Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased. In vivo, astrocytic activation enhanced memory allocation; i.e., it increased neuronal activity in a task-specific way only when coupled with learning, but not in home-caged mice. Furthermore, astrocytic activation using either a chemogenetic or an optogenetic tool during acquisition resulted in memory recall enhancement on the following day. Conversely, directly increasing neuronal activity resulted in dramatic memory impairment. Our findings that astrocytes induce plasticity and enhance memory may have important clinical implications for cognitive augmentation treatments.

The consolidation and retrieval of remote memories depend on the coordinated activity of the hippocampus and frontal cortices. However, the exact time at which these regions are recruited to support memory and the interactions between them are still debated. Astrocytes can sense and modify neuronal activity with great precision, but their role in cognitive function has not been extensively explored. To investigate the role of astrocytes in remote memory we expressed the Gi-coupled receptor hM4Di in CA1 astrocytes, allowing their manipulation by a designer drug. We discovered that astrocytic modulation during learning resulted in a specific impairment in remote, but not recent, memory recall, accompanied by decreased neuronal activity in the anterior cingulate cortex (ACC) during retrieval. We revealed a massive recruitment of ACC-projecting neurons in CA1 during memory acquisition, accompanied by activation of ACC neurons. Astrocytic Gi activation disrupted CA3 to CA1 communication in-vivo, and reduced the downstream response in the ACC. This same manipulation in behaving mice induced a projection-specific inhibition of ACCprojecting CA1 neurons during learning, consequently preventing the recruitment of the ACC. Our findings suggest that the foundation of remote memory is established in the ACC during acquisition, engaging a distinct process from the one supporting consolidation of recent memory. Furthermore, the mechanism underlying remote memory involves projection-specific functions of astrocytes in regulating neuronal activity.

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1The consolidation and retrieval of remote memories depend on the coordinated activity of 2 the hippocampus and frontal cortices. However, the exact time at which these regions are 3 recruited to support memory and the interactions between them are still debated. Astrocytes 4 can sense and modify neuronal activity with great precision, but their role in cognitive 5 function has not been extensively explored. To investigate the role of astrocytes in remote 6 memory we expressed the Gi-coupled receptor hM4Di in CA1 astrocytes, allowing their 7 manipulation by a designer drug. We discovered that astrocytic modulation during learning 8 resulted in a specific impairment in remote, but not recent, memory recall, accompanied by 9 decreased neuronal activity in the anterior cingulate cortex (ACC) during retrieval. We 10 revealed a massive recruitment of ACC-projecting neurons in CA1 during memory 11 acquisition, accompanied by activation of ACC neurons. Astrocytic Gi activation disrupted 12 CA3 to CA1 communication in-vivo, and reduced the downstream response in the ACC. 13 This same manipulation in behaving mice induced a projection-specific inhibition of ACC-14 projecting CA1 neurons during learning, consequently preventing the recruitment of the 15 ACC. Our findings suggest that the foundation of remote memory is established in the ACC 16 during acquisition, engaging a distinct process from the one supporting consolidation of 17 recent memory. Furthermore, the mechanism underlying remote memory involves 18 projection-specific functions of astrocytes in regulating neuronal activity. 19 20 21 KEY WORDS 22 Astrocytes, Hippocampus, Anterior Cingulate Cortex (ACC), Fear conditioning, Remote 23 Memory, Non Associative Place Recognition, In-Vivo Recording, Chemogenetics, hM4Di, 24 Optogenetics, cFos, Neurogenesis.25 1Remote memories, weeks to decades long, continuously guide our behavior, and are 2 critically important to any organism, as the longevity of a memory is tightly connected to its 3 significance. The ongoing interaction between the hippocampus and frontal cortical regions 4 has been repeatedly shown to transform in the transition from recent (days long) to remote 5 memory 1-3 . However, the exact time at which each region is recruited, the duration for which 6 it remains relevant to memory function, and the interactions between these regions, are still 7 debated. 8Astrocytes are no longer considered to merely provide homeostatic support to neurons and 9 encapsulate synapses, as pioneering research has shown that astrocytes can also sense and 10 modify synaptic activity as an integral part of the 'tripartite synapse' 4,5 . Interestingly, 11 astrocytes demonstrate extraordinary specificity in their effects on neuronal circuits 6 , at 12 several levels: First, astrocytes differentially affect neurons based on their genetic identity. 13For example, astrocytes in the dorsal striatum selectively respond to, and modulate, the input 14 onto two populations of medium spiny neurons, expressing either D1 or D2 dopamine 15 re...

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