Publications by authors named "Hugh M Marston"

The PRISM project, funded by the EU's Innovative Medicines Initiative, has identified a transdiagnostic, pathophysiological relationship between the integrity of the default mode network (DMN) and social dysfunction. To explore the causal link between DMN integrity and social behaviour, we employed a preclinical back-translation approach, using focal demyelination of the forceps minor to disrupt DMN connectivity in mice. By applying advanced techniques such as functional ultrasound imaging and automated analysis of social behaviour, we demonstrated that reduced DMN connectivity leads to impaired social interactions and increased anxiety in mice.

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Article Synopsis
  • Current mental disorder classifications are based on convention and symptom clusters rather than biological mechanisms, leading to significant overlap and variability in diagnoses.
  • There is a need for a new diagnostic framework that incorporates neurobiology to enhance treatment options and help patients better understand their illnesses.
  • The ECNP New Frontiers Meeting 2024 aims to establish a roadmap for improved precision diagnostics by focusing on innovative technologies, the biology of mental illness, and translating this knowledge into effective treatment strategies.*
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The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area.

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The rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia and schizophrenia is, in turn, associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants. We recruited healthy adult males with no history of psychiatric disorder from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.

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In an uncertain world, the ability to predict and update the relationships between environmental cues and outcomes is a fundamental element of adaptive behaviour. This type of learning is typically thought to depend on prediction error, the difference between expected and experienced events and in the reward domain that has been closely linked to mesolimbic dopamine. There is also increasing behavioural and neuroimaging evidence that disruption to this process may be a cross-diagnostic feature of several neuropsychiatric and neurological disorders in which dopamine is dysregulated.

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The slow waves (SW) of non-rapid eye movement (NREM) sleep reflect neocortical components of network activity during sleep-dependent information processing; their disruption may therefore impair memory consolidation. Here, we quantify sleep-dependent consolidation of motor sequence memory, alongside sleep EEG-derived SW properties and synchronisation, and SW-spindle coupling in 21 patients suffering from schizophrenia and 19 healthy volunteers. Impaired memory consolidation in patients culminated in an overnight improvement in motor sequence task performance of only 1.

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Goal-directed motivated behaviour is crucial for everyday life. Such behaviour is often measured, in rodents, under a progressive ratio (PR) schedule of reinforcement. Previous studies have identified a few brain structures critical for supporting PR performance.

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Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments.

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Understanding brain function at the cell and circuit level requires representation of neuronal activity through multiple recording sites and at high sampling rates. Traditional tethered recording systems restrict movement and limit the environments suitable for testing, while existing wireless technology is still too heavy for extended recording in mice. Here we tested TaiNi, a novel ultra-lightweight (<2 g) low power wireless system allowing 72-hours of recording from 16 channels sampled at ~19.

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Recent advances in the understanding of psychosis have uncovered potential for a paradigm shift in related drug discovery efforts. The study of psychosis is evolving from its origins in serendipity and empiricism to more formal, hypothesis driven accounts of the cognitive substrates underlying hallucinations and delusions. Recent evidence suggests that misattribution of salience and abnormal prediction error might underlie some forms of psychosis.

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Successive negative contrast (SNC) describes a change in an animal's behaviour following a downshift in the quantitative or qualitative value of a reward. Previous studies suggest both consummatory and instrumental paradigms have the potential to provide an objective measure of affective state in rodents. We first investigated whether an SNC effect is observed in an operant task based on the 5 choice serial reaction time task.

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Chronic mild stress (CMS)-induced 'anhedonia' is a predictive model of antidepressant activity. We assessed the reversal of CMS-induced behavioral changes by asenapine, the antidepressant imipramine, and the atypical antipsychotics olanzapine and risperidone. Secondarily, the ability of these agents to facilitate intracranial self-stimulation (ICSS) was assessed to ensure that any attenuation of CMS-induced anhedonia was not associated with an overt hedonic profile.

