Different effects of unexpected changes in environmental conditions on prepulse inhibition in rats and humans.

The reduction of the startle response to an auditory stimulus caused by the presentation of another stimulus of lower intensity closely preceding it, a phenomenon known as prepulse inhibition (PPI), can be modulated by changes in dopaminergic activity. Schmajuk, Larrauri, De la Casa, and Levin (2009) demonstrated that this dopaminergic modulation of PPI in rats can be influenced by manipulating the experimental context, specifically by introducing changes in the ambient lighting condition that include novel elements. In this paper we analyze the effects of introducing changes in context illumination on PPI in male rats (Experiment 1) and humans (Experiment 2). The results with rats showed a reduction of PPI when the illumination condition switched from dark to light, but not from light to dark. In the experiment with human participants the reduction of PPI occurred for both changes in illumination conditions. The animal experiment results are interpreted in terms of competing exploratory behavior that appear when the context is illuminated after the dark-light transition; while in the case of human participants a perceptual and/or attentional mechanism after both illumination transitions is proposed, which may result in a reduced processing of the prepulse and subsequent lower PPI.

Effects of unexpected changes in visual scenes on the human acoustic startle response and prepulse inhibition.

Prepulse inhibition (PPI) refers to the process wherein startle responses to salient stimuli (e.g., startling sound pulses) are attenuated by the presentation of another stimulus (e.g., a brief pre-pulse) immediately before the startling stimulus. Accordingly, deficits in PPI reflect atypical sensorimotor gating that is linked to neurobehavioral systems underlying responsivity to emotionally evocative cues. Little is known about the effects of changes in visual contextual information in PPI among humans. In this study, the effects of introducing unexpected changes in the visual scenes presented on a computer monitor on the human auditory startle response and PPI were assessed in young adults. Based on our animal data showing that unexpected transitions from a dark to a light environment reduce the startle response and PPI in rats after the illumination transition, it was hypothesized that novel changes in visual scenes would produce similar effects in humans. Results show that PPI decreased when elements were added to or removed from visual scenes, and that this effect declined after repeated presentations of the modified scene, supporting the interpretation that the PPI reduction was due to novel information being processed. These findings are the first to demonstrate that novel visual stimuli can impair sensorimotor gating of auditory stimuli in humans.

Effects of context novelty vs. familiarity on latent inhibition with a conditioned taste aversion procedure.

The latent inhibition phenomenon is observed when a conditioned stimulus is preexposed without any consequence before conditioning. The result of this manipulation is a reduction in conditioned response intensity to such a stimulus. In this study, we analyse the role of context novelty/familiarity on LI modulation by changing the context using a three-stage conditioned taste aversion procedure. Experiment 1 revealed that, similar to other learning procedures, a context change between preexposure and conditioning/testing (but not between preexposure/conditioning and testing) resulted in LI attenuation when the experimental contexts were novel. Experiment 2, using animals' home cages as one of the contexts, revealed a different pattern of results, with an unexpected increase in LI magnitude when the context change was introduced between conditioning and test stages. The Schmajuk et al. (1996) computational model explains these results in terms of the increased novelty of the conditioned stimulus during preexposure, conditioning, and testing.

Attenuation of auditory startle and prepulse inhibition by unexpected changes in ambient illumination through dopaminergic mechanisms.

We investigated the role of dopaminergic mechanisms in the attenuation of the acoustic startle response and prepulse inhibition (PPI) in rats by the introduction of unexpected changes in environment illumination. Experiment 1 showed that Dark-to-Light transitions robustly reduce startle responses and PPI. Experiment 2 showed that this phenomenon habituates across repeated testing sessions and reappears after an interval without testing. Experiment 3 demonstrated that haloperidol blocks the startle and PPI-reducing effect of the Dark-to-Light transition. We show how a computational model of acoustic startle response and prepulse inhibition can be extended to incorporate the empirical effects demonstrated in this study. We conclude that sensory gating as measured by prepulse inhibition is markedly attenuated in situations where novel stimuli are introduced during a test session and that dopaminergic systems may be involved in the dynamic changes evoked by the onset of illumination.

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.

A pre-clinical study showing how dopaminergic drugs administered during pre-exposure can impair or facilitate latent inhibition.

