7 months) effect of DBS in non-MPTP-treated monkeys (D series). Brains were aldehyde-fixed and processed for routine Nissl staining and tyrosine hydroxylase immunocytochemistry. Our results showed that there were significantly more (20-24%) dopaminergic cells in the substantia nigra pars compacta (SNc) of the MPTP-treated monkeys that had STN alteration, either with kainic acid lesion or DBS, compared to the non-MPTP-treated monkeys (intact animals). We suggest that this saving or neuroprotection was due to a reduction in glutamate excitotoxicity, as a result of the loss or reduction of the STN input to the SNc. Our results also showed that SNc cell number in the B1 and C1 series were very similar to those in the B2 and C2 series. In the cases that had long-term DBS of the STN (D series), there was no adverse impact on SNc cell number. In summary, these results indicated that STN alteration offered neuroprotection to dopaminergic cells that would normally die as part of the disease process.

Metabolic activity of cerebellar and basal ganglia-thalamic neurons is reduced in parkinsonism

We have examined whether degeneration of nigrostriatal dopaminergic neurons causes dysfunction of both the basal ganglia-thalamic and cerebello-thalamic pathways. Changes in the activity of thalamic neurons receiving input from the basal ganglia or the cerebellum were examined in two models of Parkinson's disease, 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Metabolic activity of the neurons was evaluated at the cellular level by quantitative in situ hybridization, using the expression of messenger RNA for subunit I of cytochrome oxidase (COI), encoded by the mitochondrial genome, as the marker. COI mRNA expression decreased significantly in thalamocortical neurons receiving input from the substantia nigra (-50.6%) or the cerebellum (-45%) in 6-OHDA-lesioned rats compared with controls. The decrease was observed in all thalamic neurons whether or not they were retrogradely labelled with a tracer injected into the motor cortex. Similarly, COI mRNA expression decreased in projection neurons and interneurons of the thalamus receiving input from the substantia nigra (-39 and -38%, respectively), the internal pallidum (-20 and -42.4%, respectively) and the cerebellum (-36.2 and -50%, respectively) of MPTP-treated monkeys compared with controls. These decreases in COI mRNA levels show that nigrostriatal denervation results in a decrease in the metabolic activity of thalamic neurons in the territories innervated by the substantia nigra, pallidum and cerebellum, which in turn is indicative of a decrease in their neuronal activity. The decrease did not concern the entire thalamus, however, since metabolic activity was unchanged in two thalamic nuclei considered to be limbic structures, the laterodorsal nucleus in 6-OHDA-lesioned rats and the anterior nucleus in MPTP-treated monkeys. Hypoactivity of both the basal ganglia-thalamic and cerebellar-thalamic pathways might therefore be implicated in the development of parkinsonian symptoms.

The thalamic connections of motor, premotor, and prefrontal areas of cortex in a prosimian primate ( Otolemur garnetti)

Connections of motor areas in the frontal cortex of prosimian galagos ( Otolemur garnetti) were determined by injecting tracers into sites identified by microstimulation in the primary motor area (M1), dorsal premotor area (PMD), ventral premotor area (PMV), supplementary motor area (SMA), frontal eye field (FEF), and granular frontal cortex. Retrogradely labeled neurons for each injection were related to architectonically defined thalamic nuclei. Nissl, acetylcholinesterase, cytochrome oxidase, myelin, parvalbumin, calbindin, and Cat 301 preparations allowed the ventral anterior and ventral lateral thalamic regions, parvocellular and magnocellular subdivisions of ventral anterior nucleus, and anterior and posterior subdivisions of ventral lateral nucleus of monkeys to be identified. The results indicate that each cortical area receives inputs from several thalamic nuclei, but the proportions differ. M1 receives major inputs from the posterior subdivision of ventral lateral nucleus while premotor areas receive major inputs from anterior parts of ventral lateral nucleus (the anterior subdivision of ventral lateral nucleus and the anterior portion of posterior subdivision of ventral lateral nucleus). PMD and SMA have connections with more dorsal parts of the ventral lateral nucleus than PMV. The results suggest that galagos share many subdivisions of the motor thalamus and thalamocortical connection patterns with simian primates, while having less clearly differentiated subdivisions of the motor thalamus.

