Biomedical subjects

A G Sadile

Publications and source records attributed to A G Sadile.

At least 37 records · Page 2Linked to original sources

PubMed1996

Reduced CaMKII-positive neurones in the accumbens shell of an animal model of attention-deficit hyperactivity disorder.

THIS study aimed at investigating putative neural substrates of attention-deficit hyperactivity disorder in children using the spontaneously hypertensive rat (SHR) as animal model and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) as a marker in the nucleus accumbens, an interface between limbic and motor systems. In prehypertensive male SHR and Wistar-Kyoto rats image analysis of CaMKII immunocytochemistry showed more positive elements in the shell than in the core, and in the former a lower level in SHR. The data indicate a reduced number of nucleus accumbens modules available for limbic-motor integration revealing putative substrates of the altered attentional and reinforcement mechanisms demonstrated in the SHR and in children with attention-deficit hyperactivity disorder.

Animals↗

PubMed1996

NMDA and non-NMDA sensitive [L-3H]glutamate receptor binding in the brain of the Naples high- and low-excitability rats: an autoradiographic study.

The Naples high-excitability (NHE) and low-excitability (NLE) rat lines, selectively bred for high and low activity in a Làt maze, respectively, are used as an animal model in the study of hippocampal functions. The aim of this study was to investigate the anatomical distribution of N-methyl-D-aspartate (NMDA) and non-NMDA sensitive [3H]glutamate receptor binding by quantitative autoradiography in the brain of the NHE and NLE rats with a randomly bred line (NRB) as controls. Twenty-micron-thick cryostat sagittal sections were incubated at 4 degrees C with 150 nM [L-3H]glutamate alone or in the presence of 100 microM NMDA or 2.5 microM quisqualate (QA). Non-specific binding was determined in the presence of 1 mM of non-labeled glutamate. The sections were exposed to tritium-sensitive films for 3 weeks at 4 degrees C. Quantitative analysis revealed: (1) higher levels of total binding in NHE than in NRB and NLE rats in all areas but the cerebellum; (2) fewer binding sites for both NMDA and QA receptors and larger binding sites for QA receptors in the hippocampus of NLE and NHE rats, respectively; (3) a positive correlation between total binding sites and activity level in a Làt maze in all areas, except the cerebellar molecular layer with NLE < NHE, which was due to differential contribution from NMDA and non-NMDA types. Thus, the brain of the NHE rats shows an imbalance between NMDA and non-NMDA sensitive [L-3H]glutamate receptors.

Animals↗

PubMed1995

Unscheduled brain DNA synthesis, long-term potentiation, and depression at the perforant path-granule cell synapse in the rat.

We investigated the effect of long-term potentiation (LTP) of the perforant path-granule cell synapse, on the synthesis of DNA in the target area and in polysynaptically stimulated hippocampal (CA3/CA1) and cortical areas (entorhinal, temporal, and occipital cortices) in the rat. The contralateral nonstimulated side was used as a control. The degree of LTP was indexed by the field EPSP and population spike amplitude recorded in the dentate area of the stimulated side before and after high frequency stimulation (250 Hz, 250 ms) every 30 min. DNA synthesis was evaluated in tissue homogenates after a 3-h period of incorporation of 3H-thymidine. DNA synthesis was significantly lower in the stimulated side in the hippocampal cortex CA3/CA1 (-25%), and in the entorhinal cortex (-50%), but not in the dentate area. In addition, the occurrence of preparations without expression of LTP allowed the analysis of unscheduled brain DNA synthesis (UBDS) in a supposedly long-term depression (LTD) subgroup. UBDS was higher in the group without LTP (no-LTP group) than in that with a significant LTP expression (LTP-group) on both sides of the brain. Furthermore, correlative analyses revealed that UBDS covaried with LTP of the EPSP (but not of population spike) in the dentate area and in extratarget hippocampal subregions on both sides and in dorsal cortex on the stimulated side. Further, regional crosscorrelation analyses revealed a high degree of coupling among brain sites following LTP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Brain RNA synthesis, long-term potentiation and depression at the perforant path-granule cell synapse in the guinea pig.

