Clinicopathological features and global genomic copy number alterations of pilomyxoid astrocytoma in the hypothalamus/optic pathway: comparative analysis with pilocytic astrocytoma using array-based comparative genomic hybridization.

Pilomyxoid astrocytoma is a recently identified variant of pilocytic astrocytoma. We studied 11 circumscribed astrocytomas with focal (n=5) or diffuse (n=6) pilomyxoid features and compared them with 17 pilocytic astrocytomas from the hypothalamic/chiasmatic region in children. In one patient, a tumor that recurred after initial surgery had changed from pure-form pilomyxoid astrocytoma to the mixed form. The presence of a pilomyxoid area was associated with shorter survival. Next, we compared the comprehensive genome copy number changes in the pilomyxoid astrocytoma (n=4) with those in pilocytic astrocytoma (n=6) cases by array-based comparative genomic hybridization. The number of lost clones was larger in pilomyxoid astrocytoma than in pilocytic astrocytoma. Clones located in chromosome 8q24.3 were frequently gained in pilocytic astrocytoma (four of six) and in pilomyxoid astrocytoma (one of four). Clones located in 9p24.3 and 15q26.3 were lost in all of the pilomyxoid astrocytomas and in five of the pilocytic astrocytomas. Those in 8p23.3 showed a copy number loss in three of the pilomyxoid astrocytomas and four of the pilocytic astrocytomas. The frequency of copy number changes was significantly different between pilomyxoid astrocytoma and pilocytic astrocytoma in 47 (3.6%) clones, 20 of them having been located in 2p, 10 in 2q, and 11 in 3q. An unsupervised hierarchical clustering analysis classified the cases into three clusters: one pilomyxoid astrocytoma patient into one cluster, two pilomyxoid astrocytoma patients into another cluster, and six pilocytic astrocytoma patients and one pilomyxoid astrocytoma patient into the third cluster. In conclusion, the presence of mixed-form pilomyxoid astrocytoma, the acquisition of pilocytic astrocytoma features in a recurrent tumor in pure-form pilomyxoid astrocytoma, and the above results of the genome-wide gene copy number analysis suggest that pilomyxoid astrocytoma might be a pathologically and genetically related, aggressive variant of pilocytic astrocytoma with partially different genetic alterations.

Ventromedial hypothalamic nucleus lesions disrupt olfactory mate recognition and receptivity in female ferrets.

Previous research showed that ferrets of both sexes rely on the perception of conspecifics' body odors to identify and motivate approach towards opposite-sex mating partners, and exposure to male body odors stimulated Fos expression in an olfactory projection circuit of female, but not male, ferrets that terminates in the ventromedial hypothalamic nucleus (VMH). We asked whether the female-typical preference of ferrets to approach male as opposed to female body odors in Y-maze tests would be disrupted by VMH lesions. Sexually experienced female ferrets were ovo-hysterectomized prior to receiving bilateral electrolytic lesions of the VMH, the preoptic area/anterior hypothalamus (POA/AH) or a sham operation. Subsequently, while receiving estradiol benzoate, females that received either complete or partial bilateral lesions of the VMH approached volatile odors from an anesthetized male on significantly fewer trials than females given POA/AH lesions or a sham operation. Both groups of ferrets with VMH lesion damage reliably discriminated between volatile anal scents as well as urinary odors from the 2 sexes in home cage habituation/dishabituation tests, suggesting that their odor-based sex discrimination remained intact. Females with complete bilateral VMH lesions showed significantly lower acceptance of neck gripping from a stimulus male (receptivity) and more aggression towards the male than all other groups of female subjects. Estrogen-sensitive neurons in the VMH appear to play a central role in female-typical neural processing of odor inputs leading to a preference to seek out a male sex partner, in addition to facilitating females' sexual receptivity.

Induction of thymic hyperplasia and suppression of splenic T cells by lesioning of the anterior hypothalamus in aging Wistar rats.

The effect of destruction of the anterior hypothalamus (AHT) on the immune system was examined in rats 4-50 weeks after the treatment. The thymic weight significantly increased in the experimental group regardless of age, while a significant decrease was observed in the percentage of splenic T cells as well as their proliferative response to phytohemagglutinin (PHA). The increase of thymic weight was observed as long as 24 weeks and the decrease of splenic T cell number was observed as long as 50 weeks after the operation. Hypophysectomy gave rise to atrophy of both thymus and spleen, while either adrenalectomy or gonadectomy resulted in hypertrophy of both thymus and spleen. The results taken together suggest that development and aging of the immune system are under the balance of positive and negative signals from AHT.

