Expression of type I adenylyl cyclase in intrinsic pathways of the hippocampal formation of the macaque (Macaca nemestrina).

The mossy fiber pathway of the hippocampal formation and type 1 adenylyl cyclase (AC1) have been implicated in long-term potentiation and memory function. Using immunohistochemical labeling and light microscopy we demonstrated intense labeling of AC1 in the mossy fibers and less intense labeling in the molecular layers of both the dentate gyrus and fields CA1, CA2 and CA3 of the hippocampus, i.e. in terminal fields of the perforant pathway. These findings indicate that, in the non-human primate, AC1 is found in the mossy fibers and in terminal fields of the perforant pathway where it may play a role in long term potentiation similar to that demonstrated in the rodent.

Foundational model of neuroanatomy: implications for the Human Brain Project.

In order to meet the need for a controlled terminology in neuroinformatics, we have integrated the extensive terminology of NeuroNames into the Foundational Model of anatomy. We illustrate the application of foundational principles for the establishment of an inheritance hierarchy, which accommodates anatomical attributes of neuroanatomical concepts and provides the foundation to which other information may be linked.

Cardiovascular responses in anticipation of changes in posture and locomotion.

Measurements were made in 29 adult baboons that were housed in social groups, allowing the occurrence of the full range of species-specific behavioral interactions. The cardiovascular variables measured included blood pressure, heart rate, renal blood flow, lower limb blood flow, and occasionally mesenteric blood flow. The data were telemetered from backpacks worn by the animals and were recorded in analogue form on a polygraph, digitally on a computer and were also recorded on the audio channels of videotape being made of the behavior and social interactions of the baboons. The video and the computer recordings were synchronized by a timing system that made it possible to relate the cardiovascular responses to the behavioral responses. A numerically based behavioral code was developed that allowed the categorization of the totality of the behavior, including postural and locomotor changes. Comparisons between baseline cardiovascular values and those occurring 1 s before the initiation of a movement or posture change gave no evidence of anticipatory cardiovascular responses unless the movement was associated with behavior that included emotional content. Hypothalamic perifornical lesions reduced or eliminated these anticipatory changes.

Behavior, appetite, and urinary cortisol responses by adult female pigtailed macaques to cage size, cage level, room change, and ketamine sedation.

Pigtailed macaques (Macaca nemestrina) and longtailed macaques (M. fascicularis) show behavioral, ecological, and possible temperament differences, and their responses to the laboratory environment might therefore be quite different. We tested pigtailed macaques under the same conditions that were investigated in a previous study with longtailed macaques, using the same comprehensive set of physiological and behavioral measures of stress. First, eight adult females' adaptation to a new room in regulation-size cages was monitored, and in the third week their responses to ketamine sedation were measured. Then they spent two weeks singly housed in each of four cage sizes (USDA regulation size, one size larger, one size smaller, and a very small cage). Half of the subjects were in upper-level cages and the remainder in lower-level cages for the entire study. Cage size, ranging from 20% to 148% of USDA regulation floor area, was not significantly related to abnormal behavior, self-grooming, manipulating the environment, eating/drinking, activity cycle, cortisol excretion, or biscuit consumption. Locomotion and frequency of behavior change were significantly reduced in the smallest cage, but did not differ in cage sizes ranging from 77% to 148% of regulation size. The only manipulation to produce an unequivocal stress response, as measured by cortisol elevation and appetite suppression, was ketamine sedation. Room change and cage changes were associated with minimal cortisol elevation and appetite suppression. Wild-born females showed more appetite suppression after room change than captive-born females. No differences were related to cage level. Pigtailed macaques strongly resembled longtailed macaques except they showed weaker responses to the new room and cage change, probably because the pigtails had spent more time in captivity. These findings support the conclusion that increasing cage size to the next regulation size category would not have measurable positive effects on the psychological well-being of two species of laboratory macaques.

Differences in stress reactivity of laboratory macaques measured by heart period and respiratory sinus arrhythmia.

