Activation and degeneration during aging: a morphometric study of the human hypothalamus

During the course of aging both activation and degenerative changes are found in the human hypothalamus. Degeneration may start around middle-age in some neurotransmitter- or neuromodulator-containing neurons. For instance, a decreased number of vasoactive intestinal polypeptide (VIP) neurons was observed in the suprachiasmatic nucleus (SCN) of middle-aged males. The normal circadian fluctuations seen in the number of vasopressin (AVP) neurons in the SCN of young subjects diminished in subjects older than 50 years. Moreover, a sharp decline in cell number was found in the sexually dimorphic nucleus (SDN) after 50 years in males. On the other hand, many hypothalamic systems remain perfectly intact during aging like the oxytocin (OXT) neurons in the paraventricular nucleus (PVN). The AVP neurons in the PVN are activated during aging as appears from their increasing cell number. Also the corticotrophin-releasing hormone (CRH) neurons of the PVN are activated in the course of aging, as indicated by their increased number and their increased AVP coexpression. Part of the infundibular nucleus, the subventricular nucleus, contains hypertrophic neurokinin B neurons in postmenopausal women. It can be concluded that a multitude of changes in the various hypothalamic nuclei may be the biological basis for many functional changes in aging, i.e., both endocrine and central alterations, and that only a minority of the possible human hypothalamic changes have so far been studied.     

Severe loss of vasopressin-immunoreactive cells in the suprachiasmatic nucleus of aging voles coincides with reduced circadian organization of running wheel activity

Aging leads to a decrease in circadian organization of behavior. Whether this general observation is related to the finding that in older subjects the arginine-vasopressin (AVP) system in the suprachiasmatic nucleus (SCN) has deteriorated is an unsolved question. Here we assessed circadian organization of running wheel behavior and numbers of AVP cells in the SCN of old voles (n=12, 11. 5 months of age) and compared the results with data from young voles (n=16, 4.5 months of age). A third of the young voles, but three-quarter of the old voles lost circadian rhythmicity. Analysis of daily onset to onset periodicity of running wheel activity at the age of 5 and 10 months in individual voles revealed a significant loss of precision of circadian rhythmicity at the higher age. The number of AVP cells in the SCN of old voles decreased substantially, over 78% compared to young voles in general. AVP cell numbers, however, cannot be directly correlated with the state of rhythmicity in old voles; in one of the three circadian rhythmic old voles the SCN contained the least AVP cells. This study does not support the idea of a causal relationship between aging induced reduction in AVP cells in the SCN and the presence of circadian rhythmicity in behavior.     

Decrease of medullary catecholaminergic neurons in multiple system atrophy and Parkinson's disease and their preservation in amyotrophic lateral sclerosis

We investigated the number of tyrosine hydroxylase (TH)-immunoreactive neurons in the C1 and A2 regions of the medulla, the sites of the baroreflex arc, in 7 patients with multiple system atrophy (MSA), 8 with Parkinson's disease (PD), 9 with amyotrophic lateral sclerosis (ALS), and 12 age-matched normal subjects to analyze the relationship between cardiovascular dysfunction and medullary catecholaminergic neurons. Orthostatic hypotension (OH) was marked in all the MSA patients and moderate in three PD patients. Three of the five ALS patients who had been on respirators showed lability of blood pressure; paroxysmal hypertension and nocturnal hypotension without compensatory tachycardia. All the MSA patients showed extremely marked decrease of TH-immunoreactive neurons in both the C1 and A2 regions. In the patients with Parkinson's disease, numerous TH-immunoreactive neurons contained Lewy bodies that were immunostained by antibody to TH. TH-immunoreactive neurons were decreased very markedly in the A2 regions of two patients with OH, and three patients without OH showed fairly marked decreases in the C1 or A2 region. In contrast, the number of TH-immunoreactive neurons in ALS was the same as in normal subjects. In MSA and some PD patients, orthostatic hypotension may partly be due to the involvement of the medullary catecholaminergic neurons. The lability of blood pressure in ALS probably is not related to the medullary catecholaminergic neurons.     

