Rewiring of Memory Circuits: Connecting Adult Newborn Neurons With the Help of Microglia

Abstract

New neurons are continuously generated from stem cells and integrated into the adult hippocampal circuitry, contributing to memory function. Several environmental, cellular, and molecular factors regulate the formation of new neurons, but the mechanisms that govern their incorporation into memory circuits are less explored. Herein we will focus on microglia, the resident immune cells of the CNS, which modulate the production of new neurons in the adult hippocampus and are also well suited to participate in their circuit integration. Microglia may contribute to the refinement of brain circuits during development and exert a role in physiological and pathological conditions by regulating axonal and dendritic growth; promoting the formation, elimination, and relocation of synapses; modulating excitatory synaptic maturation; and participating in functional synaptic plasticity. Importantly, microglia are able to sense subtle changes in their environment and may use this information to differently modulate hippocampal wiring, ultimately impacting on memory function. Deciphering the role of microglia in hippocampal circuitry constant rewiring will help to better understand the influence of microglia on memory function.

High-Fat Diet-Induced Obesity Causes Sex-Specific Deficits in Adult Hippocampal Neurogenesis in Mice

“…6) to quantify the average area covered by cells positive for each of these antibodies, as well as their colocalization. The "inner" (bordering the hilus) and "outer" ROIs of the dentate gyrus were created separately, as microglia activity in these subregions could be differentially regulating neurogenesis (Gemma and Bachstetter, 2013;Rodríguez-Iglesias et al, 2019).…”

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

“…We found that phagocytosis of apoptotic cells reprogrammed microglia towards a neurogenic modulatory phenotype that was mostly related to their secretome, as the majority of the modulatory genes encoded secreted proteins, including neuropeptides such as VGF, and growth factors such as VEGF and FGF2, some of which have already been described to participate in the microglial regulation of neurogenesis (Kreisel et al, 2018). In addition, the microglial secretome may contain metabolites, miRNAs and extracellular vesicles, which may also alter neurogenesis (Rodriguez-Iglesias et al, 2019). When administered in vivo, the acute secretome of phagocytic microglia inhibited hippocampal neurogenesis, as it had an early tendency to decrease rNSCs that was later followed by a reduction in mature neuroblasts.…”

“…Furthermore, we found that both LPS and the secretome of LPS-stimulated microglia enhanced the production of neuroblasts in vitro, suggesting that inflammation is not as detrimental for neurogenesis as previously stated (Ekdahl et al, 2003;Monje et al, 2003) and that cytokines were not responsible for the effects of phagocytic microglial secretome on neural-committed cells. In addition, the neurogenic modulatory program initiated by phagocytosis encompassed genes involved in matrix remodeling (matrix metalloproteases) and membrane ligands (Jag1, ligand for Notch receptor), suggesting that the observed direct contact between microglia and rNSCs/neuroblasts (Sierra et al, 2010) may also participate in shaping the neurogenic niche through participating in the local control of neuroblast differentiation, survival and synaptic integration (Rodriguez-Iglesias et al, 2019).…”

Lactate: A Novel Signaling Molecule in Synaptic Plasticity and Drug Addiction

“…Furthermore, the inhibition of TXNIP‐associated oxidative stress attenuated the cognitive impairment in a model of vascular dementia . Considerable evidence indicates that microglia play a key role in synaptic plasticity, learning, and memory via the release of TNF‐α in a model related to fear memory, the production of lactate, and the modulation of structural plasticity such as LTD, synaptic pruning, axonal and dendritic growth . Thus, combining all the aforementioned findings, it is conceivable that lactate acts as a signaling molecule in synaptic plasticity and memory via modulating microglia in a neuronal activity‐dependent manner.…”

“…Cocaine-induced CPP [11,48,53,54] In [11,40,44,45,48,56] In dorsal hippocampus, increased Arc protein [57][58][59][60] www.advancedsciencenews.com www.bioessays-journal.com pruning, axonal and dendritic growth. [66][67][68] Thus, combining all the aforementioned findings, it is conceivable that lactate acts as a signaling molecule in synaptic plasticity and memory via modulating microglia in a neuronal activity-dependent manner.…”