Biomedical subjects

Joram Feldon

Publications and source records attributed to Joram Feldon.

At least 37 records · Page 2Linked to original sources

PubMed2006

Early deprivation leads to altered behavioural, autonomic and endocrine responses to environmental challenge in adult Fischer rats.

Depression is diagnosed on the basis of abnormal positive affects (anhedonia) and negative affects (low mood, helplessness, coping deficit, fatigue), and associated physiological abnormalities include hyperactivity of the HPA endocrine system and autonomic nervous system. Adverse early life environments, including parent-offspring emotional and physical neglect, are associated with traits of altered physiological and neurobiological function and long-term predisposition to depression. Animal studies based on early life adversity can potentially yield environmental models of the developmental behavioural neurobiology of depression. In Wistar rats, we demonstrated that isolation of pups from dam and littermates at room temperature for 4 h per day on P1-14 (early deprivation, ED) led to adulthood anhedonia-like traits of reduced motivation to obtain gustatory reward and reduced social motivation, relative to subjects left undisturbed during infancy (non-handling, NH). We hypothesized that the depression-like effects of ED would be even more pronounced and multiple in the stress hyper-responsive Fischer rat strain. The effects of ED were studied relative to NH and 15 min of daily isolation (early handling, EH). Relative to NH and EH, which exhibited remarkably similar phenotypes, ED led, principally in males, to chronic traits of: reduced motivation for and consumption of gustatory reward; increased activity in the pre-test and test phases of the forced swim test; reduced coping behaviour in an aversive environment; attenuated plasma corticosterone stress response to a normal plasma ACTH stress response; increased hypertensive response to a novel environment; and increased prefrontal cortical serotonin. High sensitivity to an aversive early environment in male Fischer rats therefore constitutes an important model for the study of affective development and its neurobiology.

Adrenocorticotropic Hormone↗

PubMed2005

Differential expression of PSD proteins in age-related spatial learning impairments.

Deficits in hippocampus-dependent spatial learning that are typical for a subpopulation of aged rats are not associated with loss of neurons or excitatory synapses but accompanied by significant reduction of postsynaptic density (PSD) area in perforated synapses. Here, we examined whether structural alterations in aged learning-impaired rats correlate with altered content of PSD proteins which are critically involved in normal synaptic function. Spatial memory tasks were used to separate male rats into young, aged learning-unimpaired and impaired groups. Semi-quantitative immunohistochemistry revealed significant alterations in the content of the AMPA receptor GluR1 subunit, PSD-95 and synGAP in the hippocampal formation of aged-learning impaired compared to aged-unimpaired and young rats. While synGAP expression was reduced, GluR1 and PSD95 levels were selectively increased in aged-learning-impaired subjects. These findings suggest that age-induced changes of the PSD protein expression levels are more pronounced in learning-impaired rats compared to unimpaired subjects and that the alterations in synaptic protein content may result in reduced synaptic function, potentially underlying the individual differences in mnemonic functions during aging.

Aging↗

PubMed2005

Immunological stress at the maternal-foetal interface: a link between neurodevelopment and adult psychopathology.

Maternal infection during pregnancy is associated with a higher incidence of mental disorders, including schizophrenia, in the offspring in later life. Our recent attempt to study this link between prenatal immunological challenge and subsequent psychopathology has led to the establishment of a mouse model demonstrating the emergence of multiple psychotic-like phenotypes following immunological challenge on gestation day (GD) 9. However, little is known about the impact of similar in utero challenge at different times of pregnancy. Here, we compare the efficacy of identical maternal immune stimulation induced by the exposure to polyriboinosinic-polyribocytidilic acid (Poly(I:C)) at a dose of 5mg/kg (i.v.) on distinct days of gestation (GD 6, 9, 13 or 17). The offspring derived were then compared to those collected from vehicle- and non-treated dams in two paradigms of selective associative learning: latent inhibition (LI) and the US-pre-exposure effect (USPEE). LI deficiency was observed in animals born to dams treated with Poly(I:C) on GD 6, 9 or 13, but not in those on GD17. In contrast, a loss of the USPEE was equivalently seen in all Poly(I:C) treatment groups, regardless of treatment times. Evaluation of the acute cytokine response in a separate cohort of pregnant dams receiving Poly(I:C) challenge on either GD9 or GD17 revealed that the ratio of interleukin-10/tumor necrosis factor-alpha was elevated in the GD17 relative to the GD9 group. The present report thus provides evidence that the acute cytokine reaction as well as the long-term pattern of behavioural sequelae of maternal immune challenge can be affected by its precise timing during pregnancy. The present study provides further support to the use of the prenatal Poly(I:C) model in the elucidation of mechanisms involved in the aetiology and disease process of immuno-precipitated neurodevelopmental mental diseases, including but not limited to, schizophrenia.