Flank-marking behavior and the neural distribution of vasopressin innervation in golden hamsters with suprachiasmatic lesions

In golden hamsters, microinjections of arginine-vasopressin (AVP) within the anterior hypothalamus trigger a stereotyped scent-marking behavior, flank marking. Our experiment was carried out to test the contribution of AVP neurons within the suprachiasmatic nucleus (SCN) in the control of this behavior. Our results suggest that the SCN does not contribute to flank-marking behavior. Whereas SCN lesions disrupted circadian rhythms of wheel running, the same lesions did not disrupt flank-marking. The results also suggest that neurons located outside the SCN contribute significantly to the vasopressinergic innervation of the brain and the expression of AVP-dependent behaviors, such as flank-marking behavior. Although AVP-immunoreactive fibers were severely (ca. 95%) depleted from several forebrain areas in SCN-lesioned hamsters, the effect of the lesions was much more limited within the forebrain areas involved in flank-marking behavior as well as within the midbrain and hindbrain.     

Bacteriophage P4 DNA replication

The suprachiasmatic nucleus (SCN) is the circadian pacemaker in mammals and contains a network of arginine-vasopressin-immunoreactive (AVP-ir) neurons. AVP-recipient cells contain the V1a class of receptors linked to phosphoinositol turnover and protein kinase C (PKC). The present study describes the localization of AVP and the four Ca(2+)-dependent PKC-isoforms in the mouse and rabbit SCN. An estimate of the numerical density of AVP-ir neurons at the rostral, medial, and caudal level of the SCN revealed that the mouse SCN contains more than twice the number of AVP-ir neurons than the rabbit SCN. Neurons immunostained for AVP or PKC dominated in the dorsomedial and ventrolateral aspects of the mouse SCN, while the central area of the SCN revealed only weakly stained neurons. The rabbit SCN was characterized by a more homogeneous distribution of AVP-ir and PKC-ir neurons. PKC alpha was the most abundantly expressed isozyme in both species, whereas the presence of the other isoforms differed (mouse: PKC alpha > PKC beta I > PKC beta II > PKC gamma; rabbit: PKC alpha > PKC beta II > or = PKC gamma > PKC beta I). Clear PKC gamma-positive neurons were only observed in the rabbit SCN, while the mouse SCN predominantly contained immunolabeled fiber tracts for this PKC isozyme. Astrocytes immunoreactive for each PKC isoform were frequently encountered in the rabbit SCN, but were absent in mice. Immunofluorescence double labeling showed that numerous AVP-recipient cells in the mouse SCN were immunopositive for PKC alpha, and that nearly all AVP-ir neurons express PKC alpha abundantly. These results substantiate the putative role for PKC alpha in vasopressinergic signal transduction in the SCN. The differential expression in degree and cell type of the Ca(2+)-dependent PKC-isoforms in the mouse and rabbit SCN may be related to the differences observed in circadian timekeeping between the two species.     

VIP neurons in the human SCN in relation to sex, age, and Alzheimer's disease

The brains of 46 control subjects and 21 Alzheimer's disease (AD) patients were studied to determine whether there are age-related or AD-related changes in the vasoactive intestinal polypeptide (VIP) neuron population of the human suprachiasmatic nucleus (SCN). The number of VIP expressing neurons in the SCN of females, ranging in age from 10-91 years, did not change during normal aging. In males, however, the number of VIP neurons in the SCN was highest in the young subjects (10-40 years of age), after which, a dramatic decrease occurred in middle-aged subjects. This resulted in an age-dependent sex difference in the VIP cell population of the SCN: young males had twice as many VIP expressing SCN neurons as young females, whereas in the middle-aged groups, the females had twice as many VIP SCN neurons as the males. A significant decrease in the number of VIP expressing neurons in the SCN was found in female presenile AD patients, i.e., those younger than 65 years.     

