Erythropoietin re-wires cognition-associated transcriptional networks.
Manvendra SinghYing ZhaoVinicius Daguano GastaldiSonja M WojcikYasmina CurtoRiki KawaguchiRicardo M MerinoLaura Fernandez Garcia-AgudoHolger TaschenbergerNils BroseDaniel H GeschwindKlaus-Armin NaveHannelore EhrenreichPublished in: Nature communications (2023)
Recombinant human erythropoietin (rhEPO) has potent procognitive effects, likely hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO remained obscure. Here, we provide transcriptional hippocampal profiling of male mice treated with rhEPO. Based on ~108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as 'tool', we discover populations of newly differentiating pyramidal neurons, overpopulating to ~200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.
Keyphrases
- recombinant human
- spinal cord
- white matter
- cerebral ischemia
- gene expression
- genome wide
- transcription factor
- mild cognitive impairment
- single cell
- cell proliferation
- resting state
- multiple sclerosis
- heat shock
- magnetic resonance imaging
- signaling pathway
- working memory
- functional connectivity
- spinal cord injury
- dna methylation
- single molecule
- brain injury
- solid phase extraction
- molecularly imprinted
- blood brain barrier
- high resolution
- long non coding rna
- anti inflammatory
- subarachnoid hemorrhage
- mass spectrometry
- protein kinase