Functionally Distinct Neuronal Ensembles within the Memory Engram

Sun, Xiaochen; Bernstein, Max J.; Meng, Meizhen; Rao, Siyuan; Sørensen, Andreas T.; Yao, Li; Zhang, Xiaohui; Anikeeva, Polina; Lin, Yingxi

doi:10.1016/j.cell.2020.02.055

Cited by 185 publications

(189 citation statements)

References 100 publications

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“…Rare mutations in Nlgn3 have been reported in patients with ID, SCZ and ASDs (Jamain et al, 2003;Parente et al, 2017;Yan et al, 2005). Interestingly, ASD patients show abnormalities in memory discrimination (Beversdorf et al, 2000), which is partly mediated by the activity of hippocampal Cck+ interneurons (Sun et al, 2020;Whissell et al, 2019). This autistic phenotype may be caused by abnormal trans-synaptic interactions of αNrxn1 and Nlgn3 at VGT3+ synapses.…”

Section: Discussionmentioning

confidence: 99%

A Specific Neuroligin3-αNeurexin1 Code Regulates GABAergic Synaptic Function in Mouse Hippocampus

Uchigashima

Konno

Demchak

et al. 2020

Preprint

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Synapse formation and regulation require interactions between pre-and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here, we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn-Nrxn interactions generate distinct functional properties at synapses.

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Section: Discussionmentioning

confidence: 99%

A Specific Neuroligin3-αNeurexin1 Code Regulates GABAergic Synaptic Function in Mouse Hippocampus

Uchigashima

Konno

Demchak

et al. 2020

Preprint

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“…Since TRAP is based on recombination, it would be possible to specifically express genes of interest in the Quinine-TRAPed cells. By combining with Cre-dependent optogenetic/chemogenetic tools, it would be possible to specifically manipulate the activity of TRAPed cells [23,24,28,29,31,32] in the CeA to understand their physiological roles in disgust reactions and conscious disgust [50].…”

Section: Genetic Access To Quinine-activated Neurons In the Ceamentioning

confidence: 99%

“…While the quinine-activated disgust-associated neurons in the IPAC are preferentially accessible by a targeted recombination in active populations (TRAP) method [8,19], it remains unclear whether the accessibility is restricted to the IPAC or not. It is interesting to investigate whether the quinine-activated neurons in the CeA [7] are accessible by TRAP because of the following reasons: (1) the CeA is one of the well-known emotional centers but its role in the disgust reactions remains unclear; (2) the CeA consists of functionally heterogeneous neurons, and the expression of a single molecular marker and Cre transgenics in the molecularly defined neurons likely cannot capture the functional heterogeneity in the CeA [13,20,21]; (3) the CeA neurons are not successfully TRAPed by any stimuli [19,[22][23][24][25][26][27][28][29][30][31][32]; (4) the CeA and the IPAC, where a significant number of neurons were successfully TRAPed by quinine infusion [8], are directly continuous anatomically and are grouped as a part of the distinct anatomical division, the central division of the extended amygdala [9].…”

Section: Introductionmentioning

confidence: 99%

Genetic recombination in disgust-associated bitter taste-responsive neurons of the central nucleus of amygdala in male mice

Tanaka

Mukae

et al. 2020

Preprint

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A bitter substance induces specific orofacial and somatic behavioral reactions such as gapes in mice as well as monkeys and humans. These reactions have been proposed to represent affective disgust, and therefore, understanding the neuronal basis of the reactions would pave the way to understand affective disgust. It is crucial to identify and access the specific neuronal ensembles that are activated by bitter substances, such as quinine, the intake of which induces disgust reactions. However, the method to access the quinine-activated neurons has not been fully established yet. Here, we show evidence that a targeted recombination in active populations (TRAP) method, induces genetic recombination in the quinine-activated neurons in the central nucleus of the amygdala (CeA). CeA is one of the well-known emotional centers of the brain. We found that the intraoral quinine infusion, that resulted in disgust reactions, increased both cFos-positive cells and Arc-positive cells in the CeA. By using Arc-CreER;Ai3 TRAP mice, we induced genetic recombination in the quinine-activated neurons and labelled them with fluorescent protein. We confirmed that the quinine-TRAPed fluorescently-labelled cells preferentially coexpressed Arc after quinine infusion. Our results suggest that the TRAP method can be used to access specific functional neurons in the CeA.

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“…Moreover, recent studies have shown that discrete populations of cells contributing to a memory engram have distinct cellular activity, synaptic properties, and behavioral results dependent on the immediate early gene used to identify a given cellular ensemble (Sun et al 2020).…”

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confidence: 99%

“…Specifically, cFos-mediated engrams have been implicated in promoting memory generalization, such that acute chemogenetic activation of a contextual fear memory led to reduced discrimination between distinct contexts (Sun et al 2020). In parallel, chronic activation of a fear memory in a neutral context may have promoted generalization between the neutral and conditioned context, as evident by decreased freezing in the conditioned context.…”

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confidence: 99%

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

Cincotta

Murawski

Grella

et al. 2020

Preprint

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ABSTRACTAlcohol withdrawal directly impacts the brain’s stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning, however the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair fear extinction learning, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.

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Functionally Distinct Neuronal Ensembles within the Memory Engram

Cited by 185 publications

References 100 publications

A Specific Neuroligin3-αNeurexin1 Code Regulates GABAergic Synaptic Function in Mouse Hippocampus

A Specific Neuroligin3-αNeurexin1 Code Regulates GABAergic Synaptic Function in Mouse Hippocampus

Genetic recombination in disgust-associated bitter taste-responsive neurons of the central nucleus of amygdala in male mice

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

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