Some laboratory primates are more likely than others to react to anxiety-provoking stressors. Individuals that overreact to stressors may experience diminished psychological well-being and would be inappropriate for some experiments. The differences between reactive and nonreactive individuals may be reflected in heart period and respiratory sinus arrhythmia (RSA). Using surface electrodes and radio telemetry, we measured these two cardiac variables in seven male and ten female singly caged longtailed macaques (Macaca fascicularis) when they were exposed to two stressors, a sudden noise (whistle test) and an unfamiliar technician wearing capture gloves (glove test). Behavior was videotaped during both tests. For the whistle test, cardiac data were recorded before, during, and after two 1 minute whistle blasts separated by 90 min. For the glove test, data were recorded in 1 minute blocks every 8 minutes over 96 minutes before, during, and after 1 minute exposure to the gloved technician. Heart period was decreased and RSA was suppressed during both the whistle and glove exposures. After the whistle test, the cardiac activity of most subjects returned to baseline levels within 10 minutes. The glove test produced more extended suppression, with greater individual differences, than the whistle test. There were greater individual differences in RSA than in heart period. These enhanced individual differences were used to define stress reactors that differed from nonreactors in their cardiac data profiles. Of 16 subjects that completed the glove test, five were identified as reactors.

Circulating antioxidants as determinants of the rate of biological aging in pigtailed macaques (Macaca nemestrina).

The effect of antioxidant activity on the rate of biological aging was studied in 39 pigtailed macaques (Macaca nemestrina) 7-30 years of age. Scores of seven antioxidant compounds (vitamins C and E, carotenoids, urate, bilirubin, ceruloplasmin, and albumin) were combined to produce an antioxidant variable (AOx) that was tested for correlation with a second composite variable, rate of biological aging (RBA). RBA was formed from seven physiological variables that met a stringent set of criteria as biomarkers of aging. Potential effects of disease on RBA and AOx were excluded by experimental design and by statistical control using a composite index of disease (Dis) that was based on four measures of clinical history and pathology. The study produced three salient findings: (1) there was a significant inverse relation between AOx and RBA (i.e., animals that had high AOx scores had low RBA scores and vice versa); (2) the relation was independent of Dis effects, and (3) there was no significant relation between AOx and Dis independent of RBA (i.e., the correlation between AOx and Dis was dependent on the correlation of AOx with RBA). These results further validated the RBA variable as a measure of the rate of biological aging and supported the concept that antioxidant activity influences both the rate of biological aging and vulnerability to disease.

A stereotaxic template atlas of the macaque brain for digital imaging and quantitative neuroanatomy.

A stereotaxic brain atlas of the longtailed macaque (Macaca fascicularis) is presented in a format suitable for use as a template atlas of the macaque brain. It includes most of the brain segmented to show the boundaries of landmark structures such that every point in the brain can be represented by a unique set of coordinates in three-dimensional space and ascribed unambiguously to one and only one primary structure. More than 400 structures are represented, including 360 volumetric structures, which constitute the substance of the brain, and 50 superficial features. To facilitate use with ventriculography, magnetic resonance imaging, and other noninvasive imaging techniques, the stereotaxic space is referenced to internal landmarks, viz., the anterior commissure and posterior commissure; the center of the anterior commissure at the midline is the origin of the stereotaxic axes. Reference of stereotaxis to this bicommissural space facilitates structural comparison with human brain atlases, which are commonly referenced to the biocommissural line. It also facilitates comparison of brains of different nonhuman primate species by providing a template brain against which to compare size and internal variability. Thirty-three coronal sections at 1-mm intervals from the spinomedullary junction to the rostral extreme of the caudate nucleus show most structures of the hindbrain, midbrain, and subcortical forebrain. Separately, four side views and 16 coronal sections show cortical structures. Structures are represented by outlines of their boundaries and labeled according to NeuroNames, a systematic English nomenclature of human and nonhuman primate neuroanatomy. Abbreviations are based on a protocol designed to facilitate cross-species comparisons. Instructions are provided for: (1) locating sites from the Template Atlas in the conventional stereotaxic space of an experimental animal, (2) locating sites identified by conventional stereotaxis in the Template Atlas, and (3) using the Template Atlas to collate, compare, and display image information (e.g., labeled cells, recording sites, stimulation sites, lesions) from multiple animals.

Application of a novel fiber-optic biosensor in situ to investigate the metabolic effect of lactate infusion.