Analysis of Variance↗

PubMed2005

Behavioural consequences of withdrawal from three different administration schedules of amphetamine.

Different administration schedules of amphetamine (AMPH) lead to different behavioural consequences, neurochemical changes and gene expression patterns in a variety of brain areas during drug withdrawal. However, direct comparisons of these different effects within the same experiment are rare in the literature. Accordingly, in this study, rats were tested in relevant behavioural paradigms during withdrawal from three different administration schedules of AMPH. The intermittent schedule (INT) consisted of one daily injection of 1.5 mg/kg AMPH for 6 days. The escalating administration schedule consisted of three daily injections for 6 days with increasing dosages from 1 to 5 mg/kg AMPH during the first five injections and 5 mg/kg for the following 13 injections (ESC-5). A second more severe escalating administration schedule (three injections per day for 3 days escalating from 1 to 9 mg/kg AMPH and a final 10 mg/kg AMPH injection on day 4, ESC-10) was also investigated. Control animals received saline injections according to the three administration schedules. Rats pretreated with AMPH according to the ESC-10 administration schedule exhibited a transient reduction of locomotor activity on day 1, but not day 5, of withdrawal, as well as a permanent disruption of prepulse inhibition (PPI) on days 4, 20, and 40 of withdrawal. There was no effect on anxiety measured by the elevated plus-maze on withdrawal day 2, and all the AMPH pretreated animals exhibited a similar magnitude of behavioural sensitization following an AMPH challenge irrespective of administration schedule on withdrawal day 42. These data suggest that, based on their persistent disruption of PPI, animals withdrawn from AMPH ESC-10 might model specific symptoms of schizophrenic patients.

Amphetamine↗

PubMed2005

The expression of prepulse inhibition of the acoustic startle reflex as a function of three pulse stimulus intensities, three prepulse stimulus intensities, and three levels of startle responsiveness in C57BL6/J mice.

Using the acoustic startle reflex, prepulse inhibition (PPI) is typically demonstrated by the interaction between two auditory stimuli presented in close temporal proximity. When a startle-eliciting pulse stimulus is shortly preceded by a weak prepulse stimulus, the reaction to the former is attenuated in comparison to when the pulse stimulus is presented alone. The present experiment evaluated the influence of different prepulse and pulse intensities upon the expression of PPI by additionally taking into account individual differences in startle reactivity. To this end, we subdivided a cohort of 102 mice into three subsets of equal size differing in startle responsiveness, and evaluated PPI using three levels of prepulse stimulus in combination with three intensities of pulse stimulus. Our results revealed additive as well as complex interactive effects amongst individual's reactivity, pulse intensity and prepulse intensity. At the same time, additional issues concerning the quantification of PPI are highlighted, especially when startle reactivity differs considerably between comparison groups. We concluded that the variation in pulse intensity represents a valuable addition to PPI assessment in general, and especially in genetically modified mice.

Acoustic Stimulation↗

PubMed2005

Rapid visual information processing in schizophrenic patients: the impact of cognitive load and duration of stimulus presentation. A pilot study.

The inability to sustain attention has been proposed as a core deficit in schizophrenia. The Continuous Performance Task (AX-CPT) and the Rapid Visual Information Processing Task (RVP) are widely used neuropsychological tasks to measure sustained attention. The RVP displays numbers as stimuli, whereas the AX-CPT uses letters. Ten patients with chronic schizophrenia and 18 healthy control subjects were studied using four different versions of the RVP. The versions differed with regard to stimulus presentation time (600 vs. 1,200 ms) and the number of target sequences to be memorized: either one sequence (low cognitive load) or two sequences (high cognitive load). Schizophrenic patients showed a reduced number of hits only on the task version with 600 ms stimulus duration coupled with high cognitive load. The combination of high cognitive load and short stimulus duration created a critical performance breaking point for schizophrenic patients. This finding supports the hypothesis that patients have an impaired ability to coactivate different cognitive performances; thus the results favor the theory of impaired functional connectivity in schizophrenia.

Adult↗

PubMed2005

On the feasibility to detect and to quantify prepulse-elicited reaction in prepulse inhibition of the acoustic startle reflex in humans.

The possibility that the prepulse stimulus typically employed in the studies of prepulse inhibition (PPI) can produce observable response has been questioned recently. Conflicting reports range from observations of prepulse-elicited startle reaction to a complete lack of detectable prepulse-elicited reactions in healthy volunteers. This controversy is subjected to critical examination in the present study. The ability of prepulse stimuli to induce PPI and to elicit measurable responses was examined in two separate experiments using prepulses ranging from 6 to 18dB above background (experiment 1), or 1 to 5dB above background (experiment 2). Three levels of pulse stimulus were employed: 95, 105 and 115dBA. Clear PPI and prepulse-elicited reaction were obtained in experiment 1, while neither effect was evident in experiment 2. Non-startle-eliciting prepulses that are of sufficient intensities to induce reliable PPI are associated with detectable and quantifiable response, confirming that direct evaluation of prepulse-processing is feasible and practical. This provides an additional measure of theoretical and potentially clinical relevance to PPI, and it ought to be included in future studies in patients as well as healthy subjects.

Acoustic Stimulation↗

PubMed2005

Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research.

Depression is one of the most common human illnesses and is of immense clinical and economic significance. Knowledge of the neuro-psychology, -biology and -pharmacology of depression is limited, as is the efficacy of antidepressant treatment. In terms of depression aetiology, whilst the evidence for causal mechanisms is sparse, some genomic and environmental factors associated with increased vulnerability have been identified. With regards to the latter, the environments in which human infants and children develop are fundamental to how they develop, and parental loss, emotional and physical neglect, and abuse have been shown to be associated with: traits of depression, traits of predisposition to depression triggered by subsequent life events, and associated physiological abnormalities, across the life span. Studies of postnatal environmental manipulations in rodents and primates can potentially yield evidence that abnormal early-life experience leading to dysfunction of the neurobiology, physiology and behaviour of emotion is a general mammalian characteristic, and therefore, that this approach can be used to develop animal models for depression research, with aetiological, face, construct and predictive validity. The establishment of models with such validity, if at all achievable, will require a sophisticated combination of (1) appropriate postnatal manipulations that induce acute stress responses in the infant brain which in turn lead to long-term neurobiological consequences, and (2) appropriate behavioural and physiological assays to identify and quantify any depression-like phenotypes resulting from these long-term neurobiological phenotypes. Here, we review some of the evidence-positive and negative-that neglect-like environments in rat pups and monkey infants lead to long-term, depression-like behavioural traits of reduced motivation for reward and impaired coping with adversity, and to altered activity in relevant physiological homeostatic systems.

Animals↗

PubMed2005

Effects of prenatal methylazoxymethanol acetate (MAM) treatment in rats on water maze performance.

