PubMed Health⌕ Search

Biomedical subjects

Joram Feldon

Publications and source records attributed to Joram Feldon.

At least 91 records · Page 5Linked to original sources
PubMed2003

Comparison of the effects of early handling and early deprivation on conditioned stimulus, context, and spatial learning and memory in adult rats.

Effects of manipulations of the rat pup-dam relationship on affective learning and memory in adulthood have received scant systematic investigation. The authors previously described how early handling (EH; 15 min isolation/day) and early deprivation (ED; 4 hr isolation/day) exert similar effects on spontaneous adult affect (open-field behavior, acoustic startle, endocrine stress response) relative to nonhandling (NH; C. R. Pryce, D. Bettschen, N. I. Bahr, & J. Feldon, 2001). The present study demonstrates that both EH and ED adults exhibit enhanced active avoidance relative to NH adults. Fear-conditioned context and conditioned stimulus (CS) freezing were unaffected in both EH and ED, but stress hormone responses to the CS were reduced in EH males and ED females relative to NH. In the water maze, ED adults exhibited enhanced spatial learning and memory relative to NH.

Adrenocorticotropic Hormone↗
PubMed2003

Significance of dopamine transmission in the rat medial prefrontal cortex for conditioned fear.

Previous studies have demonstrated activation of dopamine transmission in the medial prefrontal cortex (mPFC) by conditioned fear stimuli. Therefore, the present study investigated the functional significance of mPFC dopamine for a conditioned fear response to a tone. We examined the effects of inhibition or stimulation of mPFC dopamine transmission by local microinfusion of the D1/D2-receptor antagonist cis-flupenthixol or the indirect dopamine receptor agonist D-amphetamine, respectively, in a classical fear-conditioning paradigm in Wistar rats. Rats received tone-shock pairings and were later exposed to the tone alone. Freezing was used as measure of conditioned fear. Presence of the drugs in the mPFC during the tone-shock pairings did not affect freezing during subsequent presentation of the tone alone. However, when cis-flupenthixol and D-amphetamine were present in the mPFC during presentation of the tone alone, freezing to the tone was reduced. We demonstrated that the decreased freezing could be explained neither by state dependency nor infusion-induced alterations in activity. Our data indicate that mPFC dopamine transmission is important for the retrieval/expression, but not the formation, of conditioned fear. The reduction of conditioned fear by prefrontal infusion of both cis-flupenthixol and D-amphetamine may reflect normal expression of conditioned fear requires an optimal level of mPFC dopamine activity.

Animals↗
PubMed2002

Repeated parental deprivation in the infant common marmoset (Callithrix jacchus, primates) and analysis of its effects on early development.

BACKGROUND: We describe a successful demonstration that repeated early deprivation of parental care (ED), as used to study effects of early life stress in rats, can be performed in a primate and that it constitutes an early life stressor. METHODS: Seven breeding pairs of marmoset monkeys each provided control twins (CON) and twins that were subjected to ED for 30-120 min/day on postnatal days (PND) 2-28. Urine samples were obtained to monitor the acute effect of ED on cortisol and catecholamine levels. Behavior samples were obtained in the home cage to monitor the effects of ED on infant and infant-parent behavior. RESULTS: Early deprivation of parental care caused acute increases in cortisol, epinephrine, and norepinephrine. At PND 28, basal cortisol was reduced in ED compared with CON infants, and ED infants were smaller than CON infants. Early deprivation infants tended to spend more time in the suckling position than did CON. Early deprivation infants demonstrated more distress vocalization than CON infants, even though the parental care they received in the home cage was similar. Early deprivation infants tended to play less socially than did CON. CONCLUSIONS: To our knowledge, this is the first demonstration that a repeated early life stressor of the type developed in rats can also be applied to a primate species.

Animals↗
PubMed2002

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine.

