Michael R. Weed

Performance norms for a rhesus monkey neuropsychological testing battery : acquisition and long-term performance

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

Scopolamine alters rhesus monkey performance on a novel neuropsychological test battery

Rhesus monkeys (6) were trained on a test battery including cognitive tests adapted from a human neuropsychological assessment battery (CANTAB; CeNeS, Cambridge, UK) as well as a bimanual motor skill task. The complete battery included tests of memory (delayed non-match to sample, DNMS; self-ordered spatial search, SOSS), reaction time (RT), motivation (progressive ratio; PR) and fine motor coordination (bimanual). The animals were trained to asymptotic performance in all tasks and then were administered two of the four CANTAB tasks on alternate weekdays (PR/SWM; DNMS/RT) with the bimanual task being administered on each weekday. The effect of acute administration of scopolamine (3-24 microg/kg, i.m.) on performance was then determined. Although performance on DNMS was impaired there was no interaction of drug treatment with retention interval, suggesting that scopolamine does not increase the rate of forgetting in this task. Scopolamine administration produced a decrement in SOSS performance that was dependent on task difficulty as well as dose. Scopolamine also impaired motor responses, resulting in increased time required to complete the bimanual motor task and increased movement time in the RT task. Performance in the PR task was decreased in a dose-dependent fashion by scopolamine. The results suggest that scopolamine interferes with memory storage and motor responses but not memory retention/retrieval or vigilance. The findings demonstrate that the test battery is useful for distinguishing the effects of neuropharmacological manipulation on various aspects of cognitive performance in monkeys.

Antiviral treatment normalizes neurophysiological but not movement abnormalities in simian immunodeficiency virus–infected monkeys

Simian immunodeficiency virus (SIV) infection of rhesus monkeys provides an excellent model of the central nervous system (CNS) consequences of HIV infection. To discern the relationship between viral load and abnormalities induced in the CNS by the virus, we infected animals with SIV and later instituted antiviral treatment to lower peripheral viral load. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Cessation of treatment led to the reappearance of these abnormalities. In contrast, the decline in general motor activity induced by SIV infection was unaffected by antiviral treatment. An acute increase in the level of the chemokine monocyte chemoattractant protein-1 (MCP-1) was found in the cerebrospinal fluid (CSF) relative to plasma in the infected animals at the peak of acute viremia, likely contributing to an early influx of immune cells into the CNS. Examination of the brains of the infected animals after return of the electrophysiological abnormalities revealed diverse viral and inflammatory findings. Although some of the physiological abnormalities resulting from SIV infection can be at least temporarily reversed by lowering viral load, the viral-host interactions initiated by infection may result in long-lasting changes in CNS-mediated functions.

Functional Consequences of Repeated (±)3,4-Methylenedioxymethamphetamine (MDMA) Treatment in Rhesus Monkeys

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by ∼50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.

Longitudinal analysis of behavioral, neurophysiological, viral and immunological effects of SIV infection in rhesus monkeys

Abstract: A model is proposed in which a neurovirulent, microglial‐passaged, simian immunodeficiency virus (SIV) is used to produce central nervous system (CNS) pathology and behavioral deficits in rhesus monkeys reminiscent of those seen in humans infected with human immunodeficiency virus (HIV). The time course of disease progression was characterized by using functional measures of cognition and motor skill, as well as neurophysiologic monitoring. Concomitant assessment of immunological and virological parameters illustrated correspondence between impaired behavioral performance and viral pathogenesis. Convergent results were obtained from neuropathological findings indicative of significant CNS disease. In ongoing studies, this SIV model is being used to explore the behavioral sequelae of immunodeficiency virus infection, the viral and host factors leading to neurologic dysfunction, and to begin testing potential therapeutic agents.

Impaired performance on a rhesus monkey neuropsychological testing battery following simian immunodeficiency virus infection

Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS including HIV-induced central nervous system (CNS) pathology and cognitive/behavioral impairment. Recently a behavioral test battery has been developed for macaques based on the CANTAB human neuropsychological testing battery. As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles may assess function in particular brain regions. Ten rhesus monkeys were infected with SIV after being trained on two or more of the battery tasks addressing memory (delayed nonmatching to sample, DNMS), spatial working memory (using a self-ordered spatial search task, SOSS), motivation (progressive-ratio, PR), reaction time (RT), and/or fine motor skills (bimanual motor skill, BMS). Performance was compared to that of 9 uninfected monkeys. Overall, some aspect of performance was impaired in all 10 monkeys following infection. Consistent with results in human AIDS patients, individual performance was impaired most often on battery tasks thought to be sensitive to frontostriatal dopaminergic functioning such as SOSS, RT, and BMS. These results further demonstrate the similarity of behavioral impairment produced by SIV and HIV on homologous behavioral tests, and establish the utility of the testing battery for further investigations into the CNS mechanisms of the reported behavioral changes.

