Diffusible neurotrophic factors for thalamic neurons are released from target neocortex and non-target cerebellum.
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Animals↗
Biomedical subjects
F R Sharp
Publications and source records attributed to F R Sharp.
Fetal cortical transplants surviving in injured sensorimotor cortex of rats: cellular composition and function.
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Age Factors↗
A semiautomated method for measuring brain infarct volume.
An accurate, reproducible method for determining the infarct volumes of gray matter structures is presented for use with presently available image analysis systems. Areas of stained sections with optical densities above that of a threshold value are automatically recognized and measured. This eliminates the potential error and bias inherent in manually delineating infarcted regions. Moreover, the volume of surviving normal gray matter is determined rather than that of the infarct. This approach minimizes the error that is introduced by edema, which distorts and enlarges the infarcted tissue and surrounding white matter.
Animals↗
Light regulates expression of a Fos-related protein in rat suprachiasmatic nuclei.
Mammalian circadian rhythmicity is endogenously generated by a pacemaker in the suprachiasmatic nuclei and precisely entrained to the 24-hr day/night cycle by periodic environmental light cues. We show that light alters the immunoreactive levels of a transcriptional regulatory protein, Fos, in the suprachiasmatic nuclei of albino rats. Photic regulation of Fos immunoreactivity does not occur in other retino-recipient brain areas except for the intergeniculate leaflet, which appears to be involved in mediating some of the complex effects of light on expressed circadian rhythms. Our results point to a promising new functional marker for the cellular effects of light and suggest that the expression of Fos or a related nuclear protein may be part of the mechanism for photic entrainment of the circadian clock to environmental light/dark cycles.
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Glutamate increases glycogen content and reduces glucose utilization in primary astrocyte culture.
The glycogen content of primary cultured astrocytes was approximately doubled by incubation with 1 mM L-glutamate or L-aspartate. Other amino acids and excitatory neurotransmitters were without effect. The increase in glycogen level was not blocked by the glutamate receptor antagonist kynurenic acid but was completely blocked by the glutamate uptake inhibitor threo-3-hydroxy-D,L-aspartate and by removal of Na+ from the medium. Incubation with radiolabeled glucose and glutamate revealed that the increased glycogen content was derived almost entirely from glucose. Glutamate at 1 mM was also found to cause a 53 +/- 12% decrease in glucose utilization and a 112 +/- 69% increase in glucose-6-phosphate levels. These results suggest that the glycogen content of astrocytes is linked to the rate of glucose utilization and that glucose utilization can, in turn, be affected by the availability of alternative metabolic substrates. These relationships suggest a mechanism by which brain glycogen accumulation occurs during decreased neuronal activity.
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Methionine sulfoximine reduces cortical infarct size in rats after middle cerebral artery occlusion.
The methionine analogue methionine sulfoximine was administered to 10 rats 24 hours before occlusion of the proximal left middle cerebral artery. Three days later the rats were decapitated and the brain infarct volumes were compared with those in 10 control rats that received saline before middle cerebral artery occlusion. The mean volume of the infarct in the cerebral cortex was reduced by 33% in the group treated with methionine sulfoximine (p less than 0.01). This protective effect may be mediated by a presynaptic mechanism; methionine sulfoximine profoundly inhibits brain glutamine synthetase, thereby interrupting the astrocyte-neuron glutamate shuttle and impairing neuronal glutamate release. Methionine sulfoximine also increases brain glycogen stores, and this increased energy reserve may benefit penumbral tissue during the peri-infarct period. Further study of the mechanisms by which methionine sulfoximine decreases infarct volume could lead to new therapeutic approaches for stroke.
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Induction of fos-like immunoreactivity in hypothalamic corticotropin-releasing factor neurons after adrenalectomy in the rat.
