Inappropriate left ventricular mass and angiotensin converting enzyme gene polymorphism.
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Adult↗
Biomedical subjects
A Cerbone
Publications and source records attributed to A Cerbone.
The dorsal noradrenergic bundle modulates DNA remodeling in the rat brain upon exposure to a spatial novelty.
A series of experiments were designed to study the role of the dorsal noradrenergic bundle (DNB) in the modulation of genomic remodeling in the mammalian brain. A series of experiments were designed to study the role of the dorsal noradrenergic system in relation to nonassociative tasks. Adult male Sprague-Dawley rats were either bilaterally lesioned in the DNB by intrabundle microinjection of 6-hydroxydopamine or were sham lesioned. All rats were given 50 microCi [3H-methyl]-thymidine and were sacrificed 0.5 h later. After the injection of the tracer, rats were either left undisturbed in the home cage or were exposed to a Làt-maze for 15 min after 15 min had passed from the time of injection. During the exposure to the maze, corner crossings and rearings were monitored. The rate of DNA synthesis was determined in several brain regions by measuring the amount of tracer incorporated into the DNA over a 0.5-h duration pulse. Under baseline conditions DNB-lesioned rats showed an increase in DNA synthesis in the hippocampus, hypothalamus, and rest of the brain. On the other hand, following exposure to the Làt-maze, sham-lesioned rats only showed an increase in DNA synthesis in the hippocampus, as compared to baseline conditions. Conversely, DNB-lesioned rats did not show an increase in hippocampal DNA synthesis as in the sham-lesioned rats. In contrast, DNA synthesis was increased in the neocortex and rest of the brain. In conclusion, the data support a role for noradrenergic systems in modulating brain DNA synthesis, probably of the unscheduled type, during information processing and storage.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Immediate early genes and brain DNA remodeling in the Naples high- and low-excitability rat lines following exposure to a spatial novelty.
The aim of these studies was to map the neural consequences of exposure to a spatial novelty on the expression of immediate gene (IEG) and on unscheduled brain DNA synthesis (UBDS) in two genetic models of altered activity and hippocampal functions, i.e., the Naples High- (NHE) and Low-excitability (NLE) rats. Adult male rats of NLE and NHE lines, and of a random-bred stock (NRB) were tested in a Làt-maze, and corner crossings, rearings, and fecal boli were counted during two 10-min tests 24 h apart. For IEG expression, rats were exposed to a Làt-maze with nonexposed or repeatedly exposed rats used as controls, and were sacrificed at different time intervals thereafter. For UBDS, rats were sacrificed immediately after the first or the second exposure o a Làt-maze. IEG expression was measured by immunocytochemistry for the FOS and JUN proteins. NRB rats exposed for the first time to the maze showed extensive FOS and JUN positive cells in the reticular formation, the granular and pyramidal neurons of hippocampus, the amygdaloid nuclei, all layers of somatosensory cortex, and the granule cells of the cerebellar cortex. The positivity, stronger in rats exposed for the first time, was present between 2 and 6 h and was prevented by the NMDA receptor antagonist CPP (5 mg/kg). The positivity was very low in NHE rats, and it was stronger in NLE compared to NRB rats. UBDS was measured in ex vivo homogenates of brain areas by the incorporation into DNA of 3H-[methyl]-thymidine given intraventricularly 15 min before test trial 1 or 2 (pulse of 0.5 h).(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Adrenergic receptor systems and unscheduled DNA synthesis in the rat brain.
