Muscarinic receptor-mediated induction of Fos protein in rat brain.

Recent studies have shown that the centrally active muscarinic agonist pilocarpine induces c-fos mRNA in rat cortex. Here we describe the localization of muscarinic receptor-induced FOS protein, within the rat central nervous system (CNS), following administration of pilocarpine (25 mg/kg). High levels of FOS induction were apparent in many forebrain structures including the primary olfactory (piriform) cortex, nucleus accumbens, amygdala, hippocampus, neocortex and supra-optic nucleus of the hypothalamus.

MK801 induces immediate-early gene proteins and BDNF mRNA in rat cerebrocortical neurones.

Recent studies have shown that MK801, a potent phencyclidine receptor ligand, causes pathomorphological changes in rat cerebrocortical neurones. Here we report that doses of MK801 (1 and 5 mg kg-1) which have been shown to produce pathomorphological changes, induce the expression of immediate-early gene proteins (IEGPs) and brain-derived neurotrophic factor (BDNF) mRNA in rat cerebrocortical neurones. Blockade of central muscarinic receptors which has been shown to prevent MK801-induced pathomorphological changes in cerebrocortical neurones, also prevented MK801-induced expression of IEGPs and BDNF mRNA.

The regional, cellular and subcellular localization of GABAA/benzodiazepine receptors in the substantia nigra of the rat.

The regional, cellular and subcellular distribution of GABAA/benzodiazepine receptors was investigated by light and electron microscopy in the rat substantia nigra. The regional distribution and density of GABAA/benzodiazepine receptor subtypes (Type I and II) was studied using quantitative receptor autoradiography following in vitro labelling of cryostat sections with tritiated ligands. This was followed by a detailed study of the cellular and subcellular distribution and localization of GABAA/benzodiazepine receptors by light and electron microscopy using immunohistochemical techniques with a monoclonal antibody (bd-17) to the beta 2,3 subunits of the GABAA/benzodiazepine receptor complex.

Axotomized medial septal-diagonal band neurons express Jun-like immunoreactivity.

The expression of the transcription factors Fos and Jun was studied in rat brain after transection of the fornix-fimbria (FF) using polyclonal antibodies to these proteins and immunocytochemical detection methods. FF-transection lead to a massive induction of Jun-like immunoreactivity (JLI) in neurons in the medial septal nucleus and in the vertical limb of the diagonal band of Broca, within 48 hours and lasting up to 14 days after lesion. Fos was not induced in these neurons after FF-transection.

Accumulation of calcitonin-gene related peptide-like immunoreactivity after hypoxic-ischaemic brain injury in the infant rat.

Unilateral carotid ligation in immature rats, followed by either 15 min (moderate group) or 90 min (severe group) of hypoxia were used to assess the effects of hypoxia-ischaemia (HI) on the accumulation of the neuropeptide calcitonin-gene related peptide (CGRP). Severe, but not moderate, HI produced a massive time-dependent increase in CGRP-like immunoreactivity throughout the damaged regions of the brain (neocortex, caudate-putamen, hippocampus) beginning at 24 h and maximal at 3-5 days after HI. By 11 days after HI levels appeared to have returned to baseline.

Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus.

Expression of the immediate early gene zif/268 (also termed NGFI-A, Krox 24, TIS8 and Egr-1) was investigated in awake rats following various long-term potentiation (LTP) induction protocols. zif/268 mRNA (Northern blots) and protein (immunohistochemistry) levels sharply increased following LTP, and followed a time course characteristic of other immediate early genes. When measured across 3 tetanization protocols known to produce differing degrees of LTP persistence, zif/268 induction was found to be more highly correlated with LTP duration than with the magnitude of initial LTP.

Basal expression of Fos, Fos-related, Jun, and Krox 24 proteins in rat hippocampus.

The basal expression of the protein products of the inducible immediate early genes (IEGs), Fos, Jun, and Krox 24, was investigated in rat hippocampus using immunocytochemical visualization methods with antisera specific for Fos only, Fos and the Fos-related antigens (FRAs), the Jun family, and Krox 24 (previously described as TIS 8, egr-1, NGF-IA or zif 268). In the normal adult rat brain basal levels of Jun, Krox 24 and Fos-related antigens but not Fos were seen within the hippocampus. More specifically very high basal levels of Jun were seen in the dentate granule cells with high basal Krox 24 levels seen in the CA1-subiculum region of the rat hippocampus.

Induction of immediate-early gene proteins in dentate granule cells and somatostatin interneurons after hippocampal seizures.

