B. K. Yee

Latent inhibition in rats is abolished by NMDA-induced neuronal loss in the retrohippocampal region, but this lesion effect can be prevented by systemic haloperidol treatment

Latent inhibition (LI) refers to the retardation in learning about the significance of a neutral stimulus that results from its nonreinforced preexposure. There is evidence that electrolytic or aspiration lesions of the hippocampal formation can disrupt LI (see I. Weiner, 1990). It has been suggested that this effect may stem from the interruption of a projection from the retrohippocampal region to the nucleus accumbens (A. J. M. Clark et al., 1992). The present experiment assessed this possibility by comparing LI in rats with retrohippocampal N-methyl-D-aspartate (NMDA) lesions extending from the entorhinal cortex to the ventral subiculum to that seen in vehicle controls and unoperated controls. LI was abolished by the retrohippocampal lesion. The effect of the lesion on LI was prevented by treatment with systemic haloperidol (0.2 mg/kg). The results are discussed with respect to an animal model of schizophrenia.

The influence of selective lesions to components of the hippocampal system on the orientating response, habituation and latent inhibition

The contribution that components of the hippocampal system in the rat make to the modulation of attention or stimulus processing was assessed using several simple behavioural assays: the orienting response (OR) to a novel stimulus, the subsequent habituation and dishabituation of this OR, and the latent inhibition effect that typically results from repeated exposure to a stimulus. Excitotoxic lesions of components of the hippocampal system produce dissociable effects on the OR, habituation and latent inhibition: lesions of the entorhinal cortex have no effect on the OR or changes in the OR during exposure to a stimulus, but disrupt latent inhibition; lesions of the subiculum disrupt the OR but not latent inhibition; and lesions of the hippocampus disrupt the OR and latent inhibition. These effects have important implications for our understanding of habituation and latent inhibition, and the neural mechanisms involved in attentional modulation.

Involvement of the entorhinal cortex in a process of attentional modulation: evidence from a novel variant of an IDS/EDS procedure.

Novel behavioral assays were used to assess the role of the entorhinal cortex in modulating attention to components of stimulus compounds. In Stage 1, rats received discrimination training with compounds constructed from 3 dimensions (auditory, visual, and tactile); in each compound the combination of components from 2 dimensions (e.g., auditory and visual) were relevant to the solution of the discrimination, and the remaining dimension (e.g., tactile) was irrelevant. In Stage 2, rats received a different discrimination in which the relevant dimensions were either congruent (auditory and visual) or incongruent (auditory and tactile) with those that were relevant in Stage 1. Sham-operated rats acquired the congruent discrimination more rapidly than the incongruent discrimination--a finding indicative of a process of attentional modulation--whereas rats with excitotoxic lesions of the entorhinal cortex acquired both discriminations equally readily.

NADPH-diaphorase reactive pyramidal neurons in Ammon's horn and the subiculum of the rat hippocampal formation

NADPH-diaphorase histochemistry has been shown to stain cells which contain nitric oxide synthase, an enzyme responsible for the biosynthesis of the freely diffusable gas nitric oxide. A number of studies have mapped the distribution of NADPH-diaphorase-reactive neurons in the hippocampal formation but they have failed to yield consistent data. The major point of controversy concerns the presence of NADPH-diaphorase-reactive pyramidal cells in the CA1 subfield of the rat hippocampal formation. The present results show that CA1 pyramidal neurons do contain nitric oxide synthase (NOS) which can be reliably demonstrated with the appropriate histochemical procedure. One of the critical determinants of CA1 pyramidal cell NADPH-diaphorase activity is shown to be incubation of brains in sucrose solution prior to histochemical processing. Subicular pyramidal cells were also found to contain NOS and to possess NADPH-diaphorase activity. These results explain a number of contradictory reports in the literature relating to the presence of NADPH-diaphorase activity in hippocampal principal cells. Additionally, densitometric analysis carried out on 20 microns thick sections, from brains incubated in sucrose solution, indicated that there were characteristic gradients. The intensity of NADPH-diaphorase activity in pyramidal cells located in the ventral subiculum was found to be greater than those in the dorsal subiculum. A similar, yet marginal, trend was apparent for pyramidal cells in CA1 and CA3, as well as nonpyramidal cells in CA1. At both dorsal and ventral levels, NADPH-diaphorase-positive subicular pyramidal cells and CA1 nonpyramidal cells also show a greater intensity than CA1 or CA3 reactive pyramidal neurons. This study also showed that tissue incubation in sucrose solution prior to immunocytochemistry, enhanced immunoreactivity of the endothelial isoform of NOS whilst having little effect on neuronal NOS reactivity.

