Thomas G. Aigner

Visual habit formation in monkeys with neurotoxic lesions of the ventrocaudal neostriatum

Visual habit formation in monkeys, assessed by concurrent visual discrimination learning with 24-h intertrial intervals (ITI), was found earlier to be impaired by removal of the inferior temporal visual area (TE) but not by removal of either the medial temporal lobe or inferior prefrontal convexity, two of TEs major projection targets. To assess the role in this form of learning of another pair of structures to which TE projects, namely the rostral portion of the tail of the caudate nucleus and the overlying ventrocaudal putamen, we injected a neurotoxin into this neostriatal region of several monkeys and tested them on the 24-h ITI task as well as on a test of visual recognition memory. Compared with unoperated monkeys, the experimental animals were unaffected on the recognition test but showed an impairment on the 24-h ITI task that was highly correlated with the extent of their neostriatal damage. The findings suggest that TE and its projection areas in the ventrocaudal neostriatum form part of a circuit that selectively mediates visual habit formation.

Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert

Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.

Magnetic resonance imaging of the rhesus monkey brain: use for stereotactic neurosurgery

SummaryStandard stereotactic procedures rely upon external cranial landmarks and standardized atlases for localization of subcortical neural regions. Magnetic resonance imaging permits the visualization of the neural structure of the brain in vivo. A stereotactic instrument compatible with a magnetic resonance unit was constructed and together with magnetic resonance imaging a procedure was developed that overcomes the limitations and inaccuracies of the traditional stereotactic methods and allows accurate and reliable localization of subcortical targets in the rhesus monkey brain.

Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques

SummaryTo assess the contributions of the basal forebrain cholinergic nuclei to visual recognition memory in macaques, we compared the effects of lesions of (a) the nucleus basalis of Meynert, (b) the medial septal and diagonal band nuclei, and (c) all nuclei combined on performance of delayed nonmatching-to-sample with trial-unique stimuli. Whereas monkeys with the separate lesions did not differ from each other or from normal control animals, those with combined lesions showed a significant impairment. With time and extended practice, however, the performance of the animals with combined lesions recovered to normal levels. During the recovery period, these monkeys showed an initially increased sensitivity to scopolamine that later dissipated, at which time they also failed to show the improvement that follows physostigmine administration in normal animals. Postmortem assessment of cortical choline acetyltransferase activity revealed that only the group with combined lesions had significant depletion of this enzyme. The results suggest that (1) the basal forebrain cholinergic system participates in mnemonic processes in primates and that (2) extensive damage to this system is necessary before impairments in recognition memory, even transient ones, can be observed.

6-18F-L-DOPA imaging of the dopamine neostriatal system in normal and clinically normal MPTP-treated rhesus monkeys

SummaryPositron emission tomography following intravenous administration of 6-[18F]-L-fluorodopa was used to investigate the usefulness of PET for the assessment of normal and abnormal dopaminergic function. For this purpose, the incracerebral distribution of 6-[18F]-L-fluorodopa and its metabolites was evaluated in normal control and asymptomatic MPTP-treated rhesus monkeys. MPTP is a neurotoxic compound which destroys selectively the dopaminergic neurons of the nigrostriatal pathways in primates. The 18F accumulation was found to be significantly reduced in the striatum, putamen more than caudate, of the MPTP-treated animals compared to the normal controls. The 18F accumulation in dopamine-poor areas did not differ between the two groups. The ratios of striatum to dopamine-poor brain area were highly correlated to the concentrations of the dopamine metabolite, homovanillic acid, in the cerebrospinal fluid of the same animals. The findings are consistent with the hypothesis that “silent damage” to the dopaminergic nigral neurons may precede the onset of parkinsonism by many years and that PET scanner examination using 6-[18F]-L-fluorodopa may be useful in the detection of subtle dopaminergic dysfunctions as may exist in DA-related motor syndromes and neuropsychiatric disorders.

Distribution and kinetics of 3-O-methyl-6-[18F]fluoro-L-DOPA in the rhesus monkey brain

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPAs behavior in brain appear acceptable for [18F]DOPA modeling purposes.

Long-term cognitive impairment in MPTP-treated rhesus monkeys

Following MPTP administration, monkeys manifest cognitive deficits on tasks known to assess the fronto-striatal system; there are, however, no data regarding long-term cognitive effects. In this study, we examined the cognitive abilities of monkeys 10 years after MPTP administration. MPTP-treated monkeys and age-matched controls performed a spatial delayed response task with fixed and random delays. The MPTP-treated monkeys were impaired in both versions of the task. Both groups performed at the same level at very short delays suggesting that the nature of the impairment is related to a spatial memory deficit that is still apparent 10 years after treatment. These results suggest that, like Parkinsons patients, the MPTP-treated primates display spatial deficits.

Spatial memory improvement by levodopa in parkinsonian MPTP-treated monkeys

Abstract Rationale: The ameliorative effects of levodopa (l-3,4-dihydroxy-phenylalanine) on the motor impairment in Parkinson’s disease patients is well established, but characterization of its effects on the associated cognitive deficits is still incomplete. Objective: The present study determined the effect of different doses of levodopa on performance on a test of working memory in MPTP-treated rhesus monkeys, an animal model of Parkinson’s disease. Methods: Four MPTP-treated monkeys and their age-matched controls with the same experimental history as the MPTP-treated monkeys were tested on a spatial delay response task. Each daily session consisted of five trials at each of seven randomly presented delays (0, 10, 20, 30, 40, 50 and 60 s). Training was continued for 5 days in each of five different conditions. In the first condition, control and MPTP-treated animals performed the task without levodopa. In the second condition, both groups were tested with a dose of 100 mg of levodopa. In the third and fourth conditions, in which the doses of levodopa were increased to 250 and 500 mg, respectively, only the MPTP-treated animals were tested. In the final condition, the MPTP-treated animals where retested without levodopa. Results: Significant improvement was observed at all doses tested (range 100–500 mg). Conclusions: Levodopa can ameliorate memory impairments in this parkinsonian model.

Cholinergic-glutamatergic interactions in visual recognition memory of rhesus monkeys

Administration of either a non-competitive N-methyl-D-aspartatc (NMDA) receptor antagonist, MK-801 (dizocilpine), or a muscarmic antagonist, scopolamine, produces dose-related impairments in performance of a visual recognition memory task, delayed non-matching to sample (DNMS) with lists of 20 symbols, in rhesus monkeys. In the present study, low doses of these two drugs, which were ineffective when given alone, significantly impaired performance when given in combination. Moreover, the effect was greater than additive, indicating a synergistic interaction. These results suggest that interactions between cholincrgic and glutamatergic systems play an important role in regulation of visual recognition memory.

New rapid analysis method demonstrates differences in 6-[18F]fluoro-l-dopa plasma input curves with and without carbidopa and in hemi-MPTP lesioned monkeys

Kinetic modeling of the PET tracer 6-[18F]fluoro-L-dopa ([18F]Dopa), used to measure presynaptic dopamine function, requires the accurate determination of the plasma input curve. We have developed a new method that uses alumina extraction preceded by cation and anion exchange resins to determine the parent compound, [18F]Dopa and its critical metabolite 3-O-methyl-6-[18F]fluoro-L-dopa. Using this method we found that carbidopa increases the plasma input of [18F]Dopa while decreasing the rate of metabolite formation, and that previous drug treatment can significantly effect [18F]Dopa metabolism.