Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish.

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we have used zebrafish to investigate the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was pan-neuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number and size in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.

Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption.

Disruptions in attention, salience and increased distractibility are implicated in multiple psychiatric conditions. The ventral tegmental area (VTA) is a potential site for converging information about external stimuli and internal states to be integrated and guide adaptive behaviours. Given the dual role of dopamine signals in both driving ongoing behaviours (e.g., feeding) and monitoring salient environmental stimuli, understanding the interaction between these functions is crucial. Here, we investigate VTA neuronal activity during distraction from ongoing feeding. We developed a task to assess distraction exploiting self-paced licking in rats. Rats trained to lick for saccharin were given a distraction test, in which three consecutive licks within 1 s triggered a random distractor (e.g. light and tone stimulus). On each trial they were quantified as distracted or not based on the length of their pauses in licking behaviour. We expressed GCaMP6s in VTA neurons and used fibre photometry to record calcium fluctuations during this task as a proxy for neuronal activity. Distractor stimuli caused rats to interrupt their consumption of saccharin, a behavioural effect which quickly habituated with repeat testing. VTA neural activity showed consistent increases to distractor presentations and, furthermore, these responses were greater on distracted trials compared to non-distracted trials. Interestingly, neural responses show a slower habituation than behaviour with consistent VTA responses seen to distractors even after they are no longer distracting. These data highlight the complex role of the VTA in maintaining ongoing appetitive and consummatory behaviours while also monitoring the environment for salient stimuli.

Modulation of stimulated dopamine release in rat nucleus accumbens shell by GABA in vitro: Effect of sub-chronic phencyclidine pretreatment.

Dopamine signaling in nucleus accumbens (NAc) is modulated by γ-aminobutyric acid (GABA), acting through GABA-A and GABA-B receptors: dysregulation of GABAergic control of dopamine function may be important in behavioral deficits in schizophrenia. We investigated the effect of GABA-A (muscimol) and GABA-B (baclofen) receptor agonists on electrically stimulated dopamine release. Furthermore, we explored whether drug-induced changes were disrupted by pretreatment with phencyclidine, which provides a well-validated model of schizophrenia. Using brain slices from female rats, fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in NAc shell. Both muscimol and baclofen caused concentration-dependent attenuation of evoked dopamine release: neither effect was changed by dihydro-ß-erythroidine, a nicotinic acetylcholine receptor antagonist, or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), precluding indirect mechanisms using these transmitter systems in the GABAergic actions. In slices taken from rats pretreated with phencyclidine, the attenuation of evoked dopamine release by baclofen was abolished, but the attenuation by muscimol was unaffected. Since phencyclidine pretreatment was followed by drug-free washout period of at least a week, the drug was not present during recording. Therefore, disruption of GABA-B modulation of dopamine is due to long-term functional changes resulting from the treatment, rather than transient changes due to the drug's presence at test. This enduring dysregulation of GABA-B modulation of accumbal dopamine release provides a plausible mechanism through which GABA dysfunction influences accumbal dopamine leading to behavioral changes seen in schizophrenia and may provide a route for novel therapeutic strategies to treat the condition.

Synchronization in the prefrontal-striatal circuit tracks behavioural choice in a go-no-go task in rats.

Rodent striatum is involved in sensory-motor transformations and reward-related learning. Lesion studies suggest dorsolateral striatum, dorsomedial striatum and nucleus accumbens underlie stimulus-response transformations, goal-directed behaviour and reward expectation, respectively. In addition, prefrontal inputs likely control these functions. Here, we set out to study how reward-driven behaviour is mediated by the coordinated activity of these structures in the intact brain. We implemented a discrimination task requiring rats to either respond or suppress responding on a lever after the presentation of auditory cues in order to obtain rewards. Single unit activity in the striatal subregions and pre-limbic cortex was recorded using tetrode arrays. Striatal units showed strong onset responses to auditory cues paired with an opportunity to obtain reward. Cue-onset responses in both striatum and cortex were significantly modulated by previous errors suggesting a role of these structures in maintaining appropriate motivation or action selection during ongoing behaviour. Furthermore, failure to respond to the reward-paired tones was associated with higher pre-trial coherence among striatal subregions and between cortex and striatum suggesting a task-negative corticostriatal network whose activity may be suppressed to enable processing of reward-predictive cues. Our findings highlight that coordinated activity in a distributed network including both pre-limbic cortex and multiple striatal regions underlies reward-related decisions.

