The effect of vasopressin on memory processes in Macaca fascicularis]

The role of vasopressin (arginin-vasopressin) in the regulation of conditioned instrumental food-procuring reactions and different kinds of memory such as delayed reflexes, image, short-, and long-time memory was studied in monkeys. Motor and autonomic effects of vasopressin were assessed. It was found that in monkeys, vasopressin administration differently affected the simple conditioned food-procuring reactions and memory. During functional disorders of the higher nervous activity, vasopressin was more efficient in its action on memory and its restoration. Formation of two types of vasopressin effects on the higher nervous activity in evolution of mammals is discussed.     

Comparative Study of Neurochemical Compensation of Disturbed Brain Functions in Mammals

In a comparative row of mammals (hedgehogs, rabbits, monkeys), the role of the opioid neuropeptide Met-encephalin (ME) and the hypothalamic neurohormone vasopressin (VP) was studied in possibility of compensation of disturbed higher nervous functions in organic and functional pathologies of the higher nervous activity. Administration of ME and VP under conditions of destruction of neocortex in hedgehogs was found to restore predominantly congenital forms of the nervous activity. In rabbits, on administration of VP, a tendency is revealed for restoration of acquired forms of the nervous activity; however, it is of a limited character. On administration of ME and VP under conditions of functional pathology a similar regularity in restoration of disturbed higher nervous functions is observed. Injection of ME and VP to hedgehogs produced a more pronounced and longer effect on unconditioned reflexes. The effect of low doses of VP on HNA is of short-term, generally facilitating character. In rabbits, on the background of VP, the memory processes (trace conditioned responses) are briefly restored and are enhanced. In monkeys, the effect of ME and VP on acquired forms of the nervous activity and on various functional systems is of differential character. The VP compensatory effects are more pronounced after administration of low VP doses. The effects of ME and VP on congenital forms of the nervous activity are negligible. The established regularities are discussed and interpreted from the viewpoint of the concepts postulated by A.I. Karamyan about evolution of the compensatory brain activity, evolution of neocortex, and an increase of its neuroplasticity.     

Effect of neurohypophyseal peptides on the formation of a conditioned feeding reflex in the rat

The influence of intraperitoneal injection of vasopressin (LVP), oxytocin (OXY) and their fragments (DGAVP, PLG) on the acquisition and extinction of conditioned food reflex was studied in rats. It was found that vasopressin and its fragments had a more pronounced specific effect on the higher nervous activity of the animals. This effect consisted in impairment of the performance of the conditioned food reflex while oxytocin had a tendency to improve its performance. On the ground of the obtained data it is suggested that administration of vasopressin may facilitate the memory function only under specific environmental conditions.     

Behavioral stereotypy in old and young rhesus monkeys

Four old (25 years) and six young (3 years) female rhesus monkeys (Macaca mulatta) were observed individually in a laboratory cage with either an old or a young monkey present as a social partner. The behavioral repertoire was coded into ten mutually exclusive and exhaustive categories. An information analysis of the individual behavior records is presented along with subject and partner age effects on the frequency of bouts and the amount of time spent in each category of behavior. Knowledge of the relative frequencies of the behaviors tells more about the behavior of young than old monkeys; and knowledge of the preceding behavior tells more about the behavior of old than young monkeys. Further, knowledge of the relative frequencies tells more about the behavior of both old and young monkeys with junior or elder partners than with age peers; whereas knowledge of the preceding behavior is more informative for old monkeys than for young ones regardless of the partner's age. Both old and young engaged in more affiliative behaviors with age peers than with junior or elder partners. An hypothesis is proposed which relates this social homophyly to the age difference in behavioral stereotypy.     

Effect of neurosteroid dehydroepiandrosterone on the higher nervous activity of old non-human primates

The results of studies on the biological effects of the prolonged administration of physiological doses of dehydroepiandrosterone (DHEA) on behavior and state of the higher nervous activity (HNA) in old rhesus macaques that had reached the limit of biological age are presented. HNA was investigated using the procedure of motor-alimentary conditioned reflexes, which allows assessing the long-term (conditioned-reflex) memory in animals. The state of short-term (working) memory was evaluated using the test of delayed response performance. DHEA was administered intramuscularly in peach oil at a dose of 1 mg/kg every two days for three months. DHEA at the doses used improved HNA and balanced the excitatory and inhibitory processes in the brain. The motor activity and alimentary motivation were increased. The woolliness lost was restored in old monkeys under the action of DHEA; this effect persisting for a year.     