Gastric intramucosal acidosis in mechanically ventilated patients: role of mucosal blood flow

To examine the roles of Arg-vasopressin (AVP)- and vasoactive intestinal peptide (VIP)-containing neurons in the suprachiasmatic nucleus (SCN) in production of circadian rhythmicity of locomotor activity, variations in the contents of AVP and VIP in punched-out SCN tissue and locomotor activity were measured under a light-dark cycle as well as under conditions of constant light for up to 3 weeks. Under the light-dark cycle, contents of AVP and VIP, and locomotor activity showed marked circadian rhythmicity. Under constant light, AVP content showed circadian rhythmicity until 3 weeks, while VIP rhythm disappeared from the first week with decreases in its content. Locomotor activity showed a free-running circadian rhythm for more than 3 weeks under constant light conditions in most cases. These results suggest that AVP but not VIP in the SCN may be involved in the generation of locomotor activity rhythm under conditions of constant light.     

Dynamics of spontaneous beating of cardiomyocytes in vitro depend on the number of involved cells

The hypothalamic suprachiasmatic nucleus (SCN) is the predominant pacemaker of the mammalian brain that generates and controls circadian rhythms of various endocrine and behavioral processes. Different lines of evidence suggest that stress interferes with the maintenance of such rhythms. As a first approach to investigate whether the neuropeptide arginine vasopressin (AVP), which shows circadian rhythms of synthesis and release within the SCN, might contribute to this stress-induced alterations in circadian rhythms, we monitored acute effects of swim stress on the intra-SCN release of AVP in male rats by means of the microdialysis technique. A 10-min forced swimming session triggered a marked but relatively short-lasting increase in the intranuclear release of AVP (to approx. 440%). This effect was restricted to the area containing predominantly somata and dendrites of vasopressinergic neurons, since no changes in AVP release could be measured in one of their major projection areas, the nucleus of the dorsomedial hypothalamus. Our data provide evidence that the amount of AVP released within the SCN can vary widely not only in accordance with AVP's intrinsically regulated circadian rhythm but also in response to a physiologically relevant stressor. In this way, the neuropeptide may contribute to the regulation of endocrine and behavioral rhythms particularly in challenging situations associated with resettings of the endogenous clock.     

Sex differences in the daily rhythm of vasoactive intestinal polypeptide but not arginine vasopressin messenger ribonucleic acid in the suprachiasmatic nuclei

The timing of the preovulatory surge of LH in female rodents is tightly coupled to the environmental light/dark cycle. This coupling is mediated by the circadian pacemaker located in the suprachiasmatic nuclei (SCN). Studies indicate that vasoactive intestinal polypeptide (VIP) and arginine vasopressin (AVP), which are synthesized in the SCN, transmit circadian information from the SCN to GnRH neurons, thereby regulating the timing of the LH surge. However, to date, the rhythmic expression of these two peptides in the SCN has only been examined in males. The pattern of VIP expression in males is difficult to reconcile with its role in the LH surge. The purpose of the present study was to assess the rhythm of VIP messenger RNA (mRNA) levels in the SCN of female rats under several endocrine conditions. We compared this rhythm to that in males and to AVP mRNA rhythms in all experimental groups. In all groups of females, VIP mRNA levels were rhythmic, with peak expression occurring during the light phase and a nadir occurring during the dark phase. The rhythm was approximately 12 h out of phase compared with that in males. The rhythmic expression of AVP mRNA in the SCN was virtually identical in all groups of animals. Based on these results, we conclude that 1) the rhythm of VIP seen in the SCN of females during the day may serve as a facilitory signal from the SCN to GnRH neurons; 2) the sex-specific pattern of VIP mRNA does not depend on estradiol; and 3) AVP gene expression within the SCN is not sexually differentiated or altered by estradiol.     

Arginine vasopressin levels in nursing home residents with nighttime urinary incontinence

