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PubMed2002

Developmental expression of the zinc finger transcription factor DRRF (dopamine receptor regulating factor).

Dopamine receptor regulating factor (DRRF) is a novel transcription factor with unique anatomical distribution and functional properties, suggesting its importance in regulating dopaminergic neurotransmission. To gain insight into the in vivo function of this factor during embryogenesis, we studied its distribution at embryonic days E8-E16 in the mouse using in situ hybridization. DRRF mRNA is expressed uniquely during development at all time points tested with high levels observed at E12, E14 and E16 in various tissues. DRRF expression is also found in particular brain regions, such as the neopallial cortex, olfactory lobe and corpus striatum. This pattern of DRRF distribution during embryogenesis overlaps with that found in the adult brain, and with the expression profile of dopamine receptors both in the adult and during development.

Animals↗
PubMed1998

The central 5-HT3 receptor in CNS disorders.

Among the characterized 5-HT receptors of the central nervous system, the type 3 receptor subtype (5-HT3R) is the only one known to be a ligand-gated ion channel. Its early pharmacological characterization and mapping by radioligand binding autoradiography suggested that this receptor may, among other actions, regulate dopamine release in the nigro-striatal pathway and reduce alcohol consumption in experimental animals while antagonists of this receptor have been reported to treat anxiety disorders. Following the cloning of this receptor in 1991, direct cellular localization was made possible by in situ hybridization and immunohistochemical analysis. Here we summarize our recent efforts showing that 5-HT3R-expressing neurons are mainly GABA containing cells in the rat neocortex, olfactory cortex, hippocampus, and amygdala which also often contain cholecystokinin (CCK) immunoreactivity. These results provide a means to unify some of the initial pharmacological observations.

Animals↗
PubMed1980

Odor discrimination and memory in Korsakoff's psychosis.

Korsakoff's syndrome is an organic brain disease, characterized by severe amnesia, that has been associated with olfactory perceptual deficits. Two experiments utilized normal observers to describe the effect of similarity on odor recognition memory and to develop methodology to measure odor discrimination and memory in patients with Korsakoff's disease. The results demonstrate an impaired capacity to discriminate between odors among patients with this disease that is not attributable to impaired sensitivity or to rapid decay of memory stores. These results are compared with results from animals with lesions affecting the medial layer of the mediodorsal thalamic nucleus and its neocortical projections. This structure is consistently damaged in Korsakoff's disease and receives a major input from primary olfactory cortex.

Alcohol Amnestic Disorder↗
PubMed1985

Ischemic brain damage in rats following cardiac arrest using a long-term recovery model.

A model is described in which transient complete cerebral ischemia is induced in rats by intracardiac injection of potassium chloride. The animals were intubated and mechanically ventilated with a nitrous oxide/oxygen (70:30) mixture. Cardiac arrest was achieved following a brief period of ventricular fibrillation. After 5-6 min, the circulation was restored by cardiopulmonary resuscitation and partial exchange transfusion. Local CBF (LCBF) during ischemia and cardiac resuscitation was studied by injection of [14C]iodoantipyrine into the right auricle at various periods during cardiac arrest, and was subsequently analyzed by autoradiography. No radioactive tracer could be visualized in any brain structure, demonstrating the absence of CBF during the cardiac standstill. LCBF was also studied at 5 min and 6.5 h after cardiac resuscitation. Five minutes of recirculation showed an increase in blood flow in all brain structures studied, ranging between 130 and 400% of control values. After 6.5 h of recirculation, the CBF was decreased in 13 of 24 brain structures by 20-50%, concomitantly with the depressed rate of glucose utilization found in 15 brain structures. The neocortical, hippocampal, and striatal concentrations of labile phosphates, lactate, pyruvate, phosphocreatine, glucose, and glycogen were measured 5 min after cardiac arrest. Extensive energy failure and elevation of lactate levels were observed and were similar to earlier reported values. One week following recovery from the ischemic insult, the animals were perfusion-fixed with formaldehyde. The brains were embedded in paraffin, subserially sectioned, and stained with cresyl violet/acid fuchsin. Histopathological changes were assessed by light microscopy as the number of acidophilic or pyknotic neurons. Morphological changes were observed in the hilus of the dentate gyrus, the hippocampal CA1 and subicular regions, the dorsal and lateral septum, the olfactory tubercle, the primary olfactory cortex, the entorhinal cortex, the amygdaloid nuclei, and the reticular nucleus of the thalamus. The distribution of the morphological changes suggests a transsynaptic mechanism, causing neuronal necrosis primarily in the limbic brain areas.