Changes in the neuronal activity in the pedunculopontine nucleus in chronic MPTP-treated primates: an in situ hybridization study of cytochrome oxidase subunit I, choline acetyl transferase and substance P mRNA expression

The pedunculopontine nucleus is a mesencephalic nucleus that has widespread and reciprocal connections with the basal ganglia. It has been implicated in the physiopathology of akinesia, rigidity, gait failure and sleep disorders associated with Parkinson's disease. In this study, in situ hybridization was used to examine the changes in neuronal metabolic activity (measuring cytochrome oxidase subunit I) and in the level of acetylcholine and Substance P synthesis in the pedunculopontine nucleus of monkeys chronically treated with MPTP. Significant reductions were observed in cytochrome oxidase subunit I (p = 0.001), choline acetyl transferase (p = 0.003) and substance P (p = 0.006) mRNA expression in parkinsonian animals compared with controls, indicating that pedunculopontine cholinergic neurons activity decreases with parkinsonism.

Comparison of Reward Modulation in the Frontal Eye Field and Caudate of the Macaque

The frontal eye field (FEF) influences saccade generation via direct projections to the superior colliculus and an indirect pathway through the basal ganglia. To test whether different reward information is represented in the FEF and the basal ganglia, we recorded from the FEF and the caudate nucleus in monkeys performing an asymmetrically rewarded memory-guided saccade task. A peripheral cue at one of two opposing positions was flashed briefly to indicate the saccade target. In a given block, one position was associated with big reward and the other with small reward. Big-reward position was alternated between blocks. In this task, the FEF and caudate displayed similar prevalence of neuronal activity before cue onset that was larger in blocks with specific big reward-cue position associations. They also exhibit comparable reward modulation of visual responses that were spatially selective. In contrast, visual responses that were specific to expected reward size, instead of spatial locations, were commonly observed in caudate but rarely seen in the FEF. Thus, both the FEF and basal ganglia may contribute to reward bias in saccade generation, with the FEF providing spatially relevant reward information and the basal ganglia providing additional reward-specific information.

Chronic ethanol drinking reduces native T-type calcium current in the thalamus of nonhuman primates

Background:Chronic ethanol use is known to disrupt normal sleep rhythms, but the cellular basis for this disruption is unknown. An important contributor to normal sleep patterns is a low-threshold calcium current mediated by T-type calcium channels. The T-type calcium current underlies burst responses in thalamic nuclei that are important to spindle propagation, and we recently observed that this current is sensitive to acute low doses of ethanol. Methods:We used a combination of current clamp and voltage clamp recordings in an in vitro brain slice preparation of the dorsal lateral geniculate nucleus (LGN) of macaque monkeys that have chronically self-administered ethanol to determine whether chronic ethanol exposure may affect T-type currents. Results:Current clamp recordings from the LGN of ethanol naive macaques showed characteristic burst responses. However, recordings from the LGN in macaques that self-administered ethanol revealed a significant attenuation of bursts across a range of voltages (n = 5). Voltage clamp recordings from control LGN neurons (n = 16) and neurons (n = 29) from brain slices from chronically drinking macaques showed no significant differences (P > 0.05) in T-type current kinetics or in the membrane resistance of the thalamic cells between the two cohorts. However, mean T-type current amplitude measured in the chronically drinking animals was reduced by 31% (P < 0.01). Conclusions:We conclude that chronic ethanol self-administration reduces calcium currents in thalamic relay cells without altering underlying current kinetics, which may provide a mechanistic framework for the well-documented disruptions in sleep/wake behavior in subjects with chronic ethanol exposure.

