Brain aging and neuronal plasticity.
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Aging↗
Biomedical subjects
L F Agnati
Publications and source records attributed to L F Agnati.
Evidence for a substrate of neuronal plasticity based on pre- and postsynaptic neurotensin-dopamine receptor interactions in the neostriatum.
The major mechanism underlying the neuroleptic action of the tridecapeptide neurotensin (NT) appears to be an interaction with dopamine receptor mechanisms based on biochemical binding and behavioral experiments. In vivo microdialysis was used in conscious rats to investigate the effects of local perfusion with NT on the sensitivity of striatal dopamine D1 and D2 receptors for their selective agonists by monitoring extracellular dopamine, 3,4-dihydroxyphenylacetic acid, homovanilic acid, and gamma-aminobutyric acid levels in the awake unrestrained male rat. Perfusion with NT (10 nM) counteracted the inhibitory effects of the dopamine D2 agonist pergolide (500 nM) on extracellular levels of dopamine and gamma-aminobutyric acid. In contrast, NT (10 mM) significantly enhanced the reduction of extracellular striatal levels of dopamine after perfusion with the D1 agonist SKF 38393 (5 microM), and this combined treatment also resulted in a significant increase in the extracellular striatal levels of gamma-aminobutyric acid. These results provide in vivo evidence that NT regulates central dopamine transmission by reducing pre-and postsynaptic dopamine D2 and enhancing D1 receptor sensitivity possibly through an antagonistic NT receptor-D2 receptor interaction. This heteroregulation has the potential to substantially increase the plasticity within the dopamine synapse.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Morphometric evaluation of populations of neuronal profiles (cell bodies, dendrites, and nerve terminals) in the central nervous system.
Morphometric techniques have been developed to quantitatively characterize groups of transmitter-identified neuronal profiles, such as cell groups, dendrite and nerve terminal fields. These morphometric techniques will be illustrated by introducing some general tools for image analysis which can be considered as a background for the present specific applications. The following methods have been included: (1) methods to identify and quantitatively characterize, from both numerical and geometrical standpoints, groups of profiles in a two- and three-dimensional frame; (2) methods to evaluate the evenness of a certain distribution of profiles in the plane; (3) methods to identify subgroups of profiles based on their different spatial or optical density; and (4) methods to compare the distributions of two or more groups of profiles. The applications of these general tools to some neuroanatomical problems, such as cell group definition and description, have been illustrated. Practical examples performed on immunocytochemical preparations of neuronal profile populations are also given. Finally, the potentiality of numerical classification to classify and compare morphometric data has been shown. As an example, numerical classification methods have been applied to the morphometric and microdensitometric analysis of adrenaline/neuropeptide Y costoring neuronal systems of the brainstem in adult and aged rats.
Animals↗
Detection of free radicals during brain ischemia and reperfusion by spin trapping and microdialysis.
Extracellular free radicals were detected in rat striatal perfusate samples by intracerebral microdialysis coupled to the spin trapping technique. Five Sprague-Dawley rats were subjected to 30 min of global ischemia followed by reperfusion; throughout the experimental period the intrastriatal dialysing probe was perfused with Ringer's solution containing the spin trap agent pyridyl-N-oxide-t-butylnitrone (100 mM) together with the iron chelating agent diethylentriaminepentacetic acid (100 microM). A radical adduct occurred during ischemia and early reperfusion, but not in basal conditions; the spin adduct was characterized as a carbon centered radical, consistent with the presence of an oxidative attack on membrane lipids. The direct evidence of the formation of free radicals supports the hypothesis that free radicals play a role in the pathogenesis of the histological damage during brain ischemia.
Animals↗
Feeding and drinking responses to neuropeptide Y injections in the paraventricular hypothalamic nucleus of aged rats.
Neuropeptide Y (NPY), a peptide of the pancreatic polypeptide family, exerts a potent stimulatory action on eating when injected into the paraventricular hypothalamic nucleus (PVN) in rats. Several NPY-containing systems are altered with advancing age, and aged rodents develop anorexia and a modified daily cycle pattern of feeding. These findings suggest that a relationship may exist between the aging-related anorexia and the reduced function of NPY-containing systems projecting to the PVN. In the present study eating and drinking behavior in satiated or fasted young (3 months) and aged (24 months) rats have been investigated over 22 h after NPY injection into the PVN. The levels of NPY immunoreactivity (IR) in PVN were also evaluated by means of semiquantitative immunocytochemistry. NPY injections into PVN increased food and water consumption in both young and aged satiated rats 30, 90 and 240 min after injection. However, the feeding and drinking responses elicited by 0.05, 0.10 and 1.0 nmol of NPY were significantly attenuated in the aged rats when compared to young rats. In aged rats, 24 h of food and water deprivation produced significant increase of food consumption measured at 30, 90 min and 22 h, which was equivalent to that induced by 1.0 nmol NPY injection. Administration of 1.0 nmol NPY in PVN did not further increase the 24 h deprivation effect on feeding in both groups of rats, but enhanced drinking in deprived young rats. This effect was not present in aged rats. In addition, aged rats showed a stronger response to 24 h deprivation than to 1.0 nmol NPY administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.
Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Involvement of local ischemia in endothelin-1 induced lesions of the neostriatum of the anaesthetized rat.
The present study examines the possibility that lesions induced by intrastriatal injections of endothelin-1 (ET-1, 0.43 nmol/0.5 microliter) are ischemic in nature due to a vasoconstriction of the cerebral microvessels. In time course and dose-response experiments with ET-1 and in comparisons with ET-3, the volume of the lesions has been determined based mainly on the disappearance of striatal nerve cells, using a computer assisted morphometrical analysis. The blood flow in the neostriatum close to the site of injection of ET-1 was determined acutely by Laser-Doppler flowmetry. The acute metabolic effects of ET-1 were also studied on striatal superfusate levels of lactate, pyruvate, dopamine and its metabolites DOPAC (3,4-dihydroxyphenylacetic acid) and homovanillic acid (HVA) using an intrastriatal microdialysis probe. Dose related striatal lesions were observed with ET-1 (0.043-0.43 nmol) with a peak lesion volume after 24-48 h and the possible existence of a penumbra area. ET-3 showed a reduced potency to produce striatal lesions compared to ET-1. The lesions induced by ET-1 were prevented by coinjection with dihydralazine, a vasodilator drug. Acutely ET-1 (0.43 nmol/0.5 microliter) produced a prolonged reduction of the cerebral blood flow down to 40% of control values and temporary increases of striatal lactate and DA efflux, the latter change being very marked. Also a significant reduction of DOPAC and HVA was observed. These neurochemical changes were all prevented by treatment with dihydralazine.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Neuropeptides, excitatory amino acid and adenosine A2 receptors regulate D2 receptors via intramembrane receptor-receptor interactions. Relevance for Parkinson's disease and schizophrenia.
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Animals↗
Neuronal plasticity and ageing processes in the frame of the 'Red Queen Theory'.
On the basis of the morphofunctional evidence obtained in old brains of humans and mammals the present hypothesis has been introduced. This hypothesis states that neuronal plasticity can be used either to compensate for neuronal degeneration or to store new information. Thus, in pathological ageing the marked rate of degeneration has fully exhausted the already reduced plasticity capability of neural networks. In this way marked impairments of memory trace formation take place in pathological ageing conditions such as Alzheimer's disease. The essence of this hypothesis is that a competition for the available plasticity exists between the compensatory responses to ageing-induced degeneration and the processes necessary for memory trace formation. We have called this hypothesis the 'Red Queen Theory', an analogy borrowed from Lewis Carroll's book Through the Looking Glass. Thus, in ageing, processes responsible for plasticity must be forced to run at the highest possible rate to maintain the morphofunctional substrate of the existing networks as well as to allow the formation of new memory traces.
Aging↗
Intramembrane interactions between neurotensin receptors and dopamine D2 receptors as a major mechanism for the neuroleptic-like action of neurotensin.
Evidence has been presented that behavioral actions of NT, inducing its neuroleptic-like action, can be explained on the basis of NT-D2 intramembrane receptor-receptor interactions in the basal ganglia, unrelated to the coexistence phenomenon, leading to reduced affinity and transduction of the D2 agonist binding site. By reducing selectively D2 receptor transduction at the pre- and postsynaptic level, the NT receptor appears capable of switching the DA synapses towards a D1 receptor-mediated transduction, illustrating how receptor-receptor interactions can increase the functional plasticity of central synapses (FIG. 12).
Animals↗
Siagoside selectively attenuates morphological and functional striatal impairments induced by transient forebrain ischemia in rats.