Delayed response task performance as a function of age in cynomolgus monkeys (Macaca fascicularis)

We compared delayed response task performance in young, middle-aged, and old cynomolgus monkeys using three memory tests that have been used with non-human primates. Eighteen cynomolgus monkeys—6 young (4–9 years), 6 middle-aged (10–19 years), and 6 old (above 20 years)—were tested. In general, the old monkeys scored significantly worse than did the animals in the two other age groups. Longer delays between stimulus presentation and response increased the performance differences between the old and younger monkeys. The old monkeys in particular showed signs of impaired visuo-spatial memory and deteriorated memory consolidation and executive functioning. These results add to the body of evidence supporting the utility of Macaca fascicularis in studies of cognition and as a potential translational model for age-associated memory impairment/dementia-related disorders.     

Role of Neuropeptides in Brain Asymmetry

A brief review is presented of the literature data on peculiarities of functional asymmetry of brain in animals of different phylogenetic level and asymmetry of the nervous, immune, and endocrine systems. There exposed results of chronic experiments on monkeys to study role of opioid neuropeptide, Met-encephalin (ME), and of hypothalamic neurohormones, vasopressin (VP) and thyroliberin (TL), in functional asymmetry of the monkey brain. The experiments are carried out on model of feeding behavior (complex forms of reactions of choice of side of the reinforcement). It is established that TL, VP, and ME participate in regulation of functions of different brain hemispheres. It is shown that effects of the drugs depend on their dose, initial functional state, and dominance of the particular extremity. It is revealed that administration of ME and neurohormones produces different effects on dominance of the left and right hemispheres. The issue of possible application of neuropeptides in clinics to compensate human motor disturbances after brain ischemia is discussed.     

Compensatory and antiamnestic effects of heptapeptide Selank in monkeys

The work presents results of study of role of heptapeptide Selank—an anxiolytic from group of biologically active peptides—in compensation of disturbed psychic and homeostatic functions in monkeys. New data have been obtained which indicate that an intranasal administration of Selank produces long-term changes of the monkey behavior disturbed during neurosis: elimination of fear and aggression and an increase of explorative activity as well as facilitation of handling reactions and communicational relations. It has been established that on the background of the Selank there occurs a long compensation of disturbed psychic functions (processes of memory) and of homeostatic parameters. It has been shown that unlike the earlier studied neurohormones (thyroliberin and ACTH_4?10), the antistress Selank effects do not depend on the type of neurotic disturbances and have long-term compensatory character. Comparison of the data obtained on monkeys with results of similar studies on the more low-organized mammals (rodents) allow suggesting that the new peptide preparation Selank is a promising agent for correction of various psychoemotional disturbances (alarm-and depression-like disorders).     

Senescence-induced increases in intracellular oxidative stress and enhancement of the need for ascorbic acid in human fibroblasts

Many studies have suggested that there is a close correlation among declines in internal ascorbic acid (AsA) levels, various disorders, and senescence. To clarify the relationships between age-associated changes in intracellular AsA levels and the effects of AsA administration on intracellular reactive oxygen species (ROS) levels, we investigated aging-related changes in AsA uptake, ROS levels, and the effects of AsA administration on intracellular ROS levels in young and old (senescent) human fibroblasts. Our results demonstrated that AsA uptake was increased in old cells compared with young cells, although mRNA and protein expression of sodium-dependent vitamin C transporter 2 was barely altered between the young and old cells. We also demonstrated that the intracellular superoxide anion level was higher in young cells, whereas the level of intracellular peroxides was significantly increased in old cells under both normal and oxidative stress conditions. Moreover, AsA administration markedly decreased the augmentation of intracellular peroxides in old cells, whereas there was no effect of AsA treatment in young cells under both normal and oxidative stress conditions. Therefore, our results also indicate that AsA could play an important role in regulating the intracellular ROS levels in senescent cells and that the need for AsA is enhanced by cellular senescence.     

