Functional magnetic resonance signal changes in neural structures to baroreceptor reflex activation.

The sequence of neural responses to exogenous arterial pressure manipulation remains unclear, especially for extramedullary sites. We used functional magnetic resonance imaging procedures to visualize neural responses during pressor (phenylephrine) and depressor (sodium nitroprusside) challenges in seven isoflurane-anesthetized adult cats. Depressor challenges produced signal-intensity declines in multiple cardiovascular-related sites in the medulla, including the nucleus tractus solitarius, and caudal and rostral ventrolateral medulla. Signal decreases also emerged in the cerebellar vermis, inferior olive, dorsolateral pons, and right insula. Rostral sites, such as the amygdala and hypothalamus, increased signal intensity as arterial pressure declined. In contrast, arterial pressure elevation elicited smaller signal increases in medullary regions, the dorsolateral pons, and the right insula and signal declines in regions of the hypothalamus, with no change in deep cerebellar areas. Responses to both pressor and depressor challenges were typically lateralized. In a subset of animals, barodenervation resulted in rises and falls of blood pressure that were comparable to these resulting from the pharmacological challenges but different regional neural responses, indicating that the regional signal intensity responses did not derive from global perfusion effects but from baroreceptor mediation of central mechanisms. The findings demonstrate widespread lateralized distribution of neural sites responsive to blood pressure manipulation. The distribution and time course of neural responses follow patterns associated with early and late compensatory reactions.     

Neural responses during Valsalva maneuvers in obstructive sleep apnea syndrome.

The repetitive upper airway muscle atonic episodes and cardiovascular sequelae of obstructive sleep apnea (OSA) suggest dysfunction of specific neural sites that integrate afferent airway signals with autonomic and somatic outflow. We determined neural responses to the Valsalva maneuver by using functional magnetic resonance imaging. Images were collected during a baseline and three Valsalva maneuvers in 8 drug-free OSA patients and 15 controls. Multiple cortical, midbrain, pontine, and medullary regions in both groups showed intensity changes correlated to airway pressure. In OSA subjects, the left inferior parietal cortex, superior temporal gyrus, posterior insular cortex, cerebellar cortex, fastigial nucleus, and hippocampus showed attenuated signal changes compared with controls. Enhanced responses emerged in the left lateral precentral gyrus, left anterior cingulate, and superior frontal cortex of OSA patients. The anterior cingulate, cerebellar cortex, and posterior insula exhibited altered response timing patterns between control and OSA subjects. The response patterns in OSA subjects suggest deficits in particular neural pathways that normally mediate the Valsalva maneuver and compensatory actions in other structures.     

Taurine in the developing cat: Uptake and release in different brain areas

Taurine is an important modulator of neuronal activity in the immature brain. In kittens, taurine deficiency causes serious dysfunction in the cerebellar and cerebral visual cortex. The processes of taurine transport in vitro were now studied for the first time in different brain areas in developing and adult cats. The uptake of taurine consisted initially of two saturable components, high- and low-affinity, in synaptosomal preparations from the developing cerebral cortex and cerebellum, but the high-affinity uptake component completely disappeared during maturation. The release of both endogenous and preloaded labeled taurine from brain slices measured in a superfusion system was severalfold stimulated with a slow onset by depolarizing K⁺ (50 mM) concentrations. K⁺ stimulation released markedly more taurine from the cerebral cortex, cerebellum and brain stem in kittens than in adult cats. The responses were largest in the cerebellum. Both uptake and release of taurine are thus highly efficient in the brain of kittens and may be of significance in view of the vulnerability of cats to taurine deficiency.     

Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show deficient respiratory and cardiac responses to hypoxia and hypercapnia, despite apparently intact arousal responses to hypercapnia and adequate respiratory motor mechanisms, thus providing a model to evaluate functioning of particular brain mechanisms underlying breathing. We used functional magnetic resonance imaging to assess blood oxygen level-dependent signals, corrected for global signal changes, and evaluated them with cluster and volume-of-interest procedures, during a baseline and 2-min hypoxic (15% O(2), 85% N(2)) challenge in 14 CCHS and 14 age- and gender-matched control subjects. Hypoxia elicited significant (P < 0.05) differences in magnitude and timing of responses between groups in cerebellar cortex and deep nuclei, posterior thalamic structures, limbic areas (including the insula, amygdala, ventral anterior thalamus, and right hippocampus), dorsal and ventral midbrain, caudate, claustrum, and putamen. Deficient responses to hypoxia included no, or late, changes in CCHS patients with declining signals in control subjects, a falling signal in CCHS patients with no change in controls, or absent early transient responses in CCHS. Hypoxia resulted in signal declines but no group differences in hypothalamic and dorsal medullary areas, the latter being a target for PHOX2B, mutations of which occur in the syndrome. The findings extend previously identified posterior thalamic, midbrain, and cerebellar roles for normal mediation of hypoxia found in animal fetal and adult preparations and suggest significant participation of limbic structures in responding to hypoxic challenges, which likely include cardiovascular and air-hunger components. Failing structures in CCHS include areas additional to those associated with PHOX2B expression and chemoreceptor sites.     

fMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects.

Obstructive sleep apnea (OSA) patients exhibit altered sympathetic outflow, which may reveal mechanisms underlying the syndrome. We used functional MRI (fMRI) in 16 control and 10 OSA subjects who were free of cardiovascular or mood-altering drugs to examine neural responses to a forehead cold pressor challenge, which elicits respiratory slowing, bradycardia, and enhanced sympathetic outflow. The magnitude of cold-induced bradycardia was smaller, and respiratory slowing showed greater intersubject variability and reached a nadir later in OSA patients. Both groups showed similar signal changes to cold stimulation in multiple brain sites. However, signal increases emerged in OSA over controls in anterior and posterior cingulate and cerebellar and frontal cortex, whereas signals markedly declined in the ventral thalamus, hippocampus, and insula rather than rising as in controls. Anomalous responses often paralleled changes in breathing and heart rate. Medullary, midbrain areas and lentiform and cerebellar dentate nuclei also showed lower signals in OSA cases. Cold pressor physiological responses are modified in OSA and may result from both diminished and exaggerated responses in multiple brain structures.     

Ontogenesis of the asymmetry of transcallosal responses in the cat parietal cortex

In acute experiments on 2-24 days old immobilized kittens and adult cats, studies have been made on the development of functional interhemispheric asymmetry of homotopical transcallosal responses in the parietal cortex. It was found that the number of animals with evident asymmetry increases with age. Alongside, with respect to such characters as asymmetry coefficient, mean amplitude of components of transcallosal components and the ratio of zones of direct and inverse domination, the increase in functional interhemispheric asymmetry was observed during the second week of postnatal life of kittens, which was accompanied by the inversion of its sign; in adult cats, the decrease in the asymmetry up to its complete absence was found. The data obtained are discussed with respect to peculiarities of the development and functional properties of the associative parietal cortex in cats.     

fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.     

Neural responses to intravenous serotonin revealed by functional magnetic resonance imaging.

We examined the sequence of neural responses to the hypotension, bradycardia, and apnea evoked by intravenous administration of 5-hydroxytryptamine (serotonin). Functional magnetic resonance imaging signal changes were assessed in nine isoflurane-anesthetized cats during baseline and after a bolus intravenous low dose (10 microg/kg) or high dose (20-30 microg/kg) of 5-hydroxytryptamine. In all cats, high-dose challenges elicited rapid-onset, transient signal declines in the intermediate portion of the solitary tract nucleus, caudal midline and caudal and rostral ventrolateral medulla, and fastigial nucleus of the cerebellum. Slightly delayed phasic declines appeared in the dentate and interpositus nuclei and dorsolateral pons. Late-developing responses also emerged in the solitary tract nucleus, parapyramidal region, periaqueductal gray, spinal trigeminal nucleus, inferior olivary nucleus, cerebellar vermis, and fastigial nucleus. Amygdala and hypothalamic sites showed delayed and prolonged signal increases. Intravenous serotonin infusion recruits cerebellar, amygdala, and hypothalamic sites in addition to classic brain stem cardiopulmonary areas and exhibits site-specific temporal patterns.     