Animals↗
PubMed2003

Topiramate hyperpolarizes and modulates the slow poststimulus AHP of rat olfactory cortical neurones in vitro.

1. The effects of the novel antiepileptic drug topiramate (TPM) were investigated in rat olfactory cortex neurones in vitro using a current/voltage clamp technique. 2. In 80% of recorded cells, bath application of TPM (20 microm) reversibly hyperpolarized and inhibited neuronal repetitive firing by inducing a slow outward membrane current, accompanied by a conductance increase. The response was reproducible after washout, and was most likely carried largely by K(+) ions, although other ionic conductances may also have contributed. 3. In 90% of cells, TPM (20 microm) also enhanced and prolonged the slow (Ca(2+)-dependent) poststimulus afterhyperpolarization (sAHP) and underlying slow outward tail current (sI(AHP)). This effect was due to a selective enhancement/prolongation of an underlying L-type Ca(2+) current that was blocked by nifedipine (20 microm); the TPM response was unlikely to involve an interaction at PKA-dependent phosphorylation sites. 4. The carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ, 20 microm) and the poorly membrane permeant inhibitor benzolamide (BZ, 50 microm) both mimicked the membrane effects of TPM, in generating a slow hyperpolarization (slow outward current under voltage clamp) and sAHP enhancement. ACTZ and BZ occluded the effects of TPM in generating the outward current response, but were additive in producing the sAHP modulatory effect, suggesting different underlying response mechanisms. 5. In bicarbonate/CO(2)-free, HEPES-buffered medium, all the membrane effects of TPM and ACTZ were reproducible, therefore not dependent on CA inhibition. 6. We propose that both novel effects of TPM and ACTZ exerted on cortical neurones may contribute towards their clinical effectiveness as anticonvulsants.

Acetazolamide↗
PubMed2003

Imaging brain phospholipase A2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats.

Fluoxetine, a selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT(2A/2C) receptors. These receptors can be coupled via a G-protein to phospholipase A(2) (PLA(2)), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k(*) of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k(*) in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT(2A/2C) receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA(2)-mediated signal transduction in vivo in response to fluoxetine.

Animals↗
PubMed2006

Gene transcription alterations associated with decrease of ethanol intake induced by naltrexone in the brain of Wistar rats.

Preclinical and clinical studies suggest that the administration of the opioid antagonist naltrexone decreases the intake of ethanol. However, the neuroplastic adaptations in the brain associated to reduction of ethanol consumption remains to be elucidated. The aim of the study was to identify gene transcription alterations underlying the attenuation of voluntary ethanol intake by administration of naltrexone in rats. Increasing doses of naltrexone (0.7 mg/kg, 4 days and 1.4 mg/kg/day, 4 days) to rats with acquired high preferring ethanol consumption (>3.5 g of ethanol/kg/day) decreased voluntary ethanol intake (50%). Voluntary ethanol consumption altered mu-opioid receptor function in the cingulate cortex, caudate-putamen (CPu), nucleus accumbens core (Acb C) and shell (Acb S), the expression of tyrosine hydroxylase (TH) in the ventral tegmental area and substantia nigra, proenkephalin (PENK) in the piriform cortex, olfactory tubercle, CPu, Acb C and Acb S, ventromedial nucleus (VMN) and paraventricular nucleus (PVN) of the hypothalamus, corticotropin releasing factor (CRF) in PVN, cannabinoid CB(1) receptor (CB1-R) in the CPu, hippocampus and VMN, and serotonin transporter (5-HTT) in the dorsal and median raphe nuclei. The reduction of ethanol intake induced by naltrexone was associated with a blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. These results point to a role for the mu-opioid receptor, TH, PENK, CRF, CB1-R, and 5-HTT genes in specific brain regions in the modulation of neuroadaptative mechanisms associated to the decrease of ethanol intake induced by naltrexone.

Alcohol Drinking↗
PubMed1998

Corticotropin-releasing factor receptor type 1 from Tupaia belangeri--cloning, functional expression and tissue distribution.