To identify brain sites responding to the removal of corticosterone feedback by adrenalectomy (ADX), rat brains were processed for fos immunocytochemistry 1, 3, and 7 days after ADX, sham-ADX, or no surgery using a polyclonal antiserum to fos residues 132-154. Compared to SHAM, ADX rats exhibited strong fos-like immunoreactivity (FLI) only in the parvocellular neurons of the paraventricular hypothalamic nuclei (PVN) 1, 3, and 7 days after surgery. Replacement with a corticosterone pellet at the time of adrenalectomy (ADX + B) prevented this increase in PVN FLI in three of four rats at 1 day, all rats at 3 days, and two of seven rats 7 days after surgery; 100 micrograms/ml corticosterone in the drinking water for 2 days before perfusion reversed ADX-induced increases in PVN FLI in 7-day ADX rats. Providing 25 micrograms/ml corticosterone in the drinking water to ADX rats for 5 days after surgery did not prevent expression of PVN FLI, even though this dose has been shown to normalize morning basal ACTH levels in ADX rats. Virtually all parvocellular PVN neurons expressing FLI after ADX costained for CRF. Some parvocellular neurons also expressed both fos and vasopressin. In all rats, many brain regions expressed FLI that was not related to adrenalectomy. We conclude that the changes in neuronal FLI correlate with demonstrated changes in neuroendocrine activity after ADX; however, suppression of ADX-induced FLI may require higher replacement levels of corticosterone than inhibition of ADX-induced ACTH secretion.
Adrenalectomy↗
14C-2-deoxyglucose uptake in the ground squirrel brain during entrance to and arousal from hibernation.
Neuronal activity underlying various phases of the mammalian hibernation cycle was investigated using the 14C-2-deoxyglucose (2DG) method. Relative 2DG uptake (R2DGU) values were computed for 96 brain regions across 7 phases of the hibernation cycle: euthermia, 3 body temperature (Tb) intervals during entrance into hibernation, stable deep hibernation, and 2 Tb intervals during arousal from hibernation. Multivariate statistical techniques were employed to identify objectively groups of brain regions whose R2DGU values showed a similar pattern across all phases of hibernation. Factor analysis revealed that most of the variability in R2DGU values for the 96 brain regions across the entire cycle could be accounted for by 3 principal factors. These factors could accurately discriminate the various phases of hibernation on the basis of the R2DGU values alone. Three hypothalamic and 3 cortical regions were identified as possibly mediating the entrance into hibernation because they underwent a change in R2DGU early in entrance into hibernation and loaded strongly on one of the principal factors. Another 4 hypothalamic regions were similarly identified as possibly causally involved in the arousal from hibernation. These results, coupled with characteristic changes in ordinal rank of the 96 brain regions in each phase of hibernation, support the concept that mammalian hibernation is an active, integrated orchestration of neurophysiological events rather than a state entered through a passive process.
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c-fos expression and (14C) 2-deoxyglucose uptake in the caudal cerebellum of the rat during motor/sensory cortex stimulation.
Fos, the protein product of the c-fos gene, is induced in neurons in response to a variety of stimuli. In order to see if Fos could be used to map activity in the brain, the pattern of Fos staining was compared to the pattern of (14C) 2-deoxyglucose (2DG) uptake in the seventh and eighth lobules of the cerebellum during electrical stimulation of the cerebral cortex. Electrical stimulation of hindlimb motor/sensory cortex of awake rats increased 2DG uptake in the contralateral and ipsilateral cerebellum. The largest increases occurred in granule cell patches in the contralateral copula pyramidis (Cop P) and pyramis (P), the hemispheric and vermal portions of the eighth cerebellar lobule, respectively. The granule cell patches formed parasagittal bands that extended short distances mediolaterally, and extended long distances anteroposteriorly over much of the Cop P. Forelimb motor/sensory cortex stimulation increased 2DG uptake bilaterally in the seventh, paramedian (PM) cerebellar lobule. The greatest increases occurred in the granule cell layer contralateral to the stimulation. These and the above results generally agree with classical studies that localize forelimb on the seventh lobule anterior to the hindlimb on the eighth lobule. However, hindlimb cortical stimulation activated parts of the PM, and forelimb cortical stimulation activated portions of the rostral Cop P. In general, nonoverlapping portions of Cop P and PM were activated during the two types of cortical stimulation. These results are consistent with a fractured somatotopy (Welker and Shambes, '85) in which nonadjacent body parts are consistently represented in adjacent granule cell patches on each lobule, with the fractured somatotopy being different for every lobule. No region of cerebellum expressed Fos in unstimulated, electrode implanted, control subjects. However, following 15 minutes of electrical stimulation of hindlimb cortex, Fos was expressed 4 hours later in patches of granule cell nuclei in Cop P and P. These patches of Fos immunostained granule cells occurred in similar locations in Cop P to the patches of highest glucose metabolism observed with the 2DG method. Zones of Purkinje cell nuclei also expressed Fos. These Purkinje cell zones were often directly over similar sized granule cell patches in P. In the hemisphere however, the zones of Purkinje cells in ventrolateral Cop P expressing Fos only partially overlapped underlying granule cell patches that expressed Fos. Moreover, Fos was not unduced in any Purkinje cells adjacent to the Fos- stained granule cell patch in dorsolateral Cop P.(ABSTRACT TRUNCATED AT 400 WORDS)
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Induction of the c-fos gene product in rat forebrain following cortical lesions and NGF injections.
