eIF2α controls memory consolidation via excitatory and somatostatin neurons

Sharma, Vidya; Sood, Rapita; Khlaifia, Abdessattar; Eslamizade, Mohammad Javad; Hung, Tzu-Yu; Lou, Danning; Asgarihafshejani, Azam; Lalzar, Maya; Kiniry, Stephen J; Stokes, Matthew P.; Cohen, Noah; Nelson, Alissa J.; Abell, Kathryn; Possemato, Anthony; Gal-Ben-Ari, Shunit; Truong, Vinh Tai; Wang, Peng; Yiannakas, Adonis; Saffarzadeh, Fatemeh; Cuello, A. Claudio; Nader, Karim; Kaufman, Randal J.; Costa-Mattioli, Mauro; Baranov, Pavel V.; Quintana, Albert; Sanz, Elisenda; Khoutorsky, Arkady; Lacaille, Jean‐Claude; Rosenblum, Kobi; Sonenberg, Nahum

doi:10.1038/s41586-020-2805-8

Cited by 83 publications

(68 citation statements)

References 44 publications

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“…Taken together, our results point towards a learning-dependent plasticity mechanism that entrains the GABAergic system in relation to experience, as to impose a temporal code of firing onto specific excitatory circuits during recall. In line with other recent reports, we demonstrate that the ability of distinct brain regions to acquire and retrieve of information, might in fact be subserved by distinct components of the local circuit and over different time scales 21, 32 . Several upstream circuits might be involved in the modulation aIC PV activity during CTA retrieval, including thalamocortical and amygdalocortical projections 55 , as well as the parabrachial nucleus 14 and basal forebrain 56 .…”

Section: Discussionsupporting

confidence: 92%

“…Surprisingly, considering pharmacological studies 14, 15 , inhibition of aIC GAD during CTA acquisition mildly enhanced aversive responses upon retrieval testing (Figure 1D, p=0.0232). Nonetheless, this result would be consistent both with the intricacies in the function among interneuron subtypes 16 , as well as the disinhibition and augmentation of CaMKII neuron function 21 . Contrariwise, inhibition of aIC GAD acutely suppressed aversive memory retrieval (Figure 1F, p<0.0001).…”

Section: Resultssupporting

confidence: 73%

“…Currently, little is known regarding the biological mechanisms underlying memory retrieval in general, and CTA retrieval specifically 8, 13 . We and others have provided evidence that memory retrieval is improved by interventions that directly or indirectly enhance excitatory input in relevant brain structures during acquisition 21, 22, 25, 32 . Yet, cortical pyramidal neurons exhibit a multitude of activity patterns depending on the behavior and the circuitry involved, while following learning, individual neurons show relatively stable ratios of excitatory and inhibitory conductance 33 .…”

Section: Discussionmentioning

confidence: 95%

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Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala orchestrates aversive taste memory retrieval

Yiannakas

Chandran²,

Kayyal³

et al. 2021

Preprint

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Memory retrieval refers to the fundamental ability of organisms to make use of acquired, sometimes inconsistent, information about the world. While memory acquisition has been studied extensively, the neurobiological mechanisms underlying memory retrieval remain largely unknown. The anterior insula (aIC) is indispensable in the ability of mammals to retrieve associative information regarding tastants that have been previously linked with gastric malaise. Here, we show that aversive taste memory retrieval promotes cell-type-specific activation in the aIC. Aversive, but not appetitive taste memory retrieval, relies on specific changes in activity and connectivity at parvalbumin (PV) inhibitory synapses onto aIC pyramidal neurons projecting to the basolateral amygdala. PV aIC interneurons, coordinate aversive taste memory retrieval, and are necessary for its dominance when conflicting internal representations are encountered. This newly described interaction of PV and subset of excitatory neurons can explain the coherency of aversive memory retrieval, an evolutionary pre-requisite for animal survival in nature.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 95%

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Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala orchestrates aversive taste memory retrieval

Yiannakas

Chandran²,

Kayyal³

et al. 2021

Preprint

Self Cite

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“…Our findings are consistent with studies showing long-lasting synaptic potentiation in CeL SOM inhibitory neurons following threat learning that lasts at least 24 hours 17 . Moreover, expressing biallelic phosphomutant eIF2α in SOM INs brainwide results in enhanced cued and contextual LTM 28 . In a contrasting but complementary role, de novo translation in PKCδ INs serves to store the conditioned-safety response.…”

mentioning

confidence: 99%

Amygdala inhibitory neurons as loci for translation in emotional memories

Shrestha

Shan

Mamcarz

et al. 2020

Nature

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To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger 1 . Survival also depends on suppressing the threat-response during a stimulus that predicts absence of threat, i.e. safety 2 – 5 . Understanding the biological substrates of emotional memories in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as PTSD 5 . A key brain area for processing and storing threat memories is the centrolateral amygdala (CeL), which is an important node in the neuronal circuit mediating defensive responses 6 – 9 . Here, we applied intersectional chemogenetic strategies in CeL inhibitory neurons (INs) to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α), respectively. We show that de novo translation in CeL Somatostatin-expressing (SOM) INs is necessary for long-term storage of conditioned-threat response whereas de novo translation in CeL protein kinase Cδ (PKCδ)-expressing INs is necessary for conditioned-response inhibition to a safety cue. Our results provide new insight into the role of de novo protein synthesis in distinct CeL inhibitory neuron populations during consolidation of long-term memories.

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“…Moreover, noncentrosomal MTs appear to be specifically involved in these mechanisms 57,61,62 . Because eIF2a phosphorylation and PERK activity modulate memory stability and learning [63][64][65] , it will be interesting to study the relevance of our findings in these contexts. Future studies focusing on the impact of these mechanisms on directional vesicle trafficking and de novo membrane formation, which seem to be relevant for protrusion formation, may also shed light on these questions 56 .…”

mentioning

confidence: 97%

PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape

Sánchez-Álvarez

Lolo

Sailem

et al. 2021

Preprint

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The architecture of the endoplasmic reticulum (ER) is tightly controlled as a key determinant of its function. Its dynamics are linked to those of the cytoskeleton, but our understanding of how this coordination occurs and what its functional relevance is, is limited. We found the Unfolded Protein Response (UPR) transducer EIF2AK3/PERK is essential for acute stress-induced peripheral redistribution and remodeling of the ER, through eIF2a phosphorylation and translation initiation shutdown. PERK-mediated eIF2a phosphorylation can be bypassed by blocking ribosome activity; by depleting microtubule-anchoring ER proteins such as REEP4, p180/RRBP1 and Climp63/CKAP4; or by disrupting the microtubule cytoskeleton. Notably, specific disruption of non-centrosomal microtubules, but not centrosome depletion, relieved blockade of ER redistribution in PERK-deficient cells. Conversely, PERK deficiency stabilized non-centrosomal microtubules, promoting polarized protrusiveness in epithelial cells and neuroblasts. We propose that PERK coordinates ER architecture and homeostasis with cell morphogenesis by coupling ER remodeling and non-centrosomal MT dynamics.

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eIF2α controls memory consolidation via excitatory and somatostatin neurons

Abstract: Additional informationPeer review information Nature thanks the anonymous reviewers for their contribution to the peer review of this work.

Cited by 83 publications

References 44 publications

Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala orchestrates aversive taste memory retrieval

Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala orchestrates aversive taste memory retrieval

Amygdala inhibitory neurons as loci for translation in emotional memories

PERK-dependent reciprocal crosstalk between ER and non-centrosomal microtubules coordinates ER architecture and cell shape

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