BACKGROUND AND PURPOSE: Transient forebrain ischemia induced in rats by the four-vessel occlusion method is known to produce severe neural damage in the hippocampus and striatum and a behavioral syndrome the major symptom of which is a working memory deficit. Recent evidence suggests that monosialogangliosides can ameliorate postischemic symptoms. Our purpose was to study the effect of siagoside, the inner ester of GM1 ganglioside, on some behavioral and morphological impairments induced by four-vessel occlusion in rats. METHODS: Rats were injected daily with 5 mg/kg i.p. siagoside starting 4 hours after the cerebral ischemia. After 14 days the rats were tested for working memory in a water T maze or scored for apomorphine-induced stereotypy. The rats were killed 21 days after the cerebral ischemia. Histological and computer-assisted morphometric analyses were performed on cresyl violet-stained brain sections, which were graded according to a neuropathologic score, and on sections stained with a monoclonal antiserum against dopamine and cyclic adenosine-3',5'-monophosphate-regulated phosphoprotein, a marker for striatal dopaminoceptive neurons. RESULTS: Siagoside treatment reduced the stereotypy score induced by low doses of apomorphine and the extent of striatal lesions but did not affect the working memory deficit or the extent of hippocampal lesions. CONCLUSION: Daily siagoside treatment after acute cerebral ischemia attenuates some morphological and functional deficits related to striatal damage. These effects can be interpreted as a selective protective action on striatal neural populations or as a modulatory action on neural systems involved in striatal control. These data are consistent with preliminary clinical reports showing that monosialogangliosides enhance motor recovery after acute ischemic stroke.
Animals↗
Regional and cellular distribution within the rat prostate of two mRNA species undergoing opposite regulation by androgens.
We have investigated, by in-situ hybridization histochemistry, the distribution within the rat ventral prostate of the mRNAs for sulphated glycoprotein-2 (SGP-2) and ornithine decarboxylase (ODC; EC 4.1.1.17), two proteins that appear to be inversely regulated by androgens in this organ, in that the level of SGP-2 mRNA is lowered, while the activity of ODC is enhanced by the latter hormones. Low-magnification autoradiograms of whole ventral prostate sections showed that, in intact animals, the SGP-2 transcript was only detectable in restricted areas and not diffused evenly throughout the section. Reciprocally, the ODC transcript was not detectable in areas where the SGP-2 transcript was detected, but appeared distributed uniformly in the remaining parts of the section. The effect of castration on the levels of the two mRNAs was evaluated by a semiquantitative analysis of autoradiograms from whole ventral prostate sections using an autoimmune image analyser. Four days after castration, SGP-2 mRNA increased by about 11-fold, while ODC mRNA decreased by fivefold. The distribution of the two mRNAs among the different cell types, studied by treating the slides with photographic emulsion and counterstaining, showed that both were expressed exclusively in the epithelial luminal cells of the ducts. Furthermore, each of the two mRNAs preferentially accumulated in a cell population which was morphologically distinct while accumulation of the other was negligible. SGP-2 mRNA was mostly found in cuboidal epithelial cells and ODC mRNA in columnar epithelial cells. Castration caused a dramatic accumulation of SGP-2 and a decrease in ODC mRNAs in the cells of the columnar epithelium 4 days later.(ABSTRACT TRUNCATED AT 250 WORDS)
Androgens↗
Neuropeptide Y/angiotensin II interactions in central cardiovascular regulation of the rat.
Neuropeptide Y (NPY)/angiotensin II (ANG II) interactions have been studied in the central nervous system of the rat in view of their co-distribution and their opposing role in central cardiovascular control using quantitative receptor autoradiography and measurements of mean arterial blood pressure (MAP), heart rate and respiratory rate. The receptor autoradiographical experiments show that incubation with ANG II (10 nM) produces an increase in porcine (p) iodinated NPY-(1-36) [125I]pNPY-(1-36) binding within the dorsal strip (ds) of the nucleus tractus solitarius (nTS). Immunocytochemical analysis of intracisternally injected ANG II indicated that it could reach this area, in addition to the periventricular gray of the medulla oblongata, the pons and the periventricular part of the dorsal thalamus and dentate gyrus. Furthermore, a threshold dose of ANG II given intracisternally (3 nmol/rat) together with a dose (75 pmol/rat) of pNPY-(1-36) close to its ED50 value for reducing MAP, not only counteracts the vasodepressor action of pNPY-(1-36) but also leads to a marked increase of MAP. Also the bradycardic and bradypneic actions of pNPY-(1-36) are counteracted by this dose of ANG II. In contrast, a threshold dose of pNPY-(1-36) does not counteract the pressor action of an ED50 dose of ANG II (10 nmol/rat) but even enhances the peak pressor action of ANG II. These results may be explained on the basis that central ANG II receptor activation leads to an uncoupling of the NPY Y1 receptor, which mediate the vasodepressor action of pNPY-(1-36) and which is preferentially labeled by [125I]pNPY-(1-36).(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Corticosterone treatment counteracts lesions induced by neonatal treatment with monosodium glutamate in the mediobasal hypothalamus of the male rat.