The effects of long-term changes in synaptic efficacy at the perforant path-granule cell synapse on the de-novo synthesis of ribonucleic acid (RNA) were investigated in hippocampal and cortical areas in anaesthetized Guinea pig preparations. Two experiments were run with stimulating and recording microelectrodes aimed at the perforant bundle and dentate gyrus hilus on both sides. In Experiment 1, a low-frequency (LFS; 0.02 Hz, 3 h) or high-frequency stimulation (HFS; 400 Hz, 250 ms) was delivered to the left perforant bundle with the contralateral side as control. In Experiment 2, animals received LFS or HFS trains with implanted nonstimulated animals used as controls. The latency and amplitude of the field postsynaptic potentials (FPSP) and population spike (POPS) were monitored under baseline conditions and following stimulation over a 3 h period. In addition, two HFS groups were tested with few (HFS-F: every 15 min) or several test stimuli (HFS-S: every 3 min). In both experiments RNA synthesis was determined by measuring the amount of 3H-5,6-uridine incorporated into the RNA 3 h after bilateral intraventricular injection. In Exp. 1 the LFS group showed a higher synthesis of RNA than both HFS groups. The rate of RNA synthesis did not differ between the stimulated and nonstimulated side. In Exp. 2 the HFS groups showed a decreased RNA synthesis. In the HFS-F group, it pertained to the dorsal dentate area, CA1, subiculum, cingulate and dorsal cortices bilaterally, and to the ventral dentate area and CA3 on the nonstimulated side. In contrast, the HFS-S group showed decreased RNA synthesis at the dorsal dentate area and dorsal cortex on the stimulated side, and at CA1, subiculum, and cingulate cortex bilaterally. The decrease was stronger in the HFS-F than in the HFS-S group. Moreover, the subgroup with a low (0-60%) and that with a high (61-240%) level of long-term potentiation of FPSP revealed lower and higher RNA synthesis, respectively, both in homosynaptic target areas, and in heterosynaptic sites. Further, correlative analyses between FPSP, POPS and RNA synthesis revealed a complex pattern, depending upon the type of stimulation and on the brain side. Finally, cross-correlation analyses revealed a high degree of coupling among brain sites in the stimulated groups, indicating distributed covariant changes in RNA synthesis across different brain sites. Thus, changes in synaptic efficacy covary with changes in RNA synthesis, and presumably exert a modulatory role on gene expression.

Analysis of Variance↗

PubMed1995

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↗

PubMed1995

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↗

PubMed1995

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↗

PubMed1994

Nitric oxide and long-term habituation to novelty in the rat.

The role of nitric oxide in learning and memory processes has been tested in the albino rat by a histochemical and a behavioral study, following behavioral habituation to spatial novelty. Histochemically, the neural consequences of behavioral testing were mapped in the brain by staining for NADPH-d, known to be a NOS, whereas behaviorally the formation of LTH has been interfered with by posttrial NOS-inhibition. In the histochemical study, adult male Sprague-Dawley rats were tested in a Làt-maze and sacrificed at different time intervals thereafter. Handled unexposed rats served as controls. The brains were perfused with aldheide and processed for NADPH-d staining. In unexposed control rats the basal expression of NADPH-d was low and scattered. It pertained to few cells in the neostriatum, cerebral cortex, and CA1 hippocampal regions. In contrast, rats that had been exposed for the first time to the maze (spatial novelty) showed NADPH-d activity in the dorsal hippocampus (granule cells, few hilar neurons, and some CA1 pyramidal cells), the caudate-putamen complex, the cerebellum, and in all layers of somatosensory cortex. The positivity was not due to activity per se, since immediately after exposure it was not different from baseline. In contrast, it was present by 2 h and decreased significantly 24 h later. In addition, a strong neuronal discharge induced by the convulsant pentylentetrazol did not induce NADPH-d 2 h afterwards. The staining was prevented by pretreatment with the NMDA receptor antagonist CPP (5 mg/kg) or with the NOS inhibitor L-NOARG (10 mg/kg). In the behavioral study, rats were given an intraperitoneal injection of 1-10 mg/kg (L-NOARG) or vehicle immediately following exposure to a Làt-maze. The highest dose used (10 mg/kg) disrupted habituation of the vertical component only, known to be mainly of emotional meaning. Conversely, both doses disrupted emotional habituation based on defecation scores. The data indicate that the formation of LTH to novelty triggers a cascade of neurochemical events also involving NOS neurons. Further, the widespread induction of NADPH-d by exposure to novelty suggests that spatial and emotional information processing activate neural networks across different organizational levels of the CNS.