Recently developed biosensor technology, which allows near real-time measurement in situ of gas tension (pCO2 and pO2) and of pH, was applied to arterial blood, cerebrospinal fluid (CSF), and brain parenchyma during intravenous lactate infusion in monkeys. Comparison of simultaneous biosensor measurements and discrete arterial blood sampling for traditional blood gas analyses indicated a high level of correlation for pCO2, pO2, and pH. Arterial pO2 and pH values were significantly higher and pCO2 significantly lower than corresponding CSF and brain parenchyma values at baseline, during and following lactate infusion. There was a divergence between arterial and brain parenchyma pH and pO2 measurements. Lactate infusion was associated with progressive arterial pH rises, consistent with the production of a metabolic alkalosis. Cerebrospinal fluid pCO2 remained unchanged during and following lactate infusion. Brain parenchyma exhibited a complex pattern of response characterized by a trend for pO2 and pH to decrease during lactate infusion, which reversed following completion of the infusion. These observations are suggestive of a transient hypoxia from decreased cerebral blood flow and/or reduced oxyhemoglobin dissociation during lactate infusion, but verification of these results is required.

NeuroNames Brain Hierarchy.

The NeuroNames Brain Hierarchy is a structured system of neuroanatomical terminology that provides a comprehensive representation of virtually all human and nonhuman primate brain structures that are identifiable either grossly or in Niss1-stained histological sections. This system was devised for computer applications to address deficiencies in the brain terminology presented in Nomina Anatomica. English terms are listed for 783 structures in nine levels of hierarchical ranking. Abbreviations are provided for all superficial and primary volumetric structures. The substructures that constitute the total volume of every superstructure are identified. Superficial features of the brain are clearly distinguished from internal, volumetric brain structures. Structures found solely in either humans or macaques are identified. The purpose of the NeuroNames Brain Hierarchy is to bring greater standardization to the neuroanatomical terminology used by scientific investigators, clinicians, and students. This effort is consistent with the goals of the Unified Medical Language System program of the National Library of Medicine. It is hoped that the systematic construction of the NeuroNames Brain Hierarchy will facilitate use of the most widely accepted definitions of classical neuroanatomy in quantitative computerized neuroimaging applications. It should provide an accurate structural framework against which to reference the many other kinds of neuroanatomical information that are acquired by modern imaging, mapping, and histological labeling techniques.

Immunologic markers in a longitudinal study of aging in pigtailed macaques (Macaca nemestrina).

Blood lymphocyte subsets, serum immunoglobulins (Ig), response of lymphocytes to mitogens, and natural killer (NK) cell activity were evaluated as potential biomarkers for primate aging. All were evaluated in a cross-sectional study of 60 pigtailed macaques (Macaca nemestrina) ranging from 2 to 32 years of age. Lymphocyte responses to mitogens were lower in older animals than in most younger ones. NK cell activity showed no clear relation to age cohort. In a longitudinal study of lymphocyte subsets and immunoglobulins, class I restricted T cells (CD8+bri) of the memory (CD18+bri) subtype increased with age, whereas those of the naive (CD18+dull) subtype decreased with age in females. A class II restricted T-cell subset (CD4+CD45RA-), which includes memory T cells, increased with age in females. Serum IgA increased. These results support the utility of memory and naive subsets of CD8+ T cells, CD4+ T cells, and serum IgA as biomarkers for longitudinal studies. Total lymphocytes, total T cells, CD4+ T cells, and CD8+ T cells may also be useful in this species.

Integrating behavior and cardiovascular responses: posture and locomotion. I. Static analysis.

Heart rate, arterial blood pressure, and renal and mesenteric or femoral blood flow were telemetered from 11 Papio hamadryas in an untethered free-ranging situation. The animals' behavior was recorded on videotape, and the cardiovascular (CV) data were recorded on the audio channels of the tape. The behavior was coded, and the codes were linked to the CV data via a time-code generator and computer control. The CV data were digitized into 1-s intervals, and the static relations between CV measures and the postures/locomotions (P/Ls) associated with the behavior were analyzed. The total frequency distributions for heart rate, blood pressure, and renal conductance approximated Gaussian distributions, whereas femoral conductance was positively skewed. The distribution for renal conductance suggested that during normal waking conditions the kidney is not maximally dilated and may increase or decrease its blood flow. All distributions were highly influenced by the Sit category, which occupied 80% of the total time. The CV measures for all P/Ls had wide ranges, and the CV values associated with each P/L overlapped those for the other P/Ls. The heart rate and renal conductance associated with the various P/Ls showed the largest deviations from the grand means and therefore contributed the most to the ability to discriminate one P/L from another. Blood pressure varied little from one P/L to another. The patterns of CV variables served to distinguish particular P/Ls very effectively. The frequency distributions were separated best when they were parceled on the basis of the intensity of behavior associated with a particular P/L. These variations in intensity were the major cause of the overlaps in the frequency distributions associated with P/Ls.

