Biomedical subjects

J Feldon

Publications and source records attributed to J Feldon.

At least 19 recordsLinked to original sources

PubMed2006

Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: implications for schizophrenia.

Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABAA-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABAA receptor subunit alpha2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABAA receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.

Analysis of Variance↗

PubMed2006

Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice.

The present study tested whether individual differences in anxiety- and fear-related behaviour are associated with between-subjects variation in postmortem brain levels of selected neurotrophic factors. Naïve C57BL6/J mice of both sexes were subjected either to an elevated plus maze test or to a Pavlovian fear conditioning paradigm. Two days after behavioural assays, the mice were sacrificed for postmortem quantification of the protein levels of brain derived neurotrophic factors (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3) in the hippocampus and amygdala. Significant correlations between behavioural measures and postmortem regional neurotrophic factor contents were revealed. The magnitude of anxiety-like behaviour in the elevated plus maze was positively related to dorsal hippocampal BDNF levels, but negatively related to NGF levels in dorsal hippocampus and in the amygdala. On the other hand, the expression of conditioned fear is positively related to amygdala BDNF and NGF levels, and to dorsal hippocampal NGF levels. Our results add to existing reports in human as well as in animals of correlation between anxiety trait and gross measures of hippocampal volume or activation levels. Moreover, a distinction between spontaneous and learned (or conditioned) anxiety/fear would be relevant to the identification of neurotrophin signalling mechanisms in the hippocampus and amygdala implicated in anxiety and related psychopathology.

Amygdala↗

PubMed2006

Startle and prepulse inhibition as a function of background noise: a computational and experimental analysis.

Schmajuk and Larrauri [Schmajuk NA, Larrauri JA. Neural network model of prepulse inhibition. Behav Neurosci 2005;119:1546-62.] introduced a real-time model of acoustic startle, prepulse inhibition (PPI) and facilitation (PPF) in animals and humans. The model assumes that (1) positive values of changes in noise level activate an excitatory and a facilitatory pathway, and (2) absolute values of changes in noise level activate an inhibitory pathway. The model describes many known properties of the phenomena and the effect of brain lesions on startle, PPI, and PPF. The purpose of the present study is to (a) establish the magnitude of startle and PPI as a function of pulse, prepulse, and background intensity, and (b) test the model predictions regarding an inverted-U function that relates startle to the intensity of the background noise.

Acoustic Stimulation↗

PubMed2005

Withdrawal from repeated amphetamine administration leads to disruption of prepulse inhibition but not to disruption of latent inhibition.

The present study represents a continuous effort to develop an animal model of schizophrenia based on the "endogenous dopamine sensitization" hypothesis. To achieve this goal, withdrawal from an escalating amphetamine (AMPH) regime administration [three injections per day over a period of 4 days and increasing doses from 1 to 10 mg/kg of AMPH or an equivalent volume of saline (SAL)] was employed. Animals exposed to this treatment were evaluated on their performance in attentional (Latent inhibition, LI) and sensorimotor gating (Prepulse inhibition, PPI) tasks in a drug free state and tested for locomotor sensitization following a low dose of AMPH challenge administration.LI using active avoidance, tested on withdrawal day 4, was unaffected. PPI of the acoustic startle response, measured on withdrawal days 6 and 70, was disrupted. On the 76th day of withdrawal, a low challenge dose of AMPH (1 mg/kg) led to a clear locomotor sensitization effect.

Acoustic Stimulation↗

PubMed2005

Latent inhibition of conditioned taste aversion is not disrupted, but can be enhanced, by selective nucleus accumbens shell lesions in rats.

Latent inhibition is a form of negative priming in which repeated non-reinforced pre-exposures to a stimulus retard subsequent learning about the predictive significance of that stimulus. The nucleus accumbens shell and the anatomical projection it receives from the hippocampal formation have been attributed a pivotal role in the control or regulation of latent inhibition expression. A number of studies in rats have demonstrated the efficacy of selective shell lesions to disrupt latent inhibition in different associative learning paradigms, including conditioned active avoidance and conditioned emotional response. Here, we extended the test to the conditioned taste aversion paradigm, in which the effect of direct hippocampal damage on latent inhibition remains controversial. We demonstrated the expected effect of selective shell lesions on latent inhibition of conditioned emotional response and of conditioned active avoidance, before evaluating in a separate cohort of rats the effect of comparable selective lesions on latent inhibition of conditioned taste aversion: a null effect of the lesions was first obtained using parameters known to be sensitive to amphetamine treatment, then an enhancement of latent inhibition was revealed with a modified conditioned taste aversion procedure. Our results show that depending on the associative learning paradigm chosen, shell lesions can disrupt or enhance the expression of latent inhibition; and the pattern is reminiscent of that seen following hippocampal damage.

Animals↗

PubMed2005

A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction.

