Impaired Latent Inhibition Research Articles

Ultrasound-Induced Prenatal Stress: New Possibilities for Modeling Mental Disorders

The development of animal models of mental disorders is an important task since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress (PS). The use of variable frequency ultrasound (US) in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of PS induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely, to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open-field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex, and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment.

Neurobehavioral Profiles of Six Genetically-based Rat Models of Schizophrenia- related Symptoms.

Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/ neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.

Effects of 7.5% Carbon Dioxide and Nicotine Administration on Latent Inhibition.

Stratified medicine approaches have potential to improve the efficacy of drug development for schizophrenia and other psychiatric conditions, as they have for oncology. Latent inhibition is a candidate biomarker as it demonstrates differential sensitivity to key symptoms and neurobiological abnormalities associated with schizophrenia. The aims of this research were to evaluate whether a novel latent inhibition task that is not confounded by alternative learning effects such as learned irrelevance, is sensitive to (1) an in-direct model relevant to psychosis [using 7.5% carbon dioxide (CO2) inhalations to induce dopamine release via somatic anxiety] and (2) a pro-cognitive pharmacological manipulation (via nicotine administration) for the treatment of cognitive impairment associated with schizophrenia. Experiment 1 used a 7.5% CO2 challenge as a model of anxiety-induced dopamine release to evaluate the sensitivity of latent inhibition during CO2 gas inhalation, compared to the inhalation of medical air. Experiment 2 examined the effect of 2 mg nicotine administration vs. placebo on latent inhibition to evaluate its sensitivity to a potential pro-cognitive drug treatment. Inhalation of 7.5% CO2 raised self-report and physiological measures of anxiety and impaired latent inhibition, relative to a medical air control; whereas administration of 2 mg nicotine, demonstrated increased latent inhibition relative to placebo control. Here, two complementary experimental studies suggest latent inhibition is modified by manipulations that are relevant to the detection and treatment of schizophrenia. These results suggest that this latent inhibition task merits further investigation in the context of neurobiological sub-groups suitable for novel treatment strategies.

THC and CBD produce divergent effects on perception and panic behaviours via distinct cortical molecular pathways

Clinical and pre-clinical evidence demonstrates divergent psychotropic effects of THC vs. CBD. While THC can induce perceptual distortions and anxiogenic effects, CBD displays antipsychotic and anxiolytic properties. A key brain region responsible for regulation of cognition and affect, the medial prefrontal cortex (PFC), is strongly modulated by cannabinoids, suggesting that these dissociable THC/CBD-dependent effects may involve functional and molecular interplay within the PFC. The primary aim of this study was to investigate potential interactions and molecular substrates involved in PFC-mediated effects of THC and CBD on differential cognitive and affective behavioural processing. Male Sprague Dawley rats received intra-PFC microinfusions of THC, CBD or their combination, and tested in the latent inhibition paradigm, spontaneous oddity discrimination test, elevated T-maze and open field. To identify local, drug-induced molecular modulation in the PFC, PFC samples were collected and processed with Western Blotting. Intra-PFC THC induced strong panic-like responses that were counteracted with CBD. In contrast, CBD did not affect panic-like behaviours but blocked formation of associative fear memories and impaired latent inhibition and oddity discrimination performance. Interestingly, these CBD effects were dependent upon 5-HT1A receptor transmission but not influenced by THC co-administration. Moreover, THC induced robust phosphorylation of ERK1/2 that was prevented by CBD, while CBD decreased phosphorylation of p70S6K, independently of THC. These results suggest that intra-PFC infusion of THC promotes panic-like behaviour associated with increased ERK1/2 phosphorylation. In contrast, CBD impairs perceptive functions and latent inhibition via activation of 5-HT1A receptors and reduced phosphorylation of p70S6K.

The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans.

Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

Postanesthetic effects of isoflurane on behavioral phenotypes of adult male C57BL/6J mice.