The effects of glucocorticoids on monosodium glutamate-induced neurotoxicity in the neonatal basal hypothalamus were studied by means of semiquantitative immunocytochemistry for tyrosine hydroxylase, growth hormone releasing factor and luteinizing hormone releasing hormone. Neonatal monosodium glutamate treatment induced a marked decrease in tyrosine hydroxylase immunoreactive neurons in the arcuate nucleus and growth hormone releasing factor immunoreactive nerve terminals in the median eminence. These effects were significantly antagonized by the coadministration of corticosterone. Corticosterone alone had no effect on the parameters studied. No significant change in luteinizing hormone releasing hormone immunoreactivity in the median eminence was detected after any treatment. These results demonstrate that corticosterone, possibly acting via type II corticosterone receptors which are highly enriched in the arcuate neurons, can exert a protective action on glutamate-induced neurotoxicity.
Animals↗
Decrease in mRNA levels but not in the density of D2 dopamine receptors in rat striatum after transient forebrain ischemia.
D2 dopamine receptor mRNA was analyzed by in situ hybridization histochemistry in rat striatum 7 days after transient forebrain ischemia. A patchy disappearance of the D2 receptor mRNA was observed in the dorsolateral striatum. In the same area, a disappearance of D1 binding sites occurred in the absence of significant changes in D2 receptor density. These results suggest that, although D2 receptors seem to be apparently unaffected after forebrain ischemia, a long-lasting impairment of their neosynthesis may be present in striatal D2 dopaminoceptive neurons.
Animals↗
Changes in striatal mu and delta opioid receptors after transient forebrain ischemia: a quantitative autoradiographic study.
Transient forebrain ischemia induces specific changes in several neurochemical markers in the dorsolateral striatum. In the present paper, the density and distribution of mu and delta opioid receptors were analyzed in rat striatum 7 days after 30 min forebrain ischemia using the 4-vessel occlusion model. A marked (about 70%) decrease in the density of both opioid receptor subtypes was found in the dorsolateral striatum overlapping the areas of histological damage and of D1 dopamine receptor disappearance. Moreover, the density of delta opioid receptors and of the diffuse mu opioid receptors was also affected (30% decrease) in the ventromedial striatum, an area which is substantially spared by the ischemic lesion. In contrast, the striatal patches of mu opioid receptors were not affected in the ventro-medial striatum and were preserved to a large extent in the area of lesion, although their area and receptor density resulted markedly reduced. The impairment of both opioid receptor subtypes suggests that opiate systems, like dopaminergic systems, are involved in the neurochemical changes observed in the striatum after transient forebrain ischemia.
Animals↗
Selective reduction of glucocorticoid receptor immunoreactivity in the hippocampal formation and central amygdaloid nucleus of the aged rat.
Hippocampal cell loss during aging has been related to the toxic effects of corticosterone on this cell population. It is not known which receptor mediates corticosterone cytotoxicity. At least two types of receptors for corticosterone have been recognized in the rat brain, type I (corticosterone preferring receptor, CR) and type II (glucocorticoid receptor, GR). In the present study the possible changes in GR immunoreactivity (IR) in various tel- and diencephalic regions of the aged rat have been investigated using immunocytochemistry coupled with computer-assisted image analysis. Male Sprague-Dawley rats of 3, 12 and 24 months of age were used (n = 5/group). A selective decrease of GR-IR was observed in the CA1 hippocampal field and central amygdaloid nucleus of the 24-month-old with respect to both 3- and 12-month-old rats. While in the former region GR-IR decrease was paralleled by a decrease of IR field area, no age-related decrease of GR-IR profile number was detected in central amygdaloid nucleus. A significant decrease of GR-IR and IR field area was also observed in the dentate gyrus of 24- vs 12-month-old rats but not vs 3-month-old rats. The analysis of adjacent sections stained with Cresyl violet showed a pattern of age-related changes (decrease of neuronal profiles in CA1 field pyramidal layer and dentate gyrus granular layer, and no change in the central amygdaloid nucleus of aged rats) which paralleled the observed changes in GR-IR in the same areas. This study provides evidence that GR are selectively decreased in the hippocampal formation and in the central amygdaloid nucleus of the aged rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Galanin increases potassium evoked release of [3H]5-hydroxytryptamine from rat hypothalamic synaptosomal preparations.
The effects of galanin (GAL) have been evaluated on the depolarization evoked release of [3H]5-HT (serotonin or 5-hydroxytryptamine) from rat hypothalamic synaptosomal preparations, using low concentrations of potassium (15 mM). In the same preparation effects of GAL were also evaluated on [3H]5-HT uptake, using kinetic analysis to determine effects on Vmax values and Km values. GAL concentrations of 0.1-10 nM caused a concentration-related increase of the depolarization-evoked release of [3H]5-HT without influencing [3H]5-HT uptake. The results indicate the existence of high affinity GAL receptors on the hypothalamic 5-HT nerve terminals, exerting a facilitatory influence on depolarization-evoked [3H]5-HT release.
Animals↗