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.

Amphetamine↗

PubMed2005

Activation of dopaminergic neurotransmission in the medial prefrontal cortex by N-methyl-d-aspartate stimulation of the ventral hippocampus in rats.

Many behavioral functions-including sensorimotor, attentional, memory, and emotional processes-have been associated with hippocampal processes and with dopamine transmission in the medial prefrontal cortex (mPFC). This suggests a functional interaction between hippocampus and prefrontal dopamine. The anatomical substrate for such an interaction is the intimate interconnection between the ventral hippocampus and the dopamine innervation of the mPFC. The present study yielded direct neurochemical evidence for an interaction between ventral hippocampus and prefrontal dopamine transmission in rats by demonstrating that subconvulsive stimulation of the ventral hippocampus with N-methyl-d-aspartate (NMDA; 0.5 mug/side) activates dopamine transmission in the mPFC. Postmortem measurements revealed that bilateral NMDA stimulation of the ventral hippocampus, resulting in locomotor hyperactivity, increased the homovanillic acid/dopamine ratio, an index of dopamine transmission, in the mPFC; indices of dopamine transmission in any of five additionally examined forebrain regions (amygdala, nucleus accumbens shell/core, lateral prefrontal cortex, caudate putamen) were unaltered. In vivo microdialysis measurements in freely moving rats corroborated the suggested activation of prefrontal dopamine transmission by demonstrating that unilateral NMDA stimulation of the ventral hippocampus increased extracellular dopamine in the ipsilateral mPFC. The suggested influence of the ventral hippocampus on prefrontal dopamine may be an important mechanism for hippocampo-prefrontal interactions in normal behavioral processes. Moreover, it indicates that aberrant hippocampal activity, as found in neuropsychiatric diseases, such as schizophrenia and mood disorders, may contribute to disruption of certain cognitive and emotional functions which are extremely sensitive to imbalanced prefrontal dopamine transmission.

Animals↗

PubMed2005

Hippocampal alpha5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition.

Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5(H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.

Acoustic Stimulation↗

PubMed2005

Sharing of the home base: a social test in rats.

The open field provides abundant opportunities for a pair of rats to express social interactions. Rats demonstrate social proximity while exploring the open field and also during simultaneous occupancy of a home base (HB). The HB is defined as a place in the field for which rats show a long-term preference, both in terms of occupancy and as a starting and ending point of exploratory excursions. In the present study, the social proximity of pairs of rats treated with phencyclidine (PCP; 2 mg/kg) or saline (Sal), and rats treated with clozapine (CLZ; 1.3 mg/kg) alone or in combination with PCP (CLZ-PCP), was videotaped and analysed algorithmically. PCP was tested for its disruptive effects on social interactions, and CLZ was tested for its ability to reverse some forms of the disruptive effects of PCP. The results showed that PCP reduced the rate of pairs establishing a common HB and shortened social HB occupancy, but had no effect on episodes of social exploration in the field. These findings demonstrate that the antisocial effect of PCP cannot be generalized across the entire spectrum of behavioural states in the open field. CLZ further decreased rather than increased social HB occupancy. This effect was derived from the reduction in rate of pairs establishing a common HB.

Algorithms↗

PubMed2004

Apomorphine-induced disruption of prepulse inhibition that can be normalised by systemic haloperidol is insensitive to clozapine pretreatment.

RATIONALE: Prepulse inhibition (PPI) of startle refers to the phenomenon in which a weak prepulse attenuates the startle response to a succeeding intense stimulus. PPI can be disrupted by systemic apomorphine in animals, and reduced PPI has been consistently reported in schizophrenia patients. The ability of the atypical antipsychotic clozapine to reverse apomorphine-induced PPI deficit has been demonstrated in the rat, but has not yet been tested in the mouse. The present study was designed to fill this gap. OBJECTIVE AND RESULTS: We investigated the efficacy of clozapine in reversing apomorphine-induced (2.0 or 2.5 mg/kg, s.c.) PPI deficit in C57BL6 mice. Clozapine failed to restore PPI disruption in apomorphine-treated mice in two independent laboratories across two dose ranges (1-3 mg/kg, i.p., or 3-30 mg/kg, p.o.), whereas the typical antipsychotic haloperidol (1 mg/kg, i.p.) completely normalised PPI performance. CONCLUSIONS: Unlike the rat, apomorphine-induced PPI disruption in mice might be instrumental in distinguishing between typical and atypical antipsychotic drugs. This also lends further support to the suggestion that the neuropharmacology of PPI is not identical in the two rodent species.

Animals↗

PubMed2004

Regional dissociations within the hippocampus--memory and anxiety.

The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.

Animals↗

PubMed2004

Latent inhibition is spared by N-methyl-D-aspartate (NMDA)-induced ventral hippocampal lesions, but is attenuated following local activation of the ventral hippocampus by intracerebral NMDA infusion.

Repeated non-reinforced exposures of a neutral stimulus retard the development of a conditioned response to that stimulus when it is subsequently paired with a significant event. This stimulus pre-exposure effect is known as latent inhibition (LI). Early lesion studies have initially suggested an important role for the hippocampus in the normal development and expression of LI. This view has since been modified with the emergence of data derived from selective cell body lesions of the hippocampus and of the entorhinal cortex, with an abolition of LI only seen after lesions of the latter. This suggests that the significance of the hippocampus might have been overestimated in the past, possibly due to interruption of fibres en passage. However, intact behavioural expression of LI following hippocampal damage does not preclude the suggestion that the hippocampus participates in the control and regulation of LI expression in intact animals. The present study demonstrated that whilst cell body lesions of the ventral hippocampus spared LI (as expected), chemical activation of the ventral hippocampus by local N-methyl-D-aspartate infusion disrupted LI. These results parallel our earlier observations on prepulse inhibition (PPI) with similar manipulations [Neuroreport 10 (1999) 2533]. Thus, although the ventral hippocampus is itself not responsible for the behavioural manifestation of LI and PPI, it exerts at least a modulatory control over the form and/or magnitude of their expression. Our results should prompt a re-evaluation of the relative roles of the hippocampus and retrohippocampus in the development and expression of LI.

Animals↗

PubMed2004

Dissociation of function within the hippocampus: effects of dorsal, ventral and complete excitotoxic hippocampal lesions on spatial navigation.

The present study was designed to assess the possibility that sub-total ventral hippocampal lesions might leave intact a mechanism for only highly accurate navigation, whereas sub-total dorsal hippocampal lesions might leave intact a mechanism only for less precise navigation. Animals with selective dorsal, ventral or complete hippocampal lesions were tested in a water maze, in which the target platform was moved from trial to trial, but always within a defined area, instead of being at a fixed location. Hence, an animal that searched at exactly the point where the platform had been found on a previous trial would be disadvantaged, in comparison with an animal that searched in the right general area. This might favor animals capable of less precise navigation over those with very precise navigational abilities. In subsequent phases of the experiment, we additionally assessed, for comparison, performance with a fixed platform location, reversal learning in the water-maze, and performance on an elevated T-maze. Our results revealed no sign of any qualitative difference between the effects of the selective sub-total lesions when the water maze hidden platform location was varied within the defined area, and the effects in subsequent more conventionally used tests. Ventral hippocampal damage never led to a performance deficit. Dorsal hippocampal damage led to significantly poorer performance in only some test phases, and never led to any sign of improved performance.

Animals↗

PubMed2004

The impaired coping induced by early deprivation is reversed by chronic fluoxetine treatment in adult fischer rats.

The symptoms of depression include feelings of reduced coping ability and increased helplessness. Early life adversity increases vulnerability to depression. In rats, the quantification of ability to cope with adverse challenge can be achieved using preexposure to an inescapable aversive stimulus and subsequent assessment of escape or avoidance deficits in the same environment. Here we investigated the predictive validity of a model in which, in the Fischer rat strain, postnatal isolation leads in adulthood to a state of increased sensitivity to develop an escape or avoidance deficit. On days 1-14 rat pups were isolated for 4 hours (early deprivation, ED) or for 15 minutes (early handling, EH), or were left completely undisturbed (non-handling, NH). In adulthood, subjects were placed in a shuttle box and half were exposed to brief, mild foot shocks (preexposure, PE) and the other half were non-preexposed (NPE). Half of the PE and NPE subjects were then treated for 21 days with fluoxetine and the other half with vehicle. In males, although there was no overall preexposure effect on avoidance behaviour, ED-PE and ED-NPE and EH-PE and EH-NPE demonstrated an avoidance deficit relative to NH. Fluoxetine attenuated this deficit and most notably in ED-PE. In females, vehicle ED-PE demonstrated an avoidance deficit relative to NH-PE; fluoxetine attenuated this ED effect. These findings provide supportive evidence for the predictive validity of this depression model.

Adaptation, Psychological↗

PubMed2003

Ventral hippocampal lesions affect anxiety but not spatial learning.

Rats with cytotoxic ventral hippocampal lesions which removed approximately 50% of the hippocampus (including dentate gyrus) starting from the temporal pole, displayed a reduction in freezing behaviour following the delivery of an unsignalled footshock in an operant chamber. This was more plausibly a result of reduced susceptibility to fear than a result of a lesion-induced increase in general motor activity. There was no consistent difference between sham and lesioned animals in spontaneous locomotor activity, or locomotion following acute or chronic treatment with amphetamine. In contrast, ventral hippocampal lesioned animals were quicker to pass from the black to the white box during a modified version of the light/dark exploration test, and were quicker to begin eating during tests of hyponeophagia. Furthermore, rats with ventral hippocampal lesions defecated less than their sham counterparts both during open field testing and in extinction sessions following contextual conditioning. In contrast to these clear lesion effects, there were no signs of any spatial learning impairment either in the watermaze or on the elevated T-maze. Taken together these results suggest that the ventral hippocampus may play a role in a brain system (or systems) associated with fear and/or anxiety, and provide further evidence for a distinct specialisation of function along the septotemporal axis of the hippocampus.

