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Buhusi M, Brown CK, Buhusi CV. NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia. Front Behav Neurosci 2024; 18:1373556. [PMID: 38601326 PMCID: PMC11004452 DOI: 10.3389/fnbeh.2024.1373556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/12/2024] [Indexed: 04/12/2024] Open
Abstract
The neuronal cell adhesion molecule (NrCAM) is widely expressed and has important physiological functions in the nervous system across the lifespan, from axonal growth and guidance to spine and synaptic pruning, to organization of proteins at the nodes of Ranvier. NrCAM lies at the core of a functional protein network where multiple targets (including NrCAM itself) have been associated with schizophrenia. Here we investigated the effects of chronic unpredictable stress on latent inhibition, a measure of selective attention and learning which shows alterations in schizophrenia, in NrCAM knockout (KO) mice and their wild-type littermate controls (WT). Under baseline experimental conditions both NrCAM KO and WT mice expressed robust latent inhibition (p = 0.001). However, following chronic unpredictable stress, WT mice (p = 0.002), but not NrCAM KO mice (F < 1), expressed latent inhibition. Analyses of neuronal activation (c-Fos positive counts) in key brain regions relevant to latent inhibition indicated four types of effects: a single hit by genotype in IL cortex (p = 0.0001), a single hit by stress in Acb-shell (p = 0.031), a dual hit stress x genotype in mOFC (p = 0.008), vOFC (p = 0.020), and Acb-core (p = 0.032), and no effect in PrL cortex (p > 0.141). These results indicating a pattern of differential effects of genotype and stress support a complex stress × genotype interaction model and a role for NrCAM in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.
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Affiliation(s)
- Mona Buhusi
- Interdisciplinary Program in Neuroscience, Department of Psychology, Utah State University, Logan, UT, United States
| | | | - Catalin V. Buhusi
- Interdisciplinary Program in Neuroscience, Department of Psychology, Utah State University, Logan, UT, United States
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Chen EYH, Wong SMY, Tang EYH, Lei LKS, Suen YN, Hui CLM. Spurious Autobiographical Memory of Psychosis: A Mechanistic Hypothesis for the Resolution, Persistence, and Recurrence of Positive Symptoms in Psychotic Disorders. Brain Sci 2023; 13:1069. [PMID: 37509001 PMCID: PMC10376952 DOI: 10.3390/brainsci13071069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Psychotic disorders are complex disorders with multiple etiologies. While increased dopamine synthesis capacity has been proposed to underlie psychotic episodes, dopamine-independent processes are also involved (less responsive to dopamine receptor-blocking medications). The underlying mechanism(s) of the reduction in antipsychotic responsiveness over time, especially after repeated relapses, remain unclear. Despite the consistent evidence of dopamine overactivity and hippocampal volume loss in schizophrenia, few accounts have been provided based on the interactive effect of dopamine on hippocampal synapse plasticity mediating autobiographical memory processes. The present hypothesis builds upon previous works showing the potential effects of dopamine overactivity on hippocampal-mediated neuroplasticity underlying autobiographical memory, alongside known patterns of autobiographical memory dysfunction in psychosis. We propose that spurious autobiographical memory of psychosis (SAMP) produced during active psychosis may be a key mechanism mediating relapses and treatment non-responsiveness. In a hyperdopaminergic state, SAMP is expected to be generated at an increased rate during active psychosis. Similar to other memories, it will undergo assimilation, accommodation, and extinction processes. However, if SAMP fails to integrate with existing memory, a discontinuity in autobiographical memory may result. Inadequate exposure to normalizing experiences and hyposalience due to overmedication or negative symptoms may also impede the resolution of SAMP. Residual SAMP is hypothesized to increase the propensity for relapse and treatment non-responsiveness. Based on recent findings on the role of dopamine in facilitating hippocampal synapse plasticity and autobiographical memory formation, the SAMP hypothesis is consistent with clinical observations of DUP effects, including the repetition of contents in psychotic relapses as well as the emergence of treatment non-responsiveness after repeated relapses. Clinical implications of the hypothesis highlight the importance of minimizing active psychosis, integrating psychosis memory, avoiding over-medication, and fostering normalizing experiences.
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Affiliation(s)
- Eric Y H Chen
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China
| | - Stephanie M Y Wong
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Eric Y H Tang
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lauren K S Lei
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yi-Nam Suen
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Christy L M Hui
- Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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3
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Buhusi M, Griffin D, Buhusi CV. Brain-Derived Neurotrophic Factor Val66Met Genotype Modulates Latent Inhibition: Relevance for Schizophrenia. Schizophr Bull 2023; 49:626-634. [PMID: 36484490 PMCID: PMC10154718 DOI: 10.1093/schbul/sbac188] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND HYPOTHESIS Latent inhibition (LI) is a measure of selective attention and learning relevant to Schizophrenia (SZ), with 2 abnormality poles: Disrupted LI in acute SZ, thought to underlie positive symptoms, and persistent LI (PLI) in schizotypy and chronic SZ under conditions where normal participants fail to show LI. We hypothesized that Brain-Derived Neurotrophic Factor (BDNF)-Met genotype shifts LI toward the PLI pole. STUDY DESIGN We investigated the role of BDNF-Val66Met polymorphism and neural activation in regions involved in LI in mice, and the interaction between the BDNF and CHL1, a gene associated with SZ. STUDY RESULTS No LI differences occurred between BDNF-wild-type (WT) (Val/Val) and knock-in (KI) (Met/Met) mice after weak conditioning. Chronic stress or stronger conditioning disrupted LI in WT but not KI mice. Behavior correlated with activation in infralimbic and orbitofrontal cortices, and nucleus accumbens. Examination of LI in CHL1-KO mice revealed no LI with no Met alleles (BDNF-WTs), PLI in CHL1-WT mice with 1 Met allele (BDNF-HETs), and PLI in both CHL1-WTs and CHL1-KOs with 2 Met alleles (BDNF-KIs), suggesting a shift to LI persistence with the number of BDNF-Met alleles in the CHL1 model of acute SZ. CONCLUSIONS Results support a role for BDNF polymorphisms in gene-gene and gene-environment interactions relevant to SZ. BDNF-Met allele may reduce expression of some acute SZ symptoms, and may increase expression of negative symptoms in individuals with chronic SZ. Evaluation of (screening for) SZ phenotypes associated with mutations at a particular locus (eg, CHL1), may be masked by strong effects at different loci (eg, BDNF).
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Affiliation(s)
- Mona Buhusi
- Interdisciplinary Program in Neuroscience, Department Psychology, Utah State University, Logan, UT, USA
| | - Daniel Griffin
- Interdisciplinary Program in Neuroscience, Department Psychology, Utah State University, Logan, UT, USA
| | - Catalin V Buhusi
- Interdisciplinary Program in Neuroscience, Department Psychology, Utah State University, Logan, UT, USA
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Luessen DJ, Conn PJ. Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease. Pharmacol Rev 2022; 74:630-661. [PMID: 35710132 PMCID: PMC9553119 DOI: 10.1124/pharmrev.121.000540] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. SIGNIFICANCE STATEMENT: Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.
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5
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Context specificity of latent inhibition in the snail Cornu aspersum. Anim Cogn 2022; 25:1517-1526. [PMID: 35579765 PMCID: PMC9652167 DOI: 10.1007/s10071-022-01632-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/20/2022] [Accepted: 04/22/2022] [Indexed: 11/01/2022]
Abstract
The present study was conducted to assess the context specificity of latent inhibition (LI) in the snail Cornu aspersum, using the appetitive Pavlovian Conditioning procedure of tentacle lowering. Snails experienced an odorous conditioned stimulus (CS) without any consequence before being conditioned with food. The conditioned stimulus preexposure occurred in the same context than the conditioning and the test context or in the different context. The study was performed in two replicas in which the photoperiod was defined by level of illumination and time of day (circadian replica) or was defined only by light (light replica). Both replicas showed that the CS preexposure in the same context as conditioning produced a delay in the acquisition of the conditioned response (CR). However, when the CS preexposure took place in a different context than the conditioning context, an equivalent level of CR as that observed in controls without preexposition to CS was shown. These results are congruent with context specificity of LI and they provide the first evidence of this phenomenon in terrestrial mollusks. Learning processes and theories involved in this phenomenon are also debated in the paper.
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Sheardown E, Mech AM, Petrazzini MEM, Leggieri A, Gidziela A, Hosseinian S, Sealy IM, Torres-Perez JV, Busch-Nentwich EM, Malanchini M, Brennan CH. Translational relevance of forward genetic screens in animal models for the study of psychiatric disease. Neurosci Biobehav Rev 2022; 135:104559. [PMID: 35124155 PMCID: PMC9016269 DOI: 10.1016/j.neubiorev.2022.104559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 12/10/2021] [Accepted: 02/01/2022] [Indexed: 12/16/2022]
Abstract
Psychiatric disorders represent a significant burden in our societies. Despite the convincing evidence pointing at gene and gene-environment interaction contributions, the role of genetics in the etiology of psychiatric disease is still poorly understood. Forward genetic screens in animal models have helped elucidate causal links. Here we discuss the application of mutagenesis-based forward genetic approaches in common animal model species: two invertebrates, nematodes (Caenorhabditis elegans) and fruit flies (Drosophila sp.); and two vertebrates, zebrafish (Danio rerio) and mice (Mus musculus), in relation to psychiatric disease. We also discuss the use of large scale genomic studies in human populations. Despite the advances using data from human populations, animal models coupled with next-generation sequencing strategies are still needed. Although with its own limitations, zebrafish possess characteristics that make them especially well-suited to forward genetic studies exploring the etiology of psychiatric disorders.