Comparative analysis of the interactions between spontaneous active neurons of the sensomotor cortex of kittens and adult cats

The character of functional interneuronal relations in the sensorimotor cortex during spontaneous neural activity in kitten and adult cats immobilized with d-tubocurarine, was studied by the method of cross-correlations of two impulse series. The data obtained by computation revealed specific age-related interneuronal connections in investigated groups of animals. In kitten aged up to 10 days, the highest percentage of the functional connections was observed which were established mainly due to the influence of a common source. In other groups of animals (kittens of 20, 30 days of postnatal life, adult cats) the common source did not play a significant role in the formation of interneuronal connections. The results showed that inhibitory connections between neurones-are established to the end of the first month of the postnatal life.     

Posttetanic changes in the afferent and efferent activity of monosynaptic reflex in kittens

Both the afferent volleys from the dorsal root and the monosynaptic reflex discharges from the corresponding ventral root were recorded with hook electrodes during stimulation of the nerves innervating the triceps surae muscles. The effects of conditioning high frequency tetanus on the magnitudes of these afferents and reflex volleys were examined in kittens of postnatal age 1-90 days and in adult cats. In young kittens under barbiturate anaesthesia, large-amplitude monosynaptic reflex discharge can be evoked without prior conditioning. The amplitude of this reflex discharge decreased with increasing age of the animal. Application of conditioning tetanic stimuli to the muscle nerves resulted in posttetanic depression followed by posttetanic potentiation of the monosynaptic reflex. The magnitude of posttetanic depression was much higher than that of potentiation in the first postnatal week. As the age increased, the magnitude of depression decreased while the magnitude of potentiation increased. The afferent volley showed a considerable posttetanic potentiation in older kittens and cats. No significant potentiation or depression was observed in the younger animals. Possible mechanisms contributing to posttetanic depression and potentiation are discussed.     

Sleep states alter ventral medullary surface responses to blood pressure challenges

Ventral medullary surface (VMS) activity declines during rapid eye movement (REM) sleep, suggesting a potential for reduced VMS responsiveness to blood pressure challenges during that state. We measured VMS neural activity, assessed as changes in reflected 660-nm wavelength light, during pressor and depressor challenges within sleep/waking states in five adult, unrestrained, unanesthetized cats and in two control cats. Phenylephrine elevated blood pressure and elicited an initial VMS activity decline and a subsequent rise in VMS activity in all states, although the initial decline during quiet sleep occurred only in rostral placements. Phasic REM periods elicited a momentary recovery from the evoked activity rise, and arousals diminished the overall elevation in activity. A sodium nitroprusside depressor challenge increased VMS activity more in REM sleep than in quiet sleep, with the increase being even less in waking. Enhanced responses to depressor challenges during REM sleep suggest a loss of dampening of evoked activity during that state; state-related differential baroreflex sensitivity may result from sleep-waking changes in VMS responses to blood pressure challenges.     

MLR-induced inhibition of barosensory cells in the NTS

A central motor command arising from the mesencephalic locomotor region (MLR) is widely believed to be one of the neural mechanisms that reset the baroreceptor reflex upward during exercise. The nucleus tractus solitarius (NTS), a dorsal medullary site that receives input from baroreceptors, may be the site where central command inhibits baroreceptor input during exercise. We, therefore, examined the effect of electrical stimulation of the MLR on the impulse activity of cells in the NTS in decerebrate paralyzed cats. Of 129 NTS cells tested for baroreceptor input by injection of phenylephrine (7-25 microg/kg iv) or inflation of a balloon in the carotid sinus, 58 were stimulated and 19 were inhibited. MLR stimulation (80-150 microA) inhibited the discharge of 48 of the 58 cells stimulated by baroreceptor input. MLR stimulation had no effect on the discharge of the remaining 10 cells, each of which displayed no spontaneous activity. In contrast to the 77 NTS cells responsive to baroreceptor input, there was no change in activity of 52 cells when arterial pressure was increased by phenylephrine injection or balloon inflation. MLR stimulation activated each of the 52 NTS cells. For 23 of the cells, the onset latency to MLR stimulation was clearly discernable, averaging 6.4 +/- 0.4 ms. Our findings provide electrophysiological evidence for the hypothesis that the MLR inhibits the baroreceptor reflex by activating NTS interneurons unresponsive to baroreceptor input. In turn, these interneurons may release an inhibitory neurotransmitter onto NTS cells receiving baroreceptor input.     

