The molecular and cellular mechanisms of brain plasticity impairing factors
Kuupäev
2024-07-15
Autorid
Ajakirja pealkiri
Ajakirja ISSN
Köite pealkiri
Kirjastaja
Abstrakt
Aju on plastiline ehk võimeline kohanema ja muutma oma struktuuri ning funktsioone arengu käigus, õppimisel, mälu tekkel ning paranemisel pärast kahjustust. Täiskasvanuea neurogenees hipokampuses on unikaalne aju plastilisuse vorm, mis panustab mälu funktsioonidesse ja meeleolu regulatsiooni ning mille häirumist seostatakse mäluhäirete ja depressiooniga. Häired aju plastilisuses toimuvad ka sõltuvuse korral dopamiini signaaliedastusega seotud aju piirkondades. Varasemad loomuuringud on viidanud, et sõltuvuskäitumisele aluseks olevaid geeniekspressiooni muutusi ajus võivad vahendada epigeneetilised DNA modifitseerijad, DNA metüültransferaasid ja demetülaasid (DNMT ja TET perekonna ensüümid).
Käesoleva doktoritöö eesmärk oli selgitada aju plastilisust kahjustavate tegurite, nagu krooniline neuropaatiline valu, D-vitamiini defitsiit (DVD), krooniline stress ja psühhostimulandid, rakulisi ja molekulaarseid mehhanisme. Meie tulemused hiire loommudelis näitasid, et krooniline neuropaatiline valu põhjustas ärevust ja depressioonilaadset käitumist ning mäluhäireid, millega kaasnesid neurogeneesi pärssumine ning mikrogliia reaktiivsuse suurenemine. Pikaajaline DVD põhjustas hiirtel häireid lühi- ja pikaajalises mälus, ümberõppimise võimes ja enesehoolitsuskäitumises ning hipokampuses täheldasime neurogeneesi langust ja neuropõletiku ilminguid. DVD poolt põhjustatud käitumuslikud ja aju plastilisuse muutused ei võimendunud kroonilise stressi toimel. Katsetes, millega hindasime kuidas mõjutavad psühhostimulandid DNMT ja TET ensüüme inimese vere rakkude mudelis, leidsime, et korduvad töötlused psühhostimulantidega vähendasid TET ensüümide aktiivsust ja põhjustasid muutusi põletikutsütokiinide profiilis. Samaaegsed inkubatsioonid kokaiini ja DNMT inhibiitoriga inhibeerisid kokaiini toimet TET ensüümide aktiivsusele, kuid DNMT inhibeerimise ravipotentsiaal vajab täiendavaid uuringuid.
Kokkuvõtvalt aitavad käesoleva töö tulemused mõista, kuidas mõjutavad erinevad patoloogiad ja keskkonnategurid täiskasvanuea neurogeneesi ja gliiarakkude reaktiivsust ning epigeneetilisi DNA modifitseerijaid, ning selgitada, kuidas tuvastatud mehhanismid võivad panustada kaasuvate käitumuslike muutuse tekkesse. Saadud teadmised aju plastilisuse alusmehhanismidest võivad tulevikus aidata kaasa ennetus- ja ravistrateegiate väljatöötamisele.
The brain is plastic, i.e., able to adapt and change its structure and functions during development, learning, memory formation, and recovery following injury. Adult hippocampal neurogenesis is a unique form of brain plasticity that contributes to memory encoding and mood regulation, and its dysfunctions are associated with depression and memory impairments. Impairments in brain plasticity also take place in the brain's dopaminergic reward region during addiction. Animal studies have suggested that alterations in gene expression, which underlie addiction, may be mediated by epigenetic DNA editors, DNA methyltransferases, and demethylases (DNMT and TET enzymes). The current thesis aims to elucidate the cellular and molecular mechanisms of brain plasticity-impairing factors, such as chronic neuropathic pain, vitamin D deficiency (VDD), chronic stress, and psychostimulant exposure. Chronic neuropathic pain induced anxiety and depressive-like behavior, as well as memory impairments in mice, and these impairments were accompanied by reduced neurogenesis and increased microglial reactivity. Long-term VDD induced impairments in short- and long-term memory, relearning abilities, and self-care behaviors in mice co-occurred with decreased neurogenesis and signs of neuroinflammation. However, VDD did not further worsen the adverse effects of chronic stress. We also evaluated how psychostimulants affect DNMT and TET enzymes in human peripheral blood mononuclear cells. We found that repeated treatments with psychostimulants decreased the activity of TET enzymes and altered inflammatory cytokine profiles. Co-treatments with cocaine and a DNMT inhibitor reduced the effect of cocaine on the activity of TET enzymes. However, the therapeutic potential of DNMT inhibition needs further investigation. The results of the current study help to understand how different pathologies and environmental factors affect neurogenesis, glial reactivity, and epigenetic DNA modifiers. The observed reduction in neurogenesis and signs of neuroinflammation may contribute to behavioral alterations. The gained insights about fundamental brain plasticity mechanisms may contribute to developing future prevention and treatment strategies.
The brain is plastic, i.e., able to adapt and change its structure and functions during development, learning, memory formation, and recovery following injury. Adult hippocampal neurogenesis is a unique form of brain plasticity that contributes to memory encoding and mood regulation, and its dysfunctions are associated with depression and memory impairments. Impairments in brain plasticity also take place in the brain's dopaminergic reward region during addiction. Animal studies have suggested that alterations in gene expression, which underlie addiction, may be mediated by epigenetic DNA editors, DNA methyltransferases, and demethylases (DNMT and TET enzymes). The current thesis aims to elucidate the cellular and molecular mechanisms of brain plasticity-impairing factors, such as chronic neuropathic pain, vitamin D deficiency (VDD), chronic stress, and psychostimulant exposure. Chronic neuropathic pain induced anxiety and depressive-like behavior, as well as memory impairments in mice, and these impairments were accompanied by reduced neurogenesis and increased microglial reactivity. Long-term VDD induced impairments in short- and long-term memory, relearning abilities, and self-care behaviors in mice co-occurred with decreased neurogenesis and signs of neuroinflammation. However, VDD did not further worsen the adverse effects of chronic stress. We also evaluated how psychostimulants affect DNMT and TET enzymes in human peripheral blood mononuclear cells. We found that repeated treatments with psychostimulants decreased the activity of TET enzymes and altered inflammatory cytokine profiles. Co-treatments with cocaine and a DNMT inhibitor reduced the effect of cocaine on the activity of TET enzymes. However, the therapeutic potential of DNMT inhibition needs further investigation. The results of the current study help to understand how different pathologies and environmental factors affect neurogenesis, glial reactivity, and epigenetic DNA modifiers. The observed reduction in neurogenesis and signs of neuroinflammation may contribute to behavioral alterations. The gained insights about fundamental brain plasticity mechanisms may contribute to developing future prevention and treatment strategies.
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