Neuronal activity drives IGF2 expression from pericytes to form long-term memory.

Investigations of memory mechanisms have been, thus far, neuron centric, despite the brain comprising diverse cell types. Using rats and mice, we assessed the cell-type-specific contribution of hippocampal insulin-like growth factor 2 (IGF2), a polypeptide regulated by learning and required for long-term memory formation. The highest level of hippocampal IGF2 was detected in pericytes, the multi-functional mural cells of the microvessels that regulate blood flow, vessel formation, the blood-brain barrier, and immune cell entry into the central nervous system. Learning significantly increased pericytic Igf2 expression in the hippocampus, particularly in the highly vascularized stratum lacunosum moleculare and stratum moleculare layers of the dentate gyrus. Igf2 increases required neuronal activity. Regulated hippocampal Igf2 knockout in pericytes, but not in fibroblasts or neurons, impaired long-term memories and blunted the learning-dependent increase of neuronal immediate early genes (IEGs). Thus, neuronal activity-driven signaling from pericytes to neurons via IGF2 is essential for long-term memory.

A human model of asthma exacerbation reveals transcriptional programs and cell circuits specific to allergic asthma.

Asthma is a chronic disease most commonly associated with allergy and type 2 inflammation. However, the mechanisms that link airway inflammation to the structural changes that define asthma are incompletely understood. Using a human model of allergen-induced asthma exacerbation, we compared the lower airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA sequencing. In response to allergen, the asthmatic airway epithelium was highly dynamic and up-regulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. IL9-expressing pathogenic TH2 cells were specific to asthmatic airways and were only observed after allergen challenge. Additionally, conventional type 2 dendritic cells (DC2 that express CD1C) and CCR2-expressing monocyte-derived cells (MCs) were uniquely enriched in asthmatics after allergen, with up-regulation of genes that sustain type 2 inflammation and promote pathologic airway remodeling. In contrast, allergic controls were enriched for macrophage-like MCs that up-regulated tissue repair programs after allergen challenge, suggesting that these populations may protect against asthmatic airway remodeling. Cellular interaction analyses revealed a TH2-mononuclear phagocyte-basal cell interactome unique to asthmatics. These pathogenic cellular circuits were characterized by type 2 programming of immune and structural cells and additional pathways that may sustain and amplify type 2 signals, including TNF family signaling, altered cellular metabolism, failure to engage antioxidant responses, and loss of growth factor signaling. Our findings therefore suggest that pathogenic effector circuits and the absence of proresolution programs drive structural airway disease in response to type 2 inflammation.