The expression of the protein products of the immediate-early genes c-fos, Fos B, Fos-related proteins (FRAs), c-jun, jun B, jun D and krox-24 was investigated in the rat hippocampus at various times after electrically-induced hippocampal seizures. Hippocampal seizures induced all the immediate-early gene proteins in dentate granule cells with differing time-courses. In addition, Krox-24, Fos and Jun D were also induced in somatostatin-containing interneurons throughout the hippocampus and also in a small percentage of parvalbumin-containing interneurons.

A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury.

Three days after unilateral hypoxic-ischemic injury in infant rats insulin-like growth factor 1 (IGF-1) production by astrocytes was enhanced in the injured region. This was associated with increased expression of mRNA for IGF binding protein-3 but not for binding protein-1. In adult rats a single lateral cerebroventricular injection of IGF-1 two hours following a similar injury markedly reduced neuronal loss.

Distribution of excitatory and inhibitory amino acid, sigma, monoamine, catecholamine, acetylcholine, opioid, neurotensin, substance P, adenosine and neuropeptide Y receptors in human motor and somatosensory cortex.

Autoradiography was used to visualise N-methyl-D-aspartate, phencyclidine, strychnine-insensitive glycine, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, kainic acid, benzodiazepine, gamma-aminobutyric acid type A, sigma, serotonergic, dopaminergic, alpha 2-adrenergic, beta-adrenergic, muscarinic cholinergic, nicotinic, opioid, neurotensin, substance P, adenosine A1 and neuropeptide Y receptors in the human primary motor (Brodmann's area 4) and somatosensory cortex (Brodmann's areas 3, 2 and 1). With the exception of serotonin type 2 receptors, all receptor types examined had a similar distribution in area 4 which showed little dependence on the underlying distribution of cell somata, often continuing unaltered through the somatosensory cortex despite marked cytoarchitectural changes. The highest densities occurred in the outer (most superficial) 30-40% of the cortical grey matter, followed by a band of relatively low binding and then moderate levels in the inner (deeper) region.

Autoradiographic distribution of sigma receptors in human neocortex, hippocampus, basal ganglia, cerebellum, pineal and pituitary glands.

Autoradiographic distributions of [3H]1,3-di-O-tolylguanidine, [3H]DTG, binding to sigma (sigma) receptors were studied in key human brain regions. High densities occurred in the substantia nigra pars compacta and cerebellum. Pineal and pituitary levels were moderate.

Elevated expression of jun and fos-related proteins in transplanted striatal neurons.

The basal expression of the immediate-early gene protein products fos, fos-related antigens (FRA's), jun and krox-24 was examined using immunocytochemical methods in intrastriatal grafts derived from fetal striatal primordia. Whereas very few, if any, normal adult striatal neurons expressed jun, many neurons in the striatal graft expressed jun at high levels. FRA's, but not fos, were also occasionally induced in some grafted striata.

Prolonged and selective induction of Fos-related antigen(s) in striatal neurons after 6-hydroxydopamine lesions of the rat substantia nigra pars compacta.

Unilateral 6-hydroxydopamine (6-OHDA) lesions of the rat substantia nigra lead to a large widespread and long-lasting (greater than 3 months) increased expression of Fos-related antigen(s) (FRAs) in striatal neurons ipsilateral to the side of the lesion. However, Fos and Jun expression were only very slightly increased in a few scattered neurons in the dopamine-denervated striatum. These results demonstrate that FRAs are induced long-term in striatal neurons following dopamine-depletion.

Autoradiographic visualisation of [3H]DTG binding to sigma receptors, [3H]TCP binding sites, and L-[3H]glutamate binding to NMDA receptors in human cerebellum.

The autoradiographic distributions of [3H]1,3-di-ortho-tolyguanidine ([3H]DTG), [3H]1-[1-(2-thienyl) cyclohexyl] piperidine ([3H]TCP) and L-[3H]glutamate were studied in the human cerebellum. [3H]DTG is a selective label for the sigma receptor, while L-[3H]glutamate binding was carried out under conditions selective for the N-methyl-D-aspartate (NMDA) receptor. [3H]TCP binding sites and sigma receptors showed marked enrichment in the Purkinje cell layer, while L-[3H]glutamate-labelled NMDA receptors showed virtually no binding in the Purkinje cell layer.

Differential sensitivity of calbindin and parvalbumin immunoreactive cells in the striatum to excitotoxins.

The neurotoxic effects of ibotenic acid, quinolinic acid and kainic acid on cells in the rat striatum were investigated using immunocytochemistry with antibodies to the calcium binding proteins, calbindin and parvalbumin. The results showed that both ibotenic acid and quinolinic acid affected calbindin and parvalbumin cells to the same extent. However, parvalbumin immunopositive neurons were more sensitive than calbindin immunopositive neurons to the neurotoxic effects of kainic acid.

