Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation.
Joana MacedoBruna AraújoSandra I AnjoTiago Silveira-RosaPatrícia PatrícioNuno Dinis AlvesJoana Margarida SilvaFábio G TeixeiraBruno ManadasAna João RodriguesAngelo C LeporeAntónio J SalgadoEduardo D GomesLuisa PintoPublished in: Molecular psychiatry (2024)
Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.
Keyphrases
- major depressive disorder
- cerebral ischemia
- bipolar disorder
- induced apoptosis
- neuropathic pain
- traumatic brain injury
- spinal cord
- cell cycle arrest
- oxidative stress
- spinal cord injury
- white matter
- subarachnoid hemorrhage
- resting state
- brain injury
- diabetic rats
- high glucose
- blood brain barrier
- multiple sclerosis
- cell proliferation
- deep brain stimulation
- cell death
- young adults
- neural stem cells
- drug induced
- gestational age
- preterm birth