Amphetamine↗

PubMed2003

The acquisition, retention and reversal of spatial learning in the morris water maze task following withdrawal from an escalating dosage schedule of amphetamine in wistar rats.

Two experiments were carried out to evaluate the effects of amphetamine withdrawal in rats on spatial learning in the water maze. A schedule of repeated d-amphetamine administration lasting for 6 days, with three injections per day (1-5 mg/kg, i.p.), was employed. Experiment 1 demonstrated that amphetamine withdrawal did not impair the acquisition of the water maze task (third to fourth withdrawal days), but amphetamine-withdrawn rats made more target-zone visits and reached the former location of the platform quicker than controls during the probe test (fifth withdrawal day). In experiment 2, retention of the location of the escape platform was assessed in animals having been pre-trained on the water maze task before treatment. On the third withdrawal day, retention of the former platform location was assessed in a probe test. Retention was only clearly seen in the measure of target zone visits, and performance did not differ between groups. Next, the animals were trained to escape to a new location in the water maze on withdrawal days 4-5. A reversal effect could be discerned across the first four trials, as evident by the animals' tendency to search in the former target quadrant. This interfered with the new learning, but amphetamine-withdrawn animals appeared to overcome it more rapidly than saline-treated controls. This finding is consistent with the view that amphetamine withdrawal can enhance behavioural switching, which could be expressed as a reduction of proactive interference during learning; and, it is in line with our previous finding that latent inhibition is also attenuated during amphetamine withdrawal.

Amphetamine↗

PubMed2003

Amphetamine withdrawal does not produce a depressive-like state in rats as measured by three behavioral tests.

Administration of amphetamine (AMPH) can induce symptoms of psychosis in humans and locomotor sensitization in rats; in contrast, withdrawal from a period of AMPH intake is most often associated with symptoms of human endogenous depression. The aim of this study was to determine whether AMPH withdrawal produces a depressive-like state in rats. The present study examined the effects of withdrawal from an escalating-dose AMPH schedule (ESC; three daily injections over 6 days, 1-5 mg/kg, i.p.) and an intermittent-dose AMPH schedule (INT; one daily injection over 6 days, 1.5 mg/kg, i.p.) on animals' performance in three behavioral paradigms related to depression: the Porsolt swim test, the learned helplessness assay and operant responding for sucrose on a progressive ratio schedule. ESC and INT AMPH withdrawal had no effect on any of these tests or on stress responsiveness as measured by increased plasma levels of corticosterone (CORT) and adrenocorticotropin following the swim test, although basal CORT levels were higher in AMPH-withdrawn animals compared to controls. Finally, we confirmed the presence of locomotor sensitization for both AMPH schedules after 30 days of withdrawal. Our results suggest that the ability of AMPH withdrawal to produce symptoms of depression may not be evident in all behavioral screens for depressive symptoms in the rat.

Adrenocorticotropic Hormone↗

PubMed2002

Increased conditioned fear response and altered balance of dopamine in the shell and core of the nucleus accumbens during amphetamine withdrawal.

It has been suggested that neuroadaptations within the nucleus accumbens (NAC) dopaminergic (DA) projection contribute to the negative affect associated with psychostimulant withdrawal. The present study assessed the effects of amphetamine (AMPH) withdrawal on behavioral and NAC DA responses to conditioned fear stress. Animals injected with escalating-dose AMPH (1-5mg/kg, three injections/day, 6 days) or saline (SAL) acquired a tone-shock association on withdrawal day 3 and were tested for extinction of conditioned freezing to the tone on withdrawal day 4. Extracellular levels of NAC shell and core DA were monitored using in vivo microdialysis on both days. AMPH-withdrawn animals exhibited more conditioned freezing than SAL animals during both acquisition and extinction. During acquisition, DA increased more in the shell than the core of the NAC in both AMPH and SAL groups. During extinction to the tone, shell DA increased in SAL- but not AMPH-treated animals, whereas core DA activity was greater in AMPH than SAL animals. These data demonstrate that AMPH withdrawal alters the balance between shell and core DA transmission while increasing the behavioral expression of conditioned fear. Such drug-induced neuroadaptations in the NAC stress response may be involved in the exacerbation of negative emotions associated with drug withdrawal and stimulant-induced psychosis.

Amphetamine↗