Inbal Goshen

Astrocytes modulate brain processes such as neurotransmitter signaling, ion homeostasis, vascular tone, metabolism and synaptic transmission, and serve a critical role in complex brain functions. However, it remains unclear on which spatial scales these functions are organized in astrocytes and their networks: for instance, whether astrocytic interactions with neurons are organized into units at the level of individual perisynaptic processes and synapses, astrocytic domains covering synapse populations, or astrocytic networks controlling local neuronal circuits. Here we analyze astrocytic morphological features and molecular heterogeneity to define the multiple spatial scales on which astrocytes operate. We further discuss evidence regarding their intracellular and intercellular signaling, their role in neurotransmitter homeostasis and their neurotransmitter-mediated dialog with neurons, supporting the existence of astrocytic functional units with distinct spatial scales. We propose that astrocytes constitute a multilayered system of functional units that operate across multiple spatial scales, thereby increasing the degrees of freedom in brain information processing.

Recent research has revealed the crucial role of astrocytes in memory processes, challenging the traditional view of exclusively neuronal‐based cognitive functions. This review summarizes current findings on astrocytic involvement in memory, focusing on their interactions with neurotransmitters, various biomolecules, and neurons in different brain regions. We include studies that discuss how astrocytes modulate synaptic transmission and contribute to plasticity, thereby influencing memory formation, consolidation, and recall. We conclude by providing an overview of advanced techniques such as optogenetics, chemogenetics, calcium imaging, and engram research, which have provided new insights into the function of astrocytes and their role in memory processes. image

Neural and glial dysfunction are thought to underlie memory impairments in Alzheimer’s disease (AD). Conversely, astrocytes are known to play a central role in the healthy brain, and their activation has been shown to enhance memory. To test whether activation of astrocytes can correct memory deficits associated with AD, we expressed hM3Dq in CA1 astrocytes of 7 months old 5XFAD AD model mice, enabling astrocytic chemogenetic Gq pathway activation, following exposure to CNO. We report that astrocytic activation results in complete memory correction, and even memory improvement of AD model mice beyond that of untreated WT levels. We went further to discover the mechanisms underlying this memory improvement in AD mice: First, using 2-photon imaging and electrophysiology, we observed increased neuronal activity (displayed as elevated cFos expression and amplified awake Ca ²⁺ events) as well as augmented in-vivo long term plasticity following astrocytic activation. Subsequently, we observed increased astrocytic endocytosis of Aβ plaques. Finally, we report that the beneficial effects of astrocytic activation remained stable for an entire year, and persisted beyond the window of astrocytic Gq activation. Our findings that astrocytes correct memory impairments in an AD model could have important clinical implications towards treating this disease.

Recent and remote memories are encoded throughout the brain in ‘Engrams’: cell ensembles formed during acquisition, and upon their reactivation, a specific memory can be recalled. The maturation of engrams from recent to remote time points involves the recruitment of CA1 neurons projecting to the anterior cingulate cortex (CA1→ACC). Various modifications to CA1 astrocytes, to the Gq- or Gi-GPCR pathways, during memory acquisition were shown to affect recent and remote recall in seemingly contradictory ways. To address the inconsistency, we applied transgenic approaches for ensemble identification, CLARITY, retro-AAV virus for circuit mapping, and chemogenetics in astrocytes for functional investigation. We manipulated the activity of either Gq- or Gi-pathways in CA1 astrocytes during memory acquisition and tagged cFos+ engram cells and CA1→ACC cells during recent and remote recall in the same animals. The behavioral results were coupled with changes in the recruitment of CA1→ACC projection cells to the engram, demonstrated by the number of CA1→ACC projecting cells in the engram as well as the number of axons projecting from the CA1 engram toward the ACC: Gq pathway activation in astrocytes caused enhancement of recent recall alone and was accompanied by earlier recruitment of CA1→ACC projecting cells to the engram. In contrast, when activating the Gi pathway in astrocytes during acquisition, only remote recall was impaired, and CA1→ACC projecting cells were not recruited during remote memory. Finally, we provide a simple working model, hypothesizing that astrocytes control behavioral performance by targeting the CA1→ACC projection. Specifically, that Gq- and Gi-pathway activation affect memory differently, but do so by modulating the same mechanism. These findings illuminate the importance of astrocytes in the acquisition of fear memory and their implications on recent and remote recall.

Astrocytic calcium dynamics has been implicated in the encoding of sensory information^1,2,3,4,5, and modulation of calcium in astrocytes has been shown to affect behaviour^6,7,8,9,10. However, longitudinal investigation of the real-time calcium activity of astrocytes in the hippocampus of awake mice is lacking. Here we used two-photon microscopy to chronically image CA1 astrocytes as mice ran in familiar or new virtual environments to obtain water rewards. We found that astrocytes exhibit persistent ramping activity towards the reward location in a familiar environment, but not in a new one. Shifting the reward location within a familiar environment also resulted in diminished ramping. After additional training, as the mice became familiar with the new context or new reward location, the ramping was re-established. Using linear decoders, we could predict the location of the mouse in a familiar environment from astrocyte activity alone. We could not do the same in a new environment, suggesting that the spatial modulation of astrocytic activity is experience dependent. Our results indicate that astrocytes can encode the expected reward location in spatial contexts, thereby extending their known computational abilities and their role in cognitive functions.

Remote memories play an important role in how we perceive the world and are rooted in ensembles in the CA1 and ACC, however the evolution of these components during systems consolidation has not yet been comprehensively addressed. By applying transgenic approaches for ensemble identification, CLARITY, retro-AAV and rabies virus for circuit mapping, and chemogenetics for functional interrogation, we addressed the dynamics of CA1-ACC ensembles and their connectivity as well as the contribution of astrocytes to the process. We found that the CA1 engrams remain stable between recent and remote recall, and, the inhibition of the engram for recent recall during remote recall functionally impairs memory. We also found that the new cells in the remote recall engram in the CA1 are not added randomly, but differ according to their connections: First, the anterograde CA1 → ACC engram cell projection grows larger. Second, in the retrograde projections, the ACC reduces input to CA1 engram cells, while input from the entorhinal cortex and paraventricular nucleus of the thalamus increases. Finally, we found that activating CA1 astrocytes during acquisition improves recent but not remote recall, and that CA1 → ACC projecting cells are recruited earlier when the astrocytes are stimulated. Our results shine fresh light on systems consolidation by providing a deeper understanding of engram stability and maturation in the transition from recent to remote memory.