Biomedical subjects

J Feldon

Publications and source records attributed to J Feldon.

At least 145 records · Page 8Linked to original sources

PubMed1991

Anti-neuronal antibodies similar to those found in Alzheimer's disease induce memory dysfunction in rats.

Although the etiology and pathogenesis of the cholinergic degeneration in Alzheimer's disease are not known, several reports implicate immunological mechanisms. Recently we have shown that sera of Alzheimer's disease patients contain antibodies which bind specifically to the heavy molecular weight neurofilament protein of Torpedo cholinergic neurons. In the present study we investigated the possibility that such antibodies play a role in neuronal degeneration by examining the behavioral and cellular effects of immunizing rats with the heavy neurofilament protein of Torpedo cholinergic neurons. The immunized rats developed antibodies which were specific to the heavy neurofilament protein of Torpedo cholinergic neurons and which cross-reacted with rat brain neurofilaments. Immunohistochemical studies revealed the accumulation of antibodies in the perikarya and neurites of neurons in the septum and hippocampus of the cholinergic neurofilament immunized rats and in white matter tracts in their forebrains. No such staining was seen in adjuvant immunized control rats. Behavioral tests revealed that rats immunized with the heavy cholinergic neurofilament protein performed significantly worse than controls in a T-maze alternation test and that their performance deteriorated profoundly after the introduction of a 20-s delay in the paradigm, indicating a deficit in short term memory. In contrast, both groups performed similarly in a T-maze discrimination test, indicating that long term reference memory was not affected by immunization with the heavy cholinergic neurofilament protein. Further experiments revealed that the rats immunized with the heavy cholinergic neurofilament protein were also deficient in a reversal of choice paradigm in a position discrimination test.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗

PubMed1991

Characterization of an experimental autoimmune dementia model in the rat.

Alzheimer's disease (AD) and other age-related cognitive deficits are associated with autoimmune phenomena. We recently showed that AD sera contain IgG that binds specifically to the heavy molecular weight neurofilament protein (NF-H) of Torpedo cholinergic neurons. We presently examined the behavioral effects of the induction of such antibodies in rats by prolonged immunization with Torpedo cholinergic NF-H. Immunohistochemical studies revealed the accumulation of IgG in the septum and hippocampus and in white matter tracts of these rats. T-maze alternation and discrimination tests revealed that immunization impaired the short-term working memory of the rats but had no effect on their reference memory. This impairment in short-term memory was reversed by treatment with the acetylcholinesterase inhibitor physostigmine. This animal model, termed experimental autoimmune dementia (EAD), may replicate immunologically induced pathogenic processes in AD.

Alzheimer Disease↗

PubMed1990

Section of the descending columns of the fornix produces delay- and interference-dependent working memory deficits.

Rats were allocated to one of three surgical treatment groups, and given either sham operations (SHAM), transection of the descending columns of the fornix (DCF), or transection of fibres at the base of the lateral septal nuclei (SC). They were trained on a rewarded alternation task, run as a spatial working memory task on an elevated T-maze, with a minimal intratrial interval. There were no differences between the SHAM and the SC rats. The DCF rats showed an initial impairment in acquisition, but their performance gradually improved to control levels. The imposition of a 20-s intratrial interval impaired choice accuracy in all groups, but the extent of the impairment was significantly greater in the DCF group. Addition of an extra, and conflicting, 'information run', to provide a source of proactive interference, also impaired performance in all groups, but the impairment was again greatest in the DCF group, suggesting that this lesion increases intrusion errors. Subsequent testing in the acquisition of 2-way active avoidance revealed that the DCF lesion facilitated learning with respect to the other two groups. The results indicate that there are clear functional differences between the different outputs from the subiculum, and that the descending subicular output plays a significant role in normal memory.

Animals↗

PubMed1990

The effects of pre- and postweaning rearing conditions on latent inhibition and partial reinforcement extinction effect in male rats.