Prenatal methylazoxymethanol acetate (MAM) treatment has been shown to induce morphological abnormalities in cortical areas of the offspring. Based on the neuroanatomical and behavioural abnormalities, this treatment has been suggested as a useful animal model for schizophrenia. In a previous study (Jongen-Relo AL, Leng A, Luber M, Pothuizen HHJ, Weber L, Feldon J. The prenatal methylazoxymethanol acetate treatment: a neurodevelopmental animal model for schizophrenia? Behav Brain Res 2004;149:159-81) we have studied MAM-treated animals in a series of behavioural tests related to schizophrenia, such as latent inhibition and pre-pulse inhibition of the acoustic startle response to establish the validity of prenatal MAM treatment (20mg/kg i.p. on gestational days 9-15; MAM 9-MAM 15). We found that, apart from a marginal effect of increased activity in the open field, the MAM treatment on gestational day 15 was behaviourally ineffective. Here, we extended our previous study to a water maze experiment conducted in the same batch of animals as presented previously (MAM 12-MAM 15). MAM-treated animals showed similar water maze performance compared with control animals during the acquisition phase and the probe tests. However, during the reversal phase, MAM 15 animals showed impaired acquisition of the new platform location. This might indicate some cognitive deficits in MAM 15 animals in terms of working memory or behavioural flexibility. However, in combination with the lack of behavioural abnormalities of MAM 12-MAM 15 animals in several other tests related to schizophrenia in the previously reported study, the use of MAM treatment (MAM 12-MAM 15) as a valid model for schizophrenia still remains debatable.

Analysis of Variance↗

PubMed2005

Early deprivation under specific conditions leads to reduced interest in reward in adulthood in Wistar rats.

Early life adversity can lead to increased vulnerability to psychiatric disease including depression, with symptoms of depressed mood, impaired coping with negative events, anhedonia, reduced appetite, and elevated stress hormone activity. In rats, postnatal manipulation studies have focused on behavioural and endocrine anxiety effects, and have demonstrated that mild pup stimulation in the form of early handling (EH) is chronically anxiolytic relative to no stimulation in the form of non-handling (NH). Furthermore, apparently severe manipulations in the form of 3-4 h daily litter-dam separation (maternal separation) or pup-litter-dam separation (early deprivation, ED) are either without effect or even EH-like, relative to NH. In this Wistar rat study, we investigated the effects of ED under different circadian and thermal conditions on adulthood behavioural and endocrine responsiveness to environmental challenge, relative to NH. ED was performed on days 1-14, during either the Light or Dark phase and at either 21 degrees C (cold) or 32 degrees C (warm). Dark-cold ED adults exhibited reduced motivation to obtain sucrose in a progressive ratio schedule, tended to be less mobile in a forced swim test, but did not exhibit an escape deficit in a foot-shock pre-exposure/shuttle box test, or altered basal or stress endocrine activity. Light ED was completely without effect on adult phenotype. Even relative to stringent NH comparison, dark-cold ED leads to a long-term trait of mild gustatory anhedonia in Wistar rats.

Adrenocorticotropic Hormone↗

PubMed2005

Early social and physical deprivation leads to reduced social motivation in adulthood in Wistar rats.

Behavioural abnormalities in adulthood may have their origin in a disturbed interaction with the environment during postnatal development. We tested the consequences for adult social motivation of early deprivation (ED) of rat pups from mothers and littermates relative to nonhandled (NH) pups. Early deprivation was performed at room or warm ambient temperatures, cold-ED and warm-ED, respectively, and during either the dark or light phase of the daily cycle. In adulthood, rats that were unrelated and unfamiliar but of the same treatment group were introduced in pairs to an open field for a 30-min test. Social behaviour in home base and exploration modes was assessed using algorithmic analysis of the XY locations of the two rats. Findings revealed that Cold-ED induced a preference for a separate home base, which limited significantly the episodes of social interactions, in comparison to NH. Warm-ED had no comparable effect on the rats' social behaviour. These findings indicate that ED under ambient conditions that constitute severe thermal stress for rat pups leads to development of reduced social motivation in adulthood.

Analysis of Variance↗

PubMed2005

Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys.