Neocortical lesions and NGF injections into neocortex induce the immunostaining of Fos, the c-fos gene product, in neuronal nuclei in ipsilateral cortex, and amygdala. Adjacent structures including hippocampus, septal nuclei, globus pallidus, and thalamus were unaffected. It is hypothesized that trophic molecules or other chemicals are released at the injury site and these induce the c-fos gene in cells throughout the ipsilateral hemisphere. Fos induction might mediate metabolic or plasticity responses to the focal injury.
Animals↗
Function and quality of life results after ileal pouch surgery for chronic ulcerative colitis and familial polyposis.
The aim of this study was to assess gastrointestinal function and quality of life, including occupational, social, and sexual function, in 75 patients who underwent pelvic pouch construction between November 1984 and May 1988 at our institution. Complications occurred in 45 percent of patients after pouch construction and in 17 percent after ileostomy closure. One patient died from sepsis caused by an anastomotic leak after ileostomy closure. The most common complication was a pouch-anal anastomotic stricture (22 percent), and the complication with the greatest potential morbidity was pouch-anal dehiscence (8 percent), which was highly predictive of pouch failure. Functional results were assessed by questionnaire during the 3-month period after ileostomy closure in all 58 patients who successfully attained intestinal continuity. A second assessment was performed at 15 +/- 11 months after ileostomy closure in 52 patients whose continuity had been restored for longer than 3 months. In an overall assessment, 94 percent of all patients with restored intestinal continuity (73 percent of entire patient group) rated the pouch as being superior to a permanent ileostomy and 92 percent (71 percent of entire group) would go through another pouch procedure. These results support the continued recommendation of this procedure as an acceptable alternative to proctocolectomy and permanent ileostomy in patients with ulcerative colitis or familial polyposis.
Adenomatous Polyposis Coli↗
Heat shock proteins as markers of neural injury.
Systemic or intracerebral injections of kainic acid induced immunoreactivity for the 72 kDa heat shock protein (HSP72) in individual neurons of the rat brain in patterns matching the known histopathology of the particular injury. HSP72 immunostaining was also induced in and around areas of infarction following experimental strokes. These results suggest that HSP72 immunocytochemistry may be used as a marker of cellular injury in the mammalian brain.
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Trigeminal nerve section induces Fos-like immunoreactivity (FLI) in brainstem and decreases FLI in sensory cortex.
Transecting the infraorbital nerve to the rat whiskers induced Fos-like immunoreactivity (FLI) in lamina I and II neuronal nuclei of the spinal trigeminal nucleus pars caudalis (Sp5c). The Fos-like immunostaining persisted for several weeks. The prolonged expression of FLI in Sp5c could be related to persistent activity in the sectioned nerve, or to trophic effects of injured ganglion neurons on brainstem cells. We postulate that Fos and related proteins may be involved in mediating alterations in gene expression associated with relatively long-term CNS adaptations to peripheral nerve injuries. Surprisingly, FLI decreased in contralateral sensory cortex, mainly in layers 2, 3 and 6, up to several days after the lesion. These decreases of cortical FLI may be due to decreased sensory neuronal activity, and/or to reducing the trophic influence of thalamic inputs on cortical neurons.
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Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study.
The distribution and time course of altered cerebral metabolism following permanent focal ischemia was studied in rat using the 2-deoxyglucose (2DG) technique. Increased 2DG uptake preceded decreased 2DG uptake and infarction in the caudate putamen and cortex. Decreased 2DG uptake without infarction was observed for 72 h in thalamus and for 24 h in hippocampus (areas remote from the ischemic zones). This study supports the concept of cell excitation as a pathophysiologic process in permanent focal ischemia. The time course of increased metabolism may demarcate the time window of opportunity for the previously demonstrated attenuation of stroke size with inhibition of cell excitation by pharmacologic blockade of excitatory amino acid neurotransmission.