Male rats were either handled daily or left undisturbed (nonhandled) during the first 21 days of life. At weaning (Day 22) animals in each early treatment condition were assigned to two housing conditions, isolated or grouped, creating four early/late treatment conditions: Handled-Grouped (HG), Handled-Isolated (HI), Nonhandled-Grouped (NHG), and Nonhandled-Isolated (NHI). At maturity, all animals were tested in the latent inhibition (LI, Experiment 1) and the partial reinforcement extinction effect (PREE, Experiment 2) paradigms. In LI, animals receiving prior nonreinforced preexposure to a stimulus (PE) show subsequently retarded conditioning to that stimulus as compared to nonpreexposed (NPE) controls. In the PREE, partially reinforced (PRF) animals exhibit higher resistance to extinction as compared to continuously reinforced (CRF) controls. LI and PREE were obtained in the HG condition, but were impaired in NHG and HI animals. The pattern of impairment was different in the two conditions. The absence of LI in NHG males was due to increased suppression in the PE group, whereas in HI males, was due to decreased suppression in the NPE group. Likewise, the attenuation of the PREE in NHG males stemmed primarily from decreased resistance to extinction in the PRF group, whereas in HI males, it resulted from increased resistance to extinction in the CRF group. The combination of nonhandling and isolation led to the reinstatement of both LI and PREE: normal LI and PREE were obtained in the NHI animals. These results demonstrate that early rearing experience interacts with later experience differentially depending upon the later experience.

Age Factors↗

PubMed1989

Ibotenate-induced total septal lesions reduce resistance to extinction but spare the partial reinforcement extinction effect in the rat.

Rats were given sham operations, vehicle injections, or injections of the axon-sparing excitotoxin ibotenic acid into the septum. In Experiment 1, behavioural testing commenced 16 days after the operation; in Experiment 2 behavioural testing commenced following testing on another task, 31 days after the operation. The rats were trained to run in an alley for food reward given on every trial (Continuous Reinforcement, CR) or on a random fifty percent of trials (Partial Reinforcement, PR) and then the running response was extinguished. All the experimental groups showed the normal partial reinforcement extinction effect (PREE) in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. However the rats with ibotenic acid lesions also showed a significant decrease in resistance to extinction regardless of training condition. The same pattern of results was seen at each of the two post-operative testing times. The results were thus readily replicable, and entirely unlike previous reports of the behavioural effects on this task of conventional septal lesions of equivalent size. In Experiment 3, neurochemical analysis of the hippocampus in rats with ibotenic acid-induced lesions demonstrated that choline acetyl-transferase levels were reduced to the same extent as in rats with comparable conventional lesions.

Animals↗

PubMed1989

The role of subicular outputs in the development of the partial reinforcement extinction effect.

Rats were trained to run in an alley for food reward given on every trial (Continuous Reinforcement, CR) or on a random fifty percent of trials (Partial Reinforcement, PR) and the running response was then extinguished. Sham Operated controls showed the normal partial reinforcement extinction effect (PREE) in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. The PREE was abolished by a knife cut placed at the base of the lateral septum to interrupt ventral subicular fibres destined for the ventral striatum. This outcome stemmed purely from a decrease in resistance to extinction in the lesion PR group. A large lesion that also sectioned the dorsal subicular pathway in the descending columns of the fornix left the PREE intact, though there were some signs of a reduction in its size primarily due to increased resistance to extinction in the lesion CR group. We conclude that previous reports demonstrating reduction or abolition of the PREE following conventional total septal or lateral septal lesions, may have achieved their results through damage to subicular fibres en passage through the septum.

Animals↗

PubMed1989

The effects of amphetamine on a multitrial partial reinforcement extinction effect (PREE) in a runway.

Three experiments examined the effects of d-amphetamine (1 mg/kg) administration on the partial reinforcement extinction effect (PREE) using a multitrial procedure. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Experiments 1 and 2 used 6 trials/day with an intertrial interval (ITI) of 5 min. In Experiment 1 the drug was administered only during acquisition, whereas in Experiment 2 it was administered throughout acquisition and extinction. Experiment 3 used 3 trials/day with a 20 min ITI. The drug was administered throughout acquisition and extinction. In all three experiments, amphetamine-treated animals showed a normal PREE, i.e., increased resistance to extinction in PRF as compared to CRF animals. These results stand in marked contrast to the amphetamine-induced abolition of the PREE with 1 trial/day procedure.

Amphetamine↗

PubMed1989

The effects of amphetamine on a multitrial partial reinforcement extinction effect (PREE) in an operant chamber.