RATIONALE: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks. OBJECTIVE: In the present primate study, we used radioautography to describe the distribution and intensity of (3)H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated. METHODS: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3--10 mg/kg, and on the CDMP, subjects were tested at 1--3 or 3--10 mg/kg. RESULTS: Radioautography revealed a relatively low level of (3)H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP. CONCLUSIONS: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.

Animals↗

PubMed2005

Learned irrelevance is disrupted in first-episode but not chronic schizophrenia patients.

Learned irrelevance (LIrr) is a pre-exposure effect in which uncorrelated presentations of a conditioned stimulus (CS) and an unconditioned stimulus (US) retard subsequent CS-US association. LIrr is closely related to the phenomenon of latent inhibition (LI). LI refers to the retarding effects of inconsequential stimulus pre-exposure on subsequent conditioning to that stimulus, and is considered to reflect the organism's capacity to ignore irrelevant stimuli. LI is disrupted in schizophrenia patients, due to faster learning of the association between the preexposed CS and the US. A new within-subject target-recognition LIrr procedure was applied. The target was either cued by a priming signal or appeared at random, and priming signals were novel or preexposed cues. Schizophrenia patients were compared to age- and sex-matched control subjects. Normal subjects (n = 24) have shown robust LIrr, namely, faster cue-target associations of novel compared to preexposed cues. Schizophrenia patients at the early stages of their first episode (n = 7) showed LIrr disruption, namely, cue-target associations to preexposed cues were as fast as for novel cues. Chronic patients during an acute phase (n = 18) did not show LIrr as they failed to learn the cue-target association. In addition to the LIrr paradigm the same subjects were tested in a covert-orientation task. No differences were observed between the groups on this task. The possible advantages of the new LIrr paradigm are discussed.

Adult↗

PubMed2005

Brain area- and isoform-specific inhibition of synaptic plasticity by apoE4.

The allele E4 of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer's disease (AD), inhibits the improvements in learning and memory which result from exposure of apoE transgenic mice to environmental stimulation (ES). In the present study, we investigated the extent to which these cognitive deficits are associated with distinct presynaptic, postsynaptic and axonal impairments and whether these effects are brain area-specific. Exposure to an enriched environment of young mice transgenic for human apoE3, which is the AD benign apoE allele, increased the levels of the presynaptic protein synaptophysin and of the dendritic marker MAP-2 in the hippocampus and entorhinal cortex, whereas the corresponding levels of these proteins in the apoE4 transgenic mice were unaffected by the enriched environment. In contrast, the levels of synaptophysin and MAP-2 in the motor cortex were elevated by environmental stimulation in both the apoE3 and the apoE4 transgenic mice. These findings show that apoE4 inhibits synaptic plasticity following environmental stimulation and that this effect is both isoform- and brain area-specific.

Animals↗

PubMed2005

Prepulse lost and regained: a commentary on "Weak prepulses inhibit but do not elicit startle in rats and humans", Biological Psychiatry 55:98-101.

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Animals↗

PubMed2005

Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia.

Epidemiological studies have indicated an association between maternal bacterial and viral infections during pregnancy and the higher incidence of schizophrenia in the resultant offspring post-puberty. One hypothesis asserts that the reported epidemiological link is mediated by prenatal activation of the foetal immune system in response to the elevation of maternal cytokine level due to infection. Here, we report that pregnant mouse dams receiving a single exposure to the cytokine-releasing agent, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 2.5, 5.0, or 10.0 mg/kg) on gestation day 9 produced offspring that subsequently exhibited multiple schizophrenia-related behavioural deficits in adulthood, in comparison to offspring from vehicle injected or non-injected control dams. The efficacy of the PolyI:C challenge to induce cytokine responses in naïve non-pregnant adult female mice and in foetal brain tissue when injected to pregnant mice were further ascertained in separate subjects: (i) a dose-dependent elevation of interleukin-10 was detected in the adult female mice at 1 and 6h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1beta were elevated. The spectrum of abnormalities included impairments in exploratory behaviour, prepulse inhibition, latent inhibition, the US-pre-exposure effect, spatial working memory; and enhancement in the locomotor response to systemic amphetamine (2.5 mg/kg, i.p.) as well as in discrimination reversal learning. The neuropsychological parallels between prenatal PolyI:C treatment in mice and psychosis in humans, demonstrated here, leads us to conclude that prenatal PolyI:C treatment represents one of the most powerful environmental-developmental models of schizophrenia to date. The uniqueness of this model lies in its epidemiological and immunological relevance. It is, sui generis, ideally suited for the investigation of the neuropsychoimmunological mechanisms implicated in the developmental aetiology and disease processes of schizophrenia.