A cDNA clone encoding corticotropin-releasing factor (CRF) type 1 (CRF-R1) has been isolated from the tree shrew Tupaia belangeri with a PCR-based approach. The full-length cDNA encoded a 415-amino-acid protein with highest sequence identity (approximately 98%) to human CRF-R1 and slightly less identity to rat or mouse CRF-R1 (approximately 97%). Only eight amino acids (residues 3, 4, 6, 35, 36 and 39 in the N-terminus, residue 232 in transmembrane domain 4 and residue 410 in the C-terminus) differed between tree shrew CRF-R1 (tCRF-R1) and human CRF-R1 (hCRF-R1). tCRF-R1 mRNA was detected by semiquantitative RT-PCR and RNase protection analysis in the pituitary and in brain areas such as amygdala, brainstem, cerebellum, cortex, olfactory bulb, and striatum. In peripheral organs, only weak expression of tCRF-R1 mRNA was observed in ovary, testis, and adrenal gland. Binding studies using human embryonic kidney 293 (HEK293) cells stably transfected with tCRF-R1 showed that the CRF agonists ovine CRF (KD = 1.28 nM), human/rat CRF (KD = 1.09 nM), urocortin (KD = 0.37 nM) and sauvagine (KD = 0.77 nM), respectively, were bound with significantly higher affinities than the CRF antagonist astressin (KD = 12.4 nM). In agreement with the binding data half maximum effective EC50 values of 0.83 nM (human/rat CRF), 1.41 nM (ovine CRF), 1.25 nM (rat urocortin) and 0.71 nM (sauvagine) were calculated when the cAMP production in HEK293 cells stably transfected with tCRF-R1 was stimulated with the four CRF analogues. These data underline the close relationship between human and tree shrew CRF-R1.

Amino Acid Sequence↗
PubMed2000

Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit.

The auxiliary calcium channel alpha2delta subunit comprises a family of three genes, alpha2delta-1 to 3, which are expressed in a tissue-specific manner. alpha2delta-2 mRNA is found in the heart, skeletal muscle, brain, kidney, liver and pancreas. We report here for the first time the identification and functional characterization of alpha2delta-2 splice variants and their mRNA distribution in the mouse brain. The splice variants differ in the alpha2 and delta protein by eight and three amino acid residues, respectively, and are differentially expressed in cardiac tissue and human medullary thyroid carcinoma (hMTC) cells. In situ hybridization of mouse brain sections revealed the highest expression of alpha2delta-2 mRNA in the Purkinje cell layer of the cerebellum, habenulae and septal nuclei, and a lower expression in the cerebral cortex, olfactory bulb, thalamic and hypothalamic nuclei, as well as the inferior and superior colliculus. As the in situ data did not suggest a specific colocalization with any alpha1 subunit, coexpression studies of alpha2delta-2 were carried out either with the high-voltage-gated calcium channels, alpha1C, alpha1E or alpha1A, or with the low-voltage-gated calcium channel, alpha1G. Coexpression of alpha2delta-2 increased the current density, shifted the voltage dependence of channel activation and inactivation of alpha1C, alpha1E and alpha1A subunits in a hyperpolarizing direction, and accelerated the decay and shifted the steady-state inactivation of the alpha1G current.

Alternative Splicing↗
PubMed2002

Learning-induced reduction in post-burst after-hyperpolarization (AHP) is mediated by activation of PKC.

We studied the role of protein kinase C (PKC) and protein kinase A (PKA) in mediating learning-related long lasting reduction of the post-burst after-hyperpolarization (AHP) in cortical pyramidal neurons. We have shown previously that pyramidal neurons in the rat piriform (olfactory) cortex from trained (TR) rats have reduced post-burst AHP for 3 days after odour-discrimination learning, and that this reduction is due to decreased conductance of calcium-dependent potassium current. In the present study, we examined whether this long-lasting reduction in AHP is mediated by second messenger systems. The broad-spectrum kinase inhibitor, H7, increased the AHP in neurons from TR rats, but not in neurons from pseudo-trained (pseudo-TR) and naive rats. Consequently, the difference in AHP amplitude between neurons from TR and control animals was diminished. This effect was also obtained by application of the specific PKC inhibitor, GF-109203x. The PKC activator, 1-Oleoyl-2-acetyl-sn-glycerol (OAG), significantly reduced the AHP in neurons from naive and pseudo-TR rats, but not in neurons from TR rats, so that the difference between the groups was abolished. The PKA-specific inhibitor, H-89, increased the AHP in neurons from all groups to a similar extent, and the difference in AHP amplitude between neurons from TR rats and neurons from controls was maintained. We suggest that while the post-burst AHP in piriform cortex pyramidal neurons is modulated by both PKC and PKA, a PKC-dependent process maintains the learning-related reduction of the AHP in these cells.

Action Potentials↗
PubMed1995

Heterogeneous expression of transketolase in rat brain.