Neurohypophyseal principles and memory.

The neurohypophyseal hormones vasopressin and oxytocin modulate memory processes. Vasopressin facilitates, while oxytocin attenuates memory consolidation and retrieval. These influences are located in different regions of the molecules. Thus, the neurohypophyseal hormones act as precursor molecules for neuropeptides involved in memory processes. The covalent ring structures of both vasopressin and oxytocin mainly affect consolidation; the linear parts, retrieval processes; while nearly the whole oxytocin or vasotocin molecule is needed for attenuation of consolidation and retrieval. Regional studies, utilizing microdissection techniques in combination with a sensitive radioenzymatic catecholamine assay, revealed a distinct pattern of effects on cerebral alpha-methyl-p-tyrosine methylester-induced catecholamine disappearance following intraventricular vasopressin administration in limbic midbrain structures. In situations in which the amount of bioavailable vasopressin in the brain is absent, as is the case in the Brattleboro rat with hereditary diabetes insipidus, or neutralized in normal Wistar rats following the intraventricular administration of antivasopressin serum, regional catecholamine disappearance in most cases is altered in a direction opposite to that observed after intracerebroventricular vasopressin administration. These results indicate that vasopressin modulates memory processes by modulation of neurotransmission in distinct catecholamine systems. Recent experiments suggest that the influence of vasopressin on memory consolidation is mediated by the dorsal noradrenergic bundle via terminal regions of this bundle.     

Age-related changes in diurnal rhythms and levels of gonadotropins, testosterone, and inhibin B in male rhesus monkeys (Macaca mulatta)

Testosterone shows circadian rhythms in monkeys with low serum levels in the morning hours. The decline relies on a diminished frequency of LH pulses. Inhibin B shows no diurnal patterns. In elderly men, the diurnal rhythm of testosterone is blunted and inhibin levels fall. Here we explore whether aging exerts similar effects in the rhesus monkey. We collected blood samples from groups of young (6-9 yr) and old (12-16 yr) male rhesus monkeys at 20-min intervals for a period of 24 h under remote sampling via a venous catheter. We determined moment-to-moment changes in plasma levels of testosterone, FSH, and LH by RIA, and of inhibin B by ELISA. We found significant diurnal patterns of testosterone in both groups. The circadian rhythm in testosterone was enhanced in older monkeys. Testosterone levels and pulse frequencies dropped significantly below those of young monkeys during midday hours. Diminished pulse frequency of LH appeared to be responsible for the midday testosterone decrease in old monkeys, while LH and testosterone pulse frequency did not change in young monkeys at corresponding time points. Old monkeys showed extended periods of LH-pulse quiescence in the morning and midday hours. Inhibin B and FSH levels were generally lower in old monkeys compared with the young group, but neither inhibin B nor FSH showed circadian rhythms. We conclude from these data that old rhesus monkeys have a more prominent circadian rhythm of LH and testosterone resulting from an extended midday period of quiescence in the hypothalamus-pituitary-gonadal axis.     

Effects of heated hydrotherapy on muscle HSP70 and glucose metabolism in old and young vervet monkeys

Increasing heat shock protein 70 (HSP70) in aged and/or insulin-resistant animal models confers benefits to healthspan and lifespan. Heat application to increase core temperature induces HSPs in metabolically important tissues, and preliminary human and animal data suggest that heated hydrotherapy is an effective method to achieve increased HSPs. However, safety concerns exist, particularly in geriatric medicine where organ and cardiovascular disease commonly will preexist. We evaluated young vervet monkeys compared to old, insulin-resistant vervet monkeys (Chlorocebus aethiops sabaeus) in their core temperatures, glucose tolerance, muscle HSP70 level, and selected safety biomarkers after 10 sessions of hot water immersions administered twice weekly. Hot water immersion robustly induced the heat shock response in muscles. We observed that heat-treated old and young monkeys have significantly higher muscle HSP70 than control monkeys and treatment was without significant adverse effects on organ or cardiovascular health. Heat therapy improved pancreatic responses to glucose challenge and tended to normalize glucose excursions. A trend for worsened blood pressure and glucose values in the control monkeys and improved values in heat-treated monkeys were seen to support further investigation into the safety and efficacy of this intervention for metabolic syndrome or diabetes in young or old persons unable to exercise.     

