Ja Eun Choi

All Publications

• Aberrant ERIC signaling in astrocytes impairs learning and memory in RASopathy-associated<i> BRAF</i> mutant mouse models JOURNAL OF CLINICAL INVESTIGATION Icang, M., Choi, J., Han, J., Araki, T., Icim, S., Ryu, H., Klm, M., Klm, S., Jang, H., Klm, S., Hwang, K., Klm, S., Yoo, M., Lee, J., Klm, K., Park, P., Choi, J., Han, D., Km, Y., Klm, J., Chang, S., Icaang, B., Ko, J., Cheon, K., An, J., Klm, S., Park, H., Neel, B. G., Klm, C., Lee, Y. 2025; 135 (8)

  View details for DOI 10.1172/JCI176631

  View details for Web of Science ID 001517378500002

• Processing of pain and itch information by modality-specific neurons within the anterior cingulate cortex in mice NATURE COMMUNICATIONS Ko, H., Jung, H., Han, S., Choi, D., Lee, C., Choi, J., Oh, J., Kwak, C., Han, D., Kim, J., Ye, S., Lee, J., Lee, J., Lee, K., Lee, J., Zhuo, M., Kaang, B. 2025; 16 (1): 2137

  Abstract

  Pain and itch are aversive sensations with distinct qualities, processed in overlapping pathways and brain regions, including the anterior cingulate cortex (ACC), which is critical for their affective dimensions. However, the cellular mechanisms underlying their processing in the ACC remain unclear. Here, we identify modality-specific neuronal populations in layer II/III of the ACC in mice involved in pain and itch processing. Using a synapse labeling tool, we show that pain- and itch-related neurons selectively receive synaptic inputs from mediodorsal thalamic neurons activated by pain and itch stimuli, respectively. Chemogenetic inhibition of these neurons reduced pruriception or nociception without affecting the opposite modality. Conversely, activation of these neurons did not enhance stimulus-specific responses but commonly increased freezing-like behavior. These findings reveal that the processing of itch and pain information in the ACC involves activity-dependent and modality-specific neuronal populations, and that pain and itch are processed by functionally distinct ACC neuronal subsets.

  View details for DOI 10.1038/s41467-025-57041-z

  View details for Web of Science ID 001439697700034

  View details for PubMedID 40038260

  View details for PubMedCentralID PMC11880300

• Review: Dopamine, Serotonin, and the Translational Neuroscience of Aggression in Autism Spectrum Disorder. JAACAP open Martin, H., Choi, J. E., Rodrigues, A. R., Eshel, N. 2025; 3 (1): 29-41

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a 1% to 2% prevalence in children. In addition to social communication deficits and restricted or repetitive behavior, ASD is often characterized by a heightened propensity for aggression. In fact, aggressive behavior is the primary reason for hospitalization in children with ASD, and current treatment options, despite some efficacy, are often associated with prominent side effects. Despite such high clinical toll, the neurobiology of aggression in ASD remains poorly understood.The neural circuits linked to both ASD and aggression were reviewed, with the goal of identifying overlapping components to help guide future treatment development. In discussing the clinical phenotype of aggression in ASD, some of the triggers and risk factors were noted to differ from those that cause aggression in neurotypical children. Preclinical and clinical studies on the neurobiology of aggression and ASD were synthesized to combine evidence from genetics, neuroimaging, pharmacology, and circuit manipulations. Dopamine and serotonin, 2 neuromodulators that contribute to development and behavioral control, were specifically studied.The literature indicates that the intricate interplay of the dopamine and serotonin systems has a pivotal role in shaping behavior, including the expression of aggression.Understanding the balance between dopamine as an accelerator and serotonin as a brake may provide insights into the mechanisms of aggression in children with ASD. Although much work remains to be done, new perspectives promise to bridge the gap between human and animal studies and pinpoint the neurobiology of aggression in ASD.One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group.

  View details for DOI 10.1016/j.jaacop.2024.01.010

  View details for PubMedID 40109493

  View details for PubMedCentralID PMC11914923

• Activated somatostatin interneurons orchestrate microcircuits NEURON Kim, T., Choi, D., Choi, J., Lee, H., Jung, H., Kim, J., Sung, Y., Park, H., Kim, M., Han, D., Lee, S., Kaang, B. 2024; 112 (2): 201-208.e4

  Abstract

  Despite recent advancements in identifying engram cells, our understanding of their regulatory and functional mechanisms remains in its infancy. To provide mechanistic insight into engram cell functioning, we introduced a novel local microcircuit labeling technique that enables the labeling of intraregional synaptic connections. Utilizing this approach, we discovered a unique population of somatostatin (SOM) interneurons in the mouse basolateral amygdala (BLA). These neurons are activated during fear memory formation and exhibit a preference for forming synapses with excitatory engram neurons. Post-activation, these SOM neurons displayed varying excitability based on fear memory retrieval. Furthermore, when we modulated these SOM neurons chemogenetically, we observed changes in the expression of fear-related behaviors, both in a fear-associated context and in a novel setting. Our findings suggest that these activated SOM interneurons play a pivotal role in modulating engram cell activity. They influence the expression of fear-related behaviors through a mechanism that is dependent on memory cues.