Amino Acid Oxidoreductases↗

PubMed1994

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↗

PubMed1993

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↗

PubMed1993

Circadian activity, nociceptive thresholds, nigrostriatal and mesolimbic dopaminergic activity in the Naples High- and Low-Excitability rat lines.

These experiments were designed to further characterize the differential phenotypic constellation of the Naples High- (NHE) and Naples Low-Excitability (NLE) lines. In order to determine possible differences between NHE and NLE rats in activity and circadian rhythms, besides reactivity to novelty (selection trait), adult male rats of both strains were tested during two 10-min exposures to a Làt-maze. They were then kept in activity cages continuously for 3 days. Moreover, nociceptive thresholds were measured with the hot-plate and the tail-flick test, to probe the possibility that these rats could be differentially sensitive to nociceptive stimuli. Further, the integrity of the nigro-striatal and mesolimbic system was investigated by measuring tyrosine-hydroxylase activity in the striatum and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum as well as in the nucleus accumbens. In addition, TH activity was measured in the adrenals to probe the sympathetic section of the neurovegetative system. The results indicate that NHE and NLE rats differ by a factor of two in their phasic activity in a Làt-maze. In contrast, no differences in 24-h activity during the dark or light phase could be observed in the activity cages. However, NHE rats anticipated the light-on stimulus in the morning by reducing their activity 1 h earlier than NLE rats. Further, no difference could be found with the hot-plate and the tail-flick test. Finally, biochemical analyses revealed no difference in the NHE and NLE rats in the main terminal zone of mesolimbic system (n. accumbens) nor of nigrostriatal system (striatum) nor in the adrenal glands. In conclusion, since the only consistent difference between NHE and NLE rats appears to be reactivity to spatial novelty, an hippocampus-dependent behavioral trait (selection trait), independent of altered activity in the sympathetic system or dopaminergic activity in the major dopaminergic brain systems, the usefulness of these strains as genetic model to test current hypotheses of spatial processor device(s) in the mammalian brain is supported.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

NMDA receptors modulate long-term habituation to spatial novelty: dose- and genotype-dependent differential effects of posttrial MK-801 and CPP in rats.

To investigate the role N-methyl-D-aspartate (NMDA) receptors play in behavioral plasticity, adult male rats of the Naples high-(NHE) and low-excitability (NLE) lines, and of a random-bred Sprague-Dawley strain (NRB) received, the noncompetitive (MK-801:0.01 or 2.5 mg/kg) or the competitive (CPP: 0.01 or 5 mg/kg) NMDA receptor antagonists, or vehicle IP soon after a 10-min test in a Làt-maze. Retention was tested 1 week later. Habituation of activity and defecation score was monitored by the between-test decrement (LTH) in the frequency of corner-crossings (HA) and rearings (VA), with prevailing cognitive and noncognitive meaning, respectively, and of fecal boli. (i) In the NLE-rats, low and high doses of MK-801 facilitate LTH of HA, and a high dose of CPP facilitates LTH of HA. (ii) In the NRB-rats, MK-801 facilitates LTH of HA at a low dose and inhibits LTH of VA at a high dose, whereas CPP inhibits LTH of HA at a high dose only. In contrast, (iii) in the NHE-rats, high doses of MK-801 impair LTH of HA, and low doses of CPP facilitate LTH of HA. In conclusion, the dose- and genotype-dependent differential effects of allosteric and isosteric receptor blockade support the hypothesized modulatory role of NMDA receptors in behavioral plasticity; and the dissociation between retention of cognitive and noncognitive behavioral components suggests that NMDA receptors are involved in their parallel processing.