Two experiments investigated the effects of d-amphetamine (1 mg/kg) on the partial reinforcement extinction effect (PREE) in an operant chamber using a discrete multitrial procedure. Experiment 1 used a random 50% partial reinforcement (PRF) schedule. Experiment 2 used two 40% PRF schedules: one schedule maximized the number of nonreinforced trials preceding any given reinforced trial (maximum N-length of four) and the second maximized the number of N-R transitions (N-length of one). In both experiments, the continuously reinforced (CRF) animals received a reward on every trial. The PREE, i.e., increased resistance to extinction of PRF as compared to CRF animals, was obtained in the random 50% PRF and the schedule maximizing N-length in both the placebo and amphetamine-treated animals. Both drug and no-drug animals failed to exhibit PREE on the schedule maximizing N-R transitions. These results show that on a PRF schedule with short intertrial intervals, amphetamine-treated animals are not impaired in their capacity to learn sequences of events and to associate the outcomes of preceding trials with subsequent consequences.

Amphetamine↗

PubMed1989

Abolition of the acquisition but not the expression of latent inhibition by chlordiazepoxide in rats.

In the latent inhibition (LI) paradigm, prior nonreinforced exposure to a stimulus retards subsequent conditioning to that stimulus when it is paired with reinforcement. The development of LI reflects learning not to attend to, or ignore, stimuli which predict no significant consequences. The present experiment tested the effects of chlordiazepoxide (CDP) on LI using a conditioned emotional response (CER) procedure consisting of three stages given 24 hr apart: preexposure, in which the to-be-conditioned stimulus, tone, was presented without reinforcement; conditioning, in which the preexposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. Preexposure and conditioning were given off-baseline. CDP (5 mg/kg) was administered only in preexposure, only in conditioning, in both stages or in neither. The administration of the drug during tone-shock conditioning conducted off-baseline markedly reduced animals' suppression to the tone in a subsequent licking test which was conducted without the drug. The administration of CDP during nonreinforced preexposure to the tone abolished the development of LI, i.e., drug-treated preexposed animals did not show reduced suppression as compared to drug-treated nonpreexposed animals. These results demonstrate that CDP: a) blocks the acquisition of classically conditioned fear and b) disrupts animals' ability to learn that stimuli predict no significant outcomes.

Animals↗

PubMed1989

Immunization of rats with cholinergic neurons induces behavioral deficits.

We have previously shown that sera from patients with Alzheimer's disease (AD) contain a significantly high level of antibodies to the cell bodies (Perikarya; PK) but not to the nerve terminals (synaptosomes) of purely cholinergic neurons from the electric fish Torpedo. In the present study we examined the effect of repeated immunization of rats with either of these antigens for one year. Immunoblot studies revealed that sera of cholinergic PK immunized rats contained a high level of antibodies to cholinergic PK proteins, in particular to a 200 kilodalton protein, to which there are specifically high levels of antibodies in AD. Sera from rats immunized with cholinergic synaptosomes and from control rats contained very low levels of these antibodies. Behavioral studies performed one year after the initial immunization revealed that the cholinergic PK immunized rats were impaired in spatial learning and memory tasks (Morris swim test and T-maze alternation) when compared to control rats and that the synaptosome-immunized rats showed no such deficit. In contrast, the three groups performed similarly in general activity, active avoidance and conditioned emotional response tests. Further experiments revealed that the cholinergic PK immunized rats displayed a significant deficit in short term memory. The association of antibodies to cholinergic neurons with cognitive deficits in this rat model suggests that such antibodies may be involved in the pathogenesis of AD.

Acetylcholinesterase↗

PubMed1988

The effects of haloperidol on the partial reinforcement extinction effect (PREE): implications for neuroleptic drug action on reinforcement and nonreinforcement.

The effects of haloperidol 0.1 mg/kg on the partial reinforcement extinction effect (PREE) paradigm at one trial a day, were examined. Two groups of rats were trained to run in a straight alley. The continuously reinforced (CRF) group received food reward on every trial. The partially reinforced (PRF) group was rewarded on a quasi-random 50% schedule. All animals were then tested in extinction. Haloperidol 0.1 mg/kg was administered in a 2 x 2 design, i.e., drug-no drug in acquisition and drug-no drug in extinction. The PREE, i.e., increased resistance to extinction of partially reinforced as compared to continuously reinforced animals, was obtained in all four drug conditions. The administration of haloperidol in acquisition increased markedly resistance to extinction in CRF animals. The administration of the drug in extinction decreased resistance to extinction in both CRF and PRF animals. The results are explained in terms of two independent actions of haloperidol: the well-known effect of reduction in the effectiveness of reinforcement as well as enhancement of the effectiveness of nonreinforcement.