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Affiliation(s)
- Eva Sheardown
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | - Aleksandra M Mech
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | | | - Adele Leggieri
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | - Agnieszka Gidziela
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | - Saeedeh Hosseinian
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | - Ian M Sealy
- Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jose V Torres-Perez
- UK Dementia Research Institute at Imperial College London and Department of Brain Sciences, Imperial College London, 86 Wood Lane, London W12 0BZ, UK
| | - Elisabeth M Busch-Nentwich
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | - Margherita Malanchini
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK
| | - Caroline H Brennan
- School of Biological and Behavioural Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, England, UK.
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Millard SJ, Bearden CE, Karlsgodt KH, Sharpe MJ. The prediction-error hypothesis of schizophrenia: new data point to circuit-specific changes in dopamine activity. Neuropsychopharmacology 2022; 47:628-640. [PMID: 34588607 PMCID: PMC8782867 DOI: 10.1038/s41386-021-01188-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/23/2021] [Accepted: 09/07/2021] [Indexed: 02/07/2023]
Abstract
Schizophrenia is a severe psychiatric disorder affecting 21 million people worldwide. People with schizophrenia suffer from symptoms including psychosis and delusions, apathy, anhedonia, and cognitive deficits. Strikingly, schizophrenia is characterised by a learning paradox involving difficulties learning from rewarding events, whilst simultaneously 'overlearning' about irrelevant or neutral information. While dysfunction in dopaminergic signalling has long been linked to the pathophysiology of schizophrenia, a cohesive framework that accounts for this learning paradox remains elusive. Recently, there has been an explosion of new research investigating how dopamine contributes to reinforcement learning, which illustrates that midbrain dopamine contributes in complex ways to reinforcement learning, not previously envisioned. This new data brings new possibilities for how dopamine signalling contributes to the symptomatology of schizophrenia. Building on recent work, we present a new neural framework for how we might envision specific dopamine circuits contributing to this learning paradox in schizophrenia in the context of models of reinforcement learning. Further, we discuss avenues of preclinical research with the use of cutting-edge neuroscience techniques where aspects of this model may be tested. Ultimately, it is hoped that this review will spur to action more research utilising specific reinforcement learning paradigms in preclinical models of schizophrenia, to reconcile seemingly disparate symptomatology and develop more efficient therapeutics.
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Affiliation(s)
- Samuel J Millard
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA.
| | - Carrie E Bearden
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, 90095, USA
| | - Katherine H Karlsgodt
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, 90095, USA
| | - Melissa J Sharpe
- Department of Psychology, University of California, Los Angeles, CA, 90095, USA.
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8
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Miller DB, Rassaby MM, Collins KA, Milad MR. Behavioral and neural mechanisms of latent inhibition. Learn Mem 2022; 29:38-47. [PMID: 35042827 PMCID: PMC8774194 DOI: 10.1101/lm.053439.121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 12/01/2021] [Indexed: 02/03/2023]
Abstract
Fear is an adaptive emotion that serves to protect an organism against potential dangers. It is often studied using classical conditioning paradigms where a conditioned stimulus is paired with an aversive unconditioned stimulus to induce a threat response. Less commonly studied is a phenomenon that is related to this form of conditioning, known as latent inhibition. Latent inhibition (LI) is a paradigm in which a neutral cue is repeatedly presented in the absence of any aversive associations. Subsequent pairing of this pre-exposed cue with an aversive stimulus typically leads to reduced expression of a conditioned fear/threat response. In this article, we review some of the theoretical basis for LI and its behavioral and neural mechanisms. We compare and contrast LI and fear/threat extinction-a process in which a previously conditioned cue is repeatedly presented in the absence of aversive outcomes. We end with highlighting the potential clinical utility of LI. Particularly, we focus on how LI application could be useful for enhancing resilience, especially for individuals who are more prone to continuous exposure to trauma and stressful environments, such as healthcare workers and first responders. The knowledge to be gained from advancing our understanding of neural mechanisms in latent inhibition could be applicable across psychiatric disorders characterized by exaggerated fear responses and impaired emotion regulation.
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Affiliation(s)
- Dylan B Miller
- Department of Psychiatry, New York University Grossman School of Medicine, New York, New York 10016, USA
| | - Madeleine M Rassaby
- Department of Psychiatry, New York University Grossman School of Medicine, New York, New York 10016, USA
| | - Katherine A Collins
- Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA
| | - Mohammad R Milad
- Department of Psychiatry, New York University Grossman School of Medicine, New York, New York 10016, USA
- Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA
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9
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Hippocampal Disinhibition Reduces Contextual and Elemental Fear Conditioning While Sparing the Acquisition of Latent Inhibition. eNeuro 2022; 9:ENEURO.0270-21.2021. [PMID: 34980662 PMCID: PMC8805190 DOI: 10.1523/eneuro.0270-21.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/01/2021] [Accepted: 10/13/2021] [Indexed: 11/21/2022] Open
Abstract
Hippocampal neural disinhibition, i.e., reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signaling, which play a role in salience modulation. Consequently, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. Therefore, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response (CER) procedure. A flashing light was used as the conditioned stimulus (CS), and conditioned suppression was used to index conditioned fear. In experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin before CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls but could not be detected in picrotoxin-infused rats because of the low level of fear conditioning to the CS. In experiment 2, VH picrotoxin infusions only before CS pre-exposure did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect a disruption of neural processing both within the hippocampus and in projection sites of the hippocampus.
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Ashby DM, Dias C, Aleksandrova LR, Lapish CC, Wang YT, Phillips AG. Disruption of Long-Term Depression Potentiates Latent Inhibition: Key Role for Central Nucleus of the Amygdala. Int J Neuropsychopharmacol 2021; 24:580-591. [PMID: 33693669 PMCID: PMC8299826 DOI: 10.1093/ijnp/pyab011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/19/2021] [Accepted: 03/05/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Latent inhibition (LI) reflects an adaptive form of learning impaired in certain forms of mental illness. Glutamate receptor activity is linked to LI, but the potential role of synaptic plasticity remains unspecified. METHODS Accordingly, the present study examined the possible role of long-term depression (LTD) in LI induced by prior exposure of rats to an auditory stimulus used subsequently as a conditional stimulus to signal a pending footshock. We employed 2 mechanistically distinct LTD inhibitors, the Tat-GluA23Y peptide that blocks endocytosis of the GluA2-containing glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, or the selective glutamate n-methyl-d-aspartate receptor 2B antagonist, Ro25-6981, administered prior to the acquisition of 2-way conditioned avoidance with or without tone pre-exposure. RESULTS Systemic LTD blockade with the Tat-GluA23Y peptide strengthened the LI effect by further impairing acquisition of conditioned avoidance in conditional stimulus-preexposed rats compared with normal conditioning in non-preexposed controls. Systemic Ro25-6981 had no significant effects. Brain region-specific microinjections of the Tat-GluA23Y peptide into the nucleus accumbens, medial prefrontal cortex, or central or basolateral amygdala demonstrated that disruption of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis in the central amygdala also potentiated the LI effect. CONCLUSIONS These data revealed a previously unknown role for central amygdala LTD in LI as a key mediator of cognitive flexibility required to respond to previously irrelevant stimuli that acquire significance through reinforcement. The findings may have relevance both for our mechanistic understanding of LI and its alteration in disease states such as schizophrenia, while further elucidating the role of LTD in learning and memory.
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Affiliation(s)
- Donovan M Ashby
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Carine Dias
- Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
| | - Lily R Aleksandrova
- Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Christopher C Lapish
- Department of Psychology, Indiana University - Purdue University Indianapolis, Indianapolis, IN, United States
| | - Yu Tian Wang
- Department of Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
| | - Anthony G Phillips
- Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
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Szkudlarek HJ, Rodríguez-Ruiz M, Hudson R, De Felice M, Jung T, Rushlow WJ, Laviolette SR. THC and CBD produce divergent effects on perception and panic behaviours via distinct cortical molecular pathways. Prog Neuropsychopharmacol Biol Psychiatry 2021; 104:110029. [PMID: 32623021 DOI: 10.1016/j.pnpbp.2020.110029] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/12/2020] [Accepted: 06/21/2020] [Indexed: 12/17/2022]
Abstract
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.
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Affiliation(s)
- Hanna J Szkudlarek
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
| | - Mar Rodríguez-Ruiz
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Roger Hudson
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Marta De Felice
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Tony Jung
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Walter J Rushlow
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Psychiatry. Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada
| | - Steven R Laviolette
- Addiction Research Group, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada; Department of Psychiatry. Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.
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12
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Granger KT, Ferrar J, Caswell S, Haselgrove M, Moran PM, Attwood A, Barnett JH. Effects of 7.5% Carbon Dioxide and Nicotine Administration on Latent Inhibition. Front Psychiatry 2021; 12:582745. [PMID: 33935819 PMCID: PMC8085318 DOI: 10.3389/fpsyt.2021.582745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 02/05/2021] [Indexed: 12/01/2022] Open
Abstract
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.