Transketolase (TK; EC 2.2.1.1) is a key pentose phosphate shunt enzyme that plays an important role in the production of reducing equivalents and pentose sugars. TK activity declines in the brains of patients with Alzheimer's disease or Wernicke-Korsakoff syndrome, as well as in thiamine-deficient rats. Understanding the role of TK in the pathophysiology of these neurodegenerative conditions requires knowledge of its regional, cellular, and subcellular distribution within the brain. The current study employed in situ hybridization and immunocytochemistry to examine the distribution of TK mRNA and its encoded protein in adult rat brain. TK mRNA and protein were widely distributed throughout the brain. However, they were enriched in selective perikarya in the piriform cortex, nucleus of the diagonal band, red nucleus, dorsal raphe, pontine nucleus, locus coeruleus, trapezoid, inferior olive, and several cranial nerve nuclei. Lower expression of TK mRNA and protein occurred in layer V of cortex, olfactory tubercle, ventral pallidum, medial septal nucleus, hippocampus, thalamic and hypothalamic nuclei, mammillary body, central gray, and the substantia nigra. TK immunoreactivity also occurred in the nuclei of ubiquitously distributed glial cells, as well as ependymal cells. The heterogeneous distribution of TK may reflect a variety of metabolic activities among different brain regions but does not provide a simple molecular explanation for selective cell death in either thiamine deficiency or other conditions where TK is reduced.

Animals↗
PubMed1996

Arachidonate 5-lipoxygenase and its activating protein: prominent hippocampal expression and role in somatostatin signaling.

5-Lipoxygenase-activating protein (FLAP) is an 18-kDa integral membrane protein required, in peripheral cells, for the activation of 5-lipoxygenase (5-LO) and for the resulting synthesis of leukotrienes from arachidonic acid. In the brain, the leukotrienes have been implicated in several pathophysiological events and in the electrophysiological effect of somatostatin, yet the cellular origin and role of these messenger molecules are still poorly understood. In the present study, we used reverse transcriptase-polymerase chain reaction, in situ hybridization, and immunohistochemistry to demonstrate that 5-LO and FLAP are expressed in various regions of the rat brain, including hippocampus, cerebellum, primary olfactory cortex, superficial neocortex, thalamus, hypothalamus, and brainstem. Highest levels of expression were observed in cerebellum and hippocampus. In the latter we demonstrate the colocalization of 5-LO and FLAP in CA1 pyramidal neurons. Moreover, electrophysiological experiments show that selective inhibition of FLAP with the compound MK-886 (0.25-1 microM) prevents the somatostatin-induced augmentation of the hippocampal K+ M-current. Our results provide necessary evidence for the presence and signaling role of 5-LO and FLAP in central neurons and strongly support their proposed participation in somatostatin-receptor transmembrane signaling.

5-Lipoxygenase-Activating Proteins↗
PubMed1996

Expression of the glucagon-like peptide-1 receptor gene in rat brain.

Evidence that glucagon-like peptide-1 (GLP-1) (7-36) amide functions as a novel neuropeptide prompted us to study the gene expression of its receptor in rat brain. Northern blot analysis showed transcripts of similar size in RINm5F cells, hypothalamus, and brain-stem. First-strand cDNA was prepared by using RNA from hypothalamus, brainstem, and R1Nm5F cells and subsequently amplified by PCR. Southern blot analysis of the PCR products showed a major 1.4-kb band in all these preparations. PCR products amplified from hypothalamus were cloned, and the nucleotide sequence of one strand was identical to that described in rat pancreatic islets. In situ hybridization studies showed specific labeling in both neurons and glia of the thalamus, hypothalamus, hippocampus, primary olfactory cortex, choroid plexus, and pituitary gland. In the hypothalamus, ventromedial nuclei cells were highly labeled. These findings indicate that GLP-1 receptors are actually synthesized in rat brain. In addition, the colocalization of GLP-1 receptors, glucokinase, and GLUT-2 in the same areas supports the idea that these cells play an important role in glucose sensing in the brain.

Animals↗
PubMed1999

Transcriptional regulation of mouse type 1 inositol 1,4,5-trisphosphate receptor gene by NeuroD-related factor.

