Afferent projections to the rat nuclei raphe magnus, raphe pallidus and reticularis gigantocellularis pars alpha demonstrated by iontophoretic application of choleratoxin (subunit b).

The aim of the present study was to identify the specific afferent projections to the rostral and caudal nucleus raphe magnus, the gigantocellular reticular nucleus pars alpha and the rostral nucleus raphe pallidus. For this purpose, small iontophoretic injections of the sensitive retrograde tracer choleratoxin (subunit b) were made in each of these structures. In agreement with previous retrograde studies, after all injection sites, a substantial to large number of labeled neurons were observed in the dorsal hypothalamic area and dorsolateral and ventrolateral parts of the periaqueductal gray, and a small to moderate number were found in the lateral preoptic area, bed nucleus of the stria terminalis, paraventricular hypothalamic nucleus, central nucleus of the amygdala, lateral hypothalamic area, parafascicular area, parabrachial nuclei, subcoeruleus area and parvocellular reticular nucleus. In addition, depending on the nucleus injected, we observed a variable number of retrogradely labeled cells in other regions. After injections in the rostral nucleus raphe magnus, a large number of labeled cells were seen in the prelimbic, infralimbic, medial and lateral precentral cortices and the dorsal part of the periaqueductal gray. In contrast, after injections in the other nuclei, fewer cells were localized in these structures. Following raphe pallidus injections, a substantial to large number of labeled cells were observed in the medial preoptic area, median preoptic nucleus, ventromedial part of the periaqueductal gray, Kölliker-Fuse and lateral paragigantocellular reticular nuclei. Following injections in the other areas, a small to moderate number of cells appeared. After gigantocellular reticular pars alpha injections, a very large and substantial number of labeled neurons were found in the deep mesencephalic reticular formation and oral pontine reticular nucleus, respectively. After the other injections, fewer cells were seen. Following rostral raphe magnus or raphe pallidus injections, a substantial number of labeled cells were observed in the insular and perirhinal cortices. Following caudal raphe magnus or gigantocellular reticular pars alpha injections, fewer cells were found. After raphe magnus or gigantocellular reticular pars alpha injections, a moderate to substantial number of cells were localized in the fields of Forel, lateral habenular nucleus and ventral caudal pontine reticular nucleus. Following raphe pallidus injections, only a small number of cells were seen. Our data indicate that the rostral and caudal parts of the nucleus raphe magnus, the gigantocellular reticular nucleus pars alpha and the nucleus raphe pallidus receive afferents of comparable strength from a large number of structures. In addition, a number of other afferents give rise to stronger inputs to one or two of the four nuclei studied. Such differential inputs might be directed to populations of neurons with different physiological roles previously recorded specifically in these nuclei.

Forebrain projections of the rostral nucleus raphe magnus shown by iontophoretic application of choleratoxin b in rats.

The nucleus raphe magnus belongs to the thermoafferent system. Following iontophoretic choleratoxin b injections in its rostral part, a substantial to large number of anterogradely labeled varicose fibres were observed in the medial and lateral preoptic areas, the bed nucleus, the substantia innominata, the ventral pallidum, the median preoptic nucleus, the paraventricular hypothalamic nucleus, the central amygdaloid nucleus and the lateral and dorsal hypothalamic areas. A small to moderate number were seen in the septal nuclei, the diagonal band, the magnocellular preoptic nucleus, the anterior hypothalamic area and the paraventricular and intralaminar thalamic nuclei. After choleratoxin b injections in the preoptic, dorsal and lateral hypothalamic areas, a substantial number of retrogradely labeled serotonin immunonegative neurones were specifically found in the rostral nucleus raphe magnus. Thus, non-serotonergic rostral nucleus raphe magnus cells might directly modulate hypothalamic thermointegrative neurones.

[Ontogenesis of affect regulation]. / Ontogenese der Affektregulation.

The psychophysiological basis of biological rhythms in human adults and infants is discussed in the present paper. The significance of the influence of hormones on central nervous functions is demonstrated by neurophysiological and psychobiological evidence. Moreover, complex interactions among humoral, immune and central nervous systems referring to biological rhythms, are described.