Neural Correlates of the Dependence of Compensatory Eye Movements During Translation on Target Distance and Eccentricity

To stabilize objects of interest on the fovea during translation, vestibular-driven compensatory eye movements [translational vestibulo-ocular reflex (TVOR)] must scale with both target distance and eccentricity. To identify the neural correlates of these properties, we recorded from different groups of eye movement-sensitive neurons in the prepositus hypoglossi and vestibular nuclei of macaque monkeys during lateral and fore-aft displacements. All neuron types exhibited some increase in modulation amplitude as a function of target distance during high-frequency (4 Hz) lateral motion in darkness, with slopes that were correlated with the cell's pursuit gain, but not eye position sensitivity. Vergence angle dependence was largest for burst-tonic (BT) and contralateral eye-head (EH) neurons and smallest for ipsilateral EH and position-vestibular-pause (PVP) cells. On the other hand, the EH and PVP neurons with ipsilateral eye movement preferences exhibited the largest vergence-independent responses, which would be inappropriate to drive the TVOR. In addition to target distance, the TVOR also scales with target eccentricity, as evidenced during fore-aft motion, where eye velocity amplitude exhibits a "V-shaped " dependence and phase shifts 180 degrees for right versus left eye positions. Both the modulation amplitude and phase of BT and contralateral EH cells scaled with eye position, similar to the evoked eye movements during fore-aft motion. In contrast, the response modulation of ipsilateral EH and PVP cells during fore-aft motion was characterized by neither the V-shaped scaling nor the phase reversal. These results show that distinct premotor cell types carry neural signals that are appropriately scaled by vergence angle and eye position to generate the geometrically appropriate compensatory eye movements in the translational vestibulo-ocular reflex.

Functional Maturation of the Macaque's Lateral Geniculate Nucleus

Vision in infant primates is poor, but it is not known which structures in the eye or brain set the main limits to its development. We studied the visual response properties of 348 neurons recorded in the lateral geniculate nucleus (LGN) of macaque monkeys aged 1 week to adult. We measured spatial and temporal frequency tuning curves and contrast responses with drifting achromatic sinusoidal gratings. Even in animals as young as 1 week, the main visual response properties of neurons in the magnocellular (M) and parvocellular (P) divisions of the LGN were qualitatively normal, including the spatial organization of receptive fields and the characteristic response properties that differentiate M- and P-cells. At 1 and 4 weeks, spatial and temporal resolution were less than one-half of adult values, whereas contrast gain and peak response rates for optimal stimuli were about two-thirds of adult values. Adult levels were reached by 24 weeks. Analysis of correlations between S-potentials representing retinal inputs and LGN cells suggested that the LGN follows retinal input as faithfully in infants as in adults, implicating retinal development as the main driving force in LGN development. Comparisons with previously published psychophysical data and ideal observer models suggest that the relatively modest changes in LGN responses during maturation impose no significant limits on visual performance. In contrast to previous studies, we conclude that these limits are set by neural development in the visual cortex, not in or peripheral to the LGN.

MRI guidance improves accuracy of stereotaxic targeting for cell transplantation in parkinsonian monkeys

Accuracy of targeting is critical for the success of cell transplantation in the central nervous system. We compared the accuracy of conventional atlas-guided stereotaxis to magnetic resonance imaging (MRI)-guided stereotaxic targeting in various basal ganglia nuclei in parkinsonian monkeys. 28 monkeys underwent unilateral striatal transplantation. High-resolution 3D MR images of the brain were used in 15 monkeys fitted with a MRI-compatible stereotaxic frame for target localization. This was immediately followed by cranial surgery with the frame “in situ”. 13 additional monkeys underwent stereotaxic atlas-guided cranial surgery for placement of cell transplants. Following extensive behavioral testing and microelectrode recordings, all animals were perfused. The brains were sectioned coronally and stained to determine the morphology of needle tracts as an accuracy measure of stereotaxic placements. MRI-guided stereotaxy was completely accurate in 80% as compared to 38.5% in atlas-guided stereotaxis. The chance of missing a target completely was as high as 38.5% in atlas-guided stereotaxis, which was reduced to 6.67% when MRI was used for guidance. Targeting error occurred mostly in the anterior caudate and posterior putamen as against better accuracy in the anterior putamen. These results suggest that accuracy of stereotaxic unilateral cranial targeting into the putamen and the caudate in monkeys can be improved with high-resolution 3D MR imaging.

Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys

Drugs that target the dopamine transporter (DAT) have been proposed as pharmacotherapies to treat cocaine abuse. Accordingly, it is paramount to understand pharmacological interactions between cocaine and DAT inhibitors. The present study characterized acute interactions between cocaine and several DAT inhibitors (RTI-177, FECNT, RTI-112) that differed in selectivity for monoamine transporters on operant behavior and in vivo neurochemistry in squirrel monkeys. RTI-177 and FECNT, two DAT inhibitors with low affinity at norepinephrine transporters (NET), produced dose-dependent stimulant effects on behavior maintained by a fixed-interval schedule of stimulus termination. Compared to cocaine, RTI-177 and FECNT had a slower onset and longer duration of action. In vivo microdialysis in the caudate nucleus of awake monkeys confirmed dose-dependent increases in extracellular dopamine that corresponded to behavioral effects. Among the drugs characterized, RTI-112 is reportedly the least selective for binding to DAT, NET, and serotonin transporters (SERT). Interestingly, RTI-112 failed to produce significant behavioral-stimulant effects, and its effects on extracellular dopamine were highly variable across subjects. The results indicate that the pharmacological profile of DAT inhibitors may be influenced by actions at multiple monoamine transporters. Importantly, there was little evidence of additivity on behavioral or neurochemical measures when cocaine was administered in combination with behavioral-stimulant doses of the DAT inhibitors.

Pursuit—Vestibular Interactions in Brain Stem Neurons During Rotation and Translation

Under natural conditions, the vestibular and pursuit systems work synergistically to stabilize the visual scene during movement. How translational vestibular signals [translational vestibuloocular reflex (TVOR)] are processed in the premotor pathways for slow eye movements continues to remain a challenging question. To further our understanding of how premotor neurons contribute to this processing, we recorded neural activities from the prepositus and rostral medial vestibular nuclei in macaque monkeys. Vestibular neurons were tested during 0.5-Hz rotation and lateral translation (both with gaze stable and during VOR cancellation tasks), as well as during smooth pursuit eye movements. Data were collected at two different viewing distances, 80 and 20 cm. Based on their responses to rotation and pursuit, eye-movement-sensitive neurons were classified into position-vestibular-pause (PVP) neurons, eye-head (EH) neurons, and burst-tonic (BT) cells. We found that approximately half of the type II PVP and EH neurons with ipsilateral eye movement preference were modulated during TVOR cancellation. In contrast, few of the EH and none of the type I PVP cells with contralateral eye movement preference modulated during translation in the absence of eye movements; nor did any of the BT neurons change their firing rates during TVOR cancellation. Of the type II PVP and EH neurons that modulated during TVOR cancellation, cell firing rates increased for either ipsilateral or contralateral displacement, a property that could not be predicted on the basis of their rotational or pursuit responses. In contrast, under stable gaze conditions, all neuron types, including EH cells, were modulated during translation according to their ipsilateral/contralateral preference for pursuit eye movements. Differences in translational response sensitivities for far versus near targets were seen only in type II PVP and EH cells. There was no effect of viewing distance on response phase for any cell type. When expressed relative to motor output, neural sensitivities during translation (although not during rotation) and pursuit were equivalent, particularly for the 20-cm viewing distance. These results suggest that neural activities during the TVOR were more motorlike compared with cell responses during the rotational vestibuloocular reflex (RVOR). We also found that neural responses under stable gaze conditions could not always be predicted by a linear vectorial addition of the cell activities during pursuit and VOR cancellation. The departure from linearity was more pronounced for the TVOR under near-viewing conditions. These results extend previous observations for the neural processing of otolith signals within the premotor circuitry that generates the RVOR and smooth pursuit eye movements.