OBJECTIVES: To examine the relationship between diurnal urine volume and plasma arginine vasopressin levels (AVP) in nursing home residents with nighttime urinary incontinence and a comparison group of frail but nondemented, continent geriatric board and care residents. DESIGN: Case series. SETTING: Four nursing homes and two board and care facilities. PARTICIPANTS: Sixty-two nursing home residents and 27 board and care residents. MEASUREMENTS: Daytime (7:00 a.m. to 7:00 p.m.) and nighttime (7:00 p.m. to 7:00 a.m.) urine volumes of incontinent nursing home residents were measured over 3 days and 3 nights by reweighing preweighed adults diapers and toileting inserts emptied by research staff for the comparison group. AVP levels were drawn in the early morning (5:00 a.m. to 7:00 a.m.) before subjects arose and in the evening after an hour of lying in bed (8:00 p.m. to 11:00 p.m.), and plasma levels were determined by radioimmunoassay. RESULTS: Half of the nursing home residents and 82% of the comparison group had night/total urine volume ratios > or = 50%. Forty-nine percent of the total of 89 subjects had undetectable morning AVP levels, 61% had undetectable evening AVP levels, and 42% had undetectable AVP levels in both morning and evening. There were no significant differences in AVP levels between those with night/total urine volume ratios > or = 50% and < 50% in either the nursing home or comparison groups though the small number of comparison group subjects with ratios < 50% may have limited our statistical power to detect differences. CONCLUSION: Our data suggest that a substantial proportion of both nursing home residents with nighttime incontinence and frail geriatric patients with a reversal of the normal diurnal pattern of urine excretion have an accompanying deficiency in AVP production and/or secretion. More detailed physiologic studies are needed to understand better the pathophysiology of geriatric nocturia and nighttime incontinence and the role that AVP deficiency may play in these conditions. Until such studies are carried out, we do not recommend the routine use of exogenous AVP for geriatric patients with unexplained nocturnal polyuria.     

Vasopressin in the forebrain of common marmosets (Callithrix jacchus): studies with in situ hybridization, immunocytochemistry and receptor autoradiography

The distribution of vasopressin (AVP) producing cells, their projections and AVP receptors was examined in the brain of common marmosets (Callithrix jacchus) using in situ hybridization, immunocytochemistry and receptor autoradiography. Clusters of cells labeled for AVP mRNA or stained for AVP immunoreactivity (AVP-ir) were found in the paraventricular (PVN), supraoptic (SON) and suprachiasmatic nuclei (SCN) of the hypothalamus. Scattered AVP producing cells were also found in the lateral hypothalamus and the bed nucleus of the stria terminalis (BST). Neither AVP mRNA-labeled nor AVP-ir cells were detected in the amygdala. Although AVP-ir fibers were evident outside of the hypothalamic-neurohypophyseal tract, a plexus of fibers in the lateral septum, as observed in the rat brain, was not detected. Receptor autoradiography using 125I-linear-AVP revealed specific binding for AVP receptors in the nucleus accumbens, diagonal band, lateral septum, the BST, SCN, PVN, amygdala, anterodorsal and ventromedial nucleus of the hypothalamus, indicating sites for central AVP action in the marmoset brain. Together, these data provide a comprehensive picture of AVP pathways in the marmoset brain, demonstrating differences from rodents in the distribution of cell bodies, fibers and receptors.     

Beneficial effect of intranasal desmopressin for nocturnal polyuria in Parkinson's disease

Patients with Parkinson's disease (PD) are known to experience autonomic nervous system dysfunction: this disruptive symptomatology includes urinary urgency, frequency, and nocturnal polyuria. Anticholinergic and tricyclic medications can be beneficial in controlling these urinary symptoms, but have unpleasant side effects in some patients. Desmopressin has been used to treat nocturnal polyuria successfully in a number of conditions, such as central diabetes insipidus, enuresis, and autonomic failure. The purpose of the present study was to assess the efficacy of desmopressin in patients with PD with significant nocturia. Eight patients were recruited into the study. They were first asked to establish a baseline of number of nocturnal voids; the patients were then prescribed the intranasal form of desmopressin and asked to continue to record the number of nocturnal voids. The five patients who completed the trial demonstrated clinically and statistically significant reductions in the frequency of nocturnal voids. One patient became hyponatremic and confused during desmopressin administration; his symptoms resolved soon after the desmopressin was discontinued. Two patients failed to complete the trial due to compliance problems. Thus, desmopressin appears to be a safe and effective medication for nocturnal polyuria in PD.     