RATIONALE: Psychomotor stimulants can induce psychotic states in humans that closely resemble those observed in patients with idiopathic schizophrenia. Attentional and sensorimotor gating impairments are observed in schizophrenic patients using the latent inhibition (LI) and prepulse inhibition (PPI) behavioral assays, respectively. Our previous studies demonstrated that after 4 days of withdrawal from a period of amphetamine (AMPH) administration, animals exhibited disrupted LI but normal PPI. OBJECTIVE: The aim of the present study was to test PPI in AMPH-withdrawn rats under experimental conditions similar to those used to best demonstrate locomotor sensitization following AMPH withdrawal. METHODS: We examined the effects on PPI of (1) pairing drug injections with PPI test-associated cues, (2) administration of a low-dose dopamine agonist challenge and (3) testing following longer withdrawal periods (23, 30, 60 days). RESULTS: Although none of these conditions revealed a disruption of PPI in AMPH-withdrawn rats, we did observe that the acoustic startle response was reduced during a restricted time period following AMPH withdrawal. Similar to our previous findings, AMPH-withdrawn animals showed disrupted LI on day 16 of withdrawal and locomotor sensitization to a challenge injection of AMPH after 62 days of withdrawal. CONCLUSION: We conclude that the effects of repeated AMPH on PPI are not modulated by the same experimental parameters known to be important for eliciting locomotor sensitization and that withdrawal from the schedule of AMPH administration used in this study models only specific cognitive dysfunctions linked to schizophrenic symptoms, since LI was disrupted but PPI was not affected.

Acoustic Stimulation↗
PubMed2002

Comparison of central corticosteroid receptor expression in male Lewis and Fischer rats.

The histocompatible inbred Lewis (LEW) and Fischer (F344) rat strains exhibit marked phenotypic differences in the hormonal activity of the hypothalamic-pituitary-adrenal (HPA) axis. As such they provide an important comparative model for the study of HPA regulation including the central feedback regulation by the glucocorticoid transcription factors, the mineralocorticoid receptor (MR) and the glucocortiocoid receptor (GR). In adult male rats, basal nadir plasma corticosterone values were similar in the two strains whereas the amplitude and duration of the corticosterone response to restraint were significantly reduced in LEW. MR and GR mRNA expression were compared in LEW and F344 throughout the rostrocaudal extent of the hippocampus. Hippocampal MR expression was consistent throughout the rostrocaudal extent and similar in F344 and LEW males. Hippocampal GR expression was consistent throughout the rostrocaudal extent, but significantly greater in the rostral dentate gyrus and Cornu ammonis subfields in LEW males compared with F344 males. The LEW phenotype of relatively high hippocampal GR expression and HPA hypoactivity is shared by outbred rats exposed to neonatal handling and GR-overexpressing transgenic mice. Whether or not this relationship is causal, as well as the functional significance of the rostral-extent specific GR difference, remains to be elucidated.

Animals↗
PubMed2002

Effects of typical and atypical antipsychotics on prepulse inhibition and latent inhibition in chronic schizophrenia.

BACKGROUND: Prepulse inhibition and latent inhibition are the two animal paradigms currently dominating neuropharmacological research on attentional deficits in schizophrenia. Both paradigms have been shown to have a reasonable amount of face, predictive, and construct validity, but responsiveness to typical and atypical antipsychotics differs between the two, as indicated by animal and human studies. The relationship between the paradigms in schizophrenic patients is still unclear. METHODS: We tested prepulse inhibition and auditory latent inhibition in a sample of 33 chronic schizophrenic patients medicated either with atypical (n = 17) or typical (n = 16) antipsychotics. RESULTS: Latent inhibition was found to be intact in both patient groups. Prepulse inhibition was intact in the group receiving atypicals, but deficient in the group receiving typicals (at 60 msec lead interval condition). CONCLUSIONS: The direct comparison supports the hypothesis that atypical and typical antipsychotics have different effects on prepulse inhibition than on latent inhibition in schizophrenic patients; however, the results may also be explained by a greater sensitivity of the prepulse inhibition method. Because it is crucial to understand why there are considerable differences between the two paradigms and between human and animal studies, research should focus more strongly on comparative approaches.

Acoustic Stimulation↗
PubMed2002

Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology.

Behavioral sensitization to the locomotor activating effects of amphetamine refers to the progressive, long lasting increase in locomotor activity that occurs with repeated injections. This phenomenon is thought to result from neuroadaptations occurring in the projection fields of mesocorticolimbic dopaminergic neurons. In the present study, we investigated the effects of amphetamine sensitization on Fos immunoreactivity (Fos-IR) in subterritories of the nucleus accumbens (core and shell) and medial prefrontal cortex (mPFC; dorsal and ventral) using stereology. Rats received five daily injections of amphetamine (1.5 mg/kg, i.p.) or saline. Behavioral sensitization was measured 48 h following the last injection, in response to a challenge injection of 1.5 mg/kg amphetamine. Sensitized rats showed a greater enhancement of locomotor activity upon drug challenge compared with their saline counterparts. Densities of Fos-positive nuclei were enhanced more in the dorsal than the ventral mPFC subterritory, whereas in the nucleus accumbens, densities of Fos-positive nuclei were increased more in the core than the shell of amphetamine-sensitized rats compared to controls. These results represent, to our knowledge, the first published report using stereological methods to quantify Fos-IR in the brain and suggest functional specialization of cortical and limbic regions in the expression of behavioral sensitization to amphetamine.

