Response of cerebral blood flow to changes in PCO2 in fetal, newborn, and adult sheep

Developmental effects on the response of cerebral blood flow (Qc) and cerebral O2 consumption (CMRO2) to changes in CO2 tension were assessed in unanesthetized fetal, newborn, and adult sheep. Blood flow was measured using the radioactive microsphere technique. CMRO2 was calculated as the product of Qc and the difference in O2 content between arterial and sagittal sinus blood (CaO2 -- CVO2). The response of Qc to changes in arterial CO2 tension increased from fetus [3.53 +/- 0.56 ml.100 g-1.min-1.mmHg PaCO2(-1) (SE)] to newborn (5.16 +/- 0.59) to adult (6.20 +/- 0.63). Only the fetal-adult difference was significant (P less than 0.05). It has been suggested that developmental differences in CO2 responsiveness of cerebral blood flow are the result of differences in CMRO2. We corrected for differences in CMRO2 by looking at the response to CO2 of the variable 1/(CaO2--CVO2). According to the Fick principle 1/(CaO2--CVO2) = Qc/CMRO2, i.e., blood flow per unit O2 consumption. The fetal response was not significantly different from the newborn, but the adult was significantly different from both (P less than 0.05). Thus the difference in CO2 response of cerebral blood flow between fetus and adult cannot be explained by differences in CMRO2.     

Short periods of prenatal stress affect growth, behaviour and hypothalamo–pituitary–adrenal axis activity in male guinea pig offspring

Prenatal stress can have profound long-term influences on physiological function throughout the course of life. We hypothesized that focused periods of moderate prenatal stress at discrete time points in late gestation have differential effects on hypothalamo–pituitary–adrenal (HPA) axis function in adult guinea pig offspring, and that changes in HPA axis function will be associated with modification of anxiety-related behaviour. Pregnant guinea pigs were exposed to a strobe light for 2 h on gestational days (GD) 50, 51, 52 (PS50) or 60, 61, 62 (PS60) (gestation length ∼70 days). A control group was left undisturbed throughout pregnancy. Behaviour was assessed in male offspring on postnatal day (PND)25 and PND70 by measurement of ambulatory activity and thigmotaxis (wall-seeking behaviour) in a novel open field environment. Subsequent to behavioural testing, male offspring were cannulated (PND75) to evaluate basal and activated HPA axis function. Body weight was significantly decreased in adult PS50 and PS60 offspring and this effect was apparent soon after weaning. The brain-to-body-weight ratio was significantly increased in adult PS50 males. Basal plasma cortisol levels were elevated in PS50 male offspring throughout the 24 h sampling period compared with controls. In response to an ACTH challenge and to exposure to an acute stressor, PS60 male offspring exhibited elevated plasma cortisol responses. Plasma testosterone concentrations were strikingly decreased in PS50 offspring. Thigmotaxis in the novel environment was increased in PS50 male offspring at PND25 and PND70, suggesting increased anxiety in these animals. In conclusion, prenatal stress during critical windows of neuroendocrine development programs growth, HPA axis function, and stress-related behaviour in adult male guinea pig offspring. Further, the nature of the effect is dependant on the timing of the maternal stress during pregnancy.     

光照后胎儿脐动脉与脑动脉血流变化

为了证实胎儿对经母腹壁光照可产生应答反应，我们通过彩色多谱勒超声诊断仪观察了30名妊娠34-41周孕妇的胎儿，光照前后脐动脉、脑动脉血流变化。结果显示：光照后胎儿脐动脉及脑动脉血流量增加，经统计学处理有高显著性差异（P＜0．001），而动脉血流阻抗指数（RI）无差异性改变（P＞0．05）。说明血液流量增力。是由动脉压升高引起，而光照刺激使胎儿产生视觉，引起胎儿植物性神经功能的情绪反应，使交感神经系统活动相对亢进，是动脉压升高的原因。光照后胎儿脐动脉、脑动脉平均血流速度增加亦有高显著性差异（P＜0．001），而动脉血流速度指数（S／O）无差异性改变（P＞0．05）。说明本组胎儿的循环状态良好，光照后胎儿出现血液动力学上的明显变化，正是胎儿对光照产生的应答反应。这一研究成果为光照胎教方法提供了科学的依据。     