Cortical Local Field Potential Power Is Associated with Behavioral Detection of Near-threshold Stimuli in the Rat Whisker System: Dissociation between Orbitofrontal and Somatosensory Cortices.

There is growing evidence that ongoing brain oscillations may represent a key regulator of attentional processes and as such may contribute to behavioral performance in psychophysical tasks. OFC appears to be involved in the top-down modulation of sensory processing; however, the specific contribution of ongoing OFC oscillations to perception has not been characterized. Here we used the rat whiskers as a model system to further characterize the relationship between cortical state and tactile detection. Head-fixed rats were trained to report the presence of a vibrotactile stimulus (frequency = 60 Hz, duration = 2 sec, deflection amplitude = 0.01-0.5 mm) applied to a single vibrissa. We calculated power spectra of local field potentials preceding the onset of near-threshold stimuli from microelectrodes chronically implanted in OFC and somatosensory cortex. We found a dissociation between slow oscillation power in the two regions in relation to detection probability: Higher OFC but not somatosensory delta power was associated with increased detection probability. Furthermore, coherence between OFC and barrel cortex was reduced preceding successful detection. Consistent with the role of OFC in attention, our results identify a cortical network whose activity is differentially modulated before successful tactile detection.

Cue competition effects in the planarian.

The learning abilities of planarian worms (Dugesia tigrina) were assessed by using a number of Pavlovian conditioning paradigms. Experiment 1 showed that planaria were susceptible to basic conditioning in that they readily developed a conditioned response to a change in ambient luminance when it was consistently paired with an electric shock over a number of trials. In Experiment 2, the change in luminance was presented in a compound with a vibration stimulus during conditioning. Subsequent tests revealed poor conditioning of the elements compared with control groups in which the animals were conditioned in the presence of the elements alone, an instance of overshadowing. In Experiment 3, pre-training of one of the elements before compound conditioning resulted in blocking of learning about the other element. These results add to other studies that have reported cue competition effects in animal species belonging to different phyla (chordate, mollusk, arthropod), suggesting that learning in these phyla could be ruled by similar principles. The results are discussed adopting an evolutionary-comparative approach.

Attenuation of Stimulated Accumbal Dopamine Release by NMDA Is Mediated through Metabotropic Glutamate Receptors.

Electrically stimulated dopamine release from the nucleus accumbens is attenuated following application of N-methyl-d-aspartate (NMDA), which is likely to be mediated indirectly through intermediary neuronal mechanisms rather than by a direct action on dopamine terminals. On the basis of known modulatory processes in nucleus accumbens, the current experiments sought to test whether the effect of NMDA was mediated through cholinergic, GABA-ergic, or metabotropic glutamatergic intermediate mechanisms. Fast-scan cyclic voltammetry was used to measure electrically stimulated dopamine release in nucleus accumbens of rat brain slices in vitro. Stimulated dopamine release was attenuated by NMDA, confirming previous findings, but this attenuation was unaffected by either cholinergic or GABA-ergic antagonists. However, it was completely abolished by the nonselective group I/II/III metabotropic glutamate receptor antagonist α-methyl-4-carboxyphenylglycine (MCPG) and by the selective group II antagonist LY 341396. Therefore, group II metabotropic glutamate receptors, but not acetylcholine or GABA receptors, mediate the attenuation of stimulated dopamine release caused by NMDA, probably by presynaptic inhibition through receptors located extra-synaptically on dopamine terminals. This provides a plausible mechanism for the documented role of metabotropic glutamate receptor systems in restoring deficits induced by NMDA receptor antagonists, modeling schizophrenia, underlining the potential for drugs affecting these receptors as therapeutic agents in treating schizophrenia.

Age-dependent effects of protein restriction on dopamine release.