  View details for DOI 10.1016/j.neuron.2023.10.013

  View details for Web of Science ID 001164340700001

  View details for PubMedID 37944516

• Increased social interaction in <i>Shank2</i>-deficient mice following acute social isolation MOLECULAR BRAIN Choi, J., Kaang, B. 2023; 16 (1): 35

  Abstract

  Autism spectrum disorder (ASD) is neuropsychiatric disorder with a gender specific risk. Although social impairment in ASD is one of the well characterized phenotypes, loneliness issue resides in patients with ASD and emerging reports show gender distribution in symptoms. Acute social isolation increases the motivation to socially interact in a gender-dependent manner, as only the male mice show increase in sociability following isolation. However, it remains to be explored whether the effects of loneliness in ASD differ between genders. Here, we used Shank2-deficient (Shank2-/-) mice, one of the animal models of ASD, to examine the sociability changes after acute social isolation. While only the male wild-type (WT) mice display increased sociability following 24-h isolation, both sexes of Shank2-/- mice show an increase in social interaction following isolation. These observations provide evidence that animal models of ASD have the sensitivity to acute social isolation and further show the motivation to socially interact.

  View details for DOI 10.1186/s13041-023-01025-x

  View details for Web of Science ID 000968629800001

  View details for PubMedID 37061705

  View details for PubMedCentralID PMC10105924

• Synaptic ensembles between raphe and D1R-containing accumbens shell neurons underlie postisolation sociability in males. Science advances Choi, J. E., Choi, D. I., Lee, J., Kim, J., Kim, M. J., Hong, I., Jung, H., Sung, Y., Kim, J. I., Kim, T., Yu, N. K., Lee, S. H., Choe, H. K., Koo, J. W., Kim, J. H., Kaang, B. K. 2022; 8 (41): eabo7527

  Abstract

  Social animals expend considerable energy to maintain social bonds throughout their life. Male and female mice show sexually dimorphic behaviors, yet the underlying neural mechanisms of sociability and their dysregulation during social disconnection remain unknown. Dopaminergic neurons in dorsal raphe nucleus (DRNTH) is known to contribute to a loneliness-like state and modulate sociability. We identified that activated subpopulations in DRNTH and nucleus accumbens shell (NAcsh) during 24 hours of social isolation underlie the increase in isolation-induced sociability in male but not in female mice. This effect was reversed by chemogenetically and optogenetically inhibiting the DRNTH-NAcsh circuit. Moreover, synaptic connectivity among the activated neuronal ensembles in this circuit was increased, primarily in D1 receptor-expressing neurons in NAcsh. The increase in synaptic density functionally correlated with elevated dopamine release into NAcsh. Overall, specific synaptic ensembles in DRNTH-NAcsh mediate sex differences in isolation-induced sociability, indicating that sex-dependent circuit dynamics underlie the expression of sexually dimorphic behaviors.

  View details for DOI 10.1126/sciadv.abo7527

  View details for PubMedID 36223467

• Synaptic correlates of associative fear memory in the lateral amygdala NEURON Il Choi, D., Kim, J., Lee, H., Kim, J., Sung, Y., Choi, J., Venkat, S., Park, P., Jung, H., Kaang, B. 2021; 109 (17): 2717-+

  Abstract

  Successful adaptation to the environment requires an accurate response to external threats by recalling specific memories. Memory formation and recall require engram cell activity and synaptic strengthening among activated neuronal ensembles. However, elucidation of the underlying neural substrates of associative fear memory has remained limited without a direct interrogation of extinction-induced changes of specific synapses that encode a specific auditory fear memory. Using dual-eGRASP (enhanced green fluorescent protein reconstitution across synaptic partners), we found that synapses among activated neuronal ensembles or activated synaptic ensembles showed a significantly larger spine morphology at auditory cortex (AC)-to-lateral amygdala (LA) projections after auditory fear conditioning in mice. Fear extinction reversed these enhanced synaptic ensemble spines, whereas re-conditioning with the same tone and shock restored the spine size of the synaptic ensemble. We suggest that synaptic ensembles encode and represent different fear memory states.