Isoflurane was previously the major clinical anesthetic agent but is now mainly used for veterinary anesthesia. Studies have reported widespread sites of action of isoflurane, suggesting a wide array of side effects besides sedation. In the present study, we phenotyped isoflurane-treated mice to investigate the postanesthetic behavioral effects of isoflurane. We applied comprehensive behavioral test batteries comprising sensory test battery, motor test battery, anxiety test battery, depression test battery, sociability test battery, attention test battery, and learning test battery, which were started 7 days after anesthesia with 1.8% isoflurane. In addition to the control group, we included a yoked control group that was exposed to the same stress of handling as the isoflurane-treated animals before being anesthetized. Our comprehensive behavioral test batteries revealed impaired latent inhibition in the isoflurane-treated group, but the concentration of residual isoflurane in the brain was presumably negligible. The yoked control group and isoflurane-treated group exhibited higher anxiety in the elevated plus-maze test and impaired learning function in the cued fear conditioning test. No influences were observed in sensory functions, motor functions, antidepressant behaviors, and social behaviors. A number of papers have reported an effect of isoflurane on animal behaviors, but no systematic investigation has been performed. To the best of our knowledge, this study is the first to systematically investigate the general health, neurological reflexes, sensory functions, motor functions, and higher behavioral functions of mice exposed to isoflurane as adults. Our results suggest that the postanesthetic effect of isoflurane causes attention deficit in mice. Therefore, isoflurane must be used with great care in the clinical setting and veterinary anesthesia.

Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies.

Adolescent social isolation influences cognitive function in adult rats.

Adolescence is a critical period for neurodevelopment. Evidence from animal studies suggests that isolated rearing can exert negative effects on behavioral and brain development. The present study aimed to investigate the effects of adolescent social isolation on latent inhibition and brain-derived neurotrophic factor levels in the forebrain of adult rats. Male Wistar rats were randomly divided into adolescent isolation (isolated housing, 38–51 days of age) and social groups. Latent inhibition was tested at adulthood. Brain-derived neurotrophic factor levels were measured in the medial prefrontal cortex and nucleus accumbens by an enzyme-linked immunosorbent assay. Adolescent social isolation impaired latent inhibition and increased brain-derived neurotrophic factor levels in the medial prefrontal cortex of young adult rats. These data suggest that adolescent social isolation has a profound effect on cognitive function and neurotrophin levels in adult rats and may be used as an animal model of neurodevelopmental disorders.

Impairment of Latent Inhibition in Adult Rats after Blockade of Dopaminergic Terminals in the Ventral Hippocampus during the Period of Pubertal Development

Wistar rats aged 32 days were given bilateral injections of the neurotoxin 6-hydroxydopamine in the area of the ventral hippocampus. After four weeks, “latent inhibition,” which is widely used in studies of selective attention in the context of reinforcement training, was assessed. In the present experiments, latent inhibition was formed in two classical conditioned reflex tasks – passive and active avoidance. Before acquisition of the passive avoidance reaction, animals were given 20 presentations of the conditioned contextual stimulus without reinforcement (pre-exposure stage). The active avoidance reaction was developed after pre-exposure to the conditioned light stimulus (100 presentations without reinforcement). In both behavioral tasks, the formation of latent inhibition was impaired in the operated rats as compared with the corresponding sham-operated animals. At the same time, administration of neurotoxin had no effect on acquisition of the two conditioned reactions in the absence of a pre-exposure stage. The contribution of dopamine terminals in the ventral hippocampus to the development of the neural networks responsible for suppressing attention to unimportant information in the brain is discussed.

β-Adrenergic receptors in the insular cortex are differentially involved in aversive vs. incidental context memory formation

The goal of this research was to determine the effects of β-adrenergic antagonism in the IC before or after inhibitory avoidance (IA) training or context pre-exposure in a latent inhibition protocol. Pretraining intra-IC infusion of the β-adrenergic antagonist propranolol disrupted subsequent IA retention and impaired latent inhibition of IA, but had no effect on formation of memory for an inert context (termed incidental memory). These results indicate that IC β-adrenergic receptors are necessary for memory acquisition of an aversive, but not an inconsequential, context. Nevertheless, subsequent association of a familiar and hitherto inconsequential context with an unconditioned stimulus (US) does require activation of these receptors during its initial acquisition.

Neuregulin-1 immunoglobulin-like domain mutant mice: clozapine sensitivity and impaired latent inhibition

Genetic and behavioral studies in humans and mouse mutants have implicated the gene encoding neuregulin-1 (Nrg-1) as a candidate susceptibility gene for schizophrenia. We examined the behavior of mice heterozygous for a mutation in neuregulin-1's immunoglobulin (Ig)-like domain (Ig-nrg-1 mice). We found that these animals displayed behaviors related to a schizophrenia-like phenotype, such as clozapine suppression of open-field and running wheel activity and impaired latent inhibition. Contrary to findings with other nrg-1 mutants, Ig-nrg-1 mice did not exhibit significantly elevated locomotion relative to littermate controls. These results suggest that Ig-Nrg-1's contribute to some - but not all - aspects of the schizophrenia-like phenotype of nrg-1 mutants, and further support nrg-1 as a candidate gene for schizophrenia.

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.

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.