Two experiments were carried out in the albino rat to investigate the role of brain adrenergic systems in DNA remodeling. Adult male Sprague-Dawley rats were given an intraventricular microinjection of an adrenergic drug or vehicle followed 2 h later by the intraventricular injection of 50 microCi of [3H-methyl]thymidine. The rats were sacrificed 0.5 h after the injection of the radioactive tracer. The rate of DNA synthesis was determined by measuring the amount of radioactive precursor incorporated into the DNA extracted from homogenates of several brain areas. In Experiment 1, at time 0 rats received the alpha-adrenergic antagonist phentolamine (5 micrograms), the beta antagonist propranolol (10 micrograms), the alpha agonist phenylephrine (1 microgram), the beta agonist isoproterenol (12.5 micrograms), or the vehicle. The latter decreased UBDS in neocortex, and increased it in the septum, neostriatum, hypothalamus, cerebellum, and rest of the brain. The alpha and beta agonists and antagonists induced several significant effects, depending on the brain region. In Experiment 2, rats were bilaterally lesioned in the dorsal noradrenergic bundle (DNB) by injection of 6-hydroxydopamine or were sham lesioned. One week later, at time 0 they were given the alpha agonist phenylephrine (1 microgram), the beta agonist isoproterenol (12.5 micrograms), or the vehicle. The DNB-lesioned rats showed a higher UBDS in the hippocampus, neocortex, and hypothalamus, which was reversed by the alpha or the beta agonist. The results suggest an influence of the DNB, probably as a tonic inhibitor of UBDS in the hippocampus and the hypothalamus which, in turn, are likely to be mediated by beta- and alpha-adrenergic receptors. In addition, a phasic inhibitory effect seems to be mediated by beta and alpha receptors in the neocortex, and by beta receptors in the cerebellum. A modulatory role of central adrenergic systems on unscheduled brain DNA synthesis may be inferred from these findings.
Afferent Pathways↗
Behavioral habituation to spatial novelty: interference and noninterference studies.
Long-term behavioral habituation (LTH), that is activity decrement upon repeated exposures to spatial novelty, is a relatively simple and ubiquitous form of behavioral plasticity in the animal kingdom, that can be used as a model of nonassociative learning in the freely behaving organism. Several strategies can be followed to tackle upon it. (a) Interference studies pertain to manipulation of the between-exposure interval by a variety of agents of different nature, that are known to interfere with hypothesized "consolidation process(es)" in associative learning paradigms. This approach indicates that LTH is modulated by NMDA receptors, requires polysome aggregation and protein synthesis, a functioning neocortex and both slow wave and paradoxical sleep. Further, it is modulated by endogenously released or exogenously given vasopressin and is not affected by blockade of endogenous opioids, at least through the "mu" receptor type. Moreover, LTH is disrupted by bilateral, electrolytic lesion of the locus coeruleus, but it is only impaired by 6-OH-DA bilateral lesion of the dorsal noradrenergic bundle, and it is facilitated by electrolytic lesion of the medial septal nuclei. (b) Noninterference correlative studies: Individual differences in behavioral variables can be correlated to some components of the architecture of the hippocampus to reveal structure-function relationships. (c) Noninterference maturation studies pertain to the study of the maturation of LTH during postnatal development in a scaled-down Làt-maze in normally reared rats and in rats with deranged rate of body and brain growth by litter size technique, differential stimulation or by perinatal propylthiouracil-induced hypothyroidism. (d) Noninterference development studies pertain to the formation of LTH varying the between-exposure interval. It was studied in albino rats of a Sprague-Dawley, random-bred stock (NRB) and of the Naples High (NHE) and Low-Excitability (NLE) lines. The study was carried out during the light or the dark phase of a 12:12LD cycle, by retesting at different inter-exposure intervals. Multivariate analysis of variance showed significant effects of strain, inter-exposure interval and of postexposure sleep or wakefulness. Furthermore, analysis of the temporal pattern showed the formation of LTH to follow a non linear complex function. Further, behavioral habituation consists of emotional and cognitive components that can be separated across different approaches. In conclusion, long-term habituation to a novel environmental is a useful model to study experience-induced nonassociative behavioral modifications.
Animals↗
A neurogenetic and morphogenetic approach to hippocampal functions based on individual differences and neurobehavioral covariations.
To investigate the neural substrate of information processing, the within group inter-individual behavioral differences were related to the fine variations in some components of the architecture of the intact hippocampus by multivariate analyses of variance and correlative analyses. For, the extent of the intra/infrapyramidal mossy fibers, covering the hippocampal CA3-regio inferior (IIP-MF, revealed by Timm-staining), and the individual high-affinity maximal glucocorticoid receptor binding (HCB, measured by in vitro cytosol preparations with [3H]corticosterone as ligand), were assessed in adult male albino rats of the Naples High-Excitability (NHE) and Naples Low-Excitability (NLE) psychogenetically selected lines, and of a Sprague-Dawley random-bred stock (NRB) as unselected controls. The IIP-MF and the HCB were assumed as hippocampal hardware and software traits, respectively, and entered in a matrix with activity and defecation scores in a Làt-maze as behavioral covariates. Two dimensions were identified by discriminant function analyses tentatively labelled as "spatial" and "non-spatial" by the nature of the variables contributing with a high loading to the dimension. The IIP-MF and HCB contributed mostly to spatial processes and to a lower extent to emotional processes. The neuro-behavioral covariations of IIP-MF with arousal (A) and long-term habituation (LTH), computed by correlative analyses on the overall population (all rats combined), turned out to be of inverted-U type (quadratic function), i.e. positive in NLE, negative in NHE with no correlation in NRB. For HCB receptors, the covariations were quadratic with A, and of the S-type (cubic function), i.e. positive in NLE, negative in NRB and positive in NHE with LTH. Since these rat lines are located along a "continuum" with NLE < RB < NHE, they are assumed to represent entirely this subpopulation. For, the non-linear neuro-behavioral relationships might reveal (i) constraints on the expression of arousal and habituation to novelty; and (ii) that the hippocampus appears to be one such device exerting a modulatory role in the processing of "spatial" and "non-spatial" behavioral components.