RATIONALE: It has been suggested that, in classical conditioning, dopamine (DA) codes for (a) attention to the conditioned stimulus (CS) or (b) the intensity of the unconditioned stimulus. OBJECTIVES: To clarify the role of DA in pre-clinical classical conditioning studies. METHODS: An existing model of classical conditioning presented by Schmajuk, Lam, and Gray (J Exp Psychol Anim Behav Process 22:321-349, 1996) suggests that DA cells in the ventral midbrain area code for the attentionally modulated internal representation of the CS. It is assumed that this representation is increased by dopaminergic agonists and decreased by dopaminergic antagonists. Computer simulations with the model describe the effect of nicotine and haloperidol on latent inhibition. RESULTS: Simulations replicate experimental results demonstrating that both nicotine and haloperidol affect latent inhibition when administered during the pre-exposure phase. In addition, the model reproduces data showing that administration of nicotine or haloperidol results in the impairment or facilitation of latent inhibition depending on the duration of CS or the number of CSs. CONCLUSIONS: The model demonstrates that pre-clinical experimental results, including cell activity and pharmacological data, are consistent with an attentional role for DA in classical conditioning.

Hippocampal dysfunction in schizophrenia.

Although not necessarily primary to the disease, hippocampal dysfunction in schizophrenia is suggested by morphological changes in the hippocampal formation reported in schizophrenic patients. This notion receives additional support from studies showing that 1) similar behavioral deficits are exhibited by both schizophrenics and animals with hippocampal lesions, and 2) some of these behavioral deficits are reversed by neuroleptics in both schizophrenics and lesioned animals. A brain-mapped neural network model is used to explain how some impairments in attention can be caused by hippocampal dysfunction and ameliorated by dopaminergic blockers.

Nucleus accumbens, entorhinal cortex and latent inhibition: a neural network model.

A neural network model of classical conditioning (Schmajuk, Lam, and Gray, J. Exp. Psychol.: Anim. Behav. Process, 22, 1996, 321-349) is applied to the description of the neural substrates of latent inhibition. Experimental data suggest that latent inhibition might be controlled by a circuit that involves the hippocampus, the entorhinal cortex, the nucleus accumbens, and the mesolimbic dopaminergic projection from the ventral tegmental area to the accumbens. By mapping different nodes and connections in the model onto this brain circuit, computer simulations demonstrate that, in most cases, the model provides a good quantitative description of: (1) the impairment of latent inhibition by lesions of the shell of the nucleus accumbens; (2) the restoration of latent inhibition by haloperidol following lesions of the shell; (3) the preservation of latent inhibition by lesions of the core of the nucleus accumbens; (4) the facilitation of latent inhibition by combined shell core lesions and by core lesions with extended conditioning; (5) the impairment of latent inhibition following lesions of the entorhinal cortex or the hippocampus; and (6) the restoration of latent inhibition by haloperidol following lesions of the entorhinal cortex and ventral subiculum. In addition, the model is able to describe neural activity in the nucleus accumbens.

Haloperidol reinstates latent inhibition impaired by hippocampal lesions: data and theory.

The effect of haloperidol administration on the impairment of latent inhibition produced by aspirative lesions of the hippocampus was examined in the rat eyeblink response preparation. During the preexposure phase, rats with hippocampal or control lesions were either exposed to a tone or allowed to sit in the training apparatus. During the conditioning phase, the tone was paired with an airpuff to the eye after the rats were injected with either saline or haloperidol. Although saline-injected rats with hippocampal lesions did not show latent inhibition, the phenomenon was reinstated in rats that received haloperidol injections. A possible locus of the interaction between hippocampal lesions and haloperidol is the nucleus accumbens. The reported data are well described by a neural network model of classical conditioning. This study contributes to the understanding of the neurophysiology of latent inhibition as well as the neuropsychological bases of schizophrenia.

Timing in simple conditioning and occasion setting: a neural network approach.

We present a neural network model of Pavlovian conditioning in which a timing mechanism, by which a CS can predict when the US is presented, activates an architecture in which a stimulus acts as a simple CS and/or as an occasion setter. In the model, stimuli evoke multiple traces of different duration and amplitude, peaking at different times after CS presentation [Grossberg and Schmajuk, 1989. Neural Netw. 2, 79-102]. These traces compete to become associated directly and indirectly (through hidden units) with the US [Schmajuk and DiCarlo, 1992. Psychol. Rev. 99, 268-305]. The output of the system predicts the value, moment, and duration of presentation of reinforcement. Importantly, in contrast to the model by Schmajuk and DiCarlo [Schmajuk and DiCarlo, 1992. Psychol. Rev. 99, 268-305], in the present model a stimulus may assume different roles (simple CS, occasion setter, or both) at different time moments. Moreover, while in the Schmajuk and DiCarlo model [Schmajuk and DiCarlo, 1992. Psychol. Rev. 99, 268-305], competition between CSs is purely associative, in the present model competition between CSs is both associative and temporal. CSs compete to predict not only the presence and the intensity of the US, but also its temporal characteristics: time of presentation and duration. The model is able to address both the temporal and associative properties of simple conditioning, compound conditioning, and occasion setting.