Despite the essential role of protein intake for health and development, very little is known about the impact of protein restriction on neurobiological functions, especially at different stages of the lifespan. The dopamine system is a central actor in the integration of food-related processes and is influenced by physiological state and food-related signals. Moreover, it is highly sensitive to dietary effects during early life periods such as adolescence due to its late maturation. In the present study, we investigated the impact of protein restriction either during adolescence or adulthood on the function of the mesolimbic (nucleus accumbens) and nigrostriatal (dorsal striatum) dopamine pathways using fast-scan cyclic voltammetry in rat brain slices. In the nucleus accumbens, protein restriction in adults increased dopamine release in response to low and high frequency trains of stimulation (1-20 Hz). By contrast, protein restriction during adolescence decreased nucleus accumbens dopamine release. In the dorsal striatum, protein restriction at adulthood has no impact on dopamine release but the same diet during adolescence induced a frequency-dependent increase in stimulated dopamine release. Taken together, our results highlight the sensitivity of the different dopamine pathways to the effect of protein restriction, as well as their vulnerability to deleterious diet effects at different life stages.

Repeated phencyclidine disrupts nicotinic acetylcholine regulation of dopamine release in nucleus accumbens: Implications for models of schizophrenia.

Dopaminergic dysregulation in nucleus accumbens has been implicated in the origin of schizophrenia. Accumbal cholinergic interneurons exert powerful modulatory control of local dopamine function, through nicotinic receptors located on dopamine terminals. Fast-scan cyclic voltammetry in rat brain slices in vitro was used to measure dopamine release evoked by high-frequency electrical stimulation, mimicking phasic dopamine activity. We investigated whether cholinergic regulation of stimulated dopamine release was disrupted by pretreatment with phencyclidine, a non-competitive NMDA receptor antagonist, which provides a well validated animal model of schizophrenia. Dihydro-ß-erythroidine, an antagonist at ß2-subuit containing nicotinic receptors, caused a concentration-dependent enhancement of stimulated dopamine release, indicating cholinergic inhibitory control over dopamine release. The agonist, nicotine, also caused concentration-dependent increases in release, consistent with rapid desensitisation of the receptors previously described. In slices taken from animals pretreated with phencyclidine, the augmentation of electrically-stimulated dopamine release elicited by both drugs was attenuated, particularly when each drug was applied at high concentration. In addition, the concentration-dependence of each drug effect was lost. Taken together these findings indicate that pretreatment with phencyclidine causes changes in acetylcholine systems modulating dopamine release in accumbens. Since phencyclidine treatment was terminated at least a week before the slices were taken, the effects are due to long-term changes in function resulting from the treatment, rather than from transient changes due to the presence of the drug at test. Such enduring dysregulation of cholinergic control of phasic dopamine release could account for deficits in behaviours mediated by accumbal dopamine seen in schizophrenia, and may provide a route for novel therapeutic strategies to treat the disease.

Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil.

Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. In this study we have used a behavioural platform in a phenotypic screen to identify drugs that can reduce zebrafish aggression without affecting locomotion. In a three tier screen of ninety-four drugs we discovered that caffeine and sildenafil can selectively reduce aggression. Caffeine also decreased attention and increased impulsivity in the 5-choice serial reaction time task whereas sildenafil showed the opposite effect. Imaging studies revealed that both caffeine and sildenafil are active in the zebrafish brain, with prominent activation of the thalamus and cerebellum evident. They also interact with 5-HT neurotransmitter signalling. In summary, we have demonstrated that juvenile zebrafish are a suitable model to screen for novel drugs to reduce aggression, with the potential to uncover the neural circuits and signalling pathways that mediate such behavioural effects.

The zebrafish histamine H3 receptor modulates aggression, neural activity and forebrain functional connectivity.