  View details for DOI 10.1016/j.neuron.2021.07.003

  View details for Web of Science ID 000693584400009

  View details for PubMedID 34363751

• Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a <i>DSCAM</i> mutation and in <i>Dscam-</i>knockout mice MOLECULAR PSYCHIATRY Lim, C., Kim, M., Choi, J., Islam, M., Lee, Y., Xiong, Y., Shim, K., Yang, J., Lee, R., Lee, J., Park, P., Kwak, J., Seo, H., Kim, C., Lee, J., Lee, Y., Hwang, S., Lee, K., Lee, J., Kaang, B. 2021; 26 (12): 7538-7549

  Abstract

  Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.

  View details for DOI 10.1038/s41380-021-01216-9

  View details for Web of Science ID 000672317100003

  View details for PubMedID 34253863

  View details for PubMedCentralID PMC8873012

• Circadian Regulation by REV-ERBα Mediates Hippocampal E-LTP in a Time-dependent Manner EXPERIMENTAL NEUROBIOLOGY Choi, J., Kim, S., Lee, J., Kim, K., Kaang, B. 2018; 27 (5): 344-349

  Abstract

  Circadian rhythms are driven by circadian oscillators, and these rhythms result in the biological phenomenon of 24-h oscillations. Previous studies suggest that learning and memory are affected by circadian rhythms. One of the genes responsible for generating the circadian rhythm is Rev-erbα. The REV-ERBα protein is a nuclear receptor that acts as a transcriptional repressor, and is a core component of the circadian clock. However, the role of REV-ERBα in neurophysiological processes in the hippocampus has not been characterized yet. In this study, we examined the time-dependent role of REV-ERBα in hippocampal synaptic plasticity using Rev-erbα KO mice. The KO mice lacking REV-ERBα displayed abnormal NMDAR-dependent synaptic potentiation (E-LTP) at CT12~CT14 (subjective night) when compared to their wild-type littermates. However, Rev-erbα KO mice exhibited normal E-LTP at CT0~CT2 (subjective day). We also found that the Rev-erbα KO mice had intact late LTP (L-LTP) at both subjective day and night. Taken together, these results provide evidence that REV-ERBα is critical for hippocampal E-LTP during the dark period.

  View details for DOI 10.5607/en.2018.27.5.344

  View details for Web of Science ID 000449529100002

  View details for PubMedID 30429644

  View details for PubMedCentralID PMC6221837

• Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF) JOURNAL OF NEUROSCIENCE Kim, s., Yu, N., Shim, K., Kim, J., Kim, H., Han, D., Choi, J., Lee, S., Choi, D., Kim, M., Lee, D., Lee, K., Galjart, N., Lee, Y., Lee, J., Kaang, B. 2018; 38 (22): 5042–52

  Abstract

  The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not.SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms.

  View details for DOI 10.1523/JNEUROSCI.2738-17.2018

  View details for Web of Science ID 000435410700002

  View details for PubMedID 29712785

  View details for PubMedCentralID PMC6705941

• PKCα-mediated phosphorylation of LSD1 is required for presynaptic plasticity and hippocampal learning and memory SCIENTIFIC REPORTS Lim, C., Nam, H., Lee, J., Kim, D., Choi, J., Kang, S., Kim, S., Kim, H., Kwak, C., Shim, K., Kim, S., Ko, H., Lee, R., Jang, E., Yoo, J., Shim, J., Islam, M., Lee, Y., Lee, J., Baek, S., Kaang, B. 2017; 7: 4912

  Abstract

  Lysine-specific demethylase 1 (LSD1) is a histone demethylase that participates in transcriptional repression or activation. Recent studies reported that LSD1 is involved in learning and memory. Although LSD1 phosphorylation by PKCα was implicated in circadian rhythmicity, the importance of LSD1 phosphorylation in learning and memory is unknown. In this study, we examined the roles of LSD1 in synaptic plasticity and memory using Lsd1 SA/SA knock-in (KI) mice, in which a PKCα phosphorylation site is mutated. Interestingly, short-term and long-term contextual fear memory as well as spatial memory were impaired in Lsd1 KI mice. In addition, short-term synaptic plasticity, such as paired pulse ratio and post-tetanic potentiation was impaired, whereas long-term synaptic plasticity, including long-term potentiation and long-term depression, was normal. Moreover, the frequency of miniature excitatory postsynaptic current was significantly increased, suggesting presynaptic dysfunction in Lsd1 KI mice. Consistent with this, RNA-seq analysis using the hippocampus of Lsd1 KI mice showed significant alterations in the expressions of presynaptic function-related genes. Intriguingly, LSD1n-SA mutant showed diminished binding to histone deacetylase 1 (HDAC1) compared to LSD1n-WT in SH-SY5Y cells. These results suggest that LSD1 is involved in the regulation of presynaptic gene expression and subsequently regulates the hippocampus-dependent memory in phosphorylation-dependent manner.

  View details for DOI 10.1038/s41598-017-05239-7

  View details for Web of Science ID 000404970900074

  View details for PubMedID 28687800

  View details for PubMedCentralID PMC5501860