Perplexing effects of hippocampal lesions on latent inhibition: a neural network solution.

Experimental data indicate that hippocampal lesions might impair, spare, or even facilitate latent inhibition (LI). Furthermore, when LI is impaired by the lesions, it might be reinstated by haloperidol administration. The present article applies a neural network model of classical conditioning (N. A. Schmajuk, Y. W. Lam, & J. A. Gray, 1996) to investigate the possible causes of these puzzling results. According to the model, LI is manifested because preexposure of the conditioned stimulus (CS) reduces Novelty, defined as proportional to the sum of the mismatches between predicted and observed events, thereby reducing attention to the CS and retarding conditioning. It is assumed that hippocampal lesions affect the prediction of events. Computer simulations reveal that, depending on the behavioral protocol (i.e., procedure and total time of CS preexposure), Novelty in hippocampal lesioned animals might be larger, equal, or smaller (corresponding to smaller, equal, or larger LI) than in normal controls. Reinstatement of LI by haloperidol administration is explained by assuming that dopaminergic antagonists decrease the value of Novelty, when Novelty increases following hippocampal lesions.

Occasion setting: a neural network approach.

Classical conditioning data show that a conditioned stimulus (CS) can act either as a simple CS--eliciting conditioned responses (CRs) by signaling the occurrence of an unconditioned stimulus (US)--or as an occasion setter--controlling the responses generated by another CS. In this article, the authors apply a simple extension of a network model of conditioning, originally presented by N. A. Schmajuk and J. J. DiCarlo (S-D; 1992), to the description of these 2 different CS functions. In the model, CS inputs are connected to the CR output both directly and indirectly through a hidden unit layer that codes configural stimuli. In this framework, a CS acts as (a) a simple stimulus through its direct connections with the output units and as (b) an occasion setter through its indirect configural connections via the hidden units. Computer simulations demonstrate that the network accounts for a large part of the data on occasion setting.

Psychopharmacology of latent inhibition: a neural network approach.

A neural network model of classical conditioning is applied to the description of some aspects of the psychopharmacology of latent inhibition (LI). According to the model, LI is manifested because preexposure of the conditioned stimulus (CS) reduces Novelty, defined as proportional to the sum of the mismatches between predicted and observed events, thereby reducing attention to the CS and retarding conditioning. In the framework of the model, it is assumed that indirect dopaminergic (DA) agonists (e.g. amphetamine and nicotine) increase, and DA receptor antagonists (e.g. haloperidol and alpha-flupenthixol) decrease, the effect of Novelty on attention. Computer simulations demonstrate that, under these assumptions, the model correctly describes: (1) the impairment of LI by amphetamine when a strong unconditioned stimulus (US) is used, (2) the impairment of LI by amphetamine when a nonsalient CS is used, (3) the impairment of LI by amphetamine administration when a short CS is used, (4) the facilitation of LI by alpha-flupenthixol when a weak US is used, (5) the facilitation of LI by haloperidol when a nonsalient CS is used, (6) the facilitation of LI by haloperidol with a strong US, and (7) the facilitation of LI by haloperidol with extended conditioning.

Stimulus configuration, occasion setting, and the hippocampus.

N. A. Schmajuk, J. Lamoureux, and P. C. Holland (in press) showed that an extension of a neural network model introduced by N. A. Schmajuk and J. J. DiCarlo (1992) characterizes many of the differences between simple conditioning and occasion setting. In the framework of this model, it is proposed that the hippocampus modulates (a) the competition among simple and complex stimuli to establish associations with the unconditioned stimulus, and (b) the configuration of simple stimuli into complex stimuli. Under the assumptions that (a) nonselective lesions of the hippocampal formation impair both configuration and competition, and (b) selective lesions of the hippocampus proper impair only stimulus configuration, the model correctly describes the effects of these lesions on paradigms in which stimuli act as occasion setters.

Spatial and temporal cognitive mapping: a neural network approach.