Effects of age on latency and variability of visual response in monkeys

Visual function declines during normal aging. The neural mechanisms underlying age-related changes have just begun to be revealed. It has been demonstrated that retinal ganglion cells and cells in dorsal lateral geniculate nucleus (dLGN) in old monkeys are relatively normal. However, age-related functional degradations have been found at cellular level in mammalian visual cortex. Decreased orientation and direction selectivity of neurons in primary visual cortex (V1) have been reported in both aged monkeys and cats. Similar degradation of stimulus selectivity also occurs in secondary visual cortex (V2) in old monkeys. In addition, we have reported prolonged response latency in both V1 and V2 of old primates. Response latency of neuron can be affected by several factors, including conduction speed of the axons, synaptic integration, action potential initiation and the response variability. These factors may all contribute to delayed visual response in aged animals. For example, increased response variability will affect the temporal integration in synaptic transmission, resulting in prolonged response latency in the postsynaptic neurons. On the other hand, the evaluation of latency depends on the reproducibility of response. The more variable the spike train driven by external stimulus, the longer time will be needed to reach the peak in the post-stimulus time histogram (PSTH). Thus, a prolonged latency will be observed. In the present experiment, using monkeys in early stage of senescence as subjects, we studied the effects of age on response variability and its relationship with the prolonged latency, aiming to investigate possible neural mechanisms underlying the age-related alteration of response latency. Subjects for this study were 3 young adult (5―6 years old) and 3 old (21―22 years old) male rhesus monkeys (Macaca mullata). All experimental protocols were consistent with the guidelines of the Society for Neuroscience and National Institute of Health. Monkeys were examined ophthalmoscopically to ensure that they had no optical or retinal problems that would impair visual function. Conventional acute extracellcular single unit recording technique was used to record the activity of V1 neurons of anaesthetized and paralyzed monkeys. The receptive field properties of neurons were analyzed as described previously. Visual stimuli were presented on a tangent screen positioned 171 cm from the retina (3 cm corresponds to 1° of visual angle). The visual stimulus was a flashing square within receptive field with optimal size for each cell, which is commonly used in related studies. The luminance of the stimulus used was 12.3 cd/m for white and 0.95 cd/m for black. For each cell, we presented the identical visual stimulus for 50 times, with an ON period of 0.5 s and an OFF period of 3 s, and accumulated a PSTH that represents the probability of firing as a function of time. The neurons with low response variability fire at almost the same time in 50 presentations, resulting in a sharp rising branch in PSTH. In contrast, the neurons with high response variability will produce a peak with a relative flat rising branch. Then, the rising branch of the first peak in PSTH with an amplitude equal or larger than three times of spontaneous activity was fitted by a Gaussian curve (y=y0+Aexp(-((x-x0)/ ) ) whose half-width ( ) was taken as a measure of the trial-to-trial variability, and time offset (x0) as the response latency (Peak latency). We studied the visual responses of 90 V1 cells in young monkeys and 99 V1 cells in old monkeys. Fig. 1 represents four typical PSTHs. The cells recorded in aged animals showed significant prolonged response latencies and increasing response variabilities, compared with cells in young monkeys (Table 1, Fig. 2(a), (b)). The finding of prolonged latency in aged animals is consistent with our previous study. However, the subjects we used in the present experiment were 21―22 years old monkeys, while the monkeys in our previous study were 28―32 years old. Analysis based on the sex maturation and lifespan revealed that the degree of senescence of 21―22 years old monkeys approximately equals 60―70 years old human beings, and 28―32 years old monkeys correspond to 80―90 years old human beings. The present results have demonstrated that the prolonged response latency occurs during the early stage of aging. It provided possible neural mechanisms underlying the delay in visual signal analysis and slowness of reaction time for visual stimulus in old people. The average for young monkey cells was 2.82 ms. In comparison, V1 cells in aged monkeys showed significant increased value of (4.56 ms), suggesting higher variability of response. The increase in re

Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.

Dynamics of accommodative fatigue in rhesus monkeys and humans

Changes in accommodative dynamics with repeated accommodation were studied in three anesthetized rhesus monkeys and two conscious humans. Maximum accommodation was centrally stimulated via the Edinger–Westphal nucleus in monkeys with a 4 s on, 4 s off paradigm (4 × 4) for 17 min, 4 × 1.5 for 27 min and 2 × 1 for 16 min. Humans accommodated repeatedly to visual targets (5 × 5; 5D and 2 × 2; 6D) for 30 min. In all cases, accommodation was sustained throughout. The anesthetized monkeys showed inter-individual variability in the extent of changes in accommodative dynamics over time while no systematic changes were detected in the human accommodative responses. Little accommodative fatigue was found compared to previous studies which have reported a complete loss of accommodation after 5 min of repeated stimulation in monkeys.