Angiotensin II pressor activity depends on medial and lateral anterior hypothalamic pathways.

The preoptic region of hypothalamus was disconnected from caudal structures with two different-size knife cuts in rats to investigate the pathway responsible for the effects of intracerebroventricular (ICV) and intravenous (IV) angiotensin II (ang II) on blood pressure and arginine vasopressin (AVP) release. Seven days after surgery ICV ang II (125 ng) in sham-operated (sham) rats increased mean arterial pressure (MAP) (+23 +/- 3 mmHg) and decreased heart rate (HR) (-58 +/- 5 beats/minute). However, ICV ang II had no effect on MAP or HR of rats with a large (preoptic-hypothalamic disconnection) cut. Both the pressor response (+12 +/- 2 mmHg) and the bradycardia (-39 +/- 6 beats/minute) were significantly reduced by a small (medial preoptic-hypothalamic disconnection) cut. The increased plasma AVP to ICV ang II in sham rats (9.8 +/- 3.6 pg/mL) was abolished in large-cut rats and attenuated in small-cut rats (3.2 +/- 0.7 pg/mL). IV bolus injection of ang II (125 ng) in sham rats increased MAP by 43 mmHg, whereas large-cut rats showed a blunted (25%) pressor response. The pressor response to IV infusion of ang II (8 ng/20 microL/minute for 15 minutes) was diminished in large-cut rats (+4 +/- 1 mmHg) as compared with that in sham rats (+19 +/- 2 mmHg). Both cuts transected the projection between the periventricular tissue surrounding the anteroventral third ventricle and supraoptic nucleus, but the supraoptic-neurohypophyseal pathway was severed only by the large cut.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of anterior hypothalamic deafferentation on the negative feedback of gonadal steroids on luteinizing hormone pulse frequency in the ewe.

Three experiments were performed to determined the effect of anterior hypothalamic deafferentation (AHD) on the inhibitory actions of estradiol and progesterone on luteinizing hormone (LH) pulse frequency in ovariectomized ewes during the anestrous season. The first experiment tested the effects of AHD on LH secretion in the absence of gonadal steroids. AHD was accomplished by a 180 degree knife cut (Halasz knife) placed at the posterior border of the optic chiasm (n = 4). Control ewes received sham cuts or no surgery (n = 6). LH pulses were monitored in blood samples taken every 12 min for 4 hr before and after surgery. AHD reduced LH pulse amplitude (pre 7.4 +/- 2.9 ng/ml; post 1.2 +/- 0.3 ng/ml), but had no effect on LH pulse frequency (pre 3.5 +/- 0.3/4 hr; post 3.3 +/- 0.3/4 hr) in ovariectomized ewes. In the second experiment all ewes were given a Silastic implant containing estradiol (1 cm long) and 2 d later bled at 12 min intervals for 4 hr before and after administration of pimozide (PIM, 0.08 mg/kg), a dopamine antagonist. Estradiol decreased LH pulse frequency in controls (2.8 +/- 0.4 to 1.5 +/- 0.3/4 hr) and this was reversed by PIM (2.5 +/- 0.4/4 hr). In contrast, estradiol did not decrease pulse frequency in AHD ewes (3.3 +/- 0.3 to 2.8 +/- 0.5/4 hr) and PIM did not increase it (2.7 +/- 0.7/4 hr). In the third experiment, all ewes were given Silastic implants containing progesterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypothalamic lesions that induce precocious puberty on the morphological and functional maturation of the luteinizing hormone-releasing hormone neuronal system.