Animals↗

PubMed1993

Long-term habituation to spatial novelty modifies posttrial synchronized sleep in rats.

To assess the role of posttrial synchronized sleep in the processing of a nonassociative task, adult male Sprague-Dawley rats with chronically implanted cortical electrodes for EEG recording were exposed to a Làt-maze, and horizontal (HA; corner crossing) and vertical (VA; rearings) activities were monitored during two 10-min test trials made at a 3-h (experiment 1) or 24-h (experiment 2) interval. EEG conventional recording was taken during 3 h under baseline conditions (day 1), and following exposure to the maze (day 2), and analyzed as to the amount (a), number (n), and mean duration (d) of synchronized sleep (SS) episodes followed by wakefulness (SS-->W) or by paradoxical sleep (SS-->PS). In both experiments there was a significant intertrial decrement (long-term habituation: LTH) for horizontal activity (LTH-HA), vertical activity (LTH-VA), and emotionality (LTH-E). In experiment 1, in comparison to baseline values, the posttrial SS-->PS(a) increased, mainly for the appearance of SS-->PS episodes in the 1st h. SS-->W(a) also increased in the first h. Correlative analyses among behavioral and sleep parameters showed that SS-->PS(n) and (d) covaried positively with LTH-HA relative to the entire test, and with LTH-VA relative to the second part of the test in the third h. Negative correlations were present between SS-->PS(n) and (d), and LTH-E. In experiment 2, exposed rats showed a lower SS-->PS(n) in the first hour and an increased SS-->PS(d) in the second hour. No change was observed as to SS-->W episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Distributed changes in c-Fos and c-Jun immunoreactivity in the rat brain associated with arousal and habituation to novelty.

The effects of exposure to spatial novelty on expression of the immediate early gene (IEG) products c-Fos and c-Jun were mapped in the rat brain by immunohistochemistry. Adult male Sprague-Dawley rats were tested for 10 min in a Làt-maze, and corner-crossings, rearings, and fecal boli were recorded. Rats were sacrificed at different time intervals after exposure to the maze (0.5, 2, 6, or 24 h). Unexposed rats or rats repeatedly exposed for 3 days at 24 h interval served as controls. Nonperfused brains were processed for immunocytochemistry for c-Fos and c-Jun on adjacent slices using the avidin-biotin method and diaminobenzidine as chromogen. In unexposed control rats the constitutive expression of the two IEGs products was low and scattered. In contrast, rats that had been exposed for the first time to the maze (spatial novelty) showed an extensive c-Fos- and c-Jun-like immunoreactivity in the reticular formation, the caudate-putamen complex, the hippocampus (granular and pyramidal neurons), the cerebellum (granular neurons), and all layers of somatosensory cortex. The positivity was stronger in rats exposed for the first time to the box than in repeatedly exposed or unexposed control rats. A maximal IEG expression was found in animals with postexposure survival times of 2 and 6 h. IEG expression in repeatedly exposed rats was still above baseline expression of unexposed rats but still lower than that of rats having been exposed only once to the maze.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

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↗

PubMed1991

Distributed changes in rat brain DNA synthesis with long-term habituation and potentiation of the perforant path-granule cell synapse.