Tolman suggested that cognitive behavior is purposive and can be described in terms of how differant goals are pursued. When pursuing these goals, animals and humans display a remarkable adaptability, which is the result of the combination of a goal-seeking mechanism and a cognitive map. Whereas the goal-seeking mechanism permits the animal to seek different goals, adopting alternative behavioral strategies that are independent of any set of responses, the cognitive map allows the integration of multiple independent pieces of knowledge. Although the concept of cognitive mapping has been mostly applied to spatial mapping, we describe how both spatial and temporal cognitive maps can be mechanistically implemented in terms of recurrent associative networks which store either the adjacency of spatial locations or the contiguity of temporal events. The reinjected predictions of spatial locations or temporal events in the network can be conceptualized as images and their sequences conceptualized as the process of imagining. The combination of goal-seeking systems and cognitive maps permits the description of problem solving tasks in terms of the sequence of subgoals (a plan) to be pursued to reach the goal. Whereas the hippocampus might play a major role in the storage of both spatial and temporal cognitive maps in association cortex, the frontal cortex might participate in goal-seeking tasks, decision making and planing.

Attention, configuration, and hippocampal function.

We present a neural network that characterizes a remarkably large number of classical conditioning paradigms and describes the effects of many neurophysiological manipulations. First, the network 1) describes behavior in real time 2) comprises simple and configural stimulus representations, and 3) includes attentional control of storage and retrieval. Second, mapping of the network onto the brain can be summarized by several information processing loops: 1) a hippocampal-cortical configural loop, 2) a hippocampal-cerebellar conditioned-response loop, 3) a hippocampal-accumbens-thalamic attentional loop, and 4) a hippocampal-medial raphe-medial septum error loop. Third, within this global view of brain function, it is assumed that the hippocampal formation computes 1) the aggregate prediction of environmental events and 2) the error signals for cortical learning. These assumptions are supported by rigorous computer simulations consistent with a large body of data on hippocampal and septal neural activity, induction and blockade of hippocampal long-term potentiation, administration of cholinergic agonists and antagonists, administration of haloperidol, and selective and nonselective hippocampal and cortical lesions.

Latent inhibition of the rat eyeblink response: effect of hippocampal aspiration lesions.

The effect of hippocampal aspiration lesions on latent inhibition of eyeblink conditioning in the restrained rat preparation was examined. Rats received either sham, cortical control, or hippocampal aspiration lesions. Control animals, but not animals with hippocampal lesions, showed slower conditioning after being preexposed to the conditioned stimulus (latent inhibition). Together with previous results regarding the effect of hippocampal lesions in acquisition and extinction of delay conditioning, the present study suggests that the restrained rat preparation may serve as a reliable way of investigating hippocampal participation in different classical conditioning paradigms.

Stimulus configuration, spatial learning, and hippocampal function.

Schmajuk and DiCarlo (Psychol. Rev., 99 (1992) 268-305) introduced a neural network, which utilizes a biologically plausible backpropagation procedure, to describe configural paradigms in classical conditioning. The model correctly describes many experimental results under the assumption that aspiration lesions of the hippocampus eliminate (a) the competition between simple and configural stimuli to gain association with the unconditioned stimulus and (b) the adjustment of initially random configural stimuli. The present study extends the network to describe place learning. Under the assumption that ibotenic acid lesions of the hippocampus only impair the adjustment of initially random configural stimuli, the model correctly shows that ibotenic acid lesions might spare a configural discrimination but impair place learning. In general, the results are taken to support a hippocampal role in the modulation of stimulus configuration.

Maps, routes, and the hippocampus: a neural network approach.

This study describes hippocampal participation in maze navigation in terms of a real-time, biologically plausible neural network. The system is composed of (1) a goal-seeking mechanism, (2) a cognitive map system, and (3) a route system. The goal-seeking mechanism displays exploratory behavior until either the goal is found or a sufficiently strong prediction of the goal is generated. The cognitive map is a topological map that stores associations between places and views of accessible places, and between places and reward. The route system establishes associations between cues and reward. Both systems compete with each other to establish associations with the reward, with the cognitive system generally overshadowing the route system. In agreement with previous models, it is assumed that the hippocampus modulates the storage of cognitive maps in cortical areas and mediates the competition between cognitive maps and route systems. After hippocampal lesions, animals navigate through mazes making use of the route system. Computer simulations show that the network effectively describes latent learning, detour behavior, and place learning in normal and hippocampal- and cortical-lesioned animals.