Subjective insomnia symptoms and sleep duration are not related to hypothalamic–pituitary–adrenal axis activity in older adults

Insomnia symptoms are highly prevalent in depressed older adults. This study investigates the association between hypothalamic–pituitary–adrenal (HPA) axis activity and symptoms of insomnia, respectively, sleep duration among 294 depressed and 123 non‐depressed older adults of the Netherlands Study of Depression in Older people (NESDO) study. Insomnia symptoms were defined as clinically relevant when having a score ≥ 10 points on the Women's Health Initiative Insomnia Rating Scale (WHIIRS). Sleep duration was categorized in short (≤ 6 h per night), normal (7–8 h per night) and long (≥ 9 h per night) duration. Salivary cortisol levels were used to assess the following cortisol parameters for HPA axis activity: area under the curve with respect to the increase (AUCi) and to the ground (AUCg), diurnal slope, evening cortisol level and dexamethasone suppression ratio. Clinically relevant insomnia symptoms were present in 46% of the participants. Thirty‐two per cent of the participants were short sleepers, whereas 16% were long sleepers. However, univariate analyses showed no differences in any of the HPA axis parameters between people with and without insomnia symptoms or between the three groups with different sleep duration. In addition, no significant interaction was found between a diagnosis of depression or the severity of depressive symptoms and any of the cortisol parameters in relation to insomnia symptoms or sleep duration.     

Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition

Observational studies suggest that estrogen replacement therapy (ERT) may protect against age-related memory decline and lower the risk of Alzheimer's disease (AD). This study aimed to characterize the neural substrates of those effects by comparing 2-year longitudinal changes in regional cerebral blood flow (rCBF) in 12 ERT users and 16 nonusers. Positron emission tomography (PET) measurements of rCBF were obtained under three conditions: rest, and verbal and figural recognition memory tasks. Groups showed different patterns of change in rCBF over time in a number of brain areas. These group differences, for the most part, reflected regions of increased rCBF over time in users compared to nonusers. The greatest differences between ERT users and nonusers were in the hippocampus, parahippocampal gyrus, and temporal lobe, regions that form a memory circuit and that are sensitive to preclinical AD. Across a battery of standardized neuropsychological tests of memory, users obtained higher scores than did nonusers of comparable intellect. Group differences in longitudinal change in rCBF patterns may reflect one way through which hormones modulate brain activity and contribute to enhanced memory performance among ERT users.     

Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland

Although the fetal pineal gland does not secrete melatonin, the fetus is exposed to melatonin of maternal origin. In the non-human primate fetus, melatonin acts as a trophic hormone for the adrenal gland, stimulating growth while restraining cortisol production. This latter physiological activity led us to hypothesize that melatonin may influence some fetal functions critical for neonatal adaptation to extrauterine life. To test this hypothesis we explored (i) the presence of G-protein-coupled melatonin binding sites and (ii) the direct modulatory effects of melatonin on noradrenaline (norepinephrine)-induced middle cerebral artery (MCA) contraction, brown adipose tissue (BAT) lypolysis and ACTH-induced adrenal cortisol production in fetal sheep. We found that melatonin directly inhibits the response to noradrenaline in the MCA and BAT, and also inhibits the response to ACTH in the adrenal gland. Melatonin inhibition was reversed by the melatonin antagonist luzindole only in the fetal adrenal. MCA, BAT and adrenal tissue displayed specific high-affinity melatonin binding sites coupled to G-protein ( K _d values: MCA 64 ± 1 p m , BAT 98.44 ± 2.12 p m and adrenal 4.123 ± 3.22 p m ). Melatonin binding was displaced by luzindole only in the adrenal gland, supporting the idea that action in the MCA and BAT is mediated by different melatonin receptors. These direct inhibitory responses to melatonin support a role for melatonin in fetal physiology, which we propose prevents major contraction of cerebral vessels, restrains cortisol release and restricts BAT lypolysis during fetal life.     