Amphetamine↗
PubMed2002

Hippocampal lesioned rats are able to learn a spatial position using non-spatial strategies.

In the last two decades, many experiments have demonstrated that the hippocampus plays a role in the learning and processing of spatial and contextual information. Despite these demonstrations, some recent publications have indicated that the hippocampus is not the only structure involved in spatial learning and that even after hippocampal lesions, rats can perform spatial tasks. However, it is not well established whether animals with hippocampal dysfunction still have some spatial learning capacities or develop non-spatial solutions; these may require lengthier acquisition training. We now report the effects of conventional, dorsal hippocampal ablation on rats' performance on the water maze. We tested rats using a short (4 days) versus a long (16 days) acquisition period. We demonstrated that animals with dorsal hippocampal lesions have some residual capacity for learning the localization of a hidden escape platform in a pool during both a reference memory task and a working memory task. The animals with dorsal hippocampal lesions learned to escape at a fixed location, but only with extended training. It is suggested that these animals used non-spatial strategies to compensate for a spatial memory impairment. The results are discussed with respect to the experimental procedure and the strategy applied by the lesioned rats.

Animals↗
PubMed2002

Effect of excitotoxic lesions of rat medial prefrontal cortex on spatial memory.

The involvement of medial prefrontal cortex (mPFC) in spatial learning was examined in two memory tasks using spatial components, the Morris water maze and the three-panel runway. Using the Morris water maze task, with an invisible platform, the effects of NMDA mPFC lesions were assessed in a procedure reflecting spatial learning and memory, including a spatial reversal. In the three-panel runway, a delayed matching-to-position procedure was used in which rats were required to find food at the end of the runway after passing through one of three panel gates set into four barriers spaced equally apart along the maze. In addition, mPFC lesions were assessed behaviorally in two behavioral tests known to be sensitive to mPFC dysfunction: the food hoarding paradigm and spontaneous locomotion in the open field. Consistent with the documented effects of mPFC damage, NMDA mPFC lesions impaired food hoarding behavior and increased spontaneous exploratory locomotion. In the Morris water maze and the three-panel runway, mPFC-lesioned rats showed relatively few effects, supporting the conclusion that the damage inflicted to the mPFC had no consequence for the processing of spatial information. However, mPFC lesioned animals showed slower acquisition during both the training trial in the three-panel runway and the reversal training in the Morris water maze. These results suggest that spatial memory did not depend on mPFC integrity in the Morris water maze and the three-panel runway experiments, and address the issue of deficits induced by mPFC lesions in memory tasks dependent on non-mnemonic processes such as attentional processes and/or a reduced behavioral flexibility to environmental changes.

Animals↗
PubMed2002

Overexpression of Parkinson's disease-associated alpha-synucleinA53T by recombinant adeno-associated virus in mice does not increase the vulnerability of dopaminergic neurons to MPTP.

Mutations in the alpha-synuclein gene are linked to a rare dominant form of familial Parkinson's disease, and alpha-synuclein is aggregated in Lewy bodies of both sporadic and dominant Parkinson's disease. It has been proposed that mutated alpha-synuclein causes dopaminergic neuron loss by enhancing the vulnerability of these neurons to a variety of insults, including oxidative stress, apoptotic stimuli, and selective dopaminergic neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test this hypothesis in vivo, we overexpressed human alpha-synuclein(A53T) in the substantia nigra of normal and MPTP-treated mice by rAAV-mediated gene transfer. Determination of dopaminergic neuron survival, striatal tyrosine hydroxylase fiber density, and striatal content of dopamine and its metabolites in rAAV-injected and uninjected hemispheres demonstrated that alpha-synuclein(A53T) does not increase the susceptibility of dopaminergic neurons to MPTP. Our findings argue against a direct detrimental role for (mutant) alpha-synuclein in oxidative stress and/or apoptotic pathways triggered by MPTP, but do not rule out the possibility that alpha-synuclein aggregation in neurons exposed to oxidative stress for long periods of time may be neurotoxic.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Behavioral and anatomical effects of long-term L-dihydroxyphenylalanine (L-DOPA) administration in rats with unilateral lesions of the nigrostriatal system.