Animals↗

PubMed1988

Long-term attentional deficit in nonhandled males: possible involvement of the dopaminergic system.

Latent inhibition (LI) is a behavioral paradigm in which nonreinforced pre-exposure to a stimulus retards subsequent conditioning to that stimulus. The development of LI is considered to reflect learning not to attend to, or ignore, irrelevant stimuli. In our previous studies investigating the effects of early handling on LI, we have shown that normal LI was obtained in handled males and females, as well as in nonhandled females. In contrast, nonhandled males failed to show LI. This finding pointed to a long-term attentional deficit in nonhandled males. Since there is evidence that the development of LI is mediated by the dopaminergic system, the present experiments tested the possibility that the attentional deficit of nonhandled males may be related to a dopaminergic dysfunction. Experiment 1 tested whether the administration of haloperidol, which was shown to enhance LI in normal animals, would reinstate the LI effect in nonhandled males. Infantile handled (Days 1-22) and nonhandled male and female rats were tested in maturity in the LI paradigm, using a conditioned emotional response procedure. Experiment 2 tested the locomotor response of handled and nonhandled males to 0.3, 1 and 2.5 mg/kg D-amphetamine. Experiment 1 showed that handled males, handled females and nonhandled females showed a normal LI effect, whereas nonhandled males failed to develop LI. Haloperidol enhanced LI in all the groups, but this effect was most dramatic in nonhandled males, in which the drug reinstated LI. Experiment 2 showed that nonhandled males exhibited a reduced locomotor response to D-amphetamine.

Aging↗

PubMed1988

Disruption of latent inhibition by acute administration of low doses of amphetamine.

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. Three experiments investigated the effects of acute amphetamine administration on LI in rats. Experiments 1 and 3 used a conditioned emotional response (CER) procedure and Experiment 2 used two-way active avoidance procedure. Experiments 1 and 2 showed that, in both the CER and avoidance procedures, 1.5 mg/kg dl-amphetamine administered either in the preexposure or the conditioning stage alone did not disrupt LI. In contrast, amphetamine administered in both of the stages abolished LI. Experiment 3 showed that the abolition of LI was obtained when the preexposure and conditioning were given 24 hr apart but not when the two stages were given in one session.

Animals↗

PubMed1987

Early handling and latent inhibition in the conditioned suppression paradigm.

Latent inhibition (LI) is a behavioral paradigm in which repeated exposure to stimuli not followed by meaningful consequences renders these stimuli ineffective for subsequent learning. The development of LI is considered to reflect learning not to attend, to ignore, or tune out irrelevant stimuli. The present study investigated the differences in the development of LI between handled and nonhandled males and females. Infantile handled (days 1-22) and nonhandled, male and female Wistar rats were tested in maturity in the LI paradigm, using a conditioned emotional response (CER) procedure. The procedure consisted of three stages: preexposure, in which the to-be-conditioned stimulus, tone, was presented without being followed by reinforcement; acquisition, in which the preexposed tone was paired with shock; and test, in which LI was indexed by animals' suppression of licking during tone presentation. Handled animals exhibited less conditioned suppression as compared to nonhandled animals. LI was obtained in both the handled and the nonhandled females, but only the handled males showed the LI effect. Nonhandled males failed to develop LI. These results replicate our previous findings on LI in conditioned avoidance in demonstrating that: the effects of handling are evident in learning tasks that do not involve motivational-emotional variables, i.e., learning to ignore irrelevant stimuli; handling differentially affects males and females; the nonhandling procedure has deleterious consequences on adult behavior.

Animals↗

PubMed1987

Facilitation of discrimination transfers under amphetamine: the relative control by S+ and S- and general transfer effects.

