Astrocytes Contribute to Remote Memory Formation by Modulating Hippocampal-Cortical Communication During Learning

Abstract

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...

Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways

“…One explanation for this finding is that activation of V1 astrocytes is sufficient to recruit subcortical circuitry, such as thalamocortical circuits, that can underlie brain-wide synchronous events ( Steriade, 2006 ; Crunelli et al, 2018 ). This hypothesis is supported by studies showing subcortical ‘bottom-up’ regulation of slow oscillations ( Steriade et al, 1993 ; Siclari et al, 2014 ; Bernardi et al, 2018 ) and a role of astrocytes in mediating communication between different brain areas ( Kol, 2019 ; Sardinha et al, 2017 ), and could be tested by simultaneously recording from thalamus and cortex during astrocyte activation.…”

Training-Induced Circuit-Specific Excitatory Synaptogenesis is Required for Effort Control

“…Indeed, astrocytes can sense and regulate neuronal activity (Martín et al, 2015;Ma et al, 2016;Stobart et al, 2018;Corkrum et al, 2020). Moreover, manipulating astrocytic activity is sufficient to impact animal behavior and control learning and memory (Suzuki et al, 2011;Adamsky et al, 2018;Kol et al, 2020). It has also been reported that astrocytes in the striatum and in the medial prefrontal cortex can control locomotor behaviors and goal-directed actions by mediating changes in synaptic and neuronal activity (Nagai et al, 2019;Mederos et al, 2020;Corkrum et al, 2020).…”

“…ACC is known to receive VGluT1 inputs from the Claustrum (CLA) and Hippocampus (Chia et al, 2020;Kol et al, 2020;Qadir et al, 2018;White et al, 2018). Moreover, it also receives a plethora of neuromodulatory inputs from the Ventral Tegmental Area (VTA) and the Raphe nuclei (Sun et al, 2019;Elston et al, 2019).…”

Impairments in remote memory caused by the lack of Type 2 IP3 receptors

“…Note added in proof: An independent report corroborating the ability of astrocytic signaling to modulate the strength of the CA3‐CA1 synapse and remote, but not recent, memory has recently appeared in bioRxiv (Kol et al, ). In this elegant study, additional mechanistic insights on this topic are examined.…”