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Regional brain glycogen stores and metabolism during complete global ischaemia.
Microwave fixation in situ was used to assess regional glycogen and glucose stores in normal rat brain. Glycogen levels were highest in the cerebellum and pons/medulla (38.0 and 35.6 nmol/mg protein), and lowest in the striatum and cerebral cortex (17.4 and 23.6 nmol/mg protein respectively). Glucose concentrations paralleled glycogen, ranging from 5.9 to 10.8 nmol/mg protein. Glycogen, glucose, and lactate were measured during complete global ischaemia (decapitation) to assess regional differences in ischaemic metabolism. Those regions which in normal brain contain higher glycogen and glucose stores were found to maintain significantly higher levels of glycogen and glucose for at least 2 minutes of ischaemia. Lactate accumulated to highest levels after 30 minutes of ischaemia in those regions with highest glucose and glycogen stores. Lactate levels did not, however, rise above 90 nmol/mg protein in any brain region, a level well below that considered potentially neurotoxic. The data indicate considerable regional differences in normal and ischaemic glycogen metabolism that might contribute to known regional differences in vulnerability to global ischaemia.
Animals↗
Regulation of glycogen content in primary astrocyte culture: effects of glucose analogues, phenobarbital, and methionine sulfoximine.
Compounds known to affect glycogen metabolism in vivo or in cell-free preparations were used to investigate the regulation of glycogen content in intact astrocytes cultured from newborn rat cortex. Compounds were added with fresh medium to culture dishes, and astrocyte glucose and glycogen content determined 24 h later. Increasing the medium glucose concentration from 7.5 mM to 30 mM increased cell glycogen content 80%. Addition of 2-deoxyglucose or 3-O-methyl glucose (2.5-10 mM) also increased cell glycogen content, 50-100%, suggesting a regulatory rather than mass action effect of glucose on astrocyte glycogen content. The phosphorylase b inhibitors 2,2',4,4',5,5'-hexabromobiphenyl and riboflavin had no effect on astrocyte glycogen content, consistent with negligible phosphorylase b activity in normal astrocytes. Phenobarbital and L-methionine-DL-sulfoximine (MSO) are both known to induce astrocyte glycogen accumulation in vivo. The addition of phenobarbital (2 mM) had no effect on the glycogen content of cultured astrocytes, suggesting an indirect mechanism for the in vivo effect. MSO at 1 mM, however, induced a 300% increase in glycogen content. The time course of glucose and glycogen content after MSO administration suggests this increase to be the result of slowed glycogenolysis rather than accelerated glycogen synthesis.
3-O-Methylglucose↗
Suprachiasmatic nucleus: phase-dependent activation during the hibernation cycle.
The suprachiasmatic nucleus (SCN) of the golden-mantled ground squirrel undergoes a phase-dependent change in its accumulation of 2-[14C]deoxy-D-glucose (2-DG) relative to other brain structures during the hibernation cycle. The greatest relative 2-DG uptake (R2DGU) is observed in the SCN during entrance into and during deep hibernation. A circadian fluctuation in R2DGU of the SCN is not evident in the euthermic ground squirrel but can be increased during the subjective day by photic stimulation. An increase in R2DGU by the paraventricular nucleus (PVN) correlates with the increase in R2DGU by the SCN during entrance to hibernation but not with the increase in SCN R2DGU evoked by photic stimulation during euthermia. The periventricular nuclei of the hypothalamus (PEV) also have high levels of R2DGU during the latter phase of the entrance. These observations support the hypothesis that the SCN, PEV, and PVN may play important roles in hibernation and suggest progressive activation of synaptic input to and within the SCN during entrance into this state.
Animals↗
Expression of c-fos protein in brain: metabolic mapping at the cellular level.
The proto-oncogene c-fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters. In order to determine whether the c-fos protein (Fos) and Fos-related proteins can be induced in response to polysynaptic activation, rat hindlimb motor/sensory cortex was stimulated electrically and Fos expression examined immunohistochemically. Three hours after the onset of stimulation, focal nuclear Fos staining was seen in motor and sensory thalamus, pontine nuclei, globus pallidus, and cerebellum. Moreover, 24-hour water deprivation resulted in Fos expression in paraventricular and supraoptic nuclei. Fos immunohistochemistry therefore provides a cellular method to label polysynaptically activated neurons and thereby map functional pathways.
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