AIM: Aggression is a behavioural trait characterized by the intention to harm others for offensive or defensive purposes. Neurotransmitters such as serotonin and dopamine are important mediators of aggression. However, the physiological role of the histaminergic system during this behaviour is currently unclear. Here, we aimed to better understand histaminergic signalling during aggression by characterizing the involvement of the histamine H3 receptor (Hrh3). METHODS: We have generated a novel zebrafish Hrh3 null mutant line using CRISPR-Cas9 genome engineering and investigated behavioural changes and alterations to neural activity using whole brain Ca2+ imaging in zebrafish larvae and ribosomal protein S6 (rpS6) immunohistochemistry in adults. RESULTS: We show that genetic inactivation of the histamine H3 receptor (Hrh3) reduces aggression in zebrafish, an effect that can be reproduced by pharmacological inhibition. In addition, hrh3-/- zebrafish show behavioural impairments consistent with heightened anxiety. Larval in vivo whole brain Ca2+ imaging reveals higher neuronal activity in the forebrain of mutants, but lower activity in specific hindbrain areas and changes in measures of functional connectivity between subregions. Adult hrh3-/- zebrafish display brain region-specific neural activity changes in response to aggression of both key regions of the social decision-making network, and the areas containing histaminergic neurons in the zebrafish brain. CONCLUSION: These results highlight the importance of zebrafish Hrh3 signalling for aggression and anxiety and uncover the brain areas involved. Targeting this receptor might be a potential novel therapeutic route for human conditions characterized by heightened aggression.

Serotonin (5-HT) neuron-specific inactivation of Cadherin-13 impacts 5-HT system formation and cognitive function.

Genome-wide screening approaches identified the cell adhesion molecule Cadherin-13 (CDH13) as a risk factor for neurodevelopmental disorders, nevertheless the contribution of CDH13 to the disease mechanism remains obscure. CDH13 is involved in neurite outgrowth and axon guidance during early brain development and we previously provided evidence that constitutive CDH13 deficiency influences the formation of the raphe serotonin (5-HT) system by modifying neuron-radial glia interaction. Here, we dissect the specific impact of CDH13 on 5-HT system development and function using a 5-HT neuron-specific Cdh13 knockout mouse model (conditional Cdh13 knockout, Cdh13 cKO). Our results show that exclusive inactivation of CDH13 in 5-HT neurons selectively increases 5-HT neuron density in the embryonic dorsal raphe, with persistence into adulthood, and serotonergic innervation of the developing prefrontal cortex. At the behavioral level, adult Cdh13 cKO mice display delayed acquisition of several learning tasks and a subtle impulsive-like phenotype, with decreased latency in a sociability paradigm alongside with deficits in visuospatial memory. Anxiety-related traits were not observed in Cdh13 cKO mice. Our findings further support the critical role of CDH13 in the development of dorsal raphe 5-HT circuitries, a mechanism that may underlie specific clinical features observed in neurodevelopmental disorders.

Disruption of latent inhibition by subchronic phencyclidine pretreatment in rats.

Repeated subchronic treatment with the NMDA-receptor antagonist, phencyclidine, causes behavioural changes in rats, which resemble cognitive and negative symptoms of schizophrenia. However, its effects on behaviours modelling positive symptoms are less clear. This study investigated whether subchronic phencyclidine pretreatment affected latent inhibition: impaired conditioning following repeated preexposure of the to-be-conditioned stimulus. Female Lister-hooded rats were pretreated with phencyclidine or saline twice/day for 5 days, then remained drug-free for 10 days before latent inhibition testing. Saline pretreated animals showed latent inhibition, as expected. However, phencyclidine pretreated animals showed no latent inhibition: the effect of preexposure was attenuated, with no change in basic learning. Thus subchronic phencyclidine pretreatment does disrupt latent inhibition, and, importantly, this occurs after withdrawal from the drug, implicating changes in brain function enduring well beyond the time that the drug is present in the brain. In a separate task, discrimination of a novel object was significantly impaired by phencyclidine pretreatment confirming that five days of subchronic pretreatment was sufficient to invoke behavioural impairment previously reported after seven days pretreatment.

Endothelin neurotransmitter signalling controls zebrafish social behaviour.