Adrenal Cortex↗
Evidence for and against the Naples high- and low-excitability rats as genetic model to study hippocampal functions.
The Naples high- (NHE) and low-excitability (NLE) are two rat lines, selectively bred for high and low activity levels in a Làt-maze, respectively. Because the activity level in a novel environment depends mainly on the integrity of the hippocampal formation, and NLE and NHE rats differ with a similar background of emotionality, arterial blood pressure, and learning ability, they have been proposed as animal model to study hippocampal functions. Our aim is to prove evidence in favor and against this hypothesis. The evidence in favor indicates that NLE/NHE rats have a defective spatial processing, and pertains to (a) Differential activity in a spatial novelty situation (selection trait), proportional to the stimulus complexity rats are exposed to (NHE are hyper- and NLE-rats hypoactive); and (b) Impaired working memory in a six-arm non-reinforced tunnel maze in both lines compared to random-bred rats, that was reversed by the introduction of a reinforcer. In addition, multiple evidence of (i) lower intra- + infrapyramidal mossy fiber terminals in both NLE/NHE vs. controls; (ii) increased sensitivity of hippocampal elements to microinjections of vasopressin (but not oxytocin) and of "delta" (but not "mu") opioids; (iii) lower number of high-affinity glucocorticoid receptors; (iv) lower number of alpha- but not beta-adrenergic receptors in the hippocampus and hypothalamus of NHE rats only; and (v) the genotype-dependent behavior of a DNA fraction with fast turnover, suggest that both NHE/NLE are "disintegrated" at the hippocampal interface. Further, neurobehavioral covariations among individual differences reveal nonlinear, complex relationships, an evidence apparently against the hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Fibrinogen and mechanisms of thrombosis. A difficult link.
Epidemiological observations indicate that high plasma fibrinogen levels are strongly correlated to the frequency of two major thrombotic complications of atherosclerosis: stroke and myocardial infarction. Thrombosis is increasingly recognized as a central mechanism in stroke and myocardial infarction, and fibrinogen is involved in events thought to play a major role in thrombosis. Therefore, elucidation of the relationship between fibrinogen and thrombosis may strengthen the predictive value of this protein and define new interventions against stroke and myocardial infarction. In addition, advances in the understanding of the atherogenic potential of several risk factors of coronary heart disease took advantage of information emerging from the measurement of the factor in population-based studies. Thus, it is conceivable that measuring plasma fibrinogen to predict stroke and myocardial infarction is a major direction to be followed to gain insight into the thrombogenic potential on this protein and inspire new strategies against thrombotic complications of atherosclerosis.
Blood Viscosity↗
Adrenocorticoid receptor binding in the rat hippocampus: strain-dependent covariations with arousal and habituation to novelty.
