Contributions of hippocampal cellular damage and NMDA receptor dysfunction to behavioral markers of schizophrenia.

Pathological changes in the hippocampal formation have been noted in schizophrenic patients and manipulation of neurochemical functions within the limbic system has been shown to yield behavioral changes consistent with schizophrenia. The present study evaluated the impact of kainic acid induced hippocampal cellular damage and manipulation of NMDA receptor function (agonism and antagonism) on common behavioral markers of schizophrenia (habituation and prepulse inhibition of the acoustic startle response in rats). Cellular damage significantly impaired habituation and NMDA antagonism disrupted prepulse inhibition. Damage induced impairment of habituation is consistent with effects on latent inhibition (which is also unaffected by NMDA antagonism) while the antagonist disruption of prepulse inhibition is consistent with effects on associative plasticity. The current findings provide further support for a diverse neurobiological substrate of schizophrenic symptoms suggesting that pharmacologic intervention may need to be multifaceted and could involve competing mechanisms. Cognitive impairments may reflect diminished NMDA receptor function whereas positive symptoms may reflect heightened engagement of anatomically disturbed cellular elements.

Unilateral hippocampal damage impairs spatial cognition in rats.

Unilateral temporal lobectomy to treat seizure disorders in humans often results in cognitive impairment after the surgery. To determine the potential utility of a rodent model of unilaterally induced cognitive deficits, the present experiment evaluated spatial cognition in adult rats after either left or right hemisphere lesioning of temporal neocortex and underlying hippocampal regions. Evaluation of performance in the eight arm radial maze revealed that both lesioned groups committed more reference memory errors than did nonoperated controls. Working memory errors did not differ statistically between groups. The production of a spatial learning deficit by unilateral damage suggests that this rodent model could serve to test potential improvements in interventional strategies aimed at attenuating cognitive effects of the surgical treatment.

Developmental stress disrupts habituation but spares prepulse inhibition in young rats.

Stress has long been recognized as a factor that contributes to the induction of schizophrenia and results in abnormal sensorimotor functioning and information processing. Patients with schizophrenia show disrupted habituation and prepulse inhibition of the acoustic startle response. This study examined the effects of maternal isolation in rats on the habituation of startle and PPI to assess the potential impact of developmental stress on schizophrenic symptomatology. Evaluation of performance in young adulthood (3-4 months) revealed a disruption of habituation in the isolated group; response amplitude increased over time. PPI was not altered. These results suggest that the disruption of habituation may involve acute effects of elevated stress hormones on neuronal functions. In contrast, disturbance of PPI may require an accrual of neuronal insult and damage to ultimately undermine neurologic function, possibly through impact on N-methyl-D-aspartate-mediated transmission. An analysis of effects at middle age is planned to address this possibility.

Manipulation of NMDA-receptor activity alters extinction of an instrumental response in rats.

The effects of pharmacologically manipulating N-methyl-D-aspartate(NMDA)-receptor activity were examined during extinction of an appetitive instrumental response in rats. After reaching acquisition criterion, subjects were treated with the antagonist dizocilpine maleate (MK801; 0.1 mg/kg), the agonist D-cycloserine (3 mg/kg), or vehicle-alone (control) and tested during a non-reinforced (extinction) session. The antagonist decreased the average number of responses occurring during the test session whereas the agonist increased the average number in contrast to controls. The effect on retention performance may be mediated by differential influence on the N-methyl-D-aspartate-dependent synaptic plasticity that occurs during associative learning. In conjunction with other studies, these data suggest that N-methyl-D-aspartate agonism may be an effective intervention for memory dysfunction.

Hippocampus in delay eyeblink classical conditioning: essential for nefiracetam amelioration of learning in older rabbits.