[Ontogenesis of sleep-wakefulness regulation]. / Ontogenese der Schlaf-Wach-Regulation.

In addition to traditional opinions endogenous sleep factors play an important role in modern concepts concerning sleep-wake regulation. The recent development of neurochemical research including experiments with neuropeptides has modified the classical theories of sleeping and waking. Moreover, the influence of hormones as cortisol or prolactin on neurotransmitters involved in sleep-wake regulation, special problems of the endogenous sleep-rhythms, and the conditions of the ontogenetic development are discussed. In addition, a new concept, the so-called Stimulation theory is described.

[Chronic heat stress modulates the immune system in the preclinical phase of murine lupus erythematosus]. / Chronischer thermischer Stress moduliert das Immunsystem in der präklinischen Phase des murinen Lupus erythematodes.

Repetitive thermal stress induces a reduction in the characteristic Thy1.2+B220+ lymphocyte subpopulation in lupus mice which were studied before the onset of disease. The immunomodulating effect was systemic, and alterations were not related to corticosterone serum levels.

Changes in cold- and heat-defence following electrolytic lesions of raphe nuclei in the guinea-pig.

In conscious guinea-pigs the effects of electrolytic lesions of the nucleus raphe magnus (NRM) and of adjacent areas in the lower brainstem on cold- and heat-defence were studied. Changes in core temperature, heat production and heat loss effectors as well as their threshold temperatures were compared in the same animals before and after lesioning. As an additional index of heat loss, ear skin temperature and a derived parameter--vasomotor index--were also measured. Three days after NRM lesion the fall in core temperature evoked by an exposure to 14-15 degrees C was smaller than before lesion, furthermore the body temperature threshold for shivering increased. Cold-induced heat production was also higher following NRM lesions. Lesions outside the NRM or sham-operation did not influence cold-defence. After NRM lesion heat-defence was also improved; the rise in core temperature elicited by an exposure to 36-37 degrees C was smaller and the body temperature threshold for ear skin vasoconstriction during recovery from hyperthermia decreased. No change in respiratory evaporative heat loss could be observed after NRM lesion. Lesions outside the NRM or sham-operation did not influence heat-defence. An attempt has been made to explain the observed improvements in cold- and heat-defence by discussing relevant data on mechanisms in central temperature control.

Influence of cold and warm acclimation on neuronal responses in the lower brain stem.

Neurons in two lower brain stem areas, the nucleus raphe magnus and the subcoeruleus region, have been shown to be part of the thermoafferent system. It is concluded from microcut experiments in unanaesthetized guinea pigs that inhibition of shivering caused by nucleus raphe magnus stimulation is mediated partly by ascending and partly by descending efferents of the nucleus raphe magnus. Electrical stimulation of the subcoeruleus area caused excitatory metabolic responses. Interruption of the ascending efferents of the subcoeruleus area did not prevent the metabolic activation. It is concluded that the excitatory responses are partly mediated by descending efferents of the subcoeruleus area. The descending pathways project mainly to motoneurone pools and to dorsal horn cells. In cold-acclimated guinea pigs, the average maximum activity of bell-shaped subcoeruleus cold-responsive units was reduced significantly in comparison with cold-responsive neurons in animals acclimated to normal room temperature. Furthermore, peak activity of warm-responsive units in the nucleus raphe magnus was larger in cold-acclimated animals than in animals acclimated to normal room temperature. These neuronal changes may contribute via descending lower loops and via ascending upper loops to long-term slope reduction of metabolic cold defence and shivering threshold displacements.

Central short-term cold adaptation in the guinea-pig.