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Affiliation(s)
- Kiri T Granger
- Cambridge Cognition, Cambridge, United Kingdom.,School of Psychology, University of Nottingham, Nottingham, United Kingdom.,Monument Therapeutics, Cambridge, United Kingdom
| | - Jennifer Ferrar
- Cambridge Cognition, Cambridge, United Kingdom.,Alcohol & Tobacco Research Group, University of Bristol, Bristol, United Kingdom
| | - Sheryl Caswell
- Cambridge Cognition, Cambridge, United Kingdom.,Monument Therapeutics, Cambridge, United Kingdom
| | - Mark Haselgrove
- School of Psychology, University of Nottingham, Nottingham, United Kingdom
| | - Paula M Moran
- School of Psychology, University of Nottingham, Nottingham, United Kingdom
| | - Angela Attwood
- Alcohol & Tobacco Research Group, University of Bristol, Bristol, United Kingdom
| | - Jennifer H Barnett
- Cambridge Cognition, Cambridge, United Kingdom.,Monument Therapeutics, Cambridge, United Kingdom.,Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
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13
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Burch GSJ, Hemsley DR, Pavelis C, Corr PJ. Personality, creativity and latent inhibition. EUROPEAN JOURNAL OF PERSONALITY 2020. [DOI: 10.1002/per.572] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The current study set out to investigate the relationship between creativity, multi‐dimensional schizotypy and personality more generally. This was achieved by analysing scores on a range of personality scales and measures of creativity, where it was found that the creativity measures were more closely related to asocial‐schizotypy than positive‐schizotypy. The study also sought to test Eysenck's prediction (1993, 1995) that, given the putative relationship between creativity and psychosis‐proneness, high psychosis‐prone scoring individuals and high creativity scoring individuals would demonstrate the same cognitive style of ‘overinclusiveness’ on latent inhibition. However, the results failed to demonstrate any evidence of a shared ‘widening of the associative horizon’ between high creativity and high psychosis‐prone scorers. The findings are discussed in relation to multi‐dimensional schizotypy. Copyright © 2006 John Wiley & Sons, Ltd.
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Affiliation(s)
- Giles St J. Burch
- Department of Management and Employment Relations, The University of Auckland Business School, New Zealand
- Department of Psychology, Institute of Psychiatry, King's College London, UK
| | - David R. Hemsley
- Department of Psychology, Institute of Psychiatry, King's College London, UK
| | - Christos Pavelis
- Department of Psychology, Goldsmiths College, University of London, UK
| | - Philip J. Corr
- Department of Psychology, University of Wales Swansea, UK
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14
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Granger KT, Talwar A, Barnett JH. Latent inhibition and its potential as a biomarker for schizophrenia. Biomark Neuropsychiatry 2020. [DOI: 10.1016/j.bionps.2020.100025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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15
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Cortico-Hippocampal Computational Modeling Using Quantum Neural Networks to Simulate Classical Conditioning Paradigms. Brain Sci 2020; 10:brainsci10070431. [PMID: 32645988 PMCID: PMC7407954 DOI: 10.3390/brainsci10070431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/26/2020] [Accepted: 07/03/2020] [Indexed: 11/16/2022] Open
Abstract
Most existing cortico-hippocampal computational models use different artificial neural network topologies. These conventional approaches, which simulate various biological paradigms, can get slow training and inadequate conditioned responses for two reasons: increases in the number of conditioned stimuli and in the complexity of the simulated biological paradigms in different phases. In this paper, a cortico-hippocampal computational quantum (CHCQ) model is proposed for modeling intact and lesioned systems. The CHCQ model is the first computational model that uses the quantum neural networks for simulating the biological paradigms. The model consists of two entangled quantum neural networks: an adaptive single-layer feedforward quantum neural network and an autoencoder quantum neural network. The CHCQ model adaptively updates all the weights of its quantum neural networks using quantum instar, outstar, and Widrow–Hoff learning algorithms. Our model successfully simulated several biological processes and maintained the output-conditioned responses quickly and efficiently. Moreover, the results were consistent with prior biological studies.
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16
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Aberg KC, Kramer EE, Schwartz S. Neurocomputational correlates of learned irrelevance in humans. Neuroimage 2020; 213:116719. [PMID: 32156624 DOI: 10.1016/j.neuroimage.2020.116719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 02/24/2020] [Accepted: 03/06/2020] [Indexed: 01/12/2023] Open
Abstract
Inappropriate behaviors may result from acquiring maladaptive associations between irrelevant information in the environment and important events, such as reward or punishment. Pre-exposure effects are believed to prevent the expression of irrelevant associations. For example, learned irrelevance delays the expression of associations between conditioned (CS) and unconditioned (US) stimuli following their uncorrelated presentation. The neuronal substrates of pre-exposure effects in humans are largely unknown because these effects rapidly attenuate when using traditional pre-exposure paradigms. The latter are therefore incompatible with neuroimaging approaches that require many trial repetitions. Moreover, large methodological differences between animal and human research on pre-exposure effects challenge the presumption of shared neurocognitive substrates, and question the prevalent use of pre-exposure effects in animals to model symptoms of human mental disorders. To overcome these limitations, we combined a novel learned irrelevance task with model-based fMRI. We report the results of a model that describes learned irrelevance as a dynamic process, which evolves across trials and integrates the weighting between two state-action values pertaining to 'CS-no US' associations (acquired during pre-exposure) and 'CS-US' associations (acquired during subsequent conditioning). This relative weighting correlated i) positively with the learned irrelevance effect observed in the behavioral task, ii) positively with activity in the entorhinal cortex, and iii) negatively with activity in the nucleus accumbens (NAcc). Furthermore, the model updates the relative weighting of the two state-action values via two separate prediction error (PE) signals that allow the dynamic accumulation of evidence for the CS to predict the 'US' or a 'no US' outcome. One PE signal, designed to increase the relative weight of 'CS-US' associations following 'US' outcomes, correlated with activity in the NAcc, while another PE signal, designed to increase the relative weight of 'CS-no US' associations following 'no US' outcomes, correlated with activity in the basolateral amygdala. By extending previous animal observations to humans, the present study provides a novel approach to foster translational research on pre-exposure effects.
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Affiliation(s)
| | - Emily Elizabeth Kramer
- Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Sophie Schwartz
- Department of Neuroscience, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Swiss Center for Affective Sciences, University of Geneva, Geneva, Switzerland; Geneva Neuroscience Center, University of Geneva, Geneva, Switzerland
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17
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Green model to adapt classical conditioning learning in the hippocampus. Neuroscience 2020; 426:201-219. [PMID: 31812493 DOI: 10.1016/j.neuroscience.2019.11.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/27/2022]
Abstract
Compared with the biological paradigms of classical conditioning, non-adaptive computational models are not capable of realistically simulating the biological behavioural functions of the hippocampal regions, because of their implausible requirement for a large number of learning trials, which can be on the order of hundreds. Additionally, these models did not attain a unified, final stable state even after hundreds of learning trials. Conversely, the output response has a different threshold for similar tasks in various models with prolonged transient response of unspecified status via the training or even testing phases. Accordingly, a green model is a combination of adaptive neuro-computational hippocampal and cortical models that is proposed by adaptively updating the whole weights in all layers for both intact networks and lesion networks using instar and outstar learning rules with adaptive resonance theory (ART). The green model sustains and expands the classical conditioning biological paradigms of the non-adaptive models. The model also overcomes the irregular output response behaviour by using the proposed feature of adaptivity. Further, the model successfully simulates the hippocampal regions without passing the final output response back to the whole network, which is considered to be biologically implausible. The results of the Green model showed a significant improvement confirmed by empirical studies of different tasks. In addition, the results indicated that the model outperforms the previously published models. All the obtained results successfully and quickly attained a stable, desired final state (with a unified concluding state of either "1" or "0") with a significantly shorter transient duration.
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18
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Radulescu A, Niv Y. State representation in mental illness. Curr Opin Neurobiol 2019; 55:160-166. [PMID: 31051434 DOI: 10.1016/j.conb.2019.03.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 03/10/2019] [Accepted: 03/25/2019] [Indexed: 10/26/2022]
Abstract
Reinforcement learning theory provides a powerful set of computational ideas for modeling human learning and decision making. Reinforcement learning algorithms rely on state representations that enable efficient behavior by focusing only on aspects relevant to the task at hand. Forming such representations often requires selective attention to the sensory environment, and recalling memories of relevant past experiences. A striking range of psychiatric disorders, including bipolar disorder and schizophrenia, involve changes in these cognitive processes. We review and discuss evidence that these changes can be cast as altered state representation, with the goal of providing a useful transdiagnostic dimension along which mental disorders can be understood and compared.