This study investigated behavioral and anatomical changes induced by long periods of L-DOPA treatment in the unilateral rat model of Parkinson's disease. After daily injections of L-DOPA (50 mg/kg, ip) given for 1, 4, 8, or 16 weeks, behavioral sensitization, expressed by contralateral turning and changes in its pattern, increased within the first week of treatment and remained unchanged thereafter. Dyskinetic movements, affecting the trunk and limbs of all treated rats, also developed within the first week of treatment and increased further during the 16 weeks of L-DOPA treatment. L-DOPA responsiveness was also accompanied by changes at the neuronal level, as shown by changes in the expression of c-fos in the dopamine-depleted striatum. Following 1 week of L-DOPA treatment there was a marked decrease in striatal c-fos expression, compared to single injections, especially evident in the medial and ventral regions and to a lesser extent in the dorsolateral regions of the striatum. This specific regional expression of c-fos was maintained throughout the 16 weeks of L-DOPA treatment. Overall, our results show that behavioral sensitization to L-DOPA starts relatively early during the treatment and include not only an increase in contralateral turning rate but also an increase in dyskinetic movements. Persisting c-fos expression in the dorsolateral striatum might be implicated in the development of dyskinesias when L-DOPA treatment is extended for periods longer than 1 week.

Animals↗
PubMed2002

Specific neuronal protein: a new tool for histological evaluation of excitotoxic lesions.

An important issue in the interpretation of behavioral data obtained from animals with excitotoxic lesions is evaluation of the extent of the lesions. Animals often have to be excluded from the behavioral analysis because the lesions are either not at the intended location or extend beyond it. Therefore, a clear cut histological evaluation is imperative for a meaningful interpretation of the behavioral results. Although Nissl staining is the most commonly used histological method for the evaluation of lesions, it is very difficult, if not impossible, to obtain a clear delineation of the lesioned area in Nissl-stained sections in some regions of the brain, such as the nucleus accumbens. This is especially the case when long survival times are used. In the present study, we introduce a simple and reliable immunohistochemical marker for the evaluation of excitotoxic lesions in the brain, the neuronal nuclei (NeuN) protein. With this staining, we have been able to delineate the lesions in problematic areas, such as the shell territory of the nucleus accumbens, with far greater accuracy than conventional Nissl staining.

Animals↗
PubMed2002

Peripheral benzodiazepine receptors reflect trait (early handling) but not state (avoidance learning).

Behavioral animal paradigms and experimental neuroendocrinological and neurochemical studies have shown that early environmental manipulations have profound effects on the late response to stress. The aim of the present study was to investigate the interactive effects of environmental manipulation (early handling) and experimentally induced behavioral differences on the peripheral benzodiazepine receptor (PBR) system, which is known to be involved in the response to stressors. Adult early-handled (EH) and nonhandled (NH; control) Wistar rats were placed in a two-way active avoidance/latent inhibition (LI) paradigm, and PBR densities in the adrenal glands, kidneys, and gonads were assessed. In line with previous studies, overall avoidance learning improved in the EH group, and LI was disrupted in the NH group (primarily in males). PBR densities were up-regulated in EH subjects, and more so in females than males. However, PBR densities did not correlate with any of the behavioral measures. These findings strengthen the hypothesis that differences in PBR densities between EH and NH rats are a reflection of trait rather than state, and they suggest that the PBR system is characterized by a highly stressor-specific response.

Adrenal Glands↗
PubMed2002

Early deprivation and behavioral and physiological responses to social separation/novelty in the marmoset.

Long-term effects of adverse early environment on neurobehavioral development have been reported for rodents and primates. The present study used daily early deprivation (ED), a paradigm developed for rats, for the first time in a nonhuman primate, the common marmoset, and investigated its effects on the behavioral and physiological responses to social separation/novelty (SSN) challenge tests in juveniles. On postnatal days (PNDs) 2-28, infants (n=5 twin pairs) were removed from the parents and placed alone in an isolation chamber for 30-120 min (9 h/week). Parents and control subjects (n=5 twin pairs) were briefly restrained (CON). At Weeks 18-20, behavioral responses of ED and CON juveniles to six 60-min SSN tests in an isolated cage, comprising 45 min alone and 15 min reunion with the father, were measured. Baseline and post-test urine samples were collected for measurement of cortisol. ED subjects exhibited significantly lower basal SSN urinary cortisol than CON, whilst SSN response cortisol values were similar in ED and CON. When alone, ED subjects were significantly less mobile and emitted significantly less contact calls than CON. Following reunion, ED subjects were significantly less in contact with or being carried by the father than CON and demonstrated significantly more tail piloerection. Although they require validation by additional parameters (e.g. cardiovascular), these data strongly suggest that early-life stress alters endocrine and behavioral responsiveness to psychosocial challenge in this primate and in a direction that could model important changes in disorders of human affective state.