A system to acquire and record physiological and behavioral data remotely from nonhuman primates.

We describe an integrated system to record physiological and behavioral variables from nonhuman primates in social groups. The system records data simultaneously from two animals in family groups of five. It synchronizes behavioral and physiological data within 16 ms, either on-line or from recordings. Behavioral data are entered by trained observers on-line or from videotape. Recordings of physiological data are produced on-line as stripchart records, tape recordings on the audio channels of video cassettes, and magnetic disk files. The physiological data include two arterial blood flows, arterial blood pressure and heart rate. The data are transmitted from freely behaving animals to a central site via radio telemetry. The infrared link controls the radio transmitter and physiological signal processing electronics, as well as two sources of drugs for each animal. All of the electronics are contained in a small, light backpack that can be worn by either male or female baboons.

Integrating behavior and cardiovascular responses: the code.

The next revolution in biology is predicted to be in the integrative domain, and the need to involve physiologists in this kind of research has been recognized. This paper represents an approach to providing some of the tools required for dealing with integrative physiology at the behavioral level. Video tape recordings are made of the activities of a group of five baboons (Papio hamadryas) while simultaneous recordings of arterial blood pressure, heart rate, renal blood flow, and mesenteric or iliac blood flow are telemetered from two of the members of the group. The telemetered cardiovascular information is recorded on the two audio channels of the videotape. Subsequently the videotape is viewed, and a two-dimensional code is used to record the behavior of the two animals with the telemetry equipment. The first dimension of the code categorizes the behavior changes precisely regarding those aspects of behavior that are related to cardiovascular dynamics and does so with an accuracy of 16 ms. The second dimension codes relevant environmental changes. The paper describes the code and presents illustrations of how the code reflects the cardiovascular dynamics associated with the behavioral changes.

Neuroanatomic and neurochemical abnormalities in nonhuman primate infants exposed to weekly doses of ethanol during gestation.

Ethanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5, 3.3 or 4.1 gm/kg from the 5th week. Mean maternal peak plasma ethanol concentrations (MPPEC's) ranged from 24 +/- 6 mg/dl at the 0.3 g/kg dose to 549 +/- 71 mg/dl at the 4.1 g/kg dose. Thirty-three live born infants were assessed for abnormalities of physical and behavioral development. Ocular pathology, neuropathologic and neurochemical assessements were done on 31 animals at 6 months postnatal age. Microphthalmia was noted in three of the 26 animals exposed to ethanol. Retinal ganglion cell loss was significantly associated with intra-uterine ethanol exposure. Microphthalmia and retinal ganglion cell loss was observed in both the delayed and full-gestational exposed animals. No structural anomalies were found in the brains via gross inspection or light microscopy. Chemical abnormalities in the striatal nuclei were identified. Striatal dopamine concentrations increased with increasing MPPEC exposure (0-249 mg/dl) among animals exposed weekly to ethanol throughout gestation. Striatal dopamine concentrations decreased with increasing MPPEC exposure (260-540 mg/dl) among animals whose weekly exposure to ethanol was delayed until the 5th week of gestation. The same pattern of association was also noted between MPPEC and ultrastructural alterations in the caudate nucleus. The extent of ultrastructural alterations increased with increasing MPPEC among the full-gestational exposed animals and decreased with increasing MPPEC among the delayed-dose animals.

Constructing an instrument to measure the rate of aging in female pigtailed macaques (Macaca nemestrina).

To develop a battery of innocuous tests measuring individual differences in the rate of biological aging, longitudinal data were gathered on 28 biochemical, physiological, and morphological characteristics of 40 adult female pigtailed macaques. The change in each variable over time, i.e., the beta coefficient of linear regression, was calculated for each animal, and a matrix of correlations among the variables was constructed. Eight variables correlated well with the first principal component of the matrix. These variables (rate of fingernail growth, blood lymphocytes, mean corpuscular hemoglobin, immunoglobulin A, and serum sodium, chloride, total protein, and creatinine) represented the best subset of the potential biomarkers analyzed to produce an index covering a range of morphologic and functional systems that change with age. A similar set representing a wider range of systems and measured over a larger fraction of the life span should provide a valid index of an individual's rate of biological aging.