Project description:Recalled memories become transiently labile and require stabilization. The mechanism for specifically stabilizing memories of critical experiences essential for survival, which are often emotionally salient and repeated, remains unclear. Here, we identified an astrocytic ensemble that is transcriptionally primed by emotional experience and functionally triggered by repeated experience to stabilize labile memory. Using our novel brain-wide Fos tagging and imaging method, we found that astrocytic Fos ensembles were preferentially recruited in regions with neuronal engrams and were more widespread during fear recall than conditioning. We established the induction mechanism of the astrocytic ensemble, which involves two steps: (i) an initial fear experience inducing day-long, slow astrocytic state changes with noradrenaline (NA) receptor upregulation, and (ii) enhanced NA responses during recall, a repeated experience, enabling astrocytes to integrate coincident signals from local engrams and long-range NA projections, inducing secondary astrocytic state changes, including the upregulation of Fos and the neuromodulatory molecule Igfbp2. Pharmacological and genetic perturbation of the astrocytic ensemble signaling modulate engrams, and memory stability and precision. The astrocytic ensemble therefore is as a multiday trace left in a subset of astrocytes after experience-dependent neural activity, making them eligible to capture future repeated experiences for stabilizing memories.
Project description:Gene expression profiling following different learning paradigms may help in defining the moleular pathways of memory formation. In this study we analyzed the gene expression pattern of murine hippocampus at different time points (0.5 h, 2h, 6h) after trace fear conditioning. We compared trained mice with naive mice that remained in their homecages. Keywords: Time course We used 3 arrays for each experimental condition. Each array was hybridized witha a pool of RNA of 6 animals.
Project description:The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.
Project description:Gene expression profiling following different learning paradigms may help in defining the moleular pathways of memory formation. In this study we analyzed the gene expression pattern of murine hippocampus at different time points (0.5 h, 2h, 6h) after trace fear conditioning. We compared trained mice with naive mice that remained in their homecages. Keywords: Time course