The responses of seventeen single units to changes in skin temperature were recorded in fifteen guinea-pigs anaesthetized with urethane. All units were located in the subcoeruleus region which has been discussed as part of the thermoafferent system. Thermal stimuli were applied to different skin areas. The receptive fields of sixteen cold-responsive units were found to be parts of the abdominal and thoracic skin. The cold-responsive units could be subdivided into two groups. Ten units showed the known classic cold-responsive steady state response. A short-term thermal adaptation was seen in six units. These units had peak activities at skin temperatures between 22 degrees C and 29 degrees C and decreased their firing rates within 5 to 40 minutes when the temperature of the receptive skin area was kept constant in the range between 20 degrees C and 29 degrees C. This short-term cold-adaptive effect could be reversibly abolished by warming the corresponding skin area for a certain period of time. The short-term adapting neurones could be conceived of as the neurophysiological correlate to cold-adaptive changes in thermogenic responses seen in three guinea-pigs. Oxygen uptake and shivering activity were reduced in animals, which had reached approximately constant skin and core body temperature during sustained external cooling.

Central thermal adaptation of lower brain stem units in the guinea-pig.

Cold adaptive changes were found in single units responding to thermal skin stimulation. All units were located in the subcoeruleus region of the lower brain stem. In cold-adapted guinea-pigs (five weeks in ambient temperature of 4 degrees C), the maximum activity of cold-responsive neurones was reduced markedly in comparison with that of cold-responsive neurones in animals adapted to room temperature (ca. 21 degrees C). This decrease may be a neuronal correlate to long-term downward shifts of shivering threshold temperature known to occur within adaptation periods of several weeks in man, as well as in animals.

Responses of pontine units to skin-temperature changes in the guinea-pig.

1. The responses of fifty-five single units to changes in skin temperature were recorded in twenty-three guinea-pigs anaesthetized with urethane. Skin-temperature changes were induced by changing the temperature of the water-perfused support plate of the stereotaxic apparatus and that of the double-walled Perspex jacket that was put on the support plate.2. Thirty-three units were stereotaxically and histologically verified as being within a circumscribed area of the pontine dorsomedial reticular formation (subcoeruleus region). Twenty-one units were located in the surrounding areas, and one unit in the nucleus raphé magnus region.3. Twenty-seven of thirty-three recorded subcoeruleus units were specifically excited by cooling of the abdominal or leg skin, whereas only five units were non-thermoresponsive and one unit was warm-responsive. The cold-responsive units had peak activity at skin temperatures between 22 and 29 degrees C, in accordance with the maximum activity in cutaneous cold-receptors.4. A markedly different distribution of units was found in the surrounding areas. Only four units were cold-responsive. Thirteen units were non-thermoresponsive, and four units were warm-responsive.5. The cold-responsive subcoeruleus units were situated in regions which are known to contain accumulations of noradrenergic cell bodies, and to project to hypothalamic neurones. Electrical stimulation of these regions is known to cause excitatory metabolic responses in unanaesthetized guinea-pigs. It is concluded that part of the cutaneous cold-afferents projects to hypothalamic thermointegrative neurones via noradrenergic pathways that ascend from these subcoeruleus regions.

Thermoregulatory noradrenergic and serotonergic pathways to hypothalamic units.

1. In guinea-pigs hypothalamic single units were extracellularly tested for their response to thermal stimulation of the skin and to electrical stimulation of two different pontine areas, the nucleus raphé magnus and the dorsomedial reticular formation. Furthermore, thermoregulatory control actions were measured during the stimulations.2. Electrical stimulation of those reticular formation areas containing noradrenaline cells caused an increase of oxygen uptake, electrical muscle activity and body temperature, while stimulation of the nucleus raphé magnus, known to contain serotonin cells, brought about inhibition or had no effect.3. The recorded units could be subdivided into three groups. Cell type a. Neurones on the boundary of preoptic and anterior hypothalamic regions which increased their firing rate when the skin was cooled and decreased it when the nucleus raphé magnus was stimulated. Cell type b. Neurones in the anterior hypothalamus which did not respond to brain-stem stimulation. Cell type c. More posterior neurones which increased their firing rate when the skin was warmed or when the nucleus raphé magnus was stimulated and decreased their firing rate when the reticular formation was stimulated.4. Cell type a seems to represent interneurones which are connected to the ascending serotonergic thermoregulatory pathway. As for cell type c, it is inferred that it could represent interneurones which control the threshold for shivering and non-shivering thermogenesis.