猫小脑皮质GABA能神经元年龄相关性变化

为探讨青年猫和老年猫小脑皮质GABA能神经元及其表达的年龄相关性变化,利用Nissl染色显示小脑皮质结构及神经元,免疫组织化学ABC法标记GABA免疫阳性神经元。光镜下观察,采集图像,并利用图像分析软件对分子层、蒲肯野细胞层和颗粒层神经元及GABA免疫阳性神经元及其灰度值进行分析统计。结果显示,GABA免疫阳性神经元、阳性纤维及终末在青年猫和老年猫小脑皮质各层均有分布。与青年猫相比,老年猫分子层、蒲肯野细胞层神经元和GABA免疫阳性神经元密度及其GABA免疫阳性反应强度均显著下降(P<0.01),颗粒层神经元密度和GABA免疫阳性强度也显著下降(P<0.01),但其GABA免疫阳性神经元密度无显著变化(P>0.05);蒲肯野细胞的胞体萎缩,阳性树突分枝减少。因此认为,衰老过程中猫小脑皮质GABA能神经元的丢失和GABA表达的下降,可能是老年个体运动协调、精确调速和运动学习等能力下降的重要原因之一。     

Sympathetic regulation of adrenal medullary function during aging

Our recent studies on changes in sympathoadrenal medullary function with age in anesthetized Wistar rats were reviewed. Although secretion rates of adrenaline and noradrenaline from the adrenal gland under resting conditions varied among animals, they gradually increased after 300 days and reached a level 2-4 times higher at 800-900 days compared with that of 100 days. Spontaneous activity of a single sympathetic nerve fiber under resting conditions also increased during aging in a manner similar to the catecholamine secretion rates. Reflex responses of mass activity of adrenal sympathetic nerve fibers to stimulation of baroreceptor and cutaneous mechanoreceptors were compared in young adult (4 months old) and aged (26 months old) Wistar rats under strictly controlled conditions for anesthesia, respiration and body temperature. Under these conditions the reflex depression in response to baroreceptor stimulation and cutaneous brushing as well as reflex excitation in response to cutaneous pinching were quite well maintained in the aged rats.     

The electrophysiological properties of the conduction pathways of the stellate ganglion in the cat in postnatal ontogeny]

In new-born, 10-, and 20-day-old kittens and in adult cats, the stellate ganglia branches contained both continuous and synaptically interrupted fibres. In the course of postnatal ontogenesis, the average conduction velocity of excitation and average amplitude of the responses increased. In new-born and 10-day old kittens, these are C-fibres. Apart from the latter, A delta and B fibres appeared in 20-day old kittens. In adult cats, two subgroups of all types of the fibres appeared. Since the 10-day age, synaptically interrupted responses have been recorded in anastomoses and inferior cardiac nerve following stimulation of cranial and caudal branches of the subclavian loop, the responses being conducted in both directions in adult cats.     

幼猫单眼视剥夺和反缝过程中显示的双眼竞争机制

本研究以光栅为刺激所同时产生的图形视觉诱发电位和图形视网膜电图为指标,测定了单眼视剥夺和缝的新生幼猫个体在发育不同阶段的空间频率调谐曲线,并与同龃正常猫,成年正常猫进行了比较研究。结果显示,在０．１２－１．５ｃ／ｄ空间频率范围内,正常幼猫单独刺激其左眼和右眼所驱动的Ｐ－ＶＥＰ振幅相近,但都明显地比双眼驱动的为小。在单眼剥夺的幼猫,由剥夺眼所驱动的Ｐ－ＶＥＰ振幅大幅度下降,健康眼所驱动的Ｐ－ＶＥＰ则     