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Affiliation(s)
| | - Yael Niv
- Psychology Department, Princeton University, United States; Princeton Neuroscience Institute, Princeton University, United States
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19
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Yau JOY, McNally GP. Rules for aversive learning and decision-making. Curr Opin Behav Sci 2019. [DOI: 10.1016/j.cobeha.2018.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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20
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Nelson AJD, Powell AL, Kinnavane L, Aggleton JP. Anterior thalamic nuclei, but not retrosplenial cortex, lesions abolish latent inhibition in rats. Behav Neurosci 2018; 132:378-387. [PMID: 30321027 PMCID: PMC6188468 DOI: 10.1037/bne0000265] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The present study examined the effects of excitotoxic lesions in 2 closely related structures, the anterior thalamic nuclei and the retrosplenial cortex, on latent inhibition. Latent inhibition occurs when nonreinforced preexposure to a stimulus retards the subsequent acquisition of conditioned responding to that stimulus. Latent inhibition was assessed in a within-subject procedure with auditory stimuli and food reinforcement. As expected, sham-operated animals were slower to acquire conditioned responding to a stimulus that had previously been experienced without consequence, relative to a non-preexposed stimulus. This latent inhibition effect was absent in rats with excitotoxic lesions in the anterior thalamic nuclei, as these animals conditioned to both stimuli at equivalent rates. The retrosplenial lesions appeared to spare latent inhibition, as these animals displayed a robust stimulus preexposure effect. The demonstration here that anterior thalamic nuclei lesions abolish latent inhibition is consistent with emerging evidence of the importance of these thalamic nuclei for attentional control. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
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21
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Khokhar JY, Todd TP. Behavioral predictors of alcohol drinking in a neurodevelopmental rat model of schizophrenia and co-occurring alcohol use disorder. Schizophr Res 2018; 194:91-97. [PMID: 28285734 PMCID: PMC5591749 DOI: 10.1016/j.schres.2017.02.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 02/24/2017] [Accepted: 02/27/2017] [Indexed: 12/31/2022]
Abstract
Alcohol use disorder commonly occurs in patients with schizophrenia and contributes greatly to its morbidity. Unfortunately, the neural and behavioral underpinnings of alcohol drinking in these patients are not well understood. In order to begin to understand the cognitive and reward-related changes that may contribute to alcohol drinking, this study was designed to address: 1) latent inhibition; 2) conditioning; and 3) extinction of autoshaping in a neurodevelopmental rat model with relevance to co-occurring schizophrenia and alcohol use disorders, the neonatal ventral hippocampal lesioned (NVHL) rat. NVHL lesions (or sham surgeries) were performed on post-natal day 7 (PND7) and animals were given brief exposure to alcohol during adolescent (PND 28-42). Latent inhibition of autoshaping, conditioning and extinction were assessed between PND 72-90. On PND90 animals were given alcohol again and allowed to establish stable drinking. Latent inhibition of autoshaping was found to be prolonged in the NVHL rats; the NVHL rats pre-exposed to the lever stimulus were slower to acquire autoshaping than sham pre-exposed rats. NVHL rats that were not pre-exposed to the lever stimulus did not differ during conditioning, but were slower to extinguish conditioned responding compared to sham controls. Finally, the NVHL rats from both groups drank significantly more alcohol than sham rats, and the extent of latent inhibition predicted future alcohol intake in the pre-exposed animals. These findings suggest that the latent inhibition of autoshaping procedure can be used to model cognitive- and reward-related dysfunctions in schizophrenia, and these dysfunctions may contribute to the development of co-occurring alcohol use.
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Affiliation(s)
- Jibran Y Khokhar
- Department of Psychiatry, Geisel School of Medicine at Dartmouth, United States.
| | - Travis P Todd
- Department of Psychological and Brain Sciences, Dartmouth College, United States
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22
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Robicsek O, Ene HM, Karry R, Ytzhaki O, Asor E, McPhie D, Cohen BM, Ben-Yehuda R, Weiner I, Ben-Shachar D. Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia-Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder. Schizophr Bull 2018; 44:432-442. [PMID: 28586483 PMCID: PMC5814822 DOI: 10.1093/schbul/sbx077] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Dysfunction of mitochondria, key players in various essential cell processes, has been repeatedly reported in schizophrenia (SZ). Recently, several studies have reported functional recovery and cellular viability following mitochondrial transplantation, mostly in ischemia experimental models. Here, we aimed to demonstrate beneficial effects of isolated active normal mitochondria (IAN-MIT) transfer in vitro and in vivo, using SZ-derived induced pluripotent stem cells (iPSCs) differentiating into glutamatergic neuron, as well as a rodent model of SZ. First, we show that IAN-MIT enter various cell types without manipulation. Next, we show that IAN-MIT transfer into SZ-derived lymphoblasts induces long-lasting improvement in various mitochondrial functions including cellular oxygen consumption and mitochondrial membrane potential (Δ ψ m). We also demonstrate improved differentiation of SZ-derived iPSCs into neurons, by increased expression of neuronal and glutamatergic markers β3-tubulin, synapsin1, and Tbr1 and by an activation of the glutamate-glutamine cycle. In the animal model, we show that intra-prefrontal cortex injection of IAN-MIT in adolescent rats exposed prenatally to a viral mimic prevents mitochondrial Δ ψ m and attentional deficit at adulthood. Our results provide evidence for a direct link between mitochondrial function and SZ-related deficits both in vitro and in vivo and suggest a therapeutic potential for IAN-MIT transfer in diseases with bioenergetic and neurodevelopmental abnormalities such as SZ.
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Affiliation(s)
- Odile Robicsek
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, Haifa, Israel
| | - Hila M Ene
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, Haifa, Israel
| | - Rachel Karry
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, Haifa, Israel
| | - Ofer Ytzhaki
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, Haifa, Israel
| | - Eyal Asor
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, Haifa, Israel
| | - Donna McPhie
- Department of Psychiatry, Harvard Medical School, Boston, McLean Hospital, Belmont, MA
| | - Bruce M Cohen
- Department of Psychiatry, Harvard Medical School, Boston, McLean Hospital, Belmont, MA
| | - Rotem Ben-Yehuda
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ina Weiner
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel,Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Dorit Ben-Shachar
- Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus, B. Rappaport Faculty of Medicine and Rappaport Family Institute for Research in Medical Sciences, Technion IIT, Haifa, Israel,To whom correspondence should be addressed; Laboratory of Psychobiology, Department of Psychiatry, Rambam Health Care Campus and B. Rappaport Faculty of Medicine, Technion ITT, POB 9649, Haifa 31096, Israel; tel: +972-4-8295224, fax: +972-4-8295220, e-mail:
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23
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Abdominal Vagal Afferents Modulate the Brain Transcriptome and Behaviors Relevant to Schizophrenia. J Neurosci 2018; 38:1634-1647. [PMID: 29326171 DOI: 10.1523/jneurosci.0813-17.2017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 11/25/2017] [Accepted: 12/18/2017] [Indexed: 12/26/2022] Open
Abstract
Reduced activity of vagal efferents has long been implicated in schizophrenia and appears to be responsible for diminished parasympathetic activity and associated peripheral symptoms such as low heart rate variability and cardiovascular complications in affected individuals. In contrast, only little attention has been paid to the possibility that impaired afferent vagal signaling may be relevant for the disorder's pathophysiology as well. The present study explored this hypothesis using a model of subdiaphragmatic vagal deafferentation (SDA) in male rats. SDA represents the most complete and selective vagal deafferentation method existing to date as it leads to complete disconnection of all abdominal vagal afferents while sparing half of the abdominal vagal efferents. Using next-generation mRNA sequencing, we show that SDA leads to brain transcriptional changes in functional networks annotating with schizophrenia. We further demonstrate that SDA induces a hyperdopaminergic state, which manifests itself as increased sensitivity to acute amphetamine treatment and elevated accumbal levels of dopamine and its major metabolite, 3,4-dihydroxyphenylacetic acid. Our study also shows that SDA impairs sensorimotor gating and the attentional control of associative learning, which were assessed using the paradigms of prepulse inhibition and latent inhibition, respectively. These data provide converging evidence suggesting that the brain transcriptome, dopamine neurochemistry, and behavioral functions implicated in schizophrenia are subject to visceral modulation through abdominal vagal afferents. Our findings may encourage the further establishment and use of therapies for schizophrenia that are based on vagal interventions.SIGNIFICANCE STATEMENT The present work provides a better understanding of how disrupted vagal afferent signaling can contribute to schizophrenia-related brain and behavioral abnormalities. More specifically, it shows that subdiaphragmatic vagal deafferentation (SDA) in rats leads to (1) brain transcriptional changes in functional networks related to schizophrenia, (2) increased sensitivity to dopamine-stimulating drugs and elevated dopamine levels in the nucleus accumbens, and (3) impairments in sensorimotor gating and the attentional control of associative learning. These findings may encourage the further establishment of novel therapies for schizophrenia that are based on vagal interventions.
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24
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Pérez-Díaz F, Díaz E, Sánchez N, Vargas JP, Pearce JM, López JC. Different involvement of medial prefrontal cortex and dorso-lateral striatum in automatic and controlled processing of a future conditioned stimulus. PLoS One 2017; 12:e0189630. [PMID: 29240804 PMCID: PMC5730208 DOI: 10.1371/journal.pone.0189630] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/29/2017] [Indexed: 11/30/2022] Open
Abstract
Recent studies support the idea that stimulus processing in latent inhibition can vary during the course of preexposure. Controlled attentional mechanisms are said to be important in the early stages of preexposure, while in later stages animals adopt automatic processing of the stimulus to be used for conditioning. Given this distinction, it is possible that both types of processing are governed by different neural systems, affecting differentially the retrieval of information about the stimulus. In the present study we tested if a lesion to the dorso-lateral striatum or to the medial prefrontal cortex has a selective effect on exposure to the future conditioned stimulus (CS). With this aim, animals received different amounts of exposure to the future CS. The results showed that a lesion to the medial prefrontal cortex enhanced latent inhibition in animals receiving limited preexposure to the CS, but had no effect in animals receiving extended preexposure to the CS. The lesion of the dorso-lateral striatum produced a decrease in latent inhibition, but only in animals with an extended exposure to the future conditioned stimulus. These results suggest that the dorsal striatum and medial prefrontal cortex play essential roles in controlled and automatic processes. Automatic attentional processes appear to be impaired by a lesion to the dorso-lateral striatum and facilitated by a lesion to the prefrontal cortex.