Immunohistochemical characterization of the differentiation state of basal cell carcinomas with special interest for infiltrating relapsing tumors

Persistence of nocturia after prostatic resection in healthy patients without symptoms referred to residual bladder instability and to pathological polyuria seems to be caused by an increased urine production at night. The more accreditate mechanism involved is the relevant decreased ADH secretion pattern which occurs at night. In our study, patients with nocturnal poliuria showed significantly low plasmatic vasopressin levels compared with a control group. The aim of this study was to evaluate whether the persistence of nocturia after prostatic resection in healthy patients, without symptoms referred due to residual bladder instability and important polyuria, could be due to a decrease or a lack of increase in antidiuretic hormone (ADH) nocturnal levels following increased urine production at night. Serum ADH, atrial natriuretic peptide (ANP) and osmolality were assessed at 4-h intervals in 12 patients complaining of residual nocturia (group A) and in a control group of 13 patients who had undergone a complete resolution of nocturia after prostate ablation (group B). In the 25 patients involved in the study (mean age 65.8 years), no significant differences were observed in the two groups concerning mean age (67.5 years for group A, 64 years for group B). Mean nocturnal urine volume (1080 +/- 490 ml) in group A patients was significantly higher than in group B (500 +/- 100 ml) (p < 0.001), while no significant differences were found in diurnal diuresis. Mean plasma vasopressin levels of the 12 patients showing an increased nocturnal micturition were found to be significantly lower at all 4-h intervals when compared with the control group (p < 0.05). Individual fluctuations in serum osmolality were slight and insignificant within the normal range in all patients. The diurnal variation of plasma atrial natriuretic peptide was within the reference limits for all subjects during the 24-h period. Our results lead us to believe that residual nocturia after prostatic resection seems to be caused by an increased urine production at night due to a decreased ADH secretion pattern.     

Evidence from confocal fluorescence microscopy for a dense, reciprocal innervation between AVP-, somatostatin-, VIP/PHI-, GRP-, and VIP/PHI/GRP-immunoreactive neurons in the rat suprachiasmatic nucleus

The rat suprachiasmatic nucleus (SCN) consists of several classes of neurons which can be identified by their transmitter content. Knowledge of putative interaction between these different cell types is essential in order to understand the possibilities of information processing within the SCN. The aim of the present study was therefore to obtain more information about the mutual innervation between the main cell classes in the rat SCN, viz. those containing the neuropeptides arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), gastrin-releasing peptide (GRP) and somatostatin respectively. For this purpose, vibratome sections were double-immunolabelled for seven different peptide combinations and subsequently analysed by high-resolution confocal laser scanning fluorescence microscopy. Attention was focused on axosomatic appositions, the occurrence and frequency of which were quantitatively estimated. Our analysis of double-immunolabelled sections demonstrated that some of the VIP- and some of the GRP-immunoreactive nerve cells and endings showed colocalization. Assuming, on the basis of literature data, that VIP and PHI are always colocalized at the cellular level, the five main cell classes in the SCN appeared to be interconnected, at least axosomatically, in the following reciprocal way: AVP <--> VIP/PHI, AVP <--> GRP, AVP <--> somatostatin, somatostatin <--> VIP/PHI, somatostatin <--> GRP, VIP/PHI <--> GRP, VIP/PHI/GRP <--> GRP, VIP/PHI/GRP <--> VIP/ PHI. In addition to this heterologous axosomatic innervation, these cell groups also showed substantial homologous innervation. Supported by electron microscope data from the literature showing the existence of axodendritic synapses for some of these peptide combinations, our findings strongly suggest that the rat SCN comprises a complex synaptic network with strong interactive capabilities, which is probably a requisite for its biological clock function.     

Insular cortex and amygdala lesions induced after aversive training impair retention: effects of degree of training

Immunohistochemical observation was performed in the suprachiasmatic nucleus (SCN) and the intergeniculate leaflet (IGL) of hereditary bilaterally microphthalmic rats without the optic nerve on both sides. In the microphthalmic rats, volume of the SCN reduced to ca. 70% of the normal and numbers of the vasoactive intestinal polypeptide (VIP)-like immunoreactive (lir) neurons were significantly decreased. Although the arginine vasopressin (aVP)- and the VIP-lir neurons distributed in the dorsomedial and the ventrolateral part of the SCN, respectively, as reported in the normal one, somatostatin-lir neurons, localizing mainly in a border area between the dorsomedial and the ventrolateral region of the normal SCN, were shifted to the ventral part of the SCN in the microphthalmic rats. The ventral part of the SCN was covered with neuropeptide Y (NPY)-lir fibers in both normal and mutant rats. The IGL was hardly delineated cytologically in the lateral geniculate nucleus (LGN) of the mutant rats. NPY-lir neurons were found in the dorsal part of the ventral LGN, in contrast to their even distribution in the normal IGL. These findings suggest that the IGL-SCN tract remains in the hereditary microphthalmic rats without the retinal projections.     