Electrical stimulation of rhesus monkey nucleus reticularis gigantocellularis. II. Effects on metrics and kinematics of ongoing gaze shifts to visual targets.

Saccade kinematics are altered by ongoing head movements. The hypothesis that a head movement command signal, proportional to head velocity, transiently reduces the gain of the saccadic burst generator (Freedman 2001, Biol Cybern 84:453-462) can account for this observation. Using electrical stimulation of the rhesus monkey nucleus reticularis gigantocellularis (NRG) to alter the head contribution to ongoing gaze shifts, two critical predictions of this gaze control hypothesis were tested. First, this hypothesis predicts that activation of the head command pathway will cause a transient reduction in the gain of the saccadic burst generator. This should alter saccade kinematics by initially reducing velocity without altering saccade amplitude. Second, because this hypothesis does not assume that gaze amplitude is controlled via feedback, the added head contribution (produced by NRG stimulation on the side ipsilateral to the direction of an ongoing gaze shift) should lead to hypermetric gaze shifts. At every stimulation site tested, saccade kinematics were systematically altered in a way that was consistent with transient reduction of the gain of the saccadic burst generator. In addition, gaze shifts produced during NRG stimulation were hypermetric compared with control movements. For example, when targets were briefly flashed 30 degrees from an initial fixation location, gaze shifts during NRG stimulation were on average 140% larger than control movements. These data are consistent with the predictions of the tested hypothesis, and may be problematic for gaze control models that rely on feedback control of gaze amplitude, as well as for models that do not posit an interaction between head commands and the saccade burst generator.

Cognitive function of the brainstem cholinergic system

A major population of cholinergic projection neurons is located in the pedunculopontine and laterodorsal tegmental nuclei in the midbrain. Although much work has been performed on their role in the regulation of sleep and wakefulness, their function in the awake state is not well understood. We made single unit recordings in the pedunculopontine tegmental nucleus (PPTN) of macaque monkeys during visually guided saccade tasks. Three major types of neuron activities were observed. The first was tonic or phasic increase in activity around the time of fixation point onset and closely correlated with the performance of the monkey in the coming saccade task. The second was the activity related to preparation and execution of saccades. The third was the activity related to reward delivery. A subpopulation of PPTN neurons exhibited more than two types of activities. We conclude from these findings that the PPTN may serve as an integrative interface between various signals required for performance of purposive behaviors.

Adaptive modification of saccade size produces correlated changes in the discharges of fastigial nucleus neurons.

Saccade accuracy is known to be maintained by adaptive mechanisms that progressively reduce any visual error that consistently exists when the saccade ends. We used an experimental paradigm known to induce adaptation of saccade size while monitoring the neural correlates of this adaptation. In rhesus monkeys where the medial and lateral recti of one eye were surgically weakened, patching the unoperated eye and forcing the monkey to use the weakened eye induced a gradual increase in saccade size in both eyes until the viewing, weak eye almost acquired the target in one step. Subsequent patching of the weakened eye gradually reversed the situation, so that the saccades in the viewing, normal eye decreased from an initial overshooting to normal. In the caudal fastigial nuclei of unadapted monkeys, neurons typically exhibit an early burst of spikes that is correlated with the onset of contraversive saccades and a later burst of spikes that is correlated with the termination of ipsiversive saccades. Comparing the discharges of the same fastigial neurons recorded before and during adaptation, this basic pattern did not change, but some parameters of the discharges did. The most consistent changes were in the latency of the burst for ipsiversive saccades, which was positively correlated with saccade size (1.28 ms/deg), and in the number of spikes associated with contraversive saccades, which was also positively correlated (0.55 spikes/deg). The former was more important when saccade size was decreasing, and the latter was more important when saccade size was increasing. Based on current knowledge of the anatomical connections of fastigial neurons, as well as on the effects of cerebellar lesions and on recordings in other structures, we argue that these changes are appropriate for causing the associated changes in saccade size.