Cracking the neuronal code of episodic memory.

Hierarchical organization of memory is observed in the brains of rats.

Insulin-like growth factor-1 receptor controls the function of CNS-resident macrophages and their contribution to neuroinflammation.

Signaling by insulin-like growth factor-1 (IGF-1) is essential for the development of the central nervous system (CNS) and regulates neuronal survival and myelination in the adult CNS. In neuroinflammatory conditions including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), IGF-1 can regulate cellular survival and activation in a context-dependent and cell-specific manner. Notwithstanding its importance, the functional outcome of IGF-1 signaling in microglia/macrophages, which maintain CNS homeostasis and regulate neuroinflammation, remains undefined. As a result, contradictory reports on the disease-ameliorating efficacy of IGF-1 are difficult to interpret, together precluding its potential use as a therapeutic agent. To fill this gap, we here investigated the role of IGF-1 signaling in CNS-resident microglia and border associated macrophages (BAMs) by conditional genetic deletion of the receptor Igf1r in these cell types. Using a series of techniques including histology, bulk RNA sequencing, flow cytometry and intravital imaging, we show that absence of IGF-1R significantly impacted the morphology of both BAMs and microglia. RNA analysis revealed minor changes in microglia. In BAMs however, we detected an upregulation of functional pathways associated with cellular activation and a decreased expression of adhesion molecules. Notably, genetic deletion of Igf1r from CNS-resident macrophages led to a significant weight gain in mice, suggesting that absence of IGF-1R from CNS-resident myeloid cells indirectly impacts the somatotropic axis. Lastly, we observed a more severe EAE disease course upon Igf1r genetic ablation, thus highlighting an important immunomodulatory role of this signaling pathway in BAMs/microglia. Taken together, our work shows that IGF-1R signaling in CNS-resident macrophages regulates the morphology and transcriptome of these cells while significantly decreasing the severity of autoimmune CNS inflammation.

Autoimmune neuroinflammation triggers mitochondrial oxidation in oligodendrocytes.

Oligodendrocytes (ODCs) are myelinating cells of the central nervous system (CNS) supporting neuronal survival. Oxidants and mitochondrial dysfunction have been suggested as the main causes of ODC damage during neuroinflammation as observed in multiple sclerosis (MS). Nonetheless, the dynamics of this process remain unclear, thus hindering the design of neuroprotective therapeutic strategies. To decipher the spatio-temporal pattern of oxidative damage and dysfunction of ODC mitochondria in vivo, we created a novel mouse model in which ODCs selectively express the ratiometric H2 O2 biosensor mito-roGFP2-Orp1 allowing for quantification of redox changes in their mitochondria. Using 2-photon imaging of the exposed spinal cord, we observed significant mitochondrial oxidation in ODCs upon induction of the MS model experimental autoimmune encephalomyelitis (EAE). This redox change became already apparent during the preclinical phase of EAE prior to CNS infiltration of inflammatory cells. Upon clinical EAE development, mitochondria oxidation remained detectable and was associated with a significant impairment in organelle density and morphology. These alterations correlated with the proximity of ODCs to inflammatory lesions containing activated microglia/macrophages. During the chronic progression of EAE, ODC mitochondria maintained an altered morphology, but their oxidant levels decreased to levels observed in healthy mice. Taken together, our study implicates oxidative stress in ODC mitochondria as a novel pre-clinical sign of MS-like inflammation and demonstrates that evolving redox and morphological changes in mitochondria accompany ODC dysfunction during neuroinflammation.

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System.

The central nervous system (CNS) parenchyma is enclosed and protected by a multilayered system of cellular and acellular barriers, functionally separating glia and neurons from peripheral circulation and blood-borne immune cells. Populating these borders as dynamic observers, CNS-resident macrophages contribute to organ homeostasis. Upon autoimmune, traumatic or neurodegenerative inflammation, these phagocytes start playing additional roles as immune regulators contributing to disease evolution. At the same time, pathological CNS conditions drive the migration and recruitment of blood-borne monocyte-derived cells across distinct local gateways. This invasion process drastically increases border complexity and can lead to parenchymal infiltration of blood-borne phagocytes playing a direct role both in damage and in tissue repair. While recent studies and technical advancements have highlighted the extreme heterogeneity of these resident and CNS-invading cells, both the compartment-specific mechanism of invasion and the functional specification of intruding and resident cells remain unclear. This review illustrates the complexity of mononuclear phagocytes at CNS interfaces, indicating how further studies of CNS border dynamics are crucially needed to shed light on local and systemic regulation of CNS functions and dysfunctions.