Phenotypic and Functional Characterization of Lymphocytes from Different Age Groups of Bolivian Squirrel Monkeys (Saimiri boliviensis boliviensis)

Due to many physiological and genetic characteristic similarities to humans, squirrel monkeys provide an ideal animal model specifically for studying malaria, and transmissible spongiform encephalopathies (Creutzfeldt-Jacob disease). While squirrel monkeys three years and older are generally considered adult subjects suitable for use in medical research studies, little is known about the functional properties of lymphocytes in relation to the age of these animals, which could significantly impact the quality and quantity of innate and adaptive immune responses. In this study, we investigated differences in the phenotype and function of lymphocytes subsets of young (3–4 years), adult (8–10 years) and aged (16–19 years) squirrel monkeys. In general, animals in all three age groups exhibited comparable numbers of different lymphocyte subsets except for CD20+ B cells that were significantly lower in aged relative to young animals and T cells subsets expressing both CD4 and CD8 (double positive) were significantly higher in aged relative to young animals. With increasing age, phenotypic differences in central and effector memory T cells subsets were observed, that were more pronounced for the CD8+ T cells. Despite equal proportions of CD3+ T cells among the three age groups, responses of peripheral blood mononuclear cells to T cell mitogens PHA and Con A showed lower IFN-γ producing cells in the aged group than that in the young group. Furthermore, aged animals showed significantly higher plasma levels of inflammatory cytokines IL-6, IFN-γ, TNF-α, IL-10 and IL-12. These findings suggest that while the squirrel monkeys in general share phenotypic and functional similarities of lymphocyte subsets with humans in relation to age, specific differences exist in immune function of lymphocytes between young and old animals that could potentially impact experimental outcomes for which the measurement of immunologic endpoints are critical.     

Influence of age,sex, and dietary restriction on intracellular free calcium responses of CD4+ lymphocytes in rhesus monkeys (Macaca mulatta)

The influence of aging and dietary restriction on increase in intracellular free calcium ([Ca²⁺]_i) of CD4⁺ lymphocytes from Macaca mulatta was examined after stimulation with anti-CD3 mAb. We used a flow cytometric assay with the dye indo-1 and either direct or reciprocal immunofluorescent staining to dientify CD4⁺ cells. After stimulation with anti-CD3 mAb, intracellular free calcium responses were reduced in CD4⁺ lymphocytes from old male and female ad libitum fed monkeys compared to young and adult male or female monkeys. Old female monkeys had significantly lower [Ca²⁺]_i than did old male monkeys. The reduced responses were in part related to a decreased percentage of responding cells. Dietary restrition of males over a four-year period did not alter [Ca²⁺]_i response compared to ad libitum fed male monkeys. Female monkeys of all ages (which were restricted only for four months) also had similar [Ca²⁺]_i responses to ad libitum fed controls. Our data suggest that age-related changes in [Ca²⁺]_i responses are similar between humans and M. mulatta, and that over these intervals, no effects of caloric restrictions can be detected. © 1995 Wiley-Liss, Inc.     