Animals↗
PubMed2002

Effect of a single maternal separation at different pup ages on the corticosterone stress response in adult and aged rats.

Postnatal days (PNDs) 4-14 constitute the stress hyporesponsive period (SHRP) of the rat's pituitary-adrenal axis. The impact of manipulation of the pup-dam relationship during the SHRP on neuroendocrine and behavioural function has been the subject of considerable investigation. A single period of 24-h separation of the litter from the dam (maternal separation, MS) during the SHRP increases pup pituitary-adrenal activity and attenuates the SHRP. The MS manipulation also allows for the age-specific analysis of the chronic effects of early-life stress. Here we report on the effects of MS performed at the beginning of (PND 4), or about midway into (PND 9), or after (PND 18) the SHRP, on basal and stress-related blood corticosterone (CORT) titers in mature (month 5) and old (month 20) adult males. MS at PND 4, 9, or 18 did not affect basal CORT plasma titers. MS at each of these ontogenetic stages led to a similar and significant increase in the CORT response to restraint in adults but not in old adults. Therefore, whereas MS exerts a chronic impact on stress-related pituitary-adrenal activity in adult male rats, the effect of this postnatal experience does not depend upon the ontogenetic/SHRP status of the pup, and nor does it persist into senescence.

Age Factors↗
PubMed2002

Clozapine and haloperidol reinstate latent inhibition following its disruption during amphetamine withdrawal.

Latent inhibition (LI) is a behavioral phenomenon whereby repeated exposure to a non-reinforced stimulus retards subsequent conditioning to that stimulus. Deficits in LI may reflect an inability to ignore irrelevant stimuli and are studied as a model of the cognitive/attentional abnormalities found in schizophrenia. We recently determined that pretreatment with escalating doses of the indirect dopamine agonist amphetamine (AMPH; 3 daily injections ip, 1-5 mg/kg, over 6 days) disrupts LI in rats tested in a 2-way active avoidance paradigm during withdrawal. In the present study, we evaluated the effects of the atypical neuroleptic clozapine and the typical neuroleptic haloperidol on the expression of LI on day 4 of AMPH withdrawal. Neuroleptic injections were given either 45 min prior to each of two tone preexposure sessions and a subsequent tone-shock avoidance test session, or only prior to the test session. As expected, saline-injected control groups showed LI during the test session, as reflected by significantly reduced avoidance in tone preexposed vs. non-preexposed rats. In contrast, animals pretreated with escalating doses of AMPH did not show LI, due to the improved avoidance of the preexposed animals. Both haloperidol (0.03 mg/kg) and clozapine (5 mg/kg) largely reversed the disruptive influence of AMPH on LI regardless of whether these drugs were administered prior to both preexposure and test sessions or only prior to the test session. These results provide pharmacological validation for an AMPH withdrawal model of schizophrenic symptoms.

Amphetamine↗
PubMed2002

Effects of hippocampal N-methyl-D-aspartate infusion on locomotor activity and prepulse inhibition: differences between the dorsal and ventral hippocampus.

Prepulse inhibition (PPI) of the acoustic startle response and open-field locomotor activity were measured after bilateral infusion of N-methyl-D-aspartate into the ventral (0.10, 0.25, 0.50 microg/side) and dorsal (0.10, 0.25, 0.50, 0.70 microg/side) hippocampus of Wistar rats. Dose-dependent hyperactivity and disruption of PPI--behavioral effects related to psychotic symptoms--were observed after ventral infusions but were virtually absent after dorsal infusions. This functional dorsal-ventral difference might be related to the different connections of the dorsal and ventral hippocampus with the amygdala, nucleus accumbens, and prefrontal cortex, which have been implicated in the regulation of locomotor activity and PPI. Hippocampal overactivity has been associated with schizophrenia. The findings suggest that overstimulation of the ventral hippocampal projections may contribute to behavioral outcomes related to psychotic symptoms.

Amygdala↗