Age-related changes of structures in cerebellar cortex of cat

We studied the structures of the cerebellar cortex of young adult and old cats for age-related changes, which were statistically analysed. Nissl staining was used to visualize the cortical neurons. The immunohistochemical method was used to display glial fibrillary acidic protein (GFAP)-immunoreactive (IR) astrocytes and neurofilament-immunoreactive (NF-IR) neurons. Under the microscope, the thickness of the cerebellar cortex was measured; and the density of neurons in all the layers as well as that of GFAP-IR cells in the granular layer was analysed. Compared with young adult cats, the thickness of the molecular layer and total cerebellar cortex was significantly decreased in old cats, and that of the granular layer increased. The density of neurons in each layer was significantly lower in old cats than in young adult ones. Astrocytes in old cats were significantly denser than in young adult ones, and accompanied by evident hypertrophy of the cell bodies and enhanced immunoreaction of GFAP substance. Purkinje cells (PCs) in old cats showed much fewer NF-IR dendrites than those in young adults. The above findings indicate a loss of neurons and decrease in the number of dendrites of the PCs in the aged cerebellar cortex, which might underlie the functional decline of afferent efficacy and information integration in the senescent cerebellum. An age-dependent enhancement of activity of the astrocytes may exert a protective effect on neurons in the aged cerebellum     

Postnatal development of respiratory and vocal responses during aversive classical conditioning in cats

Respiratory rate, respiration amplitude, and vocal responses were recorded in cats of different ages during classic conditioning. Vocal responses to the conditional stimulus (CS) appeared first in 8-week-old kittens, and became prominent at older ages. An increase in respiration rate occurred after the onset of the CS in cats of all ages. Similarly, the decrease of respiration amplitude was observed at all ages, but only in 8-week-old and older subjects did this response resemble an adult pattern. In 4-week-old kittens the response was characterized by an early and brief peak, suggesting an alpha conditional response (CR). Clear and significant discrimination between a warning and a safety signal was present in both respiratory and vocal responses after the age of 8 weeks.     

Representation of Early Sensory Experience in the Adult Auditory Midbrain: Implications for Vocal Learning

Vocal learning in songbirds and humans occurs by imitation of adult vocalizations. In both groups, vocal learning includes a perceptual phase during which juveniles birds and infants memorize adult vocalizations. Despite intensive research, the neural mechanisms supporting this auditory memory are still poorly understood. The present functional MRI study demonstrates that in adult zebra finches, the right auditory midbrain nucleus responds selectively to the copied vocalizations. The selective signal is distinct from selectivity for the bird''s own song and does not simply reflect acoustic differences between the stimuli. Furthermore, the amplitude of the selective signal is positively correlated with the strength of vocal learning, measured by the amount of song that experimental birds copied from the adult model. These results indicate that early sensory experience can generate a long-lasting memory trace in the auditory midbrain of songbirds that may support song learning.     

Studies of functional connectivity in the developing and mature visual cortex

We have investigated several aspects of cortical organization in adult cats and in young kittens. First, we determined receptive field (RF) maps of correlated discharge between pairs of cortical cells. Unique bicellular RFs appear to convey high resolution information. Second, we studied the dynamics of neural interaction between pairs of cells. Using cross-correlation analysis, we studied monosynaptic and polysynaptic interactions in both kittens and cats. A somewhat surprising finding is that there were no cases of monosynaptic excitation from simple to complex cells as would be predicted by a simple hierarchical processing theory. Third, we studied length and side tuning characteristics of cortical cells and worked out the relationships between them. Fourth, we carried out an investigation of binocular processing in which we compared monocular and binocular sensitivity of cortical cells with respect to contrast. Our results are comparable to those found in psychophysical work. Fifth, we examined how stereoscopic depth information is encoded by simple cells in the visual cortex. We show that structural differences in RFs of left and right eyes may be expressed in terms of phase. Phase-based encoding appears to be a very plausible alternative to the standard position-based notion. Sixth, we attempted to induce plastic changes in connections between cell pairs by long-term activation (up to 2 h) in kittens and cats. Although connection strength between some cell pairs was increased during long-term activation, there was no consistent pattern of this effect. Seventh, we attempted to study the functional basis of reported claims of RF expansion following use of an artificial scotoma. However, we found no receptive field size change from this procedure. For some cells, there is an apparent change of gain in the form of base (spontaneous) rates and absolute response levels. Finally, we have examined RF dynamics in the central visual pathways. The standard treatment of RFs is to consider only spatial aspects. But the RF is inherently both temporal and spatial in nature and we have examined the dynamics of spatiotemporal organization of RFs in central visual pathways.