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M L Voytko

Publications and source records attributed to M L Voytko.

At least 19 recordsLinked to original sources
PubMed2004

Cognitive function and its neural mechanisms in nonhuman primate models of aging, Alzheimer disease, and menopause.

Nonhuman primates have been used as animal models in which to study cognitive changes associated with aging and age-related disease for decades. There are many advantages to using nonhuman primates for studies of aging including the capability to examine visual nonspatial cognitive processes and the ability to use operationally similar behavioral tasks to what is used with humans. Because some aspects of aging in humans do not develop naturally in nonhuman primates or do not follow the same course of natural development in monkeys, experimental models are necessary for some investigations. Research in our laboratory has identified similarities in the cognitive profiles of nonhuman primate models of aging, Alzheimer Disease, and menopause with their human counterparts. In addition, through the use of a variety of different techniques we have used these nonhuman primate models to begin to determine the neural substrates of age-related cognitive dysfunction noted with advanced age and age-related disease. In this paper, we review our observations made in nonhuman primate models of aging, Alzheimer Disease, and menopause and indicate areas for future research.

Aging↗
PubMed2004

Effects of ovariectomy on the neuroendocrine axes regulating reproduction and energy balance in young cynomolgus macaques.

Degeneration of the ovary in middle-aged women results in castrate levels of ovarian steroids and increased gonadotropin secretion from the anterior pituitary gland. Ageing in women is also accompanied by significant changes in energy homeostasis. We have observed alterations in hypothalamic morphology and gene expression in older women, including hypertrophy and increased gene expression of neurokinin B (NKB) neurones, elevated levels of gonadotropin releasing-hormone (GnRH) mRNA and decreased numbers of neurones expressing pro-opiomelanocortin (POMC) mRNA. To determine if loss of ovarian steroids could produce comparable changes in gene expression in young primates, we measured the effects of ovariectomy on NKB, GnRH and POMC gene expression in young cynomolgus monkeys. We also measured serum leptin and body weight to examine the consequences of ovariectomy on energy balance. NKB neurones in the infundibular nucleus of ovariectomized monkeys were larger, more numerous and displayed increased levels of NKB mRNA compared to those of intact controls. Moreover, ovariectomy increased the number of neurones expressing GnRH gene transcripts and elevated serum luteinizing hormone. By contrast, several parameters related to energy balance, including POMC gene expression, serum leptin and body weights, were unchanged by ovariectomy. Thus, the rise in NKB and GnRH gene expression in older women was simulated by ovariectomy in monkeys, but the changes in POMC gene expression and energy balance were not. This study provides strong support for the hypothesis that ovarian failure contributes to the increased NKB and GnRH gene expression observed in postmenopausal women.

Animals↗
PubMed2001

Cholinergic activity of aged rhesus monkeys revealed by positron emission tomography.

In the present study, the radiotracer [(18)F] (+)-4-fluorobenzyltrozamicol ((+)-[(18)F]FBT) and positron emission tomography (PET) were used to examine the vesicular acetylcholine transporter and determine if presynaptic cholinergic activity was altered with age in 23 rhesus monkeys that varied in age from 10 to 37 years. Binding of (+)-[(18)F]FBT in the basal ganglia was reduced significantly with increasing age of the monkeys. However, there were individual differences noted in that some middle-aged and aged monkeys demonstrated levels of (+)-[(18)F]FBT binding that were comparable to the binding measured in adult monkeys. These data indicate that presynaptic cholinergic function may decrease with age, but that there may be a differential susceptibility of the cholinergic system to the aging process in different individuals.

Acetylcholine↗
PubMed2001

An obligatory role for spinal cholinergic neurons in the antiallodynic effects of clonidine after peripheral nerve injury.