Day-night changes in c-fos expression in the fetal sheep suprachiasmatic nucleus at late gestation

The suprachiasmatic nucleus (SCN) is a circadian oscillator in mammals and shows day-night changes in metabolic activity. To investigate whether the fetal sheep SCN behaves as a circadian oscillator, day-night changes in c-fos expression, a marker of neuronal activity, were measured. Eight fetal sheep were sacrificed at 135 days gestation--four at day-time (1200 hours) and four at night-time (2400 hours). Fetal brains were fixed, removed and cut in 40-microns serial coronal sections. Alternate sections were incubated with anti-Fos antibody (1:500) and Fos expression was revealed with extra-avidin-peroxidase and 3,3'-diaminobenzidine or stained with cresyl violet. The number of Fos-immunoreactive (Fos-ir) neurons per mm2 in the rostral, intermediate and caudal regions of the fetal sheep SCN was counted. Fetuses sacrificed in the day-time showed a higher number of Fos-ir neurons per mm2 (mean +/- s.e.; 516.7 +/- 60.1) in the three regions of the SCN than fetuses sacrificed at night-time (140.5 +/- 21.8). In addition, at night-time Fos-ir neurons were mainly localized to the ventrolateral area of the SCN. These findings demonstrate day-night changes in molecular activity consistent with the presence of a circadian oscillator in the fetal sheep SCN.     

Distribution of Ca2+-dependent protein kinase C isoforms in the suprachiasmatic nucleus of the diurnal murid rodent, Arvicanthis niloticus

The suprachiasmatic nuclei (SCN) contain the major 'biological clock' in mammals that controls most circadian rhythms expressed by these animals. The functional importance of protein phosphorylation and intracellular Ca2+ in the mammalian circadian pacemaker is becoming increasingly apparent. Here we report the immunocytochemical localization of the four Ca2+-dependent protein kinase C (PKC) isoforms (alpha, betaI, betaII, gamma) within the SCN of the diurnal murid rodent, Arvicanthis niloticus, and the nocturnal golden hamster. In the SCN of A. niloticus, PKCalpha was the most abundant of the four isoforms. Cells containing PKCalpha were homogeneously distributed throughout the SCN. PKCbetaI cells were sparsely distributed in the perimeter of the SCN and were absent in its central area. PKCbetaII and -gamma were not found in the SCN of A. niloticus. In the SCN of the golden hamster, PKCalpha cells were most heavily concentrated in the dorsomedial region, though some were also present laterally and ventrally. The distribution of arginine-vasopressin (AVP) cells in the SCN overlapped with that of PKC in both species. Species differences in the location of the Ca2+-dependent PKC isoforms suggest differences in function such as the relaying of photic or non-photic information to the clock mechanism, or the synchronization of AVP neurons and their subsequent output signals.     

Increased contact time improves adenovirus-mediated CFTR gene transfer to nasal epithelium of CF mice