The formation of social groups is an adaptive behaviour that can provide protection from predators, improve foraging and facilitate social learning. However, the costs of proximity can include competition for resources, aggression and kleptoparasitism meaning that the decision whether to interact represents a trade-off. Here we show that zebrafish harbouring a mutation in endothelin receptor aa (ednraa) form less cohesive shoals than wild-types. ednraa-/- mutants exhibit heightened aggression and decreased whole-body cortisol levels suggesting that they are dominant. These behavioural changes correlate with a reduction of parvocellular arginine vasopressin (AVP)-positive neurons in the preoptic area, an increase in the size of magnocellular AVP neurons and a higher concentration of 5-HT and dopamine in the brain. Manipulation of AVP or 5-HT signalling can rescue the shoaling phenotype of ednraa-/- providing an insight into how the brain controls social interactions.

Reelin Signaling Controls the Preference for Social Novelty in Zebrafish.

Reelin (Reln) is an extracellular glycoprotein that is important for brain patterning. During development Reln coordinates the radial migration of postmitotic cortical neurons, cerebellar and hippocampal neurons, whereas it promotes dendrite maturation, synaptogenesis, synaptic transmission, plasticity and neurotransmitter release in the postnatal and adult brain. Genetic studies of human patients have demonstrated association between the RELN locus and autism spectrum disorder, schizophrenia, bipolar disorder, and Alzheimer's disease. In this study we have characterized the behavioral phenotype of reelin (reln) mutant zebrafish, as well as two canonical signaling pathway targets DAB adaptor protein 1a (dab1a) and the very low density lipoprotein receptor (vldlr). Zebrafish reln-/- mutants display a selective reduction in preference for social novelty that is not observed in dab1a-/- or vldlr-/- mutant lines. They also exhibit an increase in 5-HT signaling in the hindbrain that parallels but does not underpin the alteration in social preference. These results suggest that zebrafish reln-/- mutants can be used to model some aspects of human diseases in which changes to Reln signaling alter social behavior.

Metabotropic glutamate receptor modulation of dopamine release in the nucleus accumbens shell is unaffected by phencyclidine pretreatment: In vitro assessment using fast-scan cyclic voltammetry rat brain slices.

The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release. We showed that the orthosteric mGluR2 agonist LY379268 (0.1 µM, 1 µM and 10 µM) and mGluR5 positive allosteric modulator CDPPB (1 µM and 10 µM) both attenuated potassium-evoked dopamine release, underscoring their role in modulating dopamine neurotransmission in the nucleus accumbens. Sub-chronic PCP treatment, which caused cognitive deficits measured by performance in the novel object recognition task, modelling aspects of behavioral deficits seen in schizophrenia, induced neurobiological changes that enhanced dopamine release in the nucleus accumbens, but had no effect on mGluR2 or mGluR5 mediated changes in dopamine release. Therefore it is unlikely that schizophrenia-related behavioural changes seen after sub-chronic phencyclidine pre-treatment are mediated through mGluR modulation of dopamine release.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro.

The N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine, induces behavioral changes in rodents mimicking symptoms of schizophrenia, possibly mediated through dysregulation of glutamatergic control of mesolimbic dopamine release. We tested the hypothesis that NMDA receptor activation modulates accumbens dopamine release, and that phencyclidine pretreatment altered this modulation. NMDA caused a receptor-specific, dose-dependent decrease in electrically stimulated dopamine release in nucleus accumbens brain slices. This decrease was unaffected by picrotoxin, making it unlikely to be mediated through GABAergic neurones, but was decreased by the metabotropic glutamate receptor antagonist, (RS)-α-methyl-4-sulfonophenylglycine, indicating that NMDA activates mechanisms controlled by these receptors to decrease stimulated dopamine release. The effect of NMDA was unchanged by in vivo pretreatment with phencyclidine (twice daily for 5 days), with a washout period of at least 7 days before experimentation, which supports the hypothesis that there is no enduring direct effect of PCP at NMDA receptors after this pretreatment procedure. We propose that NMDA depression of accumbal dopamine release is mediated by metabotropic glutamate receptors located pre- or perisynaptically, and suggest that NMDA evoked increased extrasynaptic spillover of glutamate is sufficient to activate these receptors that, in turn, inhibit dopamine release. Furthermore, we suggest that enduring functional changes brought about by subchronic phencyclidine pretreatment, modeling deficits in schizophrenia, are downstream effects consequent on chronic blockade of NMDA receptors, rather than direct effects on NMDA receptors themselves.

Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia.

The neural mechanisms underlying cognitive deficits in schizophrenia are poorly understood. Sub-chronic treatment with the NMDA antagonist phencyclidine (PCP) produces cognitive abnormalities in rodents that reliably model aspects of the neurocognitive alterations observed in schizophrenia. Given that network activity across regions encompassing medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) plays a significant role in motivational and cognitive tasks, we measured activity across cortico-striatal pathways in PCP-treated rats to characterize neural enabling and encoding of task performance in a novel object recognition task. We found that PCP treatment impaired task performance and concurrently (1) reduced tonic NAc neuronal activity, (2) desynchronized cross-activation of mPFC and NAc neurons, and (3) prevented the increase in mPFC and NAc neural activity associated with the exploration of a novel object in relation to a familiar object. Taken together, these observations reveal key neuronal and network-level adaptations underlying PCP-induced cognitive deficits, which may contribute to the emergence of cognitive abnormalities in schizophrenia.

The role of dopamine in conditioning and latent inhibition: what, when, where and how?

It is well established that dopamine is released in the nucleus accumbens (NAC) in animals in rewarding or reinforcing situations, and widely believed that this release is the substrate of, or at least closely related to, the experience of reward. The demonstration of conditioned release of dopamine by stimuli conditioned to primary rewards has reinforced this view. However, a number of observations do not sit comfortably with this interpretation, most notably that dopamine is released equally effectively in NAC by aversive stimuli, and stimuli conditioned to them. Furthermore, additional release of dopamine is seen during conditioning, even if motivational stimuli of either type are not involved. It is suggested here that one important action of NAC dopamine release is to restore the salience of potential conditioned stimuli, when this has been reduced by prior un-reinforced experience. The paradigm of latent inhibition (LI) demonstrates a behavioural effect of this type, and extensive studies on the role of dopamine in LI have been undertaken by us and others. Those studies are reviewed here, together with some previously unpublished data, to demonstrate that (1) amphetamine disruption of LI is indeed a function of calcium-dependant dopamine release in the NAC at the time of conditioning; (2) other drugs acting on LI via changes in dopamine transmission act at the same locus; (3) the disruptive effect of indirect dopamine agonists on LI can be prevented by either D-1 selective receptor antagonists, or D-2 selective receptor antagonists. It is concluded that dopamine release in these very varied behavioural contexts (reward, punishment, conditioning, modulation of salience) must be differentiated in some way, and that this should be investigated. An alternative explanation, if they are not differentiated, would be that the release in fact does have the same functional significance in each case. We suggest that this common significance might be the broadening of attention to take in potentially conditionable stimuli, which have previously been devalued.

Disruption of learned irrelevance in acute schizophrenia in a novel continuous within-subject paradigm suitable for fMRI.

Learned irrelevance (LIrr) is closely related to latent inhibition (LI). In LI a to-be-conditioned stimulus (CS) is prexposed alone prior to the opportunity to learn an association between the CS and an unconditioned stimulus (UCS). In LIrr preexposure consists of intermixed presentations of both CS and UCS in a random relationship to each other. In both paradigms preexposure leads in normal subjects to reduced or retarded learning of the CS-UCS association. Acute schizophrenics fail to show LI. LI is usually demonstrated as a one-off, between-groups difference in trials to learning, so posing problems for neuroimaging. We have developed a novel, continuous, within-subject paradigm in which normal subjects show robust and repeated LIrr. We show that this paradigm is suitable for functional magnetic resonance imaging (fMRI) and gives rise, in normal subjects, to activation in the hippocampal formation, consistent with data from animal experiments on LI. We also report, consistent with previous studies of LI, loss (indeed, significant reversal) of LIrr in acute (first 2 weeks of current psychotic episode) schizophrenics. Chronic schizophrenics failed to demonstrate learning, precluding measurement in this group of LIrr. These findings establish the likely value of the new paradigm for neuroimaging studies of attentional dysfunction in acute schizophrenia.