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Affiliation(s)
- Francisco Pérez-Díaz
- Animal Behav & Neurosci Lab, Dpt. Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, Seville, Spain
| | - Estrella Díaz
- Animal Behav & Neurosci Lab, Dpt. Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, Seville, Spain
| | - Natividad Sánchez
- Animal Behav & Neurosci Lab, Dpt. Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, Seville, Spain
| | - Juan Pedro Vargas
- Animal Behav & Neurosci Lab, Dpt. Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, Seville, Spain
| | - John M. Pearce
- School of Psychology, Cardiff University, Cardiff, Wales, United Kingdom
- School of Psychology, University of Sydney, Sydney, Australia
| | - Juan Carlos López
- Animal Behav & Neurosci Lab, Dpt. Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, Seville, Spain
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25
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Herrmann AP, Andrejew R, Benvenutti R, Gama CS, Elisabetsky E. Effects of N-acetylcysteine on amphetamine-induced sensitization in mice. ACTA ACUST UNITED AC 2017; 40:169-173. [PMID: 29236922 PMCID: PMC6900759 DOI: 10.1590/1516-4446-2017-2337] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/11/2017] [Indexed: 12/20/2022]
Abstract
Objective: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. Methods: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. Results: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. Conclusion: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.
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Affiliation(s)
- Ana P Herrmann
- Grupo de Estudos Biológicos e Clínicos em Patologias Humanas, Universidade Federal da Fronteira Sul (UFFS), Chapecó, SC, Brazil.,Programa de Pós-Graduação em Ciências Biológicas, Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Roberta Andrejew
- Programa de Pós-Graduação em Ciências Biológicas, Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | | | - Clarissa S Gama
- Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.,Programa de Pós-Graduação em Psiquiatria e Ciências do Comportamento, UFRGS, Porto Alegre, RS, Brazil
| | - Elaine Elisabetsky
- Programa de Pós-Graduação em Ciências Biológicas, Bioquímica, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
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26
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Buhusi M, Brown CK, Buhusi CV. Impaired Latent Inhibition in GDNF-Deficient Mice Exposed to Chronic Stress. Front Behav Neurosci 2017; 11:177. [PMID: 29066960 PMCID: PMC5641315 DOI: 10.3389/fnbeh.2017.00177] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 09/07/2017] [Indexed: 12/14/2022] Open
Abstract
Increased reactivity to stress is maladaptive and linked to abnormal behaviors and psychopathology. Chronic unpredictable stress (CUS) alters catecholaminergic neurotransmission and remodels neuronal circuits involved in learning, attention and decision making. Glial-derived neurotrophic factor (GDNF) is essential for the physiology and survival of dopaminergic neurons in substantia nigra and of noradrenergic neurons in the locus coeruleus. Up-regulation of GDNF expression during stress is linked to resilience; on the other hand, the inability to up-regulate GDNF in response to stress, as a result of either genetic or epigenetic modifications, induces behavioral alterations. For example, GDNF-deficient mice exposed to chronic stress exhibit alterations of executive function, such as increased temporal discounting. Here we investigated the effects of CUS on latent inhibition (LI), a measure of selective attention and learning, in GDNF-heterozygous (HET) mice and their wild-type (WT) littermate controls. No differences in LI were found between GDNF HET and WT mice under baseline experimental conditions. However, following CUS, GDNF-deficient mice failed to express LI. Moreover, stressed GDNF-HET mice, but not their WT controls, showed decreased neuronal activation (number of c-Fos positive neurons) in the nucleus accumbens shell and increased activation in the nucleus accumbens core, both key regions in the expression of LI. Our results add LI to the list of behaviors affected by chronic stress and support a role for GDNF deficits in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.
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Affiliation(s)
- Mona Buhusi
- Interdisciplinary Program in Neuroscience, Department of Psychology, Utah State University, Logan, UT, United States
| | - Colten K Brown
- Interdisciplinary Program in Neuroscience, Department of Psychology, Utah State University, Logan, UT, United States
| | - Catalin V Buhusi
- Interdisciplinary Program in Neuroscience, Department of Psychology, Utah State University, Logan, UT, United States
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27
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An examination of the roles of glutamate and sex in latent inhibition: Relevance to the glutamate hypothesis of schizophrenia? Psychiatry Res 2017. [PMID: 28623767 DOI: 10.1016/j.psychres.2017.06.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The present study examined the effects of the glutamate receptor antagonist MK-801, the glutamate receptor agonist N-methyl-D-aspartate (NMDA), and sexual dimorphism on latent inhibition to elucidate the glutamate hypothesis of schizophrenia. During the pre-exposure phase, 56 male and 65 female Wistar rats were intracerebroventricularly administered normal saline, MK-801 or NMDA, in the left ventricle and then exposed to a passive avoidance box (or a different context) in three trials over 3 days. Then, all of the rats were placed in the light compartment of the passive avoidance box and were allowed to enter the dark compartment, where they each received a footshock (1mA, 2s) in five trials over 5 days. Injections of the glutamate drugs NMDA and MK-801 did not affect latent inhibition. Sexual dimorphism did not occur in latent inhibition. The present data on the male rats indicated that the glutamate system did not affect latent inhibition, indicating that the glutamate system was not like the dopamine system in terms of mediating the positive symptoms of schizophrenia. The glutamate system might be involved in the negative and cognitive symptoms of schizophrenia. The results may provide information for novel treatments of the negative and cognitive symptoms of schizophrenia.
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28
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Mingote S, Chuhma N, Kalmbach A, Thomsen GM, Wang Y, Mihali A, Sferrazza C, Zucker-Scharff I, Siena AC, Welch MG, Lizardi-Ortiz J, Sulzer D, Moore H, Gaisler-Salomon I, Rayport S. Dopamine neuron dependent behaviors mediated by glutamate cotransmission. eLife 2017; 6. [PMID: 28703706 PMCID: PMC5599237 DOI: 10.7554/elife.27566] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 07/06/2017] [Indexed: 12/11/2022] Open
Abstract
Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.
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Affiliation(s)
- Susana Mingote
- Department of Psychiatry, Columbia University, New York, United States.,Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States
| | - Nao Chuhma
- Department of Psychiatry, Columbia University, New York, United States.,Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States
| | - Abigail Kalmbach
- Department of Psychiatry, Columbia University, New York, United States.,Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States
| | | | - Yvonne Wang
- Department of Psychiatry, Columbia University, New York, United States
| | - Andra Mihali
- Department of Psychiatry, Columbia University, New York, United States
| | | | | | - Anna-Claire Siena
- Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States
| | - Martha G Welch
- Department of Psychiatry, Columbia University, New York, United States.,Department of Pediatrics, Columbia University, New York, United States.,Department of Developmental Neuroscience, NYS Psychiatric Institute, New York, United States
| | | | - David Sulzer
- Department of Psychiatry, Columbia University, New York, United States.,Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States.,Department of Neurology, Columbia University, New York, United States.,Department of Pharmacology, Columbia University, New York, United States
| | - Holly Moore
- Department of Psychiatry, Columbia University, New York, United States.,Department of Integrative Neuroscience, NYS Psychiatric Institute, New York, United States
| | - Inna Gaisler-Salomon
- Department of Psychiatry, Columbia University, New York, United States.,Department of Psychology, University of Haifa, Haifa, Israel
| | - Stephen Rayport
- Department of Psychiatry, Columbia University, New York, United States.,Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, United States
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29
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Hadar R, Dong L, Del-Valle-Anton L, Guneykaya D, Voget M, Edemann-Callesen H, Schweibold R, Djodari-Irani A, Goetz T, Ewing S, Kettenmann H, Wolf SA, Winter C. Deep brain stimulation during early adolescence prevents microglial alterations in a model of maternal immune activation. Brain Behav Immun 2017; 63:71-80. [PMID: 27939248 DOI: 10.1016/j.bbi.2016.12.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/23/2016] [Accepted: 12/05/2016] [Indexed: 11/25/2022] Open
Abstract
In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease.
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Affiliation(s)
- Ravit Hadar
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universitaet Dresden, Germany
| | - Le Dong
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Lucia Del-Valle-Anton
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Dilansu Guneykaya
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Mareike Voget
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universitaet Dresden, Germany; International Graduate Program Medical Neurosciences, Charité - Universitaetsmedizin Berlin, Germany
| | - Henriette Edemann-Callesen
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universitaet Dresden, Germany; International Graduate Program Medical Neurosciences, Charité - Universitaetsmedizin Berlin, Germany
| | - Regina Schweibold
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Anais Djodari-Irani
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Thomas Goetz
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universitaet Dresden, Germany
| | - Samuel Ewing
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universitaet Dresden, Germany
| | - Helmut Kettenmann
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Susanne A Wolf
- Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
| | - Christine Winter
- Department of Psychiatry and Psychotherapy, Medical Faculty Carl Gustav Carus, Technische Universitaet Dresden, Germany
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Navarro SV, Alvarez R, Colomina MT, Sanchez-Santed F, Flores P, Moreno M. Behavioral Biomarkers of Schizophrenia in High Drinker Rats: A Potential Endophenotype of Compulsive Neuropsychiatric Disorders. Schizophr Bull 2017; 43:778-787. [PMID: 27872269 PMCID: PMC5472118 DOI: 10.1093/schbul/sbw141] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%-20% of chronic psychiatric patients and frequently associated with the schizophrenia diagnosis. In the present study, we investigated the relation between schizophrenia-like symptoms and biomarkers with a compulsive drinking behavior phenotype in rats. Rats that were selected for low drinking vs high drinking behavior following schedule-induced polydipsia (SIP) were assessed in a latent inhibition (LI) paradigm using tone and electrical foot shock and in a spatial reversal learning task to evaluate behavioral inflexibility. We also analyzed the myelin basic protein in different brain areas of high drinker (HD) and low drinker (LD) rats. The HD rats, which were characterized by a compulsive drinking behavior on SIP, had a reduced level of LI effect and increased behavioral inflexibility in the spatial reversal learning task in comparison to the LD group. Moreover, HD rats showed less myelination in the center of the corpus callosum, striatum, and amygdala in comparison to LD rats. These findings strengthen the validity of HD rats that were selected by SIP as a possible phenotype of compulsive neuropsychiatric disorders, as evidenced by the existence of behaviors and biological markers that are related to schizophrenia and obsessive-compulsive disorder, including a reduced LI effect, behavioral inflexibility and reduced brain myelination. Future studies could contribute to the elucidation of the mechanisms underlying the compulsive phenotype of HD rats and its relation to vulnerability to schizophrenia.
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Affiliation(s)
- Silvia V. Navarro
- Department of Psychology, University of Almería, Campus de Excelencia Internacional Agroalimentario (CEIA3), Almería, Spain
| | - Roberto Alvarez
- Department of Psychology, University of Almería, Campus de Excelencia Internacional Agroalimentario (CEIA3), Almería, Spain
| | - M. Teresa Colomina
- Department of Psychology and Research Center for Behavior Assessment (CRAMC), Universitat Rovira i Virgili, Tarragona, Spain;,Research in Neurobehavior and Health (NEUROLAB), Universitat Rovira i Virgili, Tarragona, Spain
| | - Fernando Sanchez-Santed
- Department of Psychology, University of Almería, Campus de Excelencia Internacional Agroalimentario (CEIA3), Almería, Spain
| | - Pilar Flores
- Department of Psychology, University of Almería, Campus de Excelencia Internacional Agroalimentario (CEIA3), Almería, Spain
| | - Margarita Moreno
- Department of Psychology, University of Almería, Campus de Excelencia Internacional Agroalimentario (CEIA3), Almería, Spain
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31
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Immune activation in lactating dams alters sucklings' brain cytokines and produces non-overlapping behavioral deficits in adult female and male offspring: A novel neurodevelopmental model of sex-specific psychopathology. Brain Behav Immun 2017; 63:35-49. [PMID: 28189716 DOI: 10.1016/j.bbi.2017.01.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 12/26/2016] [Accepted: 01/23/2017] [Indexed: 01/04/2023] Open
Abstract
Early immune activation (IA) in rodents, prenatal through the mother or early postnatal directly to the neonate, is widely used to produce behavioral endophenotypes relevant to schizophrenia and depression. Given that maternal immune response plays a crucial role in the deleterious effects of prenatal IA, and lactation is a critical vehicle of immunological support to the neonate, we predicted that immune activation of the lactating dam will produce long-term abnormalities in the sucklings. Nursing dams were injected on postnatal day 4 with the viral mimic poly-I:C (4mg/kg) or saline. Cytokine assessment was performed in dams' plasma and milk 2h, and in the sucklings' hippocampus, 6h and 24h following poly-I:C injection. Male and female sucklings were assessed in adulthood for: a) performance on behavioral tasks measuring constructs considered relevant to schizophrenia (selective attention and executive control) and depression (despair and anhedonia); b) response to relevant pharmacological treatments; c) brain structural changes. Maternal poly-I:C injection caused cytokine alterations in the dams' plasma and milk, as well as in the sucklings' hippocampus. Lactational poly-I:C exposure led to sex-dimorphic (non-overlapping) behavioral abnormalities in the adult offspring, with male but not female offspring exhibiting attentional and executive function abnormalities (manifested in persistent latent inhibition and slow reversal) and hypodopaminergia, and female but not male offspring exhibiting despair and anhedonia (manifested in increased immobility in the forced swim test and reduced saccharine preference) and hyperdopaminergia, mimicking the known sex-bias in schizophrenia and depression. The behavioral double-dissociation predicted distinct pharmacological profiles, recapitulating the pharmacology of negative/cognitive symptoms and depression. In-vivo imaging revealed hippocampal and striatal volume reductions in both sexes, as found in both disorders. This is the first evidence for the emergence of long-term behavioral and brain abnormalities after lactational exposure to an inflammatory agent, supporting a causal link between early immune activation and disrupted neuropsychodevelopment. That such exposure produces schizophrenia- or depression-like phenotype depending on sex, resonates with notions that risk factors are transdiagnostic, and that sex is a susceptibility factor for neurodevelopmental psychopathologies.
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32
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Buhusi M, Obray D, Guercio B, Bartlett MJ, Buhusi CV. Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia. Behav Brain Res 2017. [PMID: 28647594 DOI: 10.1016/j.bbr.2017.06.033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the 'two-hit' theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a 'two-hit' (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments.
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Affiliation(s)
- Mona Buhusi
- Interdisciplinary Program in Neuroscience, USTAR BioInnovations Center, Dept. Psychology, Utah State University, Logan UT, United States.
| | - Daniel Obray
- Interdisciplinary Program in Neuroscience, USTAR BioInnovations Center, Dept. Psychology, Utah State University, Logan UT, United States
| | - Bret Guercio
- Interdisciplinary Program in Neuroscience, USTAR BioInnovations Center, Dept. Psychology, Utah State University, Logan UT, United States
| | - Mitchell J Bartlett
- Interdisciplinary Program in Neuroscience, USTAR BioInnovations Center, Dept. Psychology, Utah State University, Logan UT, United States
| | - Catalin V Buhusi
- Interdisciplinary Program in Neuroscience, USTAR BioInnovations Center, Dept. Psychology, Utah State University, Logan UT, United States
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33
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A conditioning model of delusion. Neurosci Biobehav Rev 2017; 80:223-239. [PMID: 28601666 DOI: 10.1016/j.neubiorev.2017.05.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 05/14/2017] [Accepted: 05/29/2017] [Indexed: 11/22/2022]
Abstract
"Delusions" are beliefs that are false and persistent. It is suggested here that these characteristics can emerge from interplays between two fundamental learning processes: (1) the allocation of attentional resources among stimuli; and (2) the effects of feedback on learning. The former of these has been operationalized in the learned irrelevance and latent inhibition paradigms; the latter in studies of the effects of persistence-training. Normally, the attentional process functions to constrain persistence-training effects so that only valid associations acquire persistence. But when persistence-training is less influenced in this way, its mechanisms can interact with a noisy environment to gradually insulate maladaptive associations from disconfirming feedback. When unchecked, these dynamics likely lead to a systematic distortion of beliefs that can become increasingly persistent regardless of their validity. Delusions are therefore predicted to tend to arise whenever the balance of (1) is weakened in favour of (2), whether by experimental manipulation, trait-related factors, cultural causes or evolutionary history. Existing evidence is consistent with the model and further implications are discussed.
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34
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Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia. Mol Psychiatry 2017; 23:943-951. [PMID: 28373685 PMCID: PMC5552352 DOI: 10.1038/mp.2017.52] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 02/07/2017] [Accepted: 02/10/2017] [Indexed: 12/18/2022]
Abstract
The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.
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35
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Rutkowski TP, Schroeder JP, Gafford GM, Warren ST, Weinshenker D, Caspary T, Mulle JG. Unraveling the genetic architecture of copy number variants associated with schizophrenia and other neuropsychiatric disorders. J Neurosci Res 2016; 95:1144-1160. [PMID: 27859486 DOI: 10.1002/jnr.23970] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 09/20/2016] [Accepted: 09/26/2016] [Indexed: 12/21/2022]
Abstract
Recent studies show that the complex genetic architecture of schizophrenia (SZ) is driven in part by polygenic components, or the cumulative effect of variants of small effect in many genes, as well as rare single-locus variants with large effect sizes. Here we discuss genetic aberrations known as copy number variants (CNVs), which fall in the latter category and are associated with a high risk for SZ and other neuropsychiatric disorders. We briefly review recurrent CNVs associated with SZ, and then highlight one CNV in particular, a recurrent 1.6-Mb deletion on chromosome 3q29, which is estimated to confer a 40-fold increased risk for SZ. Additionally, we describe the use of genetic mouse models, behavioral tools, and patient-derived induced pluripotent stem cells as a means to study CNVs in the hope of gaining mechanistic insight into their respective disorders. Taken together, the genomic data connecting CNVs with a multitude of human neuropsychiatric disease, our current technical ability to model such chromosomal anomalies in mouse, and the existence of precise behavioral measures of endophenotypes argue that the time is ripe for systematic dissection of the genetic mechanisms underlying such disease. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Timothy P Rutkowski
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Jason P Schroeder
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Georgette M Gafford
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Stephen T Warren
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - David Weinshenker
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Tamara Caspary
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Jennifer G Mulle
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.,Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
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36
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Griebel G, Pichat P, Boulay D, Naimoli V, Potestio L, Featherstone R, Sahni S, Defex H, Desvignes C, Slowinski F, Vigé X, Bergis OE, Sher R, Kosley R, Kongsamut S, Black MD, Varty GB. The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia. Sci Rep 2016; 6:35320. [PMID: 27734956 PMCID: PMC5062470 DOI: 10.1038/srep35320] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 09/28/2016] [Indexed: 12/25/2022] Open
Abstract
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
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Affiliation(s)
- Guy Griebel
- Sanofi R&D, Strategy, Science Policy &External Innovation, Chilly-Mazarin, France
| | - Philippe Pichat
- Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France
| | - Denis Boulay
- Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France
| | | | - Lisa Potestio
- Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA
| | | | | | - Henry Defex
- Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA
| | | | | | - Xavier Vigé
- Sanofi R&D, Translational Sciences Unit, Chilly-Mazarin, France
| | | | - Rosy Sher
- Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA
| | | | | | - Mark D Black
- Sanofi R&D, 1041 Route 202/206, Bridgewater, NJ, USA
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37
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Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm. Eur Arch Psychiatry Clin Neurosci 2016; 266:505-12. [PMID: 26404636 DOI: 10.1007/s00406-015-0643-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/07/2015] [Indexed: 12/18/2022]
Abstract
Schizophrenia (SZ) is a severe mental disorder affecting about 1 % of the human population. Patients show severe deficits in cognitive processing often characterized by an improper filtering of environmental stimuli. Independent genome-wide association studies confirmed a number of risk variants for SZ including several associated with the gene encoding the transcription factor 4 (TCF4). TCF4 is widely expressed in the central nervous system of mice and humans and seems to be important for brain development. Transgenic mice overexpressing murine Tcf4 (Tcf4tg) in the adult brain display cognitive impairments and sensorimotor gating disturbances. To address the question of whether increased Tcf4 gene dosage may affect cognitive flexibility in an auditory associative task, we tested latent inhibition (LI) in female Tcf4tg mice. LI is a widely accepted translational endophenotype of SZ and results from a maladaptive delay in switching a response to a previously unconditioned stimulus when this becomes conditioned. Using an Audiobox, we pre-exposed Tcf4tg mice and their wild-type littermates to either a 3- or a 12-kHz tone before conditioning them to a 12-kHz tone. Tcf4tg animals pre-exposed to a 12-kHz tone showed significantly delayed conditioning when the previously unconditioned tone became associated with an air puff. These results support findings that associate TCF4 dysfunction with cognitive inflexibility and improper filtering of sensory stimuli observed in SZ patients.
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38
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Meyer U, Yee BK, Feldon J. The Neurodevelopmental Impact of Prenatal Infections at Different Times of Pregnancy: The Earlier the Worse? Neuroscientist 2016; 13:241-56. [PMID: 17519367 DOI: 10.1177/1073858406296401] [Citation(s) in RCA: 191] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Environmental insults taking place in early brain development may have long-lasting consequences for adult brain functioning. There is a large body of epidemiological data linking maternal infections during pregnancy to a higher incidence of psychiatric disorders with a presumed neurodevelopmental origin in the offspring, including schizophrenia and autism. Although specific gestational windows may be associated with a differing vulnerability to infection-mediated disturbances in normal brain development, it still remains debatable whether and/or why certain gestation periods may confer maximal risk for neurodevelopmental disturbances following the prenatal exposure to infectious events. In this review, the authors integrate both epidemiological and experimental findings supporting the hypothesis that infection-associated immunological events in early fetal life may have a stronger neurodevelopmental impact compared to late pregnancy infections. This is because infections in early gestation may not only interfere with fundamental neurodevelopmental events such as cell proliferation and differentiation, but it may also predispose the developing nervous system to additional failures in subsequent cell migration, target selection, and synapse maturation, eventually leading to multiple brain and behavioral abnormalities in the adult offspring. The temporal dependency of the epidemiological link between maternal infections during pregnancy and a higher risk for brain disorders in the offspring may thus be explained by specific spatiotemporal events in the course of fetal brain development. NEUROSCIENTIST 13(3):241—256, 2007.
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Affiliation(s)
- Urs Meyer
- Laboratory of Behavioral Neurobiology, ETH Zurich, Switzerland
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39
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Waterhouse U, Roper VE, Brennan KA, Ellenbroek BA. Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats. Dis Model Mech 2016; 9:1159-1167. [PMID: 27483346 PMCID: PMC5087828 DOI: 10.1242/dmm.025072] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 05/04/2016] [Indexed: 12/22/2022] Open
Abstract
Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI).
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Affiliation(s)
- Uta Waterhouse
- School of Psychology, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
| | - Vic E Roper
- School of Psychology, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
| | - Katharine A Brennan
- School of Psychology, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
| | - Bart A Ellenbroek
- School of Psychology, Victoria University of Wellington, P.O. Box 600, Wellington 6140, New Zealand
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Feifel D, Shilling PD, Fazlinejad AA, Melendez G. Antipsychotic drug-like facilitation of latent inhibition by a brain-penetrating neurotensin-1 receptor agonist. J Psychopharmacol 2016; 30:312-7. [PMID: 26783230 DOI: 10.1177/0269881115625360] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Latent inhibition (LI) is a measure of cognitive gating and refers to reduced conditioned learning when there is pre-exposure to the conditioned stimulus (CS) before it is paired with the unconditioned stimulus (US). Dysregulation of LI is associated with some neuropsychiatric disorders, including schizophrenia, and the ability to facilitate LI in rodents is a reasonably good predictive test for antipsychotic drugs. Converging evidence supports neurotensin-1 receptor (NTS1) agonists as novel drugs for schizophrenia. Therefore, we investigated the ability of a brain-penetrating, selective NTS1 agonist, PD149163, to facilitate LI in heterozygous Brattleboro rats, a strain that exhibits naturally low LI. Conditioned taste aversion to flavored water (FW; 0.1% saccharin) was induced by pairing it with malaise-inducing injections of lithium chloride (LiCl). Prior to LiCl-FW pairing, rats received subcutaneous injections of saline, or PD149163 (100 µg/kg or 200 µg/kg). Half the rats in each drug group had been allowed to drink FW the day before the LiCl-FW pairing (pre-exposed rats). Two days after pairing, the amount of FW each rat consumed was recorded. LI, defined as significantly greater FW drinking in the pre-exposed group compared with the non pre-exposed group, was exhibited only among rats that received 200 µg/kg of PD149163. These results further support NTS1 agonists as potentially novel drugs for the treatment of schizophrenia.
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Affiliation(s)
- D Feifel
- Department of Psychiatry, University of California, San Diego, CA, USA
| | - P D Shilling
- Department of Psychiatry, University of California, San Diego, CA, USA
| | - A A Fazlinejad
- Department of Psychiatry, University of California, San Diego, CA, USA
| | - G Melendez
- Department of Psychiatry, University of California, San Diego, CA, USA
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Granger KT, Moran PM, Buckley MG, Haselgrove M. Enhanced latent inhibition in high schizotypy individuals. PERSONALITY AND INDIVIDUAL DIFFERENCES 2016. [DOI: 10.1016/j.paid.2015.11.040] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Vargas JP, Díaz E, Portavella M, López JC. Animal Models of Maladaptive Traits: Disorders in Sensorimotor Gating and Attentional Quantifiable Responses as Possible Endophenotypes. Front Psychol 2016; 7:206. [PMID: 26925020 PMCID: PMC4759263 DOI: 10.3389/fpsyg.2016.00206] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 02/03/2016] [Indexed: 11/24/2022] Open
Abstract
Traditional diagnostic scales are based on a number of symptoms to evaluate and classify mental diseases. In many cases, this process becomes subjective, since the patient must calibrate the magnitude of his/her symptoms and therefore the severity of his/her disorder. A completely different approach is based on the study of the more vulnerable traits of cognitive disorders. In this regard, animal models of mental illness could be a useful tool to characterize indicators of possible cognitive dysfunctions in humans. Specifically, several cognitive disorders such as schizophrenia involve a dysfunction in the mesocorticolimbic dopaminergic system during development. These variations in dopamine levels or dopamine receptor sensibility correlate with many behavioral disturbances. These behaviors may be included in a specific phenotype and may be analyzed under controlled conditions in the laboratory. The present study provides an introductory overview of different quantitative traits that could be used as a possible risk indicator for different mental disorders, helping to define a specific endophenotype. Specifically, we examine different experimental procedures to measure impaired response in attention linked to sensorimotor gating as a possible personality trait involved in maladaptive behaviors.
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Affiliation(s)
- Juan P Vargas
- Animal Behavior and Neuroscience Lab, Department of Experimental Psychology, Universidad de Sevilla Seville, Spain
| | - Estrella Díaz
- Animal Behavior and Neuroscience Lab, Department of Experimental Psychology, Universidad de Sevilla Seville, Spain
| | - Manuel Portavella
- Animal Behavior and Neuroscience Lab, Department of Experimental Psychology, Universidad de Sevilla Seville, Spain
| | - Juan C López
- Animal Behavior and Neuroscience Lab, Department of Experimental Psychology, Universidad de Sevilla Seville, Spain
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Treviño M. Associative Learning Through Acquired Salience. Front Behav Neurosci 2016; 9:353. [PMID: 26793078 PMCID: PMC4708076 DOI: 10.3389/fnbeh.2015.00353] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/04/2015] [Indexed: 11/29/2022] Open
Abstract
Most associative learning studies describe the salience of stimuli as a fixed learning-rate parameter. Presumptive saliency signals, however, have also been linked to motivational and attentional processes. An interesting possibility, therefore, is that discriminative stimuli could also acquire salience as they become powerful predictors of outcomes. To explore this idea, we first characterized and extracted the learning curves from mice trained with discriminative images offering varying degrees of structural similarity. Next, we fitted a linear model of associative learning coupled to a series of mathematical representations for stimulus salience. We found that the best prediction, from the set of tested models, was one in which the visual salience depended on stimulus similarity and a non-linear function of the associative strength. Therefore, these analytic results support the idea that the net salience of a stimulus depends both on the items' effective salience and the motivational state of the subject that learns about it. Moreover, this dual salience model can explain why learning about a stimulus not only depends on the effective salience during acquisition but also on the specific learning trajectory that was used to reach this state. Our mathematical description could be instrumental for understanding aberrant salience acquisition under stressful situations and in neuropsychiatric disorders like schizophrenia, obsessive-compulsive disorder, and addiction.
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Affiliation(s)
- Mario Treviño
- Laboratorio de Plasticidad Cortical y Aprendizaje Perceptual, Instituto de Neurociencias, Universidad de Guadalajara Guadalajara, Mexico
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Mihov Y, Hasler G. Negative Allosteric Modulators of Metabotropic Glutamate Receptors Subtype 5 in Addiction: a Therapeutic Window. Int J Neuropsychopharmacol 2016; 19:pyw002. [PMID: 26802568 PMCID: PMC4966271 DOI: 10.1093/ijnp/pyw002] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 01/08/2016] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Abundant evidence at the anatomical, electrophysiological, and molecular levels implicates metabotropic glutamate receptor subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential that can be translated to the clinic. METHODS Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) and 2-Methyl-6-(phenylethynyl)pyridine (MPEP) on paradigms with cocaine, ethanol, nicotine, and food in rats. RESULTS MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine at doses ≥1mg/kg and 2.5mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine, but not food, was reduced by MTEP and MPEP in the dose range of 1 to 2mg/kg and 2.5 to 3.2mg/kg, respectively. This dose range corresponds to approximately 50% to 80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. CONCLUSION Altogether, this review suggests a therapeutic window for mGluR5 NAMs that can be translated to the treatment of substance-related and addictive disorders.
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Affiliation(s)
- Yoan Mihov
- Division of Molecular Psychiatry, Translational Research Center, Psychiatric University Hospital, University of Bern, Switzerland
| | - Gregor Hasler
- Division of Molecular Psychiatry, Translational Research Center, Psychiatric University Hospital, University of Bern, Switzerland
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Diaz E, Medellín J, Sánchez N, Vargas JP, López JC. Involvement of D1 and D2 dopamine receptor in the retrieval processes in latent inhibition. Psychopharmacology (Berl) 2015; 232:4337-46. [PMID: 26345345 DOI: 10.1007/s00213-015-4063-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 08/24/2015] [Indexed: 10/23/2022]
Abstract
RATIONALE Contemporary theories propose that latent inhibition (LI) is due to a process of interference with the context playing a key role as recovery cue. Physiological studies have demonstrated that LI is a process dependent on striatal dopamine. D2 dopamine receptors have been specifically associated with its expression, while D1 receptor has shown a limited function. However, to evaluate the role of dopamine receptors in LI, it is necessary to analyse their activity during recovery phase, where the mechanisms involved in interference processes are performed. OBJECTIVE The experiments studied the involvement of the dopaminergic system in the retrieval process of LI. We analysed the effect of the systemic administration of dopaminergic D1 (SCH-23390) and D2 (sulpiride) antagonist during the test phase on LI and on its contextual specificity. METHODS Animals were pre-exposed to saccharin solution and conditioned with a LiCl administration in conditioning phase. Dopaminergic antagonist drugs were administered during the test phase. Experiment 2 used the same context in all the phases. Experiment 3 used a new context during conditioning and test phase. RESULTS The D2 antagonist increased the LI effect and, in turn, diminished the normally suppressant effect of the context shift on LI. The opposite effect was observed under the D1 antagonist administration. This drug disrupted LI and enhanced the effect that the context shift had on this cognitive process. CONCLUSIONS D2 receptor had a relevant role on retrieval processes of pre-exposure learning, while D1 receptor was related with the contextual control of conditioning.
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Affiliation(s)
- E Diaz
- Department Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, 41018, Seville, Spain.
| | - J Medellín
- Universidad Autónoma de Tamaulipas, Matamoros, México
| | - N Sánchez
- Department Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, 41018, Seville, Spain
| | - J P Vargas
- Department Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, 41018, Seville, Spain
| | - J C López
- Department Psicología Experimental, Universidad de Sevilla, c/ Camilo Jose Cela s/n, 41018, Seville, Spain
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Abstract
The ability to change strategies in different contexts is a form of behavioral flexibility that is crucial for adaptive behavior. The striatum has been shown to contribute to certain forms of behavioral flexibility such as reversal learning. Here we report on the contribution of striatal cholinergic interneurons-a key element in the striatal neuronal circuit-to strategy set-shifting in which an attentional shift from one stimulus dimension to another is required. We made lesions of rat cholinergic interneurons in dorsomedial or ventral striatum using a specific immunotoxin and investigated the effects on set-shifting paradigms and on reversal learning. In shifting to a set that required attention to a previously irrelevant cue, lesions of dorsomedial striatum significantly increased the number of perseverative errors. In this condition, the number of never-reinforced errors was significantly decreased in both types of lesions. When shifting to a set that required attention to a novel cue, rats with ventral striatum lesions made more perseverative errors. Neither lesion impaired learning of the initial response strategy nor a subsequent switch to a new strategy when response choice was indicated by a previously relevant cue. Reversal learning was not affected. These results suggest that in set-shifting the striatal cholinergic interneurons play a fundamental role, which is dissociable between dorsomedial and ventral striatum depending on behavioral context. We propose a common mechanism in which cholinergic interneurons inhibit neurons representing the old strategy and enhance plasticity underlying exploration of a new rule.
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Beinat C, Banister SD, Herrera M, Law V, Kassiou M. The therapeutic potential of α7 nicotinic acetylcholine receptor (α7 nAChR) agonists for the treatment of the cognitive deficits associated with schizophrenia. CNS Drugs 2015; 29:529-42. [PMID: 26242477 DOI: 10.1007/s40263-015-0260-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple α7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical α7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other α7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of α7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology.
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Affiliation(s)
- Corinne Beinat
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA
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Abstract
The gastrointestinal hormone peptide tyrosine tyrosine 3-36 (PYY(3-36)) has attained broad recognition with respect to its involvement in energy homeostasis and the control of food intake. It is mainly secreted by distal intestinal enteroendocrine L-cells in response to eating and exerts neurally mediated, paracrine and endocrine effects on various target organs. In addition to its gastrointestinal effects, PYY(3-36) has long been known to inhibit food intake. Recent closer examination of the effects of PYY(3-36) revealed that this gut-derived peptide also influences a wide spectrum of behavioral and cognitive functions that are pivotal for basic processes of perception and judgment, including central information processing, salience learning, working memory, and behavioral responding to novelty. Here, we review the effects of PYY(3-36) that go beyond food intake and provide a conceptual framework suggesting that several apparently unrelated behavioral actions of PYY(3-36) may actually reflect different manifestations of modulating the central dopamine system.
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O'Connor WT, O'Shea SD. Clozapine and GABA transmission in schizophrenia disease models. Pharmacol Ther 2015; 150:47-80. [DOI: 10.1016/j.pharmthera.2015.01.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 01/06/2015] [Indexed: 11/30/2022]
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Tse MT, Piantadosi PT, Floresco SB. Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research. Biol Psychiatry 2015; 77:929-39. [PMID: 25442792 DOI: 10.1016/j.biopsych.2014.09.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 08/22/2014] [Accepted: 09/15/2014] [Indexed: 12/28/2022]
Abstract
Cognitive dysfunction in schizophrenia is one of the most pervasive and debilitating aspects of the disorder. Among the numerous neural abnormalities that may contribute to schizophrenia symptoms, perturbations in markers for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), particularly within the frontal lobes, are some of the most reliable alterations observed at postmortem examination. However, how prefrontal GABA dysfunction contributes to cognitive impairment in schizophrenia remains unclear. We provide an overview of postmortem GABAergic perturbations in the brain affected by schizophrenia and describe circumstantial evidence linking these alterations to cognitive dysfunction. In addition, we conduct a survey of studies using neurodevelopmental, genetic, and pharmacologic rodent models that induce schizophrenia-like cognitive impairments, highlighting the convergence of these mechanistically distinct approaches to prefrontal GABAergic disruption. We review preclinical studies that have directly targeted prefrontal cortical GABAergic transmission using local application of GABAA receptor antagonists. These studies have provided an important link between GABA transmission and cognitive dysfunction in schizophrenia because they show that reducing prefrontal inhibitory transmission induces various cognitive, emotional, and dopaminergic abnormalities that resemble aspects of the disorder. These converging clinical and preclinical findings provide strong support for the idea that perturbations in GABA signaling drive certain forms of cognitive dysfunction in schizophrenia. Future studies using this approach will yield information to refine further a putative "GABA hypothesis" of schizophrenia.
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Affiliation(s)
- Maric T Tse
- Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Patrick T Piantadosi
- Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Stan B Floresco
- Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
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