Regulation of stress response in first episode schizophrenia by monocytes and microglia
Kuupäev
2024-04-10
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Ajakirja pealkiri
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Abstrakt
Skisofreenia, keeruline neuropsühhiaatriline häire, mõjutab ligikaudu 1% maailma elanikkonnast ja esitab olulisi väljakutseid selle patobioloogiliste mehhanismide mõistmisel. Käesolev väitekiri keskendub monotsüütide ja mikroglia rolli lahtiharutamisele neuroinflammatoorsetes protsessides skisofreenias, eriti stressi kontekstis. Meie uurimused keskendusid esimese episoodi skisofreeniaga (FES) patsientidele ja loomade stressimudelitele, et selgitada välja nende immuunrakkude vahendatud molekulaarsed mehhanismid. FES patsientidel leiti muutusi monotsüütidega seotud transkriptoomiprofiilides, eriti mitteklassikaliste ja vahepealsete monotsüütide alamrühmades. Lisaks leiti, et suurema stressitundlikkusega FES patsientidel olid väiksemad hipokampuse struktuurid ja muutunud geeniexpressioon, mis oli seotud immuunarenguga. Mikroglia uuenemine leevendas osaliselt kroonilise ettearvamatu stressi (CUS) poolt hiirtel esile kutsutud psühhiaatrilisi käitumishäireid, mõjutades aju transkriptoomikat, mis on seotud arenguprotsessidega nagu aksionaalne ja sünaptiline moodustumine. Veelgi enam, madalama stressi tunnustega FES patsientidel olid väiksemad amügdalad ja kõrgem PLXNB2 ekspressioon, mis oli negatiivselt seotud tajutava stressi raskusega. Hiirtel põhjustas CUS Plxnb2 ekspressiooni languse ja Plxnb2 blokeerimine tekitas ärevust, amügdaloidset suurenemist ja mikroglia hargnemist. Need leiud viitavad sellele, et kuigi monotsüütide alamrühmad ja nende geenid võivad olla tervetel inimestel kahjulikud aju funktsioonile ja kognitsioonile, võivad nad arendada kohanemisvastaseid põletikuga seotud mehhanisme, et leevendada aju- ja kognitiivseid defitsiite FES-is. Mikroglia ümberprogrammeerimine võib pakkuda eeliseid skisofreenias, eriti stressitaju osas. Peale selle toob amügdaloidse mikroglia aktivatsioon, mida võib potentsiaalselt modulleerida Plxnb2, esile uue rakulise ja molekulaarse mehhanismi, mis on seotud skisofreeniaga seotud erinevate stressiomadustega. See uurimus pakub väärtuslikke teadmisi keerulise seose kohta stressi, monotsüütide/mikroglia funktsiooni ja neuronite tulemuste vahel skisofreenias, sillutades teed tulevastele uuringutele ja potentsiaalsetele terapeutilistele sekkumistele.
Schizophrenia, a complex neuropsychiatric disorder, affects approximately 1% of the global population and poses significant challenges in understanding its pathobiological mechanisms. This thesis aims to unravel the role of monocytes and microglia in neuroinflammatory processes in schizophrenia, particularly in the context of stress. Our investigations focused on first episode schizophrenia (FES) patients and animal stress models to elucidate molecular mechanisms mediated by these immune cells. In FES patients, alterations in monocyte-related transcriptomic profiles were found, notably in nonclassical and intermediate monocytic subsets. Besides, FES patients who exhibited higher stress sensitivity had smaller hippocampal structures and altered gene expression related to immune development. Microglial renewal partially mitigated psychiatric-like behavioral deficits induced by chronic unpredictable stress (CUS) in mice, via affecting brain transcriptomics involved in developmental processes, such as axonal and synaptic formation. Furthermore, FES patients with lower stress traits had smaller amygdala and higher PLXNB2 expression, which was negatively correlated with perceived stress severity. In mice, CUS led to a downregulation of Plxnb2 expression, and blocking Plxnb2 induced anxiety, amygdaloid enlargement, and microglial ramification. These findings suggest that while monocytic subsets and their genes can be detrimental for brain function and cognition in healthy individuals, they may develop maladaptive inflammation-related mechanisms to alleviate brain and cognitive deficits in FES. Microglial reprogramming might offer benefits in schizophrenia, particularly in stress perception. Furthermore, amygdaloid microglial activation, potentially modulated by Plxnb2, highlights a novel cellular and molecular mechanism underlying different stress traits associated with schizophrenia. This research provides valuable insights into the complex interplay between stress, monocytes/microglia function, and neuronal outcomes in schizophrenia, paving the way for future research and potential therapeutic interventions.
Schizophrenia, a complex neuropsychiatric disorder, affects approximately 1% of the global population and poses significant challenges in understanding its pathobiological mechanisms. This thesis aims to unravel the role of monocytes and microglia in neuroinflammatory processes in schizophrenia, particularly in the context of stress. Our investigations focused on first episode schizophrenia (FES) patients and animal stress models to elucidate molecular mechanisms mediated by these immune cells. In FES patients, alterations in monocyte-related transcriptomic profiles were found, notably in nonclassical and intermediate monocytic subsets. Besides, FES patients who exhibited higher stress sensitivity had smaller hippocampal structures and altered gene expression related to immune development. Microglial renewal partially mitigated psychiatric-like behavioral deficits induced by chronic unpredictable stress (CUS) in mice, via affecting brain transcriptomics involved in developmental processes, such as axonal and synaptic formation. Furthermore, FES patients with lower stress traits had smaller amygdala and higher PLXNB2 expression, which was negatively correlated with perceived stress severity. In mice, CUS led to a downregulation of Plxnb2 expression, and blocking Plxnb2 induced anxiety, amygdaloid enlargement, and microglial ramification. These findings suggest that while monocytic subsets and their genes can be detrimental for brain function and cognition in healthy individuals, they may develop maladaptive inflammation-related mechanisms to alleviate brain and cognitive deficits in FES. Microglial reprogramming might offer benefits in schizophrenia, particularly in stress perception. Furthermore, amygdaloid microglial activation, potentially modulated by Plxnb2, highlights a novel cellular and molecular mechanism underlying different stress traits associated with schizophrenia. This research provides valuable insights into the complex interplay between stress, monocytes/microglia function, and neuronal outcomes in schizophrenia, paving the way for future research and potential therapeutic interventions.
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