Sympathetic effects on cerebral and ocular blood flow in rabbits pretreated with indomethacin

The effects of unilateral stimulation of the cervical sympathetic chain on cerebral and ocular blood flow was investigated in 8 rabbits anesthetized with pentobarbital sodium and pretreated with indomethacin in order to inhibit the formation of prostaglandins. Blood flow determinations were made with the labelled microsphere method during normotension and acute arterial hypertension. Hypertension was induced by ligation of the thoracic aorta. Evans blue was given as a tracer for protein leakage during hypertension. Sympathetic stimulation had no significant effect on the blood flow in the brain under the two conditions studied. In the uvea marked effects of sympathetic stimulation were obtained at normotension as well as at hypertension. There were no indications of breakdown of the blood-brain barrier or the blood-aqueous barrier. Thus, there was no evidence for any prostaglandin-mediated inhibition of sympathetic effects in the brain or the eye.     

Early effects of cervical sympathetic stimulation on cerebral,ocular and cochlear blood flow

Autoregulatory mechanisms may be expected to modify effects of vasomotor nerve stimulation in many tissues. Attempts were made to reveal a distinct early, but transient effect of cervical sympathetic stimulation on cerebral, retinal and cochlear blood flow. The labelled microsphere method was used to determine regional blood flow during electrical stimulation of the cervical sympathetic chain for 15–25 s and 5 min. At a frequency of 6 Hz there was a 5% reduction in cerebral flow at 15–25 s and 7% at 5 min. In the choroid plexus the mean reduction was 22% at 15–25 s but decreased to 10% after 5 min. In the cerebellum, optic nerve and retina, sympathetic stimulation had no appreciable effect on the blood flow. In the cochlea and iris, the blood flow reductions were 25 and 32%, respectively, on both occasions. In the choroid, vasoconstriction increased with time, whereas in the masseter muscle there was a decrease. Thus in the present experiments no indication was found of an autoregulatory escape phenomenon in the brain, the eye or the cochlea. Some escape was noted in the masseter muscle.     

Measurement of cerebral blood flow in the fetal lamb with a note on the flow-distribution.

The cerebral blood flow was measured in the acutely exteriorized fetal lamb by 133Xenon washout and microsphere distribution techniques. The measurements were performed at different blood gas levels. Regional cerebral blood flow was calculated from the microsphere distribution for five different parts of the brain. This gave estimates for blood flow in both the grey and white matter of the hemispheres, which were in close agreement with the cerebral blood flow estimated by the 133Xe washout technique. The microsphere distribution shows that the fetal cerebral hemisphere has a low blood flow compared to the basel parts of the brain and that this difference is increased during hypoxia and hypercarbia.     

An on-line system for acquisition and processing of cerebral blood flow data

Regional cerebral blood flow is measured by monitoring the clearance from the brain of the gamma emitting radioisotope ¹³³Xe following an intracarotid artery bolus injection. On-line data analysis, which is performed on a PDP $\text{12}\text{30}$ digital computer, involves exponential stripping to isolate grey and white matter flows and integration of the clearance curves to infinity to enable the mean flow to be calculated. The data is displayed in real time and stored on the PDP 12 Linc tapes as a permanent record.     

Parity effects on maternal behaviour are not related to circulating oestradiol concentrations in two breeds of sheep

Primiparous females of many species, including the sheep, do not show as competent maternal behaviour as multiparous mothers. In this study we investigated whether circulating concentrations of oestradiol might be related to this response, since breed differences in oestradiol concentrations have been shown to correlate with maternal behaviours. Oestradiol concentrations were measured in plasma collected at 2-weekly intervals from primiparous and multiparous ewes of two breeds (Scottish Blackface and Suffolk) throughout gestation, and maternal behaviour was recorded at parturition. Circulating oestradiol concentrations, and the ratio of oestradiol to progesterone concentration (O:P ratio) were higher in late pregnancy in Blackface ewes, but there were no significant effects of ewe parity. However, there was a significant interaction between breed and parity as O:P ratio was lower in primiparous Suffolk ewes compared to multiparous. This relationship was not seen in Blackface ewes. Blackface ewes of both parities groomed their lambs more frequently and made more low-pitched vocalisations than Suffolk ewes. Primiparous ewes were more likely to move as the lamb attempted to suck, and to show withdrawal or aggression towards the lamb. Primiparous Suffolk ewes also made more high pitched bleats than other classes of ewe. The data support previous studies which show an effect of breed on circulating oestradiol and O:P ratio but suggest that parity effects on maternal behaviour may be mediated by sensitivity to circulating concentration of oestradiol rather than variations in the plasma concentrations of this hormone.     