Rats were trained in a Y-maze on a two-choice simultaneous black-white discrimination with either black or white as S+. Animals were then transferred to one of three discrimination tasks. In task 1 (New S-), a new stimulus, either vertical or horizontal stripes, was substituted for the original S-. In task 2 (New S+), a new stimulus, either vertical or horizontal stripes as in task 1, was substituted for the original S+. In task 3 (New S+/S-) animals were trained on horizontal-vertical discrimination. The pre-trial administration of 1 mg/kg d-amphetamine facilitated the acquisition of the original black-white discrimination with both black as S+ and white as S+. Likewise, the drug improved performance in all three transfer conditions. However, the course of learning in the three transfer tasks was different in the placebo- and amphetamine-treated animals. Amphetamine-treated animals were disrupted more by a change in S+ than by a change in S-, whereas the opposite pattern was evident in the placebo controls. When both discriminative stimuli were changed, placebo animals exhibited pronounced decrement in performance, whereas amphetamine animals exhibited excellent learning. The implications of these findings for the effects of amphetamine on discrimination learning are discussed.

Animals↗

PubMed1987

Facilitation of latent inhibition by haloperidol in rats.

Latent inhibition (LI) is a behavioral paradigm in which prior exposure to a stimulus not followed by reinforcement retards subsequent conditioning to that stimulus when it is paired with reinforcement. Two experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI as a function of number of CS pre-exposures. The investigation was carried out using a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, 40 CS pre-exposures were given. LI was obtained in both the placebo and haloperidol conditions, but the effect was much more pronounced under the drug. Experiment 2 used ten CS pre-exposures. LI was not obtained in the placebo animals but was clearly evident in animals injected with haloperidol. The implications of these findings for the effects of neuroleptics on learning are discussed.

Acoustic Stimulation↗

PubMed1987

Latent inhibition is not affected by acute or chronic administration of 6 mg/kg dl-amphetamine.

Latent inhibition (LI) is a behavioral paradigm in which animals learn to ignore a repeatedly presented stimulus not followed by meaningful consequences. We previously reported that LI was disrupted following the administration of 1.5 mg/kg dl-amphetamine. The present experiments investigated the effects of 6 mg/kg dl-amphetamine administration on LI in a conditioned emotional response (CER) procedure consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where LI was indexed by animals' suppression of licking during tone presentation. The three stages were conducted 24 h apart. In Experiment 1, the drug was administered in a 2 X 2 design, i.e. drug-no drug in pre-exposure and drug-no drug in conditioning. LI was obtained in all conditions. In Experiment 2, animals were given either 5 days of 6 mg/kg amphetamine pretreatment and amphetamine in pre-exposure and conditioning or 7 days of saline. LI was not obtained under amphetamine, but this outcome reflected a state-dependency effect. In Experiment 3, animals received either 5 days of amphetamine pretreatment and amphetamine in pre-exposure, conditioning and test or 8 days of saline. LI was obtained in both the placebo and amphetamine conditions. Experiments 4a and 4b compared the effects of two drug doses, 1.5 (4a) and 6 mg/kg (4b), administered in pre-exposure and conditioning. LI was abolished with the 1.5 mg/kg dose but not with the 6 mg/kg dose.

Amphetamine↗

PubMed1987

Facilitation of the expression but not the acquisition of latent inhibition by haloperidol in rats.

In the latent inhibition (LI) paradigm, nonreinforced preexposure to a stimulus retards subsequent conditioning to that stimulus. The administration of haloperidol in both the preexposure and the conditioning stages was found to enhance LI in the conditioned emotional response (CER) procedure (Weiner and Feldon, 1986). The present experiments investigated the effects of 0.1 mg/kg haloperidol administration on LI in a two-way avoidance procedure, consisting of two stages: preexposure, in which the to-be-conditioned stimulus, tone, was repeatedly presented without reinforcement; and conditioning, in which the animals acquired a two-way avoidance response with the tone serving as the warning signal. Experiments 1 and 2 tested whether the administration of haloperidol confirmed to the preexposure stage, where learning to ignore the nonreinforced stimulus takes place, would suffice to enhance the LI effect. In Experiment 1, preexposure and conditioning were conducted 24 hr apart. LI was obtained in both the placebo and haloperidol conditions, but the effect was not more pronounced under the drug. In addition, haloperidol-treated animals exhibited impaired avoidance performance. In Experiment 2, preexposure and conditioning were given 72 hr apart. With this interval, haloperidol did not affect avoidance performance. However, also under these conditions, the magnitude of the LI effect was not larger in the haloperidol-treated groups, indicating that the administration of the drug in the preexposure stage alone did not suffice to enhance LI.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