BACKGROUND: Indirect evidence supports a role of spinal cholinergic neurons in tonically reducing response to noxious mechanical stimulation and in effecting analgesia from alpha2-adrenergic agonists. This study directly assessed the role of cholinergic neurons in regulating the level of mechanical allodynia and in participating in the antiallodynic effect of the clinically used alpha2-adrenergic agonist, clonidine, in an animal model of neuropathic pain. METHODS: Allodynia was produced in rats by ligation of the left L5 and L6 spinal nerves. Rats received a single intrathecal injection of saline or one of three different doses of the cholinergic neurotoxin, ethylcholine mustard aziridinium ion (AF64-A; 2, 5, and 15 nmol). Seven days later, allodynia was assessed before and after intrathecal injection of 15 microg clonidine. The spinal cord was removed, and spinal cord acetylcholine content, cholinergic neuron number and distribution, and alpha2-adrenergic receptor expression were determined. RESULTS: AF64-A administration reduced both the number of cholinergic cells and the acetylcholine content of the lumbar dorsal spinal cord by 20-50% but did not affect level of mechanical allodynia. AF64-A did, however, completely block the anti-allodynic effect of clonidine. AF64-A did not reduce alpha2-adrenergic ligand binding in dorsal lumbar cord. CONCLUSIONS: These data suggest that spinal cholinergic tone does not affect the level of mechanical allodynia after peripheral nerve injury. There is a quantitative reliance on spinal cholinergic neurons in the allodynia relieving properties of intrathecal clonidine, and this reliance does not depend on alpha2-adrenergic receptors colocalized on spinal cholinergic interneurons.

Acetylcholine↗
PubMed2001

Ensuring the success of women faculty at AMCs: lessons learned from the National Centers of Excellence in Women's Health.

Since the early 1970s, the numbers of women entering medical school and, subsequently, academic medicine have increased substantially. However, women faculty have not advanced at the expected rate to senior academic ranks or positions of leadership. In 1996, to counter this trend, the U.S. Department of Health and Human Services (DHHS) Office on Women's Health included women's leadership as a required component of the nationally funded Centers of Excellence in Women's Health to identify effective strategies and initiate model programs to advance women faculty in academic medicine. The authors describe the experience of Centers at seven U.S. medical schools in initiating and sustaining leadership programs for women. The processes used for program formation, the current programmatic content, and program evaluation approaches are explained. Areas of success (e.g., obtaining support from the institution's leaders) and difficulties faced in maintaining an established program (such as institutional fiscal constraints and the diminishing time available to women to participate in mentoring and leadership activities) are reviewed. Strategies to overcome these and other difficulties (e.g., prioritize and tightly focus the program with the help of an advisory group) are proposed. The authors conclude by reviewing issues that programs for women in academic medicine will increasingly need to focus on (e.g., development of new kinds of skills; issues of recruitment and retention of faculty; and increasing faculty diversity).

Faculty, Medical↗
PubMed2000

Reproducibility of repeated measures of cholinergic terminal density using.

UNLABELLED: [18F](+)-4-fluorobenzyltrozamicol (FBT), which selectively binds to the vesicular acetylcholine transporter in the presynaptic cholinergic neuron, has previously been shown to be a useful ligand for the study of cholinergic terminal density in the basal ganglia with PET. The goal of this study was to assess the test-retest variability of [18F]FBT and PET measurements under baseline conditions in the basal ganglia. METHODS: After approval from the Animal Care and Use Committee, 6 rhesus monkeys underwent a series of 2 [18F]FBT PET scans (time between scans, 32-301 d) under isoflurane anesthesia. Each scan was initiated on the bolus injection of the radiotracer and consisted of 26 frames acquired during 180 min. Arterial blood samples were collected over the course of each scan to determine the metabolite-corrected arterial input function. Tissue time-activity curves were obtained from the scan data by drawing regions of interest over the basal ganglia and cerebellum. The distribution volume ratio for the basal ganglia was then determined for each scan by taking the ratio of the basal ganglia (specific binding) to cerebellum (nonspecific binding) distribution volume. Distribution volumes were derived using the Logan graphic analysis technique as well as a standard 3-compartment model. Additionally, the radioactivity concentration ratio was calculated as the ratio of the average [18F]FBT concentration in the basal ganglia to that in the cerebellum during the last half of the study (85-170 min). The constant K1, determined using the standard 3-compartment model, was used as an index of blood flow changes between studies. RESULTS: For all subjects, the test-retest variability was less than 15% for the distribution volume ratio and 12% for the radioactivity concentration ratio. Good agreement was found between the distribution volume ratio calculated using the graphic technique and the standard 3-compartment model. Using K1 as an index, the variability in blood flow seen in both the basal ganglia and the cerebellum was significantly reduced in their ratio. CONCLUSION: These results show the reproducibility of [18F]FBT and PET measurements in the basal ganglia.