Role of the adrenal cortex in maturation of the lymphoid system and immunological competence; the effects of aminoglutethimide in suckling mice

Newborn rats and mice have rudimentary peripheral lymphoid tissues and are immunologically incompetent. The lymphoid system matures late in the third week after birth, shortly before weaning. The adrenal cortex also is relatively inactive neonatally and begins to secrete glucocorticoids in a mature fashion two weeks after birth. These experiments were designed to test the hypothesis that adrenal glucocorticoids induce maturation of the lymphoid system and immunological competence during the third postnatal week. Mice 10–12 days old were injected daily for 4–11 days with aminoglutethimide, an inhibitor of steroid biosynthesis. The adrenal glands and lymphoid tissues were prepared for histological examination 24 hours after the last injection and evaluated without knowledge of the treatment received. Aminoglutethimide caused adrenal dysplasia with a frequency proportional to dose. Effective doses also inhibited growth, and slightly larger doses were fatal. Therefore it was concluded that large doses of aminoglutethimide caused adrenal insufficiency, but the completeness of this insufficiency in surviving animals was not ascertained. Three phases in postnatal maturation of the lymphoid system were identified by examination of untreated littermate controls and reference to previous work. During the first week after birth, the thymus-dependent lymphoid tissues grow by immigration of thymus-derived cells that soon have the capacity for cell-mediated immunity. During the second postnatal week, a new population of wandering lymphoid cells, presumptively derived from bone marrow, settles in lymphoid organs in response to antigenic stimulation, to form primary lymphoid nodules and a few plasma cells. Late in the third week after birth the machinery for humoral antibody synthesis matures with the appearance of germinal centers and numerous plasma cells, coincident with a great increase in production of immunoglobulin. This third phase of maturation was retarded in mice injected with near-fatal doses of aminoglutethimide. Because these mice suffered neither involution of lymphoid tissue nor suppression of proliferation in thymus or thymus-dependent lymphoid-tissue, it was concluded that the effects of aminoglutethimide upon the development of germinal centers and plasma cells were selective and specific. Therefore these experiments support the hypothesis that glucocorticoid secretion plays a decisive role in maturation of immunological competence during the third week after birth in mice. This role appears to be the potentiation of cellular proliferation and differentiation of B cells in response to antigens, culminating in antibody synthesis. Maturation of adrenal glucocorticoid synthesis has also been implicated in the initiation of physiological involution of the thymus and cessation of intestinal absorption of antibodies during the third postnatal week in rats and mice.     

Effect of neurotropin on regional cerebral blood flow and systemic blood pressure

Experiments on rabbits show that neurotropin has no effect on regional cerebral flow and systemic blood pressure under normal conditions, but reduces regional cerebral flow in partial circulatory hypoxia (ischemia) and recirculation. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 6, pp. 612–614, June, 1998     

大鼠脑缺血及再灌流对脑组织血流量、ATP和乳酸水平含量的影响

目的和方法：本研究采用大鼠可逆性阻塞大脑中动脉所致的局灶性脑缺血再灌流模型，观察缺血３ｈ再灌流３ｈ、缺血６ｈ再灌流３ｈ对脑组织脑局部血流量（ｒｅｇｉｏｎａｌｃｅｒｅｂｒａｌｂｌｏｏｄｆｌｏｗ，ｒＣＢＦ）、ＡＴＰ、乳酸及脑水含量的影响。结果：缺血３ｈｒＣＢＦ明显下降（Ｐ＜００１），再灌流３ｈ升至缺血前６５３％（Ｐ＜００１）。缺血３ｈ再灌流３ｈ与缺血６ｈ组比较，ＡＴＰ明显恢复（Ｐ＜００１），乳酸含量明显下降（Ｐ＜００１），脑水含量明显减少（Ｐ＜００５）。缺血６ｈ再灌流３ｈ与缺血９ｈ组比较，尽管ＡＴＰ明显恢复（Ｐ＜００１），乳酸含量下降（Ｐ＜００１），但脑水含量无显著差异（Ｐ＞０１）。结论：缺血３ｈ再灌流３ｈ保护“半暗带”的效果优于缺血６ｈ再灌流３ｈ。