Recent evidence has implicated the transforming growth factor-alpha (TGF alpha)/epidermal growth factor receptor (EGFR) system in the mechanism by which hypothalamic lesions accelerate female sexual development. Since acquisition and maintenance of reproductive functions depend on the secretory activity of LHRH neurons, the present studies were undertaken to characterize some of the cellular and molecular events that underlie lesion-induced activation of the LHRH neuronal network. Bilateral electrolytic lesions of the posterior portion of the preoptic region and anterior hypothalamic area (POA-AHA) in 22-day-old rats resulted in vaginal opening and ovulation within 7 days. Morphological maturation of LHRH neurons was assessed by the relative frequency of irregular and smooth neurons (the former being the predominant type in adult animals). Within 20 h after the lesion, there was a significant decrease in the proportion of LHRH neurons with spiny irregular contours, indicating reversal to a more immature morphological type. This change was followed by accelerated spine reformation, so that at the time of precocious proestrus, the incidence of irregular LHRH neurons was similar in lesioned and age-matched control rats. A striking increase in c-fos mRNA levels occurred within 1 h after the lesion in the area neighboring the site of injury, reflecting the immediate cell response to trauma. Immunohistochemical localization of the c-fos protein, used to estimate changes in cellular activity at the single cell level, demonstrated c-fos induction in unidentified cells near the lesion and astrocytes, but not in LHRH neurons 20 h after injury. In contrast, a selective increase in c-fos expression was observed in LHRH neurons during the initiation of precocious puberty 5-7 days later at the time of the first proestrus. An increase in plasma LH associated with a drop in LHRH content in the median eminence and an increase in pro-LHRH precursor in the POA-AHA, with no changes in LHRH mRNA, was found to antedate the first preovulatory surge of gonadotropins in lesioned rats. Assessment of the changes in PC2 mRNA, which encodes a novel dibasic endoprotease presumptively involved in tissue-specific processing of a class of prohormones that includes pro-LHRH, showed that the content of PC2 mRNA in the AHA-POA increases during normal puberty, but not in lesioned animals, thus providing a potential explanation for the divergent changes in pro-LHRH and mature decapeptide found in lesioned rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Lesions to the anterior hypothalamus prevent the melatonin-induced lengthening of delayed implantation.

The anterior hypothalamic area (AHA) has been postulated as a site of action for melatonin. We tested the hypothesis that lesions to the AHA (AHAx) would counteract the inhibitory effect of exogenous melatonin on blastocyst implantation in the spotted skunk by removing a possible site of action. Forty-seven females were treated as follows during delayed implantation. In Exp 1, five received empty Silastic capsules, five received Silastic capsules containing melatonin, six received sham AHAx plus empty capsules, none received AHAx plus empty capsules, and eight received AHAx plus capsules containing melatonin. In Exp 2, four skunks each received two empty capsules, five skunks each received two capsules containing melatonin, and five skunks received AHAx plus capsules containing melatonin. All capsules were inserted sc in the interscapular region 14-35 days after surgery in Exp 1 and 2 weeks before surgery in Exp 2. Surgery was performed between January 22 and February 12, 1988, in Exp 1 and on March 2-3, 1989, in Exp 2. The skunks were subjected to a natural photoperiod, and the duration of preimplantation was measured. In Exp 1, AHAx plus empty capsules significantly (P less than 0.05) shortened the duration of preimplantation (163 +/- 14.7 days) compared to that in sham AHAx or intact controls (193 +/- 26.1 and 188 +/- 10.6 days, respectively). Melatonin significantly (P less than 0.05) prolonged the duration of preimplantation (289 +/- 2.9 days) in intact skunks, but failed to do so in skunks with AHAx, as the preimplantation period was significantly shortened (159 +/- 6.1 days). In Exp 2, AHAx reversed the inhibitory effect of melatonin on the duration of preimplantation (191 +/- 21.5 days), as intact melatonin-treated skunks had a significantly longer preimplantation period (260 +/- 2.5 days) than skunks receiving empty capsules (191 +/- 16.4 days). The inhibitory effect of melatonin was reversible in all intact skunks, as blastocysts implanted 23 days, on the average, after cessation of treatment with melatonin. These data are consistent with the hypothesis that a portion of the AHA and/or adjacent regions play an essential role in timing blastocyst implantation in the spotted skunk. The lesions may have given this result by ablating a neural pathway controlling PRL secretion and may or may not have involved a site of action for melatonin.

Progesterone stimulates testosterone secretion in male rats.

In male rats, serum testosterone (T) and progesterone (P) levels fluctuate with daily periodicities that appear to be inversely related. To further investigate this interrelationship between serum T and P levels, we studied the effects of exogenous P on serum androgen levels. At 6--8 h after administration of P, serum T and DHT levels were consistently increased without any alterations in the serum LH and FSH levels. Following disruption of the hypothalamo-pituitary-adrenal axis either by adrenalectomy or by anterior hypothalamic deafferentiation, procedures known to abolish serum T and P periodicities, P was again effective in raising serum T concentrations without altering the serum gonadotropin values. These results show that P may directly enhance testicular secretion, and thus support the possibility that the observed adrenal influence on daily testicular T secretion pattern may be hormonally mediated via P secretion.

A study of permanent adipsia induced by medial forebrain lesions.