Rabbits acquire conditioned responses (CRs) normally with bilateral removal of the hippocampus, but alterations of the intact hippocampus can affect the rate of acquisition. The cognition-enhancing drug, nefiracetam ameliorated the acquisition of CRs in older rabbits, protected membrane dysfunction in hippocampal CA1 neurons following oxygen and glucose deprivation, and promoted the release of diverse neurotransmitters, including acetylcholine. Because the septo-hippocampal cholinergic system is demonstrated to be involved in eyeblink conditioning, this experiment was undertaken to explore whether nefiracetam ameliorates conditioning via the hippocampus. Data from 53 rabbits of a mean age of 28 months were tested under two drug conditions (10 or 0 mg/kg nefiracetam) and 4 lesion conditions (bilateral hippocampectomy, bilateral neocortical removal, sham surgery, no surgery). The three groups of nefiracetam-treated rabbits with intact hippocampus acquired CRs more rapidly than the vehicle-treated groups, but rabbits with bilateral hippocampectomy treated with nefiracetam learned like vehicle-treated rabbits. Results suggest that nefiracetam ameliorates learning via the hippocampus. Because of the parallels between conditioning in rabbits with disrupted hippocampal cholinergic systems and conditioning in Alzheimer's disease (AD), these results suggest that nefiracetam may ameliorate conditioning in AD as it ameliorates conditioning in older rabbits.

Prior instrumental conditioning improves spatial cognition and attenuates changes in hippocampal function in aged rats.

These experiments examined the effects of long-term instrumental training on subsequent radial arm maze performance and synaptic transmission within the hippocampal formation. In the first experiment, young (3 mo) and aged (18 mo) male rats underwent 12 weeks of appetitive instrumental conditioning; half were continually reinforced and the other half alternated between reinforcement and extinction. Afterward, spatial cognition was evaluated using an eight-arm radial maze. Subjects undergoing instrumental training performed at rates superior to untrained (control) animals regardless of age or training condition; age-related differences did not exist in the trained groups. In the second experiment, subjects underwent 12 weeks of instrumental training with continuous reinforcement, and excitability of the hippocampus was examined by paired-impulse stimulation of the perforant path. Training enhanced maximal facilitation of population spikes evoked in the granule cell layer of the dentate gyrus of aged subjects to the degree that no statistical difference existed between young and aged animals. Data from untrained control animals indicated a robust decline in paired-impulse excitability in aged subjects. These findings suggest that learning-induced plasticity may attenuate both behavioral and neurobiological changes observed in aged subjects. It is postulated that disuse may underlie some of the cognitive changes exhibited across the life span.

Age-related impairment in instrumental conditioning is restricted to initial acquisition.

Performance on a variety of cognitive tasks has been reported to decline across the life span. The present research evaluated appetitive instrumental learning in young and mature rats. In Experiment 1, subjects were trained to criterion, placed on extinction training to criterion, and subsequently retrained for a total of three cycles. Results indicated that mature animals were impaired in the initial acquisition of the bar-press response but reacquired the response as quickly as young animals. Resistance to extinction was not significantly impaired in the mature group, both groups increased resistance by the third extinction period, despite the brevity of reinforcement. In Experiment 2, young and mature subjects underwent appetitive instrumental training that continued beyond the acquisition criterion for the first experiment. After the response had been established (to criterion), performance levels were equivalent for young and mature subjects. The number of responses were not significantly different between young and mature groups on the day criterion was met; comparison of number of responses for 4 days after criterion also indicated no significant differences over days of training or between age groups. Examination of the number of responses occurring early in training indicated no significant group difference; hence, the earlier acquisition by young animals in Experiment 1 does not appear to reflect greater activity level in younger animals resulting in earlier and greater exposure to reinforced responses. Results may reflect the contribution of use-induced plasticity, such as long-term potentiation, within brain systems involved in learning and memory. These findings are consistent with evidence of the effects of use and disuse on neurobiological and cognitive function.

Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis.

Structural change in the hippocampal formation has become popular as a proposed neurobiological substrate for schizophrenic disorders. It is postulated that behavioral plasticity in the form of long-term potentiation of hippocampal synaptic transmission is an attractive putative mechanism for the mediation of transient psychosis. Moreover, the disturbed hippocampal neuroarchitecture found in schizophrenic brain may be susceptible to potentiation and dysfunctional to the degree that delusions and hallucinations develop. Partial and selective blockade of the receptors mediating potentiation may prove to be an efficient means of preventing psychotic episodes and avoiding further damage to the involved network. Basic research, utilizing experimental models such as intraventricular kainic acid injection, may help to clarify the anatomical and physiological substrate of psychosis.

Partial hippocampal pyramidal cell loss alters behavior in rats: implications for an animal model of schizophrenia.