3,4-Methylenedioxymethamphetamine induces Fos-like proteins in rat basal ganglia: reversal with MK 801.

Injections of 3,4-methylenedioxymethamphetamine (MDMA, 25 mg/kg, i.p.) to rats lead to an accumulation of c-fos protein (Fos) and Fos-related antigens in caudate-putamen, nucleus accumbens and olfactory tubercle.

The role of immediate early genes in the stabilization of long-term potentiation.

Immediate early genes (IEGs) are a class of genes that show rapid and transient but protein synthesis-independent increases in expression to extracellular signals such as growth factors and neurotransmitters. Many IEGs code for transcription factors that have been suggested to govern the growth and differentiation of many cell types by regulating the expression of other genes. IEGs are expressed in adult neurons both constitutively and in response to afferent activity, and it has been suggested that during learning, IEGs may play a role in the signal cascade, resulting in the expression of genes critical for the consolidation of long-term memory.

Presence and induction of Fos B-like immunoreactivity in neural, but not non-neural, cells in adult rat brain.

The presence and induction of Fos B, a novel growth factor-activated gene, was investigated in adult rat brain using an antiserum to Fos B and immunocytochemical methods. In normal rat brain immunoreactivity was detected in the nuclei of nerve cells scattered in the cerebral cortex, striatum, amygdala, hippocampus and dentate gyrus. This immunostaining was not present in adjacent brain sections incubated with anti-Fos B serum preadsorbed with the Fos B peptide.

NMDA and kainic acid receptors have a complementary distribution to AMPA receptors in the human cerebellum.

The distributions of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-S-methyl-4-isoxazole propionic acid (AMPA) and kainic acid (KA) receptors were determined in the human cerebellum using autoradiography. In contrast to the cerebral cortex, where KA receptors have a complementary distribution to NMDA and AMPA receptors, AMPA receptors were concentrated in the cerebellar molecular layer while NMDA and KA receptors were concentrated in the granular layer.

Effects of hypoxia-ischemia and seizures on neuronal and glial-like c-fos protein levels in the infant rat.

Unilateral carotid ligation in immature rats, followed by 2 h of hypoxia led to ischemic cell change from 2 h after the insult, on the ligated side of the brain. There was a time-dependent induction of immunoreactive c-fos protein in neurones but not glia or ependyma on the non-ligated side of the brain. Induction only occurred in rats that had seizures post hypoxia-ischemia.

Haloperidol induces Fos and related molecules in intrastriatal grafts derived from fetal striatal primordia.

Haloperidol induces Fos and related molecules (Fos-related antigens, FRAs) in adult striatal neurons. We tested whether a similar induction of Fos and FRAs by haloperidol injection would occur in fetal striatal neurons transplanted into adult quinolinic acid-lesioned striatum. We found that Fos and FRAs were induced in striatal neurons after haloperidol.

Induction of Fos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanesthetized rats.

Memory formation in the mammalian central nervous system may require long-lasting alterations in gene expression. However, it is not yet known whether the candidate memory mechanism long-term potentiation (LTP) requires alterations in gene expression for its maintenance, nor the extent to which the time course of LTP can be manipulated at the time of induction. In this study we influenced the time course of LTP decay for the perforant path input to the dentate gyrus in awake rats by manipulating conditions at the time of induction, and correlated the outcome with the induction of c-fos protein(s) (Fos), as measured immunohistochemically in the dentate gyrus of separate animals 2 h post-tetanization.

Induction of Fos in glia-like cells after focal brain injury but not during wallerian degeneration.

Focal brain injury or perforant-path transections respectively led to an increase in the number of glial-fibrillary acidic protein (GFAP)-immunopositive astrocytes around the focal wound or in the terminal fields of the perforant path in the dentate molecular layer. This GFAP accumulation occurred 48-72 h after focal brain injury or perforant-path transection (wallerian degeneration). Focal brain injury also led to an accumulation of c-fos protein (Fos) in glial cells, ependyma and cells in the pia mater of the brain within 6 h of injury and this effect dissipated within 72 h.

Adenosine receptor antagonism accounts for the seizure-prolonging effects of aminophylline.

The mechanism of action of aminophylline in prolonging seizures was tested in amygdala-kindled rats. Aminophylline prolonged the afterdischarge duration of kindled seizures. This seizure-prolonging action of aminophylline was strongly antagonized by the adenosine A1 agonist cyclohexyladenosine and partially antagonized by the benzodiazepine partial agonist RO 15-1788.