Animals↗
PubMed2000

The effects of long-term ovariectomy and estrogen replacement therapy on learning and memory in monkeys (Macaca fascicularis).

This study determined the effects of estrogen loss and replacement therapy on learning and memory function in monkeys (Macaca fascicularis). The ability to learn, remember, and perform reversals of object discriminations and the accuracy on a spatial delayed response task were found to be comparable in young adult surgically menopausal monkeys receiving estrogen or placebo treatment for 5 or 16 months. Learning and memory abilities were comparable with baseline values following 2, 12, or 24 months of ovariectomy in monkeys. Pre- and postoperative injections of scopolamine in a subset of monkeys revealed only subtle increases in sensitivity on the delayed response task following ovariectomy. These observations in surgically menopausal monkeys have some parallels with those made in surgically menopausal women and suggest that, in the absence of other confounding factors, certain aspects of learning and memory may not be influenced by estrogen in primates.

Animals↗
PubMed1999

Can puzzle feeders be used as cognitive screening instruments? Differential performance of young and aged female monkeys on a puzzle feeder task.

Conventional cognitive testing of monkeys is time-consuming and involves single-caging and food or water deprivation. Here we report a novel test of global cognitive performance that can be completed in a short time period without food/water or social restrictions. Nine mazes of increasing difficulty were developed using a standard puzzle feeder, and the maze-solving performance of ten young and five aged female cynomolgus monkeys (Macaca fascicularis) was tested. The young monkeys solved maze configurations at higher levels of difficulty and solved the first level of difficulty more quickly than aged monkeys. This task discriminated performance by age in nonhuman primates as do more conventional forms of cognitive testing and indicates that this task may be a quick and easy assessment of global cognitive function.

Animals↗
PubMed1999

The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause.

Menopause is associated with increased neurokinin B (NKB) gene expression and decreased proopiomelanocortin (POMC) gene expression in the human hypothalamus. In the present study, young, ovariectomized cynomolgus monkeys were used in a model of menopause to examine the effects of hormone replacement therapy (HRT) on hypothalamic neuropeptide gene expression. A secondary goal was to determine whether HRT produces signs of estrogen toxicity in the primate hypothalamus by examining POMC neurons and microglial cells. In situ hybridization was performed using synthetic, radiolabeled, 48-base oligonucleotide probes. Alpha-napthyl butyrate esterase histochemistry was used to visualize microglial cells. Both estrogen and estrogen plus progesterone treatments produced a marked suppression of the number of infundibular neurons expressing NKB gene transcripts. In contrast, HRT had no effect on the POMC system of neurons or the number of microglial cells in the infundibular nucleus. These results provide strong support for the hypothesis that the increased NKB gene expression in the hypothalamus of postmenopausal women is secondary to estrogen withdrawal. Conversely, these data suggest that the dramatic decline in the numbers of neurons expressing POMC gene transcripts in older women is caused by factors other than ovarian failure. Finally, we found no evidence that HRT, in doses designed to mimic currently prescribed regimens, produces signs of estrogen toxicity in the primate infundibular nucleus.

Animals↗
PubMed1997

17alpha-Dihydroequilenin increases hippocampal dendritic spine density of ovariectomized rats.

The effects of estradiol and 17alpha-dihydroequilenin on the apical dendrite spine density of pyramidal cells of the CA1 region of rat hippocampus were compared. 17alpha-Dihydroequilenin was as effective as estradiol in increasing spine densities relative to controls. 17alpha-Dihydroequilenin is not uterotrophic like estradiol but does have beneficial effects on the cardiovascular system, suggesting that it may be an effective single-agent hormone replacement therapy to treat menopausal symptoms and reduce chronic disease risk in menopausal women.

Animals↗
PubMed1997

Imaging of cholinergic terminals using the radiotracer [18F](+)-4-fluorobenzyltrozamicol: in vitro binding studies and positron emission tomography studies in nonhuman primates.