A putative biological substrate of schizophrenia involves cellular pathology within the hippocampus. While hippocampal dysfunction is associated with impaired learning and memory, schizophrenics have been observed to acquire simple conditioned reflexes at rates superior to controls. The present study evaluates the acquisition of shuttlebox avoidance responses in animals with partial damage to hippocampus. Intraventricular microinjections of kainic acid (0.5 or 1.5 nM) were utilized to partially destroy the pyramidal cell population. Animals in the high dosage group acquired the response at rates superior to controls; the low dosage group performed at an intermediate level. Consequently, partial loss of pyramidal neurons may be sufficient to significantly alter simple acquisition. Results are discussed in reference to the "embryological hypothesis" of schizophrenia and mechanisms for induction of schizophrenic behavior in intractable seizure disorders are considered.

Kindling facilitates acquisition of discriminative responding but disrupts reversal learning of the rabbit nictitating membrane response.

The effect of kindling the hippocampal perforant path-dentate projection on subsequent discrimination-reversal conditioning of the rabbit nictitating membrane (NM) response was examined. Kindling facilitated acquisition of the initial discriminative response but severely impaired performance during reversal training. The facilitative effect on initial acquisition is highly similar to previously reported effects of long-term potentiation on NM discrimination learning, and thus may reflect a kindling-induced increase in perforant path-dentate synaptic strength. The learning deficit during reversal training is similar to the effects of hippocampal ablation; i.e. characterized by a continued high response rate to the CS- rather than an inability to respond to the CS +. These findings demonstrate that kindling-induced seizures can have profound effects on associative learning. The effects are different for the discrimination and reversal phases of the task, however, which may reflect the multi-dimensional effects of kindling at the cellular level.

Nonlinear systems analysis of the hippocampal perforant path-dentate projection. I. Theoretical and interpretational considerations.

1. Nonlinear systems analytic procedures, based on an orthogonalized functional power series approach, were developed for study of the transformational properties of the hippocampal formation. As a testing stimulus, the procedures utilize a train of electrical impulses with randomly varying interimpulse intervals. The specific case was considered of applying such a stimulus to the perforant path, a major afferent to the hippocampal dentate gyrus that arises from the entorhinal cortex. Resulting field potentials evoked within the dentate gyrus are recorded to all impulses in the train. Computational algorithms based on cross-correlations determine the relationship between the interimpulse interval within the random train and amplitude of the evoked dentate potentials. The calculations, which reduce to averaging procedures, were derived for first- and second-order terms, or kernels, of the orthogonalized functional power series. 2. It is proposed that such an approach can be applied to a single component of the complex field potential evoked in the dentate gyrus. This component, the population spike, reflects the action potential discharge of dentate granule cells. Thus, a field potential component for which the underlying neuronal generator is well-known can be analyzed with respect to the transformational characteristics of the network of neurons that influence that generator. Other components of the complex field potential produced by other generators can be ignored. It is shown that this adaptation has the effect of greatly simplifying both the computation and presentation of kernels. 3. As a further consequence of this adaptation, the resulting first- and second-order kernels were shown to have specific interpretations. The first-order kernel represents the average response of the orthodromically driven granule cells to the set of stimuli comprising the random impulse train. The second-order kernel quantitatively characterizes the nonlinearity of the granule cell response, and may be interpreted as a generalized recovery function; i.e., the first input of any pair of stimuli in the train activates the newtork, and the second input tests the modulatory influence of the network excited by the initial input. 4. Most past investigations of nonlinearities of the perforant path-dentate projection have utilized pairs of stimulus impulses. We show here that, for a second-order system, the expected results from paired impulse experiments may be predicted from second-order kernels. Disagreement between the measured and predicted results reflects interactions of a higher order, and thus, greater system complexity.(ABSTRACT TRUNCATED AT 400 WORDS)

Hippocampal substrate of sensory associations.