Cerebral lesions involving most of the anterior wall of the ventricle, and the medial part of the septal region, induced a permanent loss of thirst in two goats. The ventral part of the lamina terminalis remained intact in one of the animals. Pronounced dehydration (10--13% loss of b.wt.) developed during periods (3--7 days) when water supplementation was omitted. Determinations of plasma arginine vasopressin in one of the animals revealed that the dehydration did not cause any significant increase in the secretion of antidiuretic hormone. However, the water deficit induced a considerable rise in plasma renin activity and tachycardia. If anything, the caroitid blood pressure became slightly elevated towards the end of 7 d dehydration periods. The lesions obviously inactivated a cerebral sensory mechanism controlling water balance. It may have been due mainly to destruction of juxtaventricular receptors in the anterior hypothalamic region, but perhaps also to a disruption of afferents from such receptors located posterior to this cerebral level.

Changes in diurnal fluctuations of plasma thyroid stimulating hormone and corticosterone following anterior hypothalamic deafferentation in the rat.

Systemic thyroid stimulating hormone (TSH) and corticosterone (B) levels were measured in serial plasma samples withdrawn from 8 adult female rats before and for several weeks after anterior hypothalamic cuts (FC), made with a modified Halász knife (1.5 mm radius). With lights on from 5:00 to 19:00 h the rats were bled by rapid venipuncture at 9:00 and 20:00 h 14 days before and 5 days after FC and by chronic intra-atrial cannulas at 9:00, 13:00, 17:00 and 20:00 h on days 25, 30 and 40 or 50 post-FC. The frontal cuts, localized later by histology to sites just rostral to the suprachiasmatic nucleus in 3 rats and just caudal to the nucleus in the other 5 brains, altered the charactersitic diurnal drop in plasma TSH and rise in B but did not eliminate marked fluctuations in hormone levels. The new hormonal platterns could not be related specifically to FC loci and appeared to be a dynamic process for each rat. At 5 days after FC the diurnal patterns were either obscured or shifted in phase. The most consistent finding at subsequent sampling intervals was that TSH and B plasma levels in each animal showed parallel fluctuations (during 9:00--20:00 h) as though synchronized in phase. The data suggest that interruption of anterior hypothalamic connections in the female rat is compatible with fluctuations in plasma TSH and B which are unique to a particular animal and may be obscured by group analysis.

Induction of persistent estrus by electrolytic lesions placed neonatally in the hypothalamus of the female rat.

Electrolytic lesions were placed in the hypothalamus of two-day-old female rats. Destruction of the mediobasal part of the preoptic area resulted in persistent vaginal estrus starting on the day of vaginal opening, while lesions placed laterally in the preoptic-anterior hypothalamic area did not interfere with normal cycles. Therefore, the mediobasal hypothalamus is capable of undergoing maturation without any postnatal influence from at least the mediobasal part of the anterior hypothalamus. Destruction of the anterior wall of the third ventricle also caused persistent or prolonged vaginal estrus preceded by normal cycles. The relationship between the loci of lesions and the occurrence of sexual cyclicity was discussed.

Investigation of luteinizing-inducing effect of pinealectomy or thyroidectomy in different types of anovulatory syndromes in rats.

The luteinizing-inducing effect of pinealectomy and of thyroidectomy was investigated in the constant estrous anovulatory (CEA) syndrome caused either by frontal hypothalamic deafferentation (FHD) or by neonatal androgen treatment (NA). Thyroidectomy failed to induce luteinization in both types of CEA syndrome. However, pinealectomy provoked the formation of corpora lutea in FHD, but not in NA induced CEA syndrome. It was concluded that the luteinizing-inducing effect of pinealectomy is a specific consequence of the removal of the pineal hormone-like principles. The differences in the mechanism of development of the CEA syndrome following FHD or NA might account for the failure of pinealectomy to elicite luteinization in the NA induced CEA rat.

Studies on the mechanism controlling growth hormone release induced by chlorpromazine in the anesthetized rat.

In intact urethane-anesthetized rats, plasma growth hormone (GH) levels were low but increased significantly following intravenous injection of chlorpromazine. Plasma GH levels were significantly elevated in rats with hypothalamic cuts such as complete deafferentiation, anterior cut and antero-lateral cut, whereas plasma GH levels in rats with posterior cut or postero-lateral cut were not significantly different from those in rats with sham-operation. Intravenous injection of chlorpromazine caused an increase of plasma GH in rats with any type of hypothalamic cut. However, the maximum increments of plasma GH following chlorpromazine were larger in rats with antero-lateral cut and smaller in rats with posterior cut than in rats with sham-operation. These results suggest that extrahypothalamic inhibiting and stimulating neurons influence the regulatory mechanism of rat GH secretion through anterior and posterior routes to the hypothalamus respectively.