Biology subjects

Kaang, B.-K.

Publications and source records attributed to Kaang, B.-K..

11 recordsLinked to original sources

bioRxiv2026

Synaptic engram underlies memory

Memory encoding cells, or engram cells, are sparsely distributed across the brain. Recent findings have shown that memory formation coincides with the strengthening of interregional synaptic connectivity between engram ensembles. However, whether this learning-induced synaptic reorganization causally supports memory, independently or in concert with heterosynaptic and intrinsic plasticity, remains elusive. Here we developed optically implemented spike-timing-dependent plasticity (oSTDP), which induces synaptic depression selectively at target synapses by controlling the relative timing of pre- and postsynaptic activity. In vivo application of oSTDP to the synapses between entorhinal cortex (EC) and dentate gyrus (DG) engram cells caused a significant synaptic depression and the resultant memory impairment. Our results demonstrate that plasticity of functional connectivity between memory-encoding ensembles causally underlies memory.

neuroscience↗

bioRxiv2025

Growth hormone is required for hippocampal engram cell maturation

Memory is thought to be stored in a sparse population of neurons or synapses 1. These neurons or synapses collectively termed the engram are necessary and sufficient for memory recall 2,3. Learning induces synaptic strengthening in engram cells at both pre- and postsynaptic sites 4,5. However, the critical time window and the molecule related to the induction of such synaptic changes are unknown. Here we show that the initial translation plays a key role in engram maturation by facilitating pre- and postsynaptic strengthening and that growth hormone (GH) is required to induce this process in the Dentate Gyrus. Using anisomycin, a protein synthesis inhibitor, we found that blocking the initial and the subsequent second wave of translation arrests the maturation of engram cells. Revisiting our hippocampal translatome during memory formation 6 proposed GH as a mediator of engram maturation. Overexpression of the dominant negative (G118R) GH blocked the maturation of the hippocampal engram cell 7. Facilitating activity-dependent GH uptake by injecting recombinant human GH (rhGH) into the animal rescued the arrestment caused by anisomycin. Together, our findings propose GH as a key mediator of hippocampal engram cell maturation.

neuroscience↗

bioRxiv2025

Protein Synthesis Blockade Prevents Fear Memory Reactivation via Inhibition of Engram Synapse Strengthening

Memory relies on ensembles of engram cells in the brain. While previous studies have established the existence of these cells, the relationship between cellular and synaptic activity remains unclear. To address this, we applied the dual e-GRASP technique in mice to examine synaptic connectivity between the ventral CA1 and the basal amygdala during memory formation. We found that contextual fear conditioning increased engram-to-engram synapse (engram synapse) density and induced structural potentiation, underscoring their importance in associative memory. Additionally, we investigated the role of protein synthesis in memory formation by inducing retrograde amnesia using anisomycin, a protein synthesis inhibitor. Mice injected with anisomycin once (1xANI) showed impaired natural recall but still displayed fear responses upon optogenetic reactivation of engram cells. In contrast, mice that received four anisomycin injections over six hours (4xANI) showed significantly impaired natural recall and failed to exhibit fear responses upon optogenetic reactivation. This behavioural phenotype was correlated with synaptic changes: 1xANI mice exhibited no significant reduction in engram synapse density but had significantly smaller spine sizes, whereas 4xANI mice showed both a significant reduction in engram synapse density and spine size. Our results indicate that protein synthesis inhibition significantly reduces engram synapse density and spine size, changes that correlate with reductions in fear memory during both natural recall and artificial reactivation.

neuroscience↗

bioRxiv2023

Astrocytic connection to engram neurons increased after learning

Astrocytes directly participate in learning and memory. However, the structural association between astrocytes and memory-encoding engram neurons after learning remains to be elucidated. We developed astrocyte-enhanced green fluorescent protein reconstitution across synaptic partners (eGRASP) to examine tripartite synapses between astrocytes and engram neurons. Using astrocyte-eGRASP, we found that astrocytes had increased connections to engram neurons after learning. Dendritic spines with astrocytic contacts showed enhanced morphology. Live-cell imaging of astrocyte-eGRASP revealed that astrocytic connections are stabilized by neuronal activity. These results indicate that astrocytes distinguish contact between engram neurons and generate engram-specific contact patterns during learning.

neuroscience↗

bioRxiv2022

Hippocampal engram networks for fear memory recruit new synapses and modify pre-existing synapses in vivo.

As basic units of neural networks, ensembles of synapses underlie cognitive functions like learning and memory. These synaptic engrams show elevated synaptic density among engram cells following contextual fear memory formation. Subsequent analysis of the CA3-CA1 engram synapse revealed larger spine sizes, as the synaptic connectivity correlated to the memory strength. Here, we elucidate the synapse dynamics between CA3 and CA1 by tracking identical synapses at multiple time points by adapting two-photon microscopy and dual-eGRASP technique in vivo. After memory formation, synaptic connections between engram populations are enhanced in conjunction with synaptogenesis within the hippocampal network. However, extinction learning specifically correlated with the disappearance of CA3 engram to CA1 engram (E-E) synapses. We observed "newly formed" synapses near pre-existing synapses, which clustered CA3-CA1 engram synapses after fear memory formation. Overall, we conclude that dynamics at CA3 to CA1 E-E synapses are key sites for modification during fear memory states. HighlightsO_LIWe adapted four-color two-photon microscopy with dual-eGRASP for a longitudinal observation of synaptic connections between CA3 and CA1. C_LIO_LISynaptogenesis according to fear memory formation was specifically observed in E-E synapses. C_LIO_LIExtinction learning significantly correlated with the disappearance of E-E synapses. C_LIO_LIParticular distribution pattern of newly formed E-E synapses was observed after memory formation. C_LI

neuroscience↗

bioRxiv2022

Ubiquitination of the GluA1 subunit of AMPA receptors is required for synaptic plasticity, memory and cognitive flexibility

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of long-term potentiation (LTP) and long-term depression (LTD), cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, and thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning and memory. Our results reveal that these mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination for bidirectional synaptic plasticity and cognition.

neuroscience↗

bioRxiv2022

Functional characterization of a neuropeptide receptor exogenously expressed in Aplysia neurons

Neuropeptides act mostly on a class of G-protein coupled receptors, and play a fundamental role in the functions of neural circuits underlying behaviors. However, the functions of neuropeptide receptors are poorly understood. Here, we used the mollusc model system Aplysia and microinjected the exogenous neuropeptide receptor apATRPR (Aplysia Allatotropin-related peptide receptor) with an expression vector (pNEX3) into Aplysia neurons that did not express the receptor. Physiological experiments demonstrated that apATRPR could mediate the excitability increase activated by its ligand, apATRP (Aplysia Allatotropin-related peptide), in the Aplysia neurons that now express the receptor. This study provides the first definitive evidence for a physiological function of a neuropeptide receptor in molluscan animals.

neuroscience↗

bioRxiv2021

Systematic analysis of brain lactate and pH levels in 65 animal models related to neuropsychiatric conditions

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2,294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimers disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

neuroscience↗

bioRxiv2020

Synaptic correlates of associative fear memory in the lateral amygdala

Successful adaptation to the environment requires accurate responding to external threats by recalling specific memories. However, elucidating underