Judith Pratt
University of Strathclyde, Glasgow, SIPBS, Faculty Member
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This paper looks at environment-environment interactions in a schizophrenia-related disease model and the impact of poly ic and thc on the developing brai
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The GPR88 orphan G protein‐coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans... more
The GPR88 orphan G protein‐coupled receptor is expressed throughout the striatum, being preferentially localised in medium spiny neurons. It is also present in lower densities in frontal cortex and thalamus. Rare mutations in humans suggest a role in cognition and motor function, while common variants are associated with psychosis. Here we evaluate the influence of genetic deletion of GPR88 upon performance in translational tasks interrogating motivation, reward evaluation and cognitive function. In an automated radial arm maze ‘N‐back’ working memory task, Gpr88 KO mice showed impaired correct responding, suggesting a role for GPR88 receptors in working memory circuitry. Associative learning performance was similar to wild‐type controls in a touchscreen task but performance was impaired at the reversal learning stage, suggesting cognitive inflexibility. Gpr88 KO mice showed higher breakpoints, reduced latencies and lengthened session time in a progressive ratio task consistent with...
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Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in the cortex. PNN maturation coincides with closure of the critical... more
Perineuronal nets (PNNs) are specialised extracellular matrix structures which preferentially enwrap fast-spiking (FS) parvalbumin interneurons and have diverse roles in the cortex. PNN maturation coincides with closure of the critical period of cortical plasticity. We have previously demonstrated that BDNF accelerates interneuron development in a c-Jun-NH2-terminal kinase (JNK)–dependent manner, which may involve upstream thousand-and-one amino acid kinase 2 (TAOK2). Chondroitinase-ABC (ChABC) enzymatic digestion of PNNs reportedly reactivates ‘juvenile-like’ plasticity in the adult CNS. However, the mechanisms involved are unclear. We show that ChABC produces an immature molecular phenotype in cultured cortical neurons, corresponding to the phenotype prior to critical period closure. ChABC produced different patterns of PNN-related, GABAergic and immediate early (IE) gene expression than well-characterised modulators of mature plasticity and network activity (GABAA-R antagonist, b...
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This paper looks at viral-mediated knockdown of ERBB4 in the rodent prefrontal cortex enhances cognitive performance
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There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for... more
There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data sugg...
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Background: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve... more
Background: Rodent behavioural assays are widely used to delineate the mechanisms of psychiatric disorders and predict the efficacy of drug candidates. Conventional behavioural paradigms are restricted to short time windows and involve transferring animals from the homecage to unfamiliar apparatus which induces stress. Additionally, factors including environmental perturbations, handling and the presence of an experimenter can impact behaviour and confound data interpretation. To improve welfare and reproducibility these issues must be resolved. Automated homecage monitoring offers a more ethologically relevant approach with reduced experimenter bias. Aim: To evaluate the effectiveness of an automated homecage system at detecting locomotor and social alterations induced by phencyclidine (PCP) in group-housed rats. PCP is an N-methyl-D-aspartate (NMDA) receptor antagonist commonly utilised to model aspects of schizophrenia. Methods: Rats housed in groups of three were implanted with ...
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Background: Aside from regulating circadian rhythms, melatonin also affects cognitive processes, such as alertness, and modulates the brain circuitry underlying psychiatric diseases, such as depression, schizophrenia and bipolar disorder,... more
Background: Aside from regulating circadian rhythms, melatonin also affects cognitive processes, such as alertness, and modulates the brain circuitry underlying psychiatric diseases, such as depression, schizophrenia and bipolar disorder, via mechanisms that are not fully clear. In particular, while melatonin MT1 receptors are thought primarily to mediate the circadian effects of the hormone, the contribution of the MT2 receptor to melatonin actions remains enigmatic. Aims: To characterise the contribution of MT2 receptors to melatonin’s effects on cognition and anxiety/sociability. Methods: Mice with a genetic deletion of the MT2 receptor, encoded by the Mtnr1b gene, were compared with wild-type littermates for performance in a translational touchscreen version of the continuous performance task (CPT) to assess attentional processes and then monitored over 3 days in an ethological home-cage surveillance system. Results: Mtnr1b knockout (KO) mice were able to perform at relatively n...
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This paper looks at the impact of modafinil on acquisition and subsequent performance of pcp -treated rats in the 5 -choice serial reaction time task
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Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521–527 (2018)]. However, while most studies have focused on the mechanisms of protein... more
Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521–527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α- l -fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis—a disease characterized by inactivating mutations in FUCA1 [Stepien et al. , Genes (Basel) 11, E1383 (2020)]—glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUC...
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Schizophrenia affects 1% of the population ranking as the ninth most prevalent cause of disability worldwide. Whilst effective pharmacological treatments exist for the positive symptoms associated with this disease the negative symptoms... more
Schizophrenia affects 1% of the population ranking as the ninth most prevalent cause of disability worldwide. Whilst effective pharmacological treatments exist for the positive symptoms associated with this disease the negative symptoms and cognitive deficits remain untreated. Here we propose a deep brain stimulation (DBS) strategy analogous to that used to great success in Parkinson's disease and describe methods for validation of this strategy in a rodent model of schizophrenia (Cochran et al. 2003; Neuropsychopharmacol. 28: 265-275; Pratt et al. 2008; Brit. J. Pharmacol. 153: S465-S470). Bipolar electrodes were fabricated by affixing pairs of 25µm, teflon insulated, nichrome wire to a supporting 100µm, stainless steel insect pin. These were implanted, bilaterally, into the medial-dorsal nucleus of the thalamus or the ventral pallidum of anaesthetised male Hooded Lister rats. High frequency stimulation (130Hz, 220µA, 100µs) was delivered unilaterally via a remotely controlled ...
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Figure S1. Correlation between CXCL10 in placenta and embryo brain. Supplementary methodsâ Luminex assay details. Table S1. F values for ANOVAs (DOCX 168 kb)
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This paper discusses the fact that exposure of cultured hippocampal neurones to cannabidiol does not induce cell death but inhibits synaptic activity.
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Research Interests: Cognition, Behavior, Attention, Cannabinoids, Dopamine, and 15 moreInsight, Humans, Animals, Animal Model, Acetylcholine, Endocannabinoid System, Cognitive impairment, Cognitive Ability, Animal models, Cognitive Function, Glutamic Acid, Cannabinoid, Cannabinoid Receptor, Haplorhini, and Medical and Health Sciences
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Research Interests: Neuroscience, Neuropsychopharmacology, Medicine, Prefrontal Cortex, Energy Metabolism, and 15 moreAnimals, Male, Auditory System, Animal Model, Haloperidol, Phencyclidine, mRna expression levels, Parvalbumin, Atypical Antipsychotics, Clozapine, Gene Expression Regulation, Neurochemical, Antipsychotic agents, Medical and Health Sciences, and mRNA expression
Research Interests: Neuroscience, Chemistry, Deep Brain Stimulation, Neuromodulation, Schizophrenia, and 15 moreMedicine, Ir, Animals, Roi, Male, PT, Rs, LAN, Rats, Neural pathways, CM, Neurosciences, Frontal Lobe, ROD, and Chemical Neuroanatomy
Research Interests: Genetics, Schizophrenia, Biology, Medicine, Gene expression, and 14 morePrefrontal Cortex, Biological Sciences, Humans, Mice, Animals, Human Molecular Genetics, Phenotype, Genotype, Single Nucleotide Polymorphism, Linkage Disequilibrium, Genetic variation, Case Control Studies, alleles, and Medical and Health Sciences
Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established... more
Background The quantification of experimentally-induced alterations in biological pathways remains a major challenge in systems biology. One example of this is the quantitative characterization of alterations in defined, established metabolic pathways from complex metabolomic data. At present, the disruption of a given metabolic pathway is inferred from metabolomic data by observing an alteration in the level of one or more individual metabolites present within that pathway. Not only is this approach open to subjectivity, as metabolites participate in multiple pathways, but it also ignores useful information available through the pairwise correlations between metabolites. This extra information may be incorporated using a higher-level approach that looks for alterations between a pair of correlation networks. In this way experimentally-induced alterations in metabolic pathways can be quantitatively defined by characterizing group differences in metabolite clustering. Taking this app...
Research Interests: Computer Science, Algorithms, Cognition, Biology, Metabolomics, and 15 moreMedicine, Prefrontal Cortex, Glutamate, Humans, Animals, Cluster Analysis, Genome, Phencyclidine, Metabolic pathway, Ligands, Glutamic Acid, GABA receptor, Gene Expression Regulation, Experimental Group, and Computational Techniques
Deep brain stimulation studies are underway in a wide variety of neuro-psychiatric disorders. Here we describe an exploratory study into the effect of high frequency deep brain stimulation of the mediodorsal thalamic nucleus. This study... more
Deep brain stimulation studies are underway in a wide variety of neuro-psychiatric disorders. Here we describe an exploratory study into the effect of high frequency deep brain stimulation of the mediodorsal thalamic nucleus. This study explores the regions activated by DBS of the mediodorsal thalamic nucleus through examination of immediate early genes as markers of neuronal activation and the consequences of this activation on open-field behaviours. Stimulation was delivered bilaterally with monophasic, anodic, constant current 100us duration pulses at a frequency of 130Hz delivered at an amplitude of 200uA. Brains were removed from anaesthetised animals, sectioned and radio-labeled for the IEGs<em> zif-268</em> and <em>c-fos</em>. In anaesthetised rats DBS of mediodorsal thalamic nucleus produced robust increases in the expression of <em>zif-268</em> but not <em>c-fos</em> localised to regions that are reciprocally connected with th...
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The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical... more
The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical circuits. Moreover, higher cognitive functions, such as working memory and attention, have been related to thalamo-cortical interactions, providing a novel perspective for the understanding of the neural substrate of cognition. The current review will support this perspective by summarizing evidence on the crucial role of neural oscillations in facilitating thalamo-cortical (TC) interactions during normal brain functioning and its potential impairment in ScZ. Specifically, we will focus on the relationship between NMDA-R mediated (glutamatergic) neurotransmission in TC-interactions. To this end, we will first review the functional anatomy and neurotransmitters in thalamic circuits, followed by a review of the oscillatory signatures and cognitive process...
The search for biomarkers to aid in the diagnosis and prognosis of psychiatric conditions and predict response to treatment is a focus of twenty-first century medicine. The current lack of biomarkers in routine use is attributable in part... more
The search for biomarkers to aid in the diagnosis and prognosis of psychiatric conditions and predict response to treatment is a focus of twenty-first century medicine. The current lack of biomarkers in routine use is attributable in part to the existing way mental health conditions are diagnosed, being based upon descriptions of symptoms rather than causal biological evidence. New ways of conceptualizing mental health disorders together with the enormous advances in genetic, epidemiological, and neuroscience research are informing the brain circuits and physiological mechanisms underpinning behavioural constructs that cut across current diagnostic DSM-5 categories. Combining these advances with ‘Big Data’, analytical approaches offer new opportunities for biomarker development. Here we provide an introductory perspective to this volume, highlighting methodological strategies for biomarker identification; ranging from stem cells, immune mechanisms, genomics, imaging, network science...
The search for biomarkers to aid in the diagnosis and prognosis of psychiatric conditions and predict response to treatment is a focus of twenty-first century medicine. The current lack of biomarkers in routine use is attributable in part... more
The search for biomarkers to aid in the diagnosis and prognosis of psychiatric conditions and predict response to treatment is a focus of twenty-first century medicine. The current lack of biomarkers in routine use is attributable in part to the existing way mental health conditions are diagnosed, being based upon descriptions of symptoms rather than causal biological evidence. New ways of conceptualizing mental health disorders together with the enormous advances in genetic, epidemiological, and neuroscience research are informing the brain circuits and physiological mechanisms underpinning behavioural constructs that cut across current diagnostic DSM-5 categories. Combining these advances with 'Big Data', analytical approaches offer new opportunities for biomarker development. Here we provide an introductory perspective to this volume, highlighting methodological strategies for biomarker identification; ranging from stem cells, immune mechanisms, genomics, imaging, network science to cognition. Thereafter we emphasize key points made by contributors on affective disorders, psychosis, schizophrenia, and autism spectrum disorder. An underlying theme is how preclinical and clinical research are informing biomarker development and the importance of forward and reverse translation approaches. In considering the exploitation of biomarkers we note that there is a timely opportunity to improve clinical trial design informed by patient 'biological' and 'psychological' phenotype. This has the potential to reinvigorate drug development and clinical trials in psychiatry. In conclusion, we are poised to move from the descriptive and discovery phase to one where biomarker panels can be evaluated in real-life cohorts. This will necessitate resources for large-scale collaborative efforts worldwide. Ultimately this will lead to new interventions and personalized medicines and transform our ability to prevent illness onset and treat complex psychiatric disorders more effectively.
Research Interests: Psychology and Medicine
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Schizophrenia is considered to develop as a consequence of genetic and environmental factors impacting on brain neural systems and circuits during vulnerable neurodevelopmental periods, thereby resulting in symptoms in early adulthood.... more
Schizophrenia is considered to develop as a consequence of genetic and environmental factors impacting on brain neural systems and circuits during vulnerable neurodevelopmental periods, thereby resulting in symptoms in early adulthood. Understanding of the impact of schizophrenia risk factors on brain biology and behaviour can help in identifying biologically relevant pathways that are attractive for informing clinical studies and biomarker development. In this chapter, we emphasize the importance of adopting a reciprocal forward and reverse translation approach that is iteratively updated when additional new information is gained, either preclinically or clinically, for offering the greatest opportunity for discovering panels of biomarkers for the diagnosis, prognosis and treatment of schizophrenia. Importantly, biomarkers for identifying those at risk may inform early intervention strategies prior to the development of schizophrenia. Given the emerging nature of this approach in t...
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Meeting abstract (S20) from: European Behavioural Pharmacology Society (EBPS) Workshop on Behavioural Genertics and Neuropsychiatric Disorders, Cork, Ireland, 25-27 Aug, 2008.
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The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical... more
The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical circuits. Moreover, higher cognitive functions, such as working memory and attention, have been related to thalamo-cortical interactions, providing a novel perspective for the understanding of the neural substrate of cognition. The current review will support this perspective by summarizing evidence on the crucial role of neural oscillations in facilitating thalamo-cortical (TC) interactions during normal brain functioning and their potential impairment in ScZ. Specifically, we will focus on the relationship between NMDA-R mediated (glutamatergic) neurotransmission in TC-interactions. To this end, we will first review the functional anatomy and neurotransmitters in thalamic circuits, followed by a review of the oscillatory signatures and cognitive proce...
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This paper looks at subanaesthetic ketamine treatment alters prefrontal cortex functional connectivity and the properties of functional brain networks
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The effects of Δ 9 -tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [ 14 C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly... more
The effects of Δ 9 -tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [ 14 C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly increased it at 1 mg/kg. ...
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The main reason for smoking tobacco is to obtain the effects of nicotine; an improved way of dealing with the pharmacological component of tobacco addiction will only come from advances in understanding both the behavioral mechanisms... more
The main reason for smoking tobacco is to obtain the effects of nicotine; an improved way of dealing with the pharmacological component of tobacco addiction will only come from advances in understanding both the behavioral mechanisms involved and the mode of action of nicotine in the CNS. This article reviews recent work which has been aimed at identifying underlying neuropharmacological mechanisms.
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The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study... more
The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study investigated the levels of cytokine mRNAs in rat brain after acute and chronic administration of PCP, in the presence and absence of antipsychotic drugs. The