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is a Ca2+ channel protein that is expressed abundantly in the CNS, such as in the cerebellar Purkinje cells and hippocampus. We previously demonstrated that the box-I element, which is located -334 relative to the transcription initiation site of the mouse IP3R1 gene and includes an E-box consensus sequence, is involved in the up-regulation of such IP3R1 gene expression. Furthermore, the previous study also indicated that some CNS-related basic helix-loop-helix (bHLH) factors bind to the box-I and activate IP3R1 gene expression. In this study, we demonstrated that one of the CNS-related bHLH factors, neuronal differentiation factor (NeuroD)-related factor (NDRF), specifically bound to the box-I sequence with a ubiquitously expressed bHLH protein, E47, and activated IP3R1 gene expression. In situ hybridization of adult mouse brain revealed that IP3R1 and NDRF mRNA were co-expressed in many subsets of neurons, highly in Purkinje cells and hippocampus and moderately in cerebral cortex, olfactory bulb, and caudate putamen. Furthermore, the spatiotemporal expression patterns of these two genes resembled one another throughout postnatal development of the mouse CNS. From these results, we suggest that NDRF is involved in the tissue-specific regulation of IP3R1 gene expression in the CNS.

Animals↗
PubMed1997

The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain.

Thyroid hormone plays an essential role in mammalian brain maturation and function, in large part by regulating the expression of specific neuronal genes. In this tissue, the type 2 deiodinase (D2) appears to be essential for providing adequate levels of the active thyroid hormone 3,5,3'-triiodothyronine (T3) during the developmental period. We have studied the regional and cellular localization of D2 mRNA in the brain of 15-day-old neonatal rats. D2 is expressed in the cerebral cortex, olfactory bulb, hippocampus, caudate, thalamus, hypothalamus, and cerebellum and was absent from the white matter. At the cellular level, D2 is expressed predominantly, if not exclusively, in astrocytes and in the tanycytes lining the third ventricle and present in the median eminence. These results suggest a close metabolic coupling between subsets of glial cells and neurons, whereby thyroxine is taken up from the blood and/or cerebrospinal fluid by astrocytes and tanycytes, is deiodinated to T3, and then is released for utilization by neurons.

Animals↗
PubMed1996

Forebrain hypoplasia following acute prenatal ethanol exposure: quantitative analysis of effects on specific forebrain nuclei.

The effects of acute prenatal exposure to ethanol on the volumes and neuronal populations of selected forebrain nuclei of postnatal animals have been examined in a mouse model. Pregnant mice were exposed to ethanol (25% ethanol, either two doses at 0.015 ml/g separated by 4 hrs, or a single dose at 0.03 ml/g) on the 8th gestational day and the cytoarchitecture of the basal forebrain, paleo- and neocortex examined quantitatively at P15. Significant reductions in the volume and total number of neurons of ventromedial and central forebrain structures, such as the olfactory bulb, septal nuclei, diagonal band nuclei and caudatoputamen, were observed in mice exposed to the divided ethanol dose, but not following the single dose. The neocortex and primary olfactory cortex were also reduced in volume in offspring exposed to the divided ethanol dose. However increased neuronal density in some neocortical regions of ethanol-exposed offspring suggests that the total number of neocortical neurons is not significantly affected by acute ethanol exposure. The findings indicate that pulse exposure to ethanol on a single day of early development causes deficits in neuronal populations of the ventromedial forebrain and caudatoputamen even in offspring without other major malformations. The results also indicate that caution should be exercised in interpreting the significance of nuclear volume reduction in human infants with fetal alcohol syndrome (FAS) in the absence of neuronal density estimates.

Animals↗
PubMed1996

Guinea pig preprodynorphin mRNA: primary structure and regional quantitation in the brain.

We isolated and sequenced genomic and cDNA clones of the guinea pig preprodynorphin (ppDyn) mRNA. The sequence of ppDyn mRNA was deduced from a combination of genomic and cDNA clones: The primary structure of two coding exons was derived from a genomic clone and 5' and 3' untranslated sequences were obtained using rapid amplification of cDNA ends (RACE). The predicted mRNA of 2,350 nucleotides coincides well with the size of transcripts in Northern blot analyses of RNA from different brain regions. The deduced amino acid sequence of guinea pig ppDyn shares 70%, 68%, and 61% identity to porcine, human, and rat ppDyn, respectively. The 5' untranslated sequences of guinea pig hippocampal and adrenal ppDyn mRNA are identical; both contain sequences of exon I and, like porcine mRNA, lack an exon (exon II) present in human and rat mRNA. Quantitative solution hybridization RNase protection analysis of total RNA from selected guinea pig brain regions was performed. The nucleus accumbens was found to have the greatest abundance of ppDyn mRNA, followed by caudate putamen, hippocampus, hypothalamus, amygdala, frontal cortex, olfactory bulb, and pons/medulla.

Adrenal Glands↗