Browsing by Author "Lagojda, Lukasz"

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    Changes in Physical Activity and Sedentary Behaviour Due to Enforced COVID-19-Related Lockdown and Movement Restrictions: A Protocol for a Systematic Review and Meta-Analysis
    (MDPI, 2021-05-14) Kite, Chris; Lagojda, Lukasz; Clark, Cain C T; Uthman, Olalekan; Denton, Francesca; McGregor, Gordon; Harwood, Amy E; Atkinson, Lou; Broom, David R; Kyrou, Ioannis; Randeva, Harpal S
    Prolonged lockdown/restriction measures due to the COVID-19 pandemic have reportedly impacted opportunities to be physically active for a large proportion of the population in affected countries globally. The exact changes to physical activity and sedentary behaviours due to these measures have not been fully studied. Accordingly, the objective of this PROSPERO-registered systematic review is to evaluate the available evidence on physical activity and sedentary behaviours in the general population during COVID-19-related lockdown/restriction measures, compared to prior to restrictions being in place. Defined searches to identify eligible studies published in English, from November 2019 up to the date of submission, will be conducted using the following databases: CENTRAL, MEDLINE, EMBASE, CINAHL, SPORTDiscus, PSYCinfo, Coronavirus Research Database, Public Health Database, Publicly Available Content Database, SCOPUS, and Google Scholar. The applied inclusion criteria were selected to identify observational studies with no restrictions placed on participants, with outcomes regarding physical activity and/or sedentary behaviour during lockdown/restriction measures, and with comparisons for these outcomes to a time when no such measures were in place. Where appropriate, results from included studies will be pooled and effect estimates will be presented in random effects meta-analyses. To the best of our knowledge, this will be the first systematic review to evaluate one complete year of published data on the impact of COVID-19-related lockdown/restriction measures on physical activity and sedentary behaviour. Thus, this systematic review and meta-analysis will constitute the most up-to-date synthesis of published evidence on any such documented changes, and so will comprehensively inform clinical practitioners, public health agencies, researchers, policymakers and the general public regarding the effects of lockdown/restriction measures on both physical activity and sedentary behaviour.
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    Investigating Cerebellar Mechanisms of Schizophrenia by Using a Pharmacological Mouse Model: Regulation of Voltage-Gated Potassium Channels
    (De Montfort University, 2021-10) Lagojda, Lukasz
    Schizophrenia is a heterogeneous psychiatric disorder which affects at least 1% of the global population. Its complex pathology involves impaired neuronal communication that leads to the onset of debilitating symptoms affecting behaviour and cognition. Voltage-gated potassium (Kv) channels are fundamental to neuronal communication because of their intricate roles in regulating neuronal excitability, thereby governing information processing in the brain. The cerebellum has a significant influence over how this information is communicated across the brain because of its interconnectivity with virtually all brain regions. To expand our understanding of Kv channels, this thesis investigates the regulation of three alpha subunits of voltage-gated potassium channels Kv2.1, Kv6.4, and Kv3.1b in the cerebellar cortex of a phencyclidine-induced mouse model of schizophrenia and explores their potential role in schizophrenia symptoms. In Chapter 3 we show using immunohistochemistry that Kv2.1 is expressed in the Purkinje cells and granule cells as membrane-bound clusters in the soma and proximal dendrites, whereas the Kv6.4 are mainly present in the cytosol. Additionally, using proximity ligation we demonstrated for the first time that Kv6.4 arrange with Kv2.1 to form heteromeric channels on the perisomatic membrane of Purkinje cells. These findings suggest that Kv2.1 and Kv6.4 may act as neuronal ‘transistors’ thereby controlling the frequency of neuronal firing in these cell populations. In Chapter 4 we describe the behavioural phenotype of our CBA/CA phencyclidine model to include altered exploratory patterns, changes in locomotor activity, and changes in rearing and grooming behaviours. We also observed dysregulation of NMDA-receptor genes in frontal cortex and the cerebellum, and abnormalities in several features of the cerebellum of the model mice. Additionally, we describe the effectiveness of concomitant antipsychotic agents haloperidol and clozapine in attenuating the acute changes in behaviour induced by phencyclidine, and we introduce specific motor function tests to assess cerebellar involvement in the model. Together, these findings support several aspects of face, construct, and predictive validity expected of a schizophrenia model. Finally in Chapter 5 we investigate the cerebellar regulation of the three Kv subunits in our animal model, where we found Kv2.1 downregulation in the cerebellar cortex which is consistent with findings from human schizophrenia subjects and from animal studies. Strikingly, we found that the Kv6.4 is upregulated in several regions of the cerebellum that was supported by upregulated Kcng4 gene, which may indicate a compensatory mechanism for Kv2.1 loss. Additionally, we observed downregulation of the Kv3.1b in the granule cell layer of the right cerebellar lateral hemisphere, which may indicate a local functional demand. In conclusion, this thesis demonstrates, by using a range of behavioural, histological, and biomolecular investigations, the cerebellar pathology resulting from subchronic phencyclidine treatment, and also elucidates the functional role of Kv channels in a schizophrenia-like pathological state.
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    Investigating the regulation of a voltage-gated potassium channel in the cerebellum of a pharmacological mouse model of schizophrenia
    (2019-04-16) Lagojda, Lukasz; Zhu, Lan
    Schizophrenia is a debilitating neurodevelopmental disorder affecting 1% of the global population. The glutamate hypothesis poses that the N-methyl-D-aspartate receptor (NMDAR) hypofunction is the key player in the development of different domains of schizophrenia symptoms. Phencyclidine (PCP) is a non-competitive NMDAR antagonist, which is widely used to generate animal models of schizophrenia1. The cerebellum has long been known for its motor related functions. Recently, an increasing body of evidence associates cerebellar structural and functional abnormalities with schizophrenia2. Voltage-gated potassium channels (Kv) play intricate roles in neuronal excitability and firing frequency. The Kv2.1 is a type of Kv which has been shown to regulate the excitability of neurons in the brain. Limited evidence suggests that the Kv2.1 gene is a schizophrenia vulnerability risk gene and the dysregulation of Kv2.1 in the brain is associated with schizophrenia3,4,5. This study aims to: 1) characterise the cellular and subcellular expression of Kv2.1 in the cerebellum; 2) investigate the regulation of Kv2.1 in a PCP mouse model of schizophrenia. Our preliminary data shows that Kv2.1 is expressed in the cerebellar Purkinje cells and granule cells and its expression is significantly downregulated in the cerebellum of the PCP mouse model (Figure 2).