Modeling a task that is sensitive to dementia of the Alzheimer's type: individual differences in acquisition of a visuo-spatial paired-associate learning task in rhesus monkeys.

Early detection of progressive diseases such as Alzheimers Disease (AD) is crucial for both the treatment and study of the disease. Performance on a visuo-spatial paired-associates learning (vsPAL) task was recently shown to reliably predict a diagnosis of AD in aged populations. The present study reports the development of this vsPAL task for use in nonhuman primates. Translation of vsPAL to a nonhuman model may provide improved preclinical tools for study of the etiology and treatment of dementia. Twelve young adult male rhesus monkeys were trained to perform the vsPAL task concurrently with tests comprising a nonhuman primate neuropsychological test battery. Monkeys successfully learned to perform vsPAL and did so in a task-difficulty ranked fashion. Despite significant individual differences in capability in the acquisition of the recognition memory aspects of the task, all monkeys evidenced the ability to learn within-trial, i.e. to improve with repeated stimulus-location pairings. These results support the use of vsPAL performance under various challenge conditions to investigate the possible substrates of early cognitive decline in AD. Comparison of performance on vsPAL with performance on other memory tasks in the battery will be of more general use in differentiating mechanisms involved in various aspects of mnemonic function.

The effects of dopaminergic agents on reaction time in rhesus monkeys

Abstract Many CNS pathologies, including Parkinson’s, Alzheimer’s and Huntington’s diseases, as well as AIDS dementia complex, involve some degree of movement dysfunction. Reaction time (RT) performance has been shown to be a sensitive measure of motor function for these disorders. Useful models of RT performance exist in a variety of species, but few are performed in the same manner as with humans. To facilitate species comparisons, the present RT task was developed from a human RT task. Dopaminergic drugs were then used to characterize the sensitivity of the model to CNS changes and to investigate their effects on RT performance in intact rhesus monkeys. With cumulative dosing, the selective dopamine receptor antagonists (D1) SCH 39166 and (D2) raclopride produced dose-dependent slowing of RT performance. Results following bolus administration of these drugs were consistent with the cumulative dosing procedure, although of smaller magnitude and higher variability. Amphetamine had no significant effect on group RT performance with either dosing scheme, but RT performance in individual monkeys was either speeded or slowed by d-amphetamine. The present results suggest that blockade of either D1-like or D2-like dopamine receptors can slow RT performance in rhesus monkeys and that this paradigm may be useful to study movement dysfunction in non-human primates.

Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [11C]MPH and [11C]raclopride dynamic PET scans were performed to image dopamine transporter and D2-like receptors, respectively. Binding potential (BPND), an index of tracer-specific binding, and amphetamine-induced changes in BPND of [11C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D2 receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

Allosteric Modulation of GABAA Receptor Subtypes: Effects on Visual Recognition and Visuospatial Working Memory in Rhesus Monkeys

Non-selective positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) are known to impair anterograde memory. The role of the various GABAAR subtypes in the memory-impairing effects of non-selective GABAAR PAMs has not been fully elucidated. The current study assessed, in rhesus monkeys, effects of modulation of α1, α2/3, and α5GABAARs on visual recognition and spatial working memory using delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) procedures, respectively. The DMTS procedure (n=8) involved selecting a previously presented ‘sample’ image from a set of multiple images presented after a delay. The SOSS procedure (n=6) involved touching a number of boxes without repeats. The non-selective GABAAR PAM triazolam and the α1GABAA preferential PAMS zolpidem and zaleplon reduced accuracy in both procedures, whereas the α5GABAA preferential PAMs SH-053-2′F-R-CH3 and SH-053-2′F-S-CH3, and the α2/3GABAA preferential PAM TPA023B were without effects on accuracy or trial completion. The low-efficacy α5GABAAR negative allosteric modulator (NAM) PWZ-029 slightly increased only DMTS accuracy, whereas the high-efficacy α5GABAAR NAMs RY-23 and RY-24 did not affect accuracy under either procedure. Finally, the slopes of the accuracy dose-effect curves for triazolam, zolpidem, and zaleplon increased with box number in the SOSS procedure, but were equivalent across DMTS delays. The present results suggest that (1) α1GABAARs, compared with α2/3 and α5GABAARs, are primarily involved in the impairment, by non-selective GABAAR PAMs, of visual recognition and visuospatial working memory in nonhuman primates; and (2) relative cognitive impairment produced by positive modulation of GABAARs increases with number of locations to be remembered, but not with the delay for remembering.