Cytotoxic lesions of the retrohippocampal region attenuate latent inhibition but spare the partial reinforcement extinction effect

Abstract Experiment 1 assessed the effect of cytotoxic retrohippocampal (entorhinal and extra-subicular cortices) lesions on the development of latent inhibition (LI) using an off-the-baseline, between-subjects, conditioned emotional response paradigm. Sham-operated controls and unoperated rats that had been pre-exposed to a light stimulus prior to light-shock pairings showed less conditioned suppression towards the light stimulus than the nonpre-exposed animals, thus demonstrating LI. However, LI was not evident in rats with retrohippocampal lesions. In experiment 2, the same animals were trained to run in an straight runway for food. Half of the animals were trained under a 50% partial reinforcement schedule (i.e. they were rewarded randomly on half of the acquisition trials) and the other half were trained under a continuous reinforcement schedule (i.e. they were rewarded on every acquisition trial). When tested in extinction, animals trained on the partial reinforcement schedule showed greater persistence than animals trained on continuous reinforcement, thus demonstrating the partial reinforcement extinction effect (PREE). Rats with retrohippocampal lesions showed a PREE that was at least as clear as that seen in the sham-operated controls and in the unoperated animals. It is concluded that cytotoxic lesions of the retrohippocampal region selectively led to an abolition of LI, but spared the PREE. The present study thus provided evidence against the hypothesis that LI and the PREE share a common neural substrate.

Potentiation of amphetamine-induced locomotor activity following NMDA-induced retrohippocampal neuronal loss in the rat

The present experiment assessed the locomotor response to a low dose (1 mg/kg) of systemic gemd-amphetamine in rats with cytotoxic lesions of the retrohippocampus (entorhinal and extra-subicular cortices), compared with vehicle-operated shams and unoperated controls. Under spontaneous and saline conditions, both the sham and the lesioned animals were more active than unoperated controls, and they did not differ from each other. Systemic gemd-amphetamine produced increased locomotion in all groups, but this effect was potentiated in animals with retrohippocampal lesions; two control groups did not differ from each other in their response to the drug. The present results are consistent with the suggestion that cell loss within the retrohippocampal region could affect the functional response of nucleus accumbens to amphetamine. The results are discussed in terms of the interaction between the retrohippocampus and nucleus accumbens in the control of mesolimbic dopamine release and the possible implications for schizophrenia.

The effects of cytotoxic entorhinal lesions and electrolytic medial septal lesions on the acquisition and retention of a spatial working memory task

Abstract Rats with lesions either of medial septal nucleus (MSN) or the entorhinal cortex (ECx) were compared postoperatively with unoperated controls in a discrete-trial, delayed matching-to-position (DMTP) task, conducted on an elevated T-maze. A DMTP trial consisted of two consecutive visits to the maze: an information run and a choice run. The animals were first forced to visit a randomly selected choice arm in the information run. In the choice run, the correct response was to match the choice arm that had been visited on the information run, regardless of whether the information run itself had been rewarded or not. MSN animals failed to succeed in this task, performing at close to chance level throughout training. On the other hand, ECx rats consistently perform at a level comparable with that of unoperated controls; both groups attained more than 90% correct after 192 trials. Long-term retention testing was carried out after an intermission of 4 weeks, when the same task was re-administered to the ECx and unoperated control animals. ECx animals showed significantly less saving than controls in the retention test. In contrast, when the retention interval within a DMTP trial was increased by the imposition of a 20-s delay between the information and choice runs, the ECx group was not selectively affected by this manipulation.

A comparison of the density of NADPH-diaphorase-reactive neurons in the fascia dentata and Ammon's horn between 6-month and 12-month old Dark Agouti rats

The present study aimed to assess the developmental progress of the hippocampal nitric oxide (NO) system within adulthood by comparing the density of NO-producing neurons in the fascia dentata and Ammons horn in two groups of adult male rats using NADPH-diaphorase (NADPH-d) histochemistry. One group comprised 6-month-old rats (early adulthood), and the other 12-month-old rats (middle-adulthood). Areal density (number of neurons per unit area) of NADPH-d positive neurons along the three hippocampal axes (septo-temporal, transverse and radial axes) were subjected to quantitative analyses. There were significant variations in the density of NADPH-d-reactive neurons along the transverse and radial axes of the hippocampus, similar to what have been described previously. Comparison between 6-month and 12-month-old rats indicated a substantial reduction in the density of NADPH-d-reactive neurons in the fascia dentata (69%) and Ammons horn (54%) of the latter group. This reduction was relatively uniform along the septotemporal and radial axes, but appeared to be more pronounced in the fascia dentata and in the proximal region of Ammons horn. Our finding showed that the hippocampal NO system can undergo significant changes within adulthood. It further highlighted the possibility that an age-related reduction in the capacity to produce NO may not be directly responsible for the cognitive decline associated with senescence, but rather predisposes neuronal degeneration in later life.