The involvement of brain deoxyribonucleic acid (DNA) synthesis in adaptive neural events was studied in the adult rat during long-term habituation (LTH) or potentiation (LTP) of the perforant path-granule cell synapse. Male Long-Evans rats were given 50 muCi [3H]thymidine intraventricularly under urethane anesthesia. Soon thereafter, field excitatory postsynaptic potential (EPSP) slope and population spike were monitored from the right dentate gyrus before and at various times (5, 10, 15, 60 min) following the delivery to the ipsilateral perforant bundle of a low frequency (LFS: 1.0 Hz, 160 s) or a high-frequency train (HFS: 400 Hz, 200 ms), repeated once after 5 min. Unstimulated implanted rats served as controls. DNA synthesis was evaluated by the incorporation of the radioactive precursor into DNA of several brain areas at the end of a 1 h incorporation period. In CA1, LTH and LTP increased DNA synthesis by 30% on the stimulated side. In the entorhinal cortex, LTH but not LTP increased DNA synthesis (by 30%) on the stimulated side. Conversely, in the frontal cortex, LTP but not LTH increased DNA synthesis (by 100%) on both sides. Long-lasting changes in synaptic efficacy covaried non-linearly with DNA synthesis in mono- and polysynaptically stimulated hippocampal regions, and in functionally associated neocortical areas. The co-variations of population spike amplitude were positive for LTH and negative for LTP in the dentate gyrus and frontal cortex of both sides, and in CA3/CA1 of the stimulated side, indicating higher DNA synthesis at lower values of LTH and LTP, and viceversa. Further, regional cross-correlation analyses revealed a high degree of synchronization among brain sites, following low- or high-frequency train pulses, indicating that (i) extra-target sites participate on the stimulated and on the contralateral side, and (ii) small distributed changes take place across the sampled neural networks. A modulatory role of information flow on brain DNA synthesis is inferred to take place in a diffuse, distributed manner.

Animals↗

PubMed1990

Hippocampal glucocorticoid receptor and behavior: a correlative study in rats and mice.

A correlation has been demonstrated between binding capacity for [3H]corticosterone in the hippocampus and the performance in passive and active avoidance in the rat, and impaired behavior in adrenalectomized rats by exogenous corticosterone is restored. On this basis we have studied the possible correlation between strain-dependent behavioral differences and the glucocorticoid binding capacity in the hippocampus in mice and rats. In Naples high- (NHE) and low-excitability (NLE) rat strains, genetically selected on the basis of divergent locomotor activity upon forced exposure to a spatial novelty situation, no differences were found in glucocorticoid maximal binding capacity while both strains had a lower capacity than Naples random-breed (NRB) control rats. However, the intra-strain correlative analysis of hippocampal glucocorticoid receptors number and behavioral scores demonstrated that motor and emotional indexes of arousal to novelty were positively correlated in NLE-and negatively in NHE- while no correlation was present in NRB rats. Using two inbred strains of mice, C57BL/6 and Balb/c, extensively investigated for learning abilities, the lower active avoidance score of C57BL/6 was associated with a lower binding capacity for [3H]corticosterone in the hippocampus. Altogether the above results support the involvement of the hippocampal glucocorticoid receptor in the modulation of some adaptive behavioral responses, while do not prove that genetic differences in behavior rest on parallel differences in binding capacity for glucocorticoid hormone.

Aging↗

PubMed1990

Post-trial NMDA receptor allosteric blockade differentially influences habituation of behavioral responses to novelty in the rat.

The involvement of glutamatergic receptors of the N-methyl-D-aspartate (NMDA) type in long-term behavioral habituation (LTH) to a novel environment was investigated. To this aim, adult male Sprague-Dawley rats were first exposed to a Làt-maze. Horizontal (corner-crossings) and vertical activity (rearings) were measured per 1-min block. Immediately after a 10-min test trial in the maze, rats were systemically injected with either 6 or 20 mg/kg of the allosteric NMDA receptor blocker ketamine-HCl (KET) or vehicle. Retention was tested one week later. LTH was expressed as the decline in horizontal and vertical activity from test trial 1 to test trial 2. The results showed a facilitation of the two components of LTH at 6 mg/kg and a disruption at 20 mg/kg. This biphasic effect pertained to vertical activity only. For both activity components, the facilitation of LTH at 6 mg/kg pertained to the first part, whereas the inhibition at 20 mg/kg pertained to the second part of the testing period. Since horizontal and vertical activity are thought to have a prevailing cognitive (spatial) and non-cognitive (emotional) meaning, subanesthetic doses of KET differentially affect the long-lasting retention of these behavioral responses to novelty. Thus, NMDA receptors seem to be involved in the coupling of spatial and emotional components of information.

Animals↗