Animals↗

PubMed2005

The effects of temporary inactivation of the core and the shell subregions of the nucleus accumbens on prepulse inhibition of the acoustic startle reflex and activity in rats.

The nucleus accumbens can be dissociated into at least two subregions: a 'core' and a 'shell'. Using temporary chemical inactivation of these subregions, we investigated whether they are differentially involved in the regulation of prepulse inhibition (PPI) of the acoustic startle reflex and activity. For this purpose, rats were bilaterally implanted with guide cannulae aimed at either the core or the shell and infused with the GABA(A) receptor agonist muscimol (0.5 microg/0.2 microl per side). The control group consisted of vehicle infused and unoperated rats. To ascertain the region selectivity of the infusions, 0.2 microl of [3H]muscimol was infused into either the core or the shell of an additional group of rats. The behavioral results demonstrated that in comparison to the control group, inactivation of the core led to a loss of the prepulse intensity dependency of PPI. Moreover, core inactivation resulted in akinesia directly after infusion, but in hyperactivity 24 and 72 h thereafter in contrast to the control group. In both experiments, inactivation of the shell was ineffective compared to controls. Analysis of the autoradiograms revealed that the spread of drug into the other subregion was minimal, supporting the region selectivity of the inactivation. These results lend further support to the existence of a functional dissociation between the core and the shell, with the former being preferentially involved in PPI and locomotion. The persistent hyperactivity after the muscimol infusion into the core could be explained by compensatory mechanisms taking place in the nucleus accumbens.

Akathisia, Drug-Induced↗

PubMed2005

Postnatal ontogeny of hippocampal expression of the mineralocorticoid and glucocorticoid receptors in the common marmoset monkey.

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are nuclear transcription factors that mediate many of the basal and stress functions and effects of the corticosteroid hormones, including those related to brain development. Despite this, relatively little is known about the postnatal ontogeny of MR and GR gene and protein expression in the central nervous system, and this is particularly true of the primates, including humans. Here we describe the postnatal ontogeny of central MR and GR gene and protein expression in the common marmoset monkey. By developing marmoset-specific riboprobes and using in situ hybridization, it was demonstrated that MR mRNA expression in the dentate gyrus and Ammon's horn was significantly greater in marmoset infants (aged 4-6 weeks) than in neonates (1-2 days), juveniles (4-5 months) and adults (3-6 years), with expression in the latter three ontogenetic stages being broadly similar. In the same subjects and ontogenetic stages, GR mRNA expression was developmentally consistent in the marmoset dentate gyrus and Ammon's horn, as well as in the paraventricular nucleus of the hypothalamus. Qualitative immunohistochemical comparison of infants and adults demonstrated that MR protein expression in the hippocampus was, as for mRNA, also greater in infants than adults, and that hippocampal GR protein was, as for mRNA, also similar in infants and adults. The increase in MR mRNA expression between the stages of neonate and infant co-occurred with a reduction in basal plasma ACTH and cortisol titres. The ontogenetic profiles of MR and GR gene expression in the marmoset monkey are therefore fundamentally different from those described for the rat and the mouse. This evidence for the postnatal ontogeny of central corticosteroid nuclear receptor expression in a primate is important for understanding both the developmental stage-specific significance of stress exposure and its potential long-term effects on health and disease.

Animals↗