The goal of the present set of studies was to characterize the in vitro binding properties and in vivo tissue kinetics for the vesicular acetylcholine transporter (VAcChT) radiotracer, [18F](+)-4-fluorobenzyltrozamicol ([18F](+)-FBT). In vitro binding studies were conducted in order to determine the affinity of the (+)- and (-)-stereoisomers of FBT for the VAcChT as well as sigma (sigma 1 and sigma 2) receptors. (+)-FBT was found to have a high affinity (Ki = 0.22 nM) for the VAcChT and lower affinities for sigma 1 (21.6 nM) and sigma 2 (35.9 nM) receptors, whereas (-)-FBT had similar affinities for the VAcChT and sigma 1 receptors (approximately 20 nM) and a lower affinity for sigma 2 (110 nM) receptors. PET imaging studies were conducted in rhesus monkeys (n = 3) with [18F](+)-FBT. [18F](+)-FBT was found to have a high accumulation and slow rate of washout from the basal ganglia, which is consistent with the labeling of cholinergic interneurons in this brain region. [18F](+)-FBT also displayed reversible binding kinetics during the 3 h time course of PET and produced radiolabeled metabolites that did not cross the blood-brain barrier. The results from the current in vitro and in vivo studies indicate that [18F](+)-FBT is a promising ligand for studying cholinergic terminal density, with PET, via the VAcChT.

Animals↗
PubMed1996

Cognitive functions of the basal forebrain cholinergic system in monkeys: memory or attention?

The cholinergic hypothesis of memory dysfunction originally proposed that dysfunction of cholinergic neurons in the basal forebrain cholinergic system (BFCS) may be responsible for the memory deficits associated with aging and Alzheimer's disease (AD). This hypothesis directed focus on the BFCS in experimental animal models of AD. In contrast to numerous studies in rodents, fewer investigations have been conducted in monkeys with BFCS lesions. The medical septal nucleus/nucleus of the diagonal band of Broca (MS/NDBB) and the nucleus basalis of Meynert (NBM) may be involved in different cognitive functions in monkeys. Although few investigations have specifically addressed the issue of cognitive functions of the MS/NDBB in monkeys, there is some indication that these regions may be important for memory. In contrast, lesions of the NBM do not consistently disrupt mnemonic functions in monkeys. Recent electrophysiological and lesion studies of monkeys indicate that the NBM may play a more important role in attention functions, impairments of which are an early and significant feature of patients with AD.

Animals↗
PubMed1996

Spatial orienting of attention in adult and aged rhesus monkeys.

Aging produces changes in a variety of neural systems that result in a distinct neuropsychological profile of cognitive deficits. To determine the extent of functional decline in cognition with aging, the authors assessed attentional ability in adult (10-15 years old) and aged (28-33 years old) rhesus monkeys (Macaca mulatta) in 3 experiments, using a paradigm adapted from M. I. Posner, J. A. Walker, F. J. Friedrich, and R. D. Rafal (1984), in which a peripheral cue indicates the probable location of a target. Orienting of attention was not disrupted in aged monkeys. Response times of aged monkeys were comparable with adult monkeys' both in the attention task and in a simple reaction time task. These results suggest that the neural systems that subserve spatial orienting of attention remain intact in aged nonhuman primates.

Aging↗
PubMed1994

Labeling of cerebral amyloid in vivo with a monoclonal antibody.

We assessed the ability of a murine monoclonal antibody to bind selectively to beta-amyloid in the brains of living nonhuman primates. To circumvent the blood-brain barrier, we injected unlabeled antibody 10D5 (murine whole IgG1 and/or Fab fragments) into the cerebrospinal fluid of the cisterna magna in three aged monkeys. A control animal was given an intracisternal injection of nonimmune mouse whole IgG plus Fab. Twenty-four hours later, the animals were perfused and prepared for immunohistochemical detection of bound murine immunoglobulin in brain. All three experimental animals showed selective binding of 10D5 to approximately 5-15% of amyloid deposits in cerebral cortex, primarily near the cortical surface. There was no labeling in the control animal. In vivo-labeled deposits were confirmed to be beta-amyloid by electron microscopy and by in vitro immunohistochemistry in adjacent sections. The animals tolerated the injection well, although some polymorphonuclear leukocytes infiltrated portions of the subarachnoid space and superficial neocortex. These results provide the first demonstration that it may be feasible to selectively direct a tagged monoclonal antibody to beta-amyloid in the brain for therapeutic or diagnostic purposes. With enhancement of labeling efficiency, the method also may be useful for studying the progression of beta-amyloidosis in experimental animals using emission tomography.

Amyloid beta-Peptides↗
PubMed1994

Basal forebrain lesions in monkeys disrupt attention but not learning and memory.