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Background: Residual dysfunction of multiple neurotransmitter systems due to chronic alcohol use is likely responsible for the occurrence of compulsive alcohol seeking during abstinence and relapse behavior. There is increasing evidence that glycine, which activates both glycine and N-methyl-D-aspartate receptors, contributes to excessive alcohol consumption. We therefore hypothesized that the blockade of glycine transporter 1 might interfere with compulsive alcohol consumption and relapse behavior.

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Background: Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats.

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Rationale: Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.

Objectives: The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.

Materials And Methods: Amphetamine-stimulated locomotor activity (Amp-LMA; 1.

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Cognitive deficits in schizophrenia are among the core symptoms of the disease, correlate with functional outcome, and are not well treated with current antipsychotic therapies. In order to bring together academic, industrial, and governmental bodies to address this great 'unmet therapeutic need', the NIMH sponsored the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. Through careful factor analysis and consensus of expert opinion, MATRICS identified seven domains of cognition that are deficient in schizophrenia (attention/vigilance, working memory, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition) and recommended a specific neuropsychological test battery to probe these domains.

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Background: Attentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease. Indeed, sustained attention/vigilance is among the leading targets for new medications designed to improve cognition in schizophrenia. Although vigilance is assessed frequently using the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.

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Rationale: Cognitive inflexibility in schizophrenia is treatment-resistant and predictive of poor outcome. This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat.

Objectives: The objective of this paper was to establish whether asenapine has a beneficial effect on the performance of rats with ibotenic acid-induced lesion of the medial prefrontal cortex (mPFC) in an intradimensional/extradimensional (ID/ED) test of cognitive flexibility.

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Article Synopsis
  • * Research shows that patients with melancholic depression have an exaggerated release of ACTH when exposed to vasopressin receptor agonists, indicating a heightened sensitivity to these receptors.
  • * A newly developed V(1B) antagonist effectively blocks ACTH release in response to stress and vasopressin receptor stimulation, but does not affect the HPA axis under normal conditions, suggesting its potential for treating stress-related disorders. *
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Article Synopsis
  • Scientists found that problems with smelling and remembering scents could be early signs of brain diseases like Alzheimer's and schizophrenia.
  • They created a test for mice to see how well they can remember different smells and noticed that special mice with a certain gene (caspase-3) had trouble with this memory test.
  • However, when these mice were given nicotine, it helped them do better on the smell memory task, showing that the test could be useful for studying brain diseases in animals.
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alpha7-Nicotinic acetylcholine receptors (alpha7-nAChR) have been implicated in a range of cognitive deficits in schizophrenia. Therefore we examined alpha7-nAChR knockout (KO), heterozygote (HT) and wildtype (WT) littermate mice in the 5-CSR (a rodent model of sustained attention) and odour span (a novel mouse working memory paradigm) tasks, and related performance to nAChR density. Whilst there was no difference between groups in baseline 5-CSR task performance, alpha7-nAChR KO's exhibited significantly higher omission levels compared to WT mice on increasing the attentional load, with HT mice performing at an intermediate level.

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In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice.

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Expression of coherent and rhythmic circadian (approximately 24 h) variation of behaviour, metabolism and other physiological processes in mammals is governed by a dominant biological clock located in the hypothalamic suprachiasmatic nuclei (SCN). Photic entrainment of the SCN circadian clock is mediated, in part, by vasoactive intestinal polypeptide (VIP) acting through the VPAC2 receptor. Here we used mice lacking the VPAC2 receptor (Vipr2-/-) to examine the contribution of this receptor to the electrophysiological actions of VIP on SCN neurons, and to the generation of SCN electrical firing rate rhythms SCN in vitro.

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The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are implicated in the photic entrainment of circadian rhythms in the suprachiasmatic nuclei (SCN). We now report that mice carrying a null mutation of the VPAC(2) receptor for VIP and PACAP (Vipr2(-/-)) are incapable of sustaining normal circadian rhythms of rest/activity behavior. These mice also fail to exhibit circadian expression of the core clock genes mPer1, mPer2, and mCry1 and the clock-controlled gene arginine vasopressin (AVP) in the SCN.

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