In order to investigate whether the genotype-dependent behaviour of the Naples high-(NHE) and low-excitability (NLE) rat strains was modulated by differences in the capacity of hippocampal adrenocorticoid receptors, a correlative analysis was made among behavioural scores from exposure to a Làt-maze and in vitro [3H]corticosterone hippocampal binding capacity in these rats and in their random-bred controls (NRB). As previously shown, NHE/NLE-rats differed markedly upon forced exposure to the maze, with the NRB group occupying an intermediate position. No differences were found in maximal binding capacity (Bmax) and dissociation constant (Kd), nor in the individual maximal binding capacity (IMBC) between the two strains, while both showed lower IMBC than NRB-rats. These results tend to exclude that the genetic differences in the behaviour of NHE/NLE-rats are due to distinct patterns in the adrenocorticoid binding capacity in the hippocampus (HPC). Moreover, the intrastrain correlative analysis among IMBC (in the whole HPC and in its dorsal and ventral portion) and the behavioural scores showed that (1) motor and emotional correlates of 'arousal' to novelty were positively correlated in NLE and negatively in NHE-, but not in NRB-rats; (2) a consistent correlation was found with the intertrial activity decrement (long-term habituation), which was negative in both strains, and it was positive in NRB-rats. These complex co-variations are envisioned as possibly due to the differential modulatory components of the activation and inhibition of novelty-induced arousal response. However, our findings support the hypothesized involvement of the HPC, where adrenocorticoid receptors are selectively concentrated, in the modulation of some adaptive behavioural responses.
Animals↗
Strain-specific correlations between hippocampal structural traits and habituation in a spatial novelty situation.
The rat strains Naples high-excitable (NHE) and Naples low-excitable (NLE) have been selectively bred since 1976 for behavioral arousal in a spatial novelty situation. The Timm-stained hippocampi of 20 NHE and 18 NLE rats were examined morphometrically for differences in the proportions (volume percentages) of terminal fields in the fascia dentata and CA3/CA4 at the mid-septotemporal level. Prior to histology animals were tested on 2 days for exploratory activity in a square alley system (Làt box). Overall, the two strains differed significantly in the percentage of stratum lacunosum molecular (NHE greater than NLE, P less than 0.001), of the intra/infrapyramidal mossy fiber (IIP-MF) projection (NLE greater than NHE, P less than 0.001), of the granule cell layer (NLE greater than NHE, P less than 0.05) and of the outer molecular layer (NHE greater than NLE, P less than 0.05). Both strains had an IIP-MF projection smaller than in any other rat strain. Most of the strain differences, however, appear to reflect genetic drift rather than a response to selective breeding. Unexpectedly, the highly active line (NHE) showed a strong correlation between the IIP-MF and overnight habituation; the larger the IIP-MF projection, the lesser the long-term habituation (r = -0.70, P less than 0.001). In the NLE rats, the IIP-MF correlated positively with overnight habituation (though not significantly, because of an outlier). In both lines, stratum oriens was negatively correlated with short-term habituation in the second exposure (NHE: r = -0.68, P less than 0.001; NLE: r = -0.66, P less than 0.01). Thus, hippocampal variability of non-genetic origin appears to be correlated with processes which modulate strain-characteristic responses to a spatial novelty situation.
Animals↗
Postnatal brain growth and behavior: evaluation of environmental factors.
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Adrenal Glands↗
Platelet dysfunction in uremia. II. Correction by arachidonic acid of the impaired exposure of fibrinogen receptors by adenosine diphosphate or collagen.
Previous studies showed that platelets from patients with uremia have a marked decrease in their aggregation response to adenosine diphosphate (ADP) and collagen as single agents or as a pair. It is known that small amounts of arachidonic acid can enhance the sensitivity of platelets to concentrations of ADP or collagen that do not cause aggregation when used singly. Stimulation of platelets by certain agonists induces the formation of fibrinogen receptors on the platelet surface. The binding of fibrinogen that follows is essential for platelet aggregation. The platelet membrane glycoprotein IIb-IIIa complex appears to be the site of the fibrinogen receptor. Therefore, we investigated the binding of iodine 125-labeled fibrinogen to uremic platelets exposed to ADP, collagen, or arachidonic acid as single agents and as pairs. When aggregation and binding were studied in response to ADP, collagen, or the combination of ADP with collagen, uremic platelets had reduced aggregation and bound abnormally low amounts of fibrinogen. In contrast, platelets from patients with uremia bound as much 125I-fibrinogen and aggregated as well as controls when ADP or collagen were used in combination with low concentrations of arachidonic acid. Studies with a monoclonal antibody (B 79.7) suggested that the number of glycoprotein IIb-IIa molecules is the same in uremic and normal platelets. We conclude that uremia impairs the exposure of fibrinogen receptors on platelets in response to ADP or collagen without affecting the glycoprotein IIb-IIa complex quantitatively. Correction by arachidonic acid of the impaired aggregation and exposure of fibrinogen receptors by ADP or collagen suggests that abnormal release of endogenous arachidonic acid plays a role in the dysfunction of platelets in uremia.
Adenosine Diphosphate↗