Cognitive impairments in humans and animals have been linked to dysfunction of neurons in the basal forebrain cholinergic system (BFCS). Degeneration of these cells may be, in part, responsible for some of the cognitive deficits observed in Alzheimer's disease (AD). Although memory deficits are associated with lesions of the BFCS in rats, impairments in memory have been more subtle following similar lesions in monkeys. To evaluate the effects of BFCS lesions on cognitive processes in monkeys, we have systematically investigated the behavioral effects of ibotenic acid injections in the medial septum, nucleus of the diagonal band of Broca, and nucleus basalis of Meynert in cynomolgus monkeys, using a large series of cognitive tasks that examined different mnemonic and attentional abilities. These lesions did not impair accuracy in delayed nonmatching-to-sample, delayed response, simple or concurrent visual discriminations, spatial discriminations, or discrimination reversals. However, these lesions disrupted attentional focusing. Similar impairments in attention have been noted in patients with AD. BFCS lesions increased sensitivity to injections of the cholinergic antagonist scopolamine in a delayed nonmatching-to-sample task, indicating that the central cholinergic system was compromised in these monkeys. In concert, the results of this study suggest that the primate basal forebrain may be more involved in attentional than mnemonic processes, and that degeneration of neurons in the BFCS in cases of AD may contribute to the attention deficits observed in these individuals.

Animals↗
PubMed1991

Basal forebrain cholinergic system: a functional analysis.

This chapter has been organized empirically, focusing on the types of approaches that have been taken to understand BFCS function. This approach reflects the state of our knowledge about the behavioral and psychological functions of the BFCS. Considerable information has been gathered in the very short time that the BFCS has been the object of intense investigation. The results from the neurotoxic lesions and from the HACU studies provide some points of consistency and some puzzling differences. Both approaches to the study of basal forebrain function suggest that the MSA is involved in tasks that require spatial working memory; MSA lesions impaired choice accuracy, and HACU in the HIP was increased after performance. The pattern of results in simpler tasks is more difficult to interpret. In a left-right reference memory discrimination in a T-maze, MSA lesions did not impair acquisition or performance, whereas HACU in the HIP was activated during performance. This pattern of results suggests that although the MSA is engaged during this type of task, its activity is not necessary for normal performance. These, and other comparisons indicate the need for a systematic analysis of task demand (Olton, 1989b). Parametric manipulations of different task demands in a systematic fashion can indicate the extent to which the BFCS is involved in the function associated with each parametric manipulation. Ultimately, of course, the organization of this material should focus on particular psychological functions, rather than the techniques and procedures used to gather the information. Achieving this goal is going to require careful attention to the design of behavioral experiments so that definitive conclusions can be made about the extent to which the BFCS is involved in a given psychological function. A systematic application of task analysis can achieve this goal (Olton, 1986, 1989a, 1989b). For example, BFCS lesions in rats impair choice accuracy in spatial working memory tasks, and performance in these tasks engages the HACU system, at least in the HIP. If the spatial functions of this task involve the BFCS, then a nonspatial version of the task should produce a different pattern of results. If the spatial nature of the task is unimportant for BFCS function, then a nonspatial version of the task should produce the same results. By systematically changing one characteristic of the task at a time, the contribution of each component can be assessed.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1987

The performance of visual tasks while segments of the inferotemporal cortex are suppressed by cold.

Cold was used to suppress the function of subdivisions of the inferotemporal cortex. Three cryodes were placed bilaterally, one over the lower bank of the superior temporal sulcus (sts), one over the middle temporal gyrus (mtg) and one over the inferior temporal gyrus (itg). The animals were tested with delayed match-to-sample (DMS) and simultaneous visual discriminations. The DMS required the animal to recall a projected image of an object over delays of 0, 15, 30 and 45 s. The 3 cryodes were cooled separately during the performance of the DMS and only itg cooling produced a deficit. This was compared to the effects of ablative bilateral lesions; damage to itg but not mtg disrupted performance of DMS. The greatest deficit was in an animal with a small lesion in the ventral pole and anterior extreme of itg. Cooling individual cryodes was without effect on a discrimination between horizontal and vertical stripes, but produced a significant deficit from each of the 3 placements on a discrimination between monkey faces. Chance performance on all visual discriminations resulted from cooling all cryodes. Unilateral cooling of all cryodes produced significant effects on the face discrimination, but there was no significant difference between the two sides in the severity of the deficit.

Animals↗