The role of the hippocampus in the association of two conditional stimuli was evaluated using the conditioned rabbit NM preparation and a sensory preconditioning paradigm. Multiple-unit activity was recorded from field CA1 during preconditioning. Paired presentations of CS1 and CS2 resulted in increased excitability which was highly correlated with later performance during CS2 test sessions. Unpaired presentations evoked a response to stimulus onset often followed by an inhibitory period. Bilateral kainic acid lesions of CA1 had no deleterious effect on traditional CS-US conditioning but abolished the association of CS1 and CS2. These data suggest that the hippocampus may be vital to the association of sensory events. Further, the SPC paradigm could provide an excellent model for evaluating simple cognitive deficits.

Retention and acquisition of classical trace conditioned responses by rabbits with hippocampal lesions.

The effects of dorsal hippocampal lesions on retention of classical trace conditioned responses were examined using the rabbit nictitating membrane preparation. Animals were trained to criteria and then lesioned either in the cortex or in the hippocampus and the cortex. Hippocampal damage had no effect on the retention of responses but produced significantly longer onset latencies. A control group of hippocampal animals acquired conditioned responses (CRs) at least as quickly as the prelesion subjects, and they also exhibited longer response onset latency. A second experiment evaluated the performance of hippocampal lesioned animals in classical trace conditioning with either a low-intensity periorbital shock or corneal air puff as the unconditioned stimulus (UCS). Hippocampal animals successfully acquired CRs under both conditions but exhibited an alteration of response onset which was dependent on the form of the UCS. Hippocampal animals displayed shorter response onset in the air-puff condition and longer response onset in the shock condition. Cortical animals timed responses consistently regardless of the UCS. These findings strongly suggest that the hippocampus modulates temporal characteristics of learned behavior.

Failure of hippocampectomy to facilitate classical conditioning at an optimal interstimulus interval is not due to a "ceiling effect".

The effects of amphetamine injection, hippocampal lesions, and cortical lesions were examined during classical conditioning of the rabbit nictitating membrane response. An optimal interstimulus interval was employed. Whereas neocortical and hippocampal damage had no significant effect on the rate of acquisition, amphetamine treatment produced a marked facilitation. A control group of amphetamine-treated animals, which received explicitly unpaired presentations of the conditioned stimulus and unconditioned stimulus, failed to exceed spontaneous response rates throughout training. The failure of hippocampectomy to accelerate conditioning under an optimal interstimulus interval (ISI) does not appear to be due to a "ceiling effect." Rather, it was suggested that the response system is predisposed to conditioned responses of a given latency. Optimal ISIs may fall within this range. Thus, in short or long intervals, temporal aspects of the motor response must be adjusted to conform to the stimulus configuration. It appears that the hippocampus is a likely source of response modulation. Thus, loss of hippocampal input accelerates conditioning under nonoptimal intervals at the expense of proper timing. Conditioning under an optimal interval would occur at normal rates because no modulation is required.

Sensory preconditioning in the rabbit following ACTH injections.

The effects of ACTH elevation on sensory preconditioning were examined using the rabbit NM response. Sensory preconditioning is an associative form of learning which is presumed to rely on a "stimulus map" provided by the hippocampus. Elevation of levels of ACTH was found to have no significant effect on SPC. This finding was interpreted as evidence that not all deficits found in hippocampal lesioned animals may be attributed to hormonal mediation. It was suggested that ACTH elevation may selectively mimic those deficits ascribed to a "neural model" process involving the hippocampus.

Differential effects of hippocampectomy on classically conditioned rabbit nictitating membrane response related to interstimulus interval.

The effects of hippocampal ablation on acquisition rates and temporal characteristics of classically conditioned nictitating membrane responses were examined in groups of rabbits trained with a 150-, 300-, or 600-ms interstimulus interval. Acquisition rates were accelerated in the 150- and 600-ms groups. No effect was present in the 300-ms group. Response onset latencies were also affected in the 150-ms group. These findings were interpreted to support the notion that the hippocampus modulates learned motor behavior by a neural model of the response to be executed.

Fimbrial lesions and sensory preconditioning.

The effects of fimbrial and cortical lesions on sensory preconditioning in the rabbit were examined. Damage to the cortex or the fimbria had no apparent effect on the acquisition of classically conditioned responses. However, fimbrial lesions virtually abolished the effects of preconditioning, whereas cortical lesions had no significant effect. Because fimbrial damage disrupts hippocampal output, these findings are interpreted to indicate that the hippocampus is vital to learning functions other than spatial cognition or working memory.