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...

Many neurodegenerative diseases are associated with the death of specific neuron types in particular brain regions. What makes the death of specific neuron types particularly harmful for the integrity and dynamics of the respective network is not well understood. To start addressing this question we used the most up-to-date biologically realistic dense neocortical microcircuit (NMC) of the rodent, which has reconstructed a volume of 0.3 mm3 and containing 31,000 neurons, ∼37 million synapses, and 55 morphological cell types arranged in six cortical layers. Using modern network science tools, we identified hub neurons in the NMC, that are connected synaptically to a large number of their neighbors and systematically examined the impact of abolishing these cells. In general, the structural integrity of the network is robust to cells’ attack; yet, attacking hub neurons strongly impacted the small-world topology of the network, whereas similar attacks on random neurons have a negligible effect. Such hub-specific attacks are also impactful on the network dynamics, both when the network is at its spontaneous synchronous state and when it was presented with synchronized thalamo-cortical visual-like input. We found that attacking layer 5 hub neurons is most harmful to the structural and functional integrity of the NMC. The significance of our results for understanding the role of specific neuron types and cortical layers for disease manifestation is discussed.

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We developed an automatic morphometric reconstruction pipeline, Pop-Rec, and used it to study the morphologies of cortical cholinergic VIP/ChAT interneurons (VChIs). Cholinergic networks control high cognitive functions, but their local modulation and stress-driven plasticity patterns remained elusive. Reconstructing thousands of local VChIs registered to their exact coordinates in multiple cleared murine cortices highlighted distinct populations of bipolar and multipolar VChIs which differed in their dendritic spatial organization. Following mild unilateral whisker deprivation, Pop-Rec found both ipsi-and contra-lateral VChI dendritic arborization changes. Furthermore, RNA-seq of FACS-sorted VChIs showed differentially expressed dendritic, synapse and axon-modulating transcripts in whisker-deprived mice. Indicating novel steady-state morphological roles, those genes also clustered distinctly in naive single cell VChIs. This VChIs morphe-ome atlas is the first example of unbiased analysis of neuronal populations and holds the possibility to compare neuronal structure-function relationships across experimental conditions.

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