A Potential Role of Central Insulin in Learning and Memory Related to Feeding

1. Hypothalamic insulin (HI) is well known for its role in feeding regulation. In addition, its concentration is modified in response to meals. Recent studies suggest that brain insulin participates in memory processes, possibly through stimulation by glucose.2. The present microdialysis study focused on local in vivo regulation of HI by glucose and on the effects of aging on HI, since aging is characterized by deterioration of memory, body weight regulation, and central glucose utilization. Glucose (8 mM) infused for 5 min increased extracellular HI levels rapidly, by 4.6-fold, and cerebellar insulin levels by 0.4-fold only, suggesting a specific area-dependent regulation of HI by glucose. Neither insulinemia nor glycemia were affected, suggesting a central mechanism. The same dose of glucose induced a modest (0.4-fold), delayed (45 min) increase in hypothalamic serotonin, suggesting that the effect of glucose on HI is independent of a previously defined local serotonin-induced insulin release. HI levels in old normal weight rats were half the levels of young rats. In genetically old obese (fa/fa) Zucker rats, HI concentration was 30% of that in young normal rats, suggesting a deterioration of HI availability when aging and obesity are combined.3. The above results, in line with recent considerations on a potential role of central insulin in learning and memory, suggest particular effects of HI on feeding and memory and probably on a specific memory for food.     

Effect of age on high-fat diet-induced hypertension

Aging and obesity both have a significant impact on central blood pressure (BP) regulation, and previous studies indicated that changes in central redox signaling with age may affect high-fat (HF) diet-induced cardiovascular responses. Therefore, we investigated the effects of 60% HF feeding on BP regulation in young adult (5 mo) and old (26 mo) Fischer-344 × Brown-Norway rats. Radiotelemetric transmitters were implanted to measure BP, heart rate (HR), locomotor activity, and spontaneous baroreflex sensitivity. Expression and activity of NADPH oxidase and ANG II type 1 receptor were assessed in the hypothalamus and in the nucleus tractus solitarii. Old animals gained more weight on HF diet compared with young, whereas central NADPH oxidase expression and activity elevated similarly in the two age groups. After an initial hypotensive and tachycardic response during the first week of HF feeding, BP in young animals increased and became significantly elevated after 6 wk of HF feeding. In contrast, BP in old animals remained depressed. Nighttime HR and locomotor activity decreased in both young and old rats fed with HF diet, but these changes were more significant in young rats. As a result, amplitudes of circadian variation of BP, HR, and activity that were originally higher in young rats declined significantly and became similar in the two age groups. In conclusion, our experiments led to the surprising finding that HF diet has a more serious impact on cardiovascular regulation in young animals compared with old.     

Late onset administration of oral antioxidants prevents age-related loss of motor co-ordination and brain mitochondrial DNA damage

We have studied the effect of aging on brain glutathione redox ratio, on brain mitochondrial DNA damage and on motor co-ordination in mice and the possible protective role of late onset administration of sulphur-containing antioxidants. Glutathione redox ratios change to a more oxidized state in whole brain with aging but the changes are much more pronounced when this ratio is measured in brain mitochondria. The levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine in mitochondrial DNA are much higher in the brain of old animals than in those of young ones. Late onset oral administration of sulphur-containing antioxidants partially prevents oxidation of mitochondrial glutathione and DNA. There is an inverse relationship between age-associated oxidative damage to mitochondrial DNA and motor co-ordination in old mice.     

人工驯养条件下食蟹猴B病毒抗体水平变化规律研究

目的研究人工驯养条件下食蟹猴B病毒抗体水平变化规律,便于有效控制自繁食蟹猴的BV感染率。方法随机选取409只对不同月龄自繁食蟹猴,采用BVELISA法进行BV抗体监测。结果新生仔猴刚出生时均携带不同程度的BV抗体,但随着月龄的增加,BV抗体水平开始下降,至5月龄时BV抗体阳性率降至最低（12．3％）,之后BV抗体水平逐渐升高。结论人工驯养条件下食蟹猴B病毒抗体水平呈由高到低再升高的趋势,5月龄时断奶可最大限度地获得BV抗体阴性猴。     

缺锌对大鼠学习记忆功能及其脑区生长抑素和加压素含量的影响

目的和方法：本实验用避暗法检测缺锌对大鼠学习记忆的影响,并用放免法测定不同脑区生长抑素和加压素含量的变化。结果：缺锌使大鼠学习记忆功能明显降低,同时下丘脑、海马和皮层等脑组织生长抑素和加压素含量明显降低。缺锌后补锌可使大鼠学习记忆功能及其海马中生长抑素和加压素含量恢复到正常状况。结论：缺锌降低大鼠学习记忆功能与锌对脑组织尤其是海马内源性生长抑素和加压素代谢的调节有关。