By combining retrograde and anterograde tracing, evidence for a bineuronal connection from the suprachiasmatic nucleus (SCN) to the intermediolateral cell column in the spinal cord (IML) was obtained. The retrograde tracer cholera toxin subunit B (ChB) was pressure-injected into the spinal cord and the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) was iontophoretically injected into the SCN. The two tracers were visualized simultaneously by a double immunohistochemical procedure. In the hypothalamus, ChB injections gave rise to retrogradely labeled cell bodies in the paraventricular nucleus, retrochiasmatic area, perifornical region, lateral hypothalamic area, and the posterior hypothalamic area. The SCN were found to project to all of these areas. Furthermore, spinal-projecting neurons were found in the brain stem, but no efferents from the SCN were observed to innervate these areas. In the most sparsely innervated areas, the lateral hypothalamic area and the perifornical region, only occasionally a PHA-L fiber in close apposition to a ChB-ir cell body was observed. This was also the case in the retrochiasmatic area and posterior hypothalamic area, although these areas received a moderate number-immunoreactive (ir) PHA-L-ir fibers. The highest number of closely apposed PHA-L-ir fibers and ChB-ir cell bodies was observed in the dorsal parvicellular and in the ventral division of the medial parvicellular paraventricular nucleus, which were also the areas receiving the densest input from the SCN. By anterograde tracing from the paraventricular nucleus of the hypothalamus, the exact topography of the terminal field formed by descending paraventricular neurons was established. Thus, it was confirmed that the paraventricular nucleus of the hypothalamus predominantly innervates the IML. The present study suggests the existence of a bineuronal link between the SCN and the IML, possibly involved in transmission of circadian signals from the endogenous clock to the pineal gland and other organs receiving sympathetic afferents.     

The topographical relationship between two neuronal mosaics in the short wavelength-sensitive system of the primate retina

Adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary is predominantly regulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) synthesized in neurons of the paraventricular nucleus (PVN) of the hypothalamus. Secretion of ACTH occurs in pulsatile bursts. To explore the relationship between hypothalamic control and the pulsatile pattern of ACTH secretion, we measured ACTH in 2 min blood samples over 4 h in rats with intact and lesioned PVN during hypovolemic-stress or control conditions and also measured median eminence (ME) levels of CRH, AVP, and oxytocin (OT). Mean plasma ACTH was highest in the sham lesioned-hypovolemic group, lowest in the sham lesioned-control group and intermediate in the two PVN-lesioned groups. CRH in the ME was negligible in the lesioned animals and correlated with OT and AVP. Pulsatile secretion was observed despite PVN ablation. Visual inspection of composite time series suggested different temporal patterns of ACTH secretion. Principal components analysis of the individual ACTH time series revealed three significant eigenvectors which correlated differentially with the three treatment groups. Neither lesioned group had the steep rise over 10 min seen in plasma ACTH in the non-lesioned groups. Delayed ACTH rise after 30-60 min occurred in all but the sham control group. Our data suggest that CRH is responsible for immediate secretion of ACTH in response to hypovolemic stress and that regulators from non-PVN sites may be responsible for more delayed secretion of ACTH in this setting. The persistence of ME AVP and OT levels in the face of > 90% reduction in ME CRH levels leaves open the question of a role for one or both of these peptides in the delayed ACTH response following stress onset and in the generation of pulsatile ACTH secretory bursts.     

Physiologic basis of pulmonary edema during intestinal reperfusion

The ventrolateral portion of the intermediate reticular formation of the medulla (ventrolateral medulla, VLM), including the C1/A1 groups of catecholaminergic neurons, is thought to be involved in control of sympathetic cardiovascular outflow, cardiorespiratory interactions, and reflex control of vasopressin release. As all these functions are affected in patients with multiple systems atrophy (MSA) with autonomic failure, we sought to test the hypothesis that catecholaminergic (tyrosine hydroxylase [TH]-positive) neurons of the VLM are depleted in these patients. Medullas were obtained at autopsy from 4 patients with MSA with prominent autonomic failure and 5 patients with no neurological disease. Patients with MSA had laboratory evidence of severe adrenergic sudomotor and cardiovagal failure. Tissue was immersion fixed in 2% paraformaldehyde at 4 degrees C for 24 hours and cut into 1-cm blocks in the coronal plane from throughout the medulla. Serial 50-microm sections were collected and one section every 300 microm was stained for TH. There was a pronounced depletion of TH neurons in the rostral VLM in all cases of MSA. There was also significant reduction of TH neurons in the caudal VLM in 3 MSA patients compared with 3 control subjects. In 2 MSA cases and in 2 control subjects, the thoracic spinal cord was available for study. There was also depletion of TH fibers and sympathetic preganglionic neurons (SPNs) in the 2 MSA cases examined. Thus, depletion of catecholaminergic neurons in the VLM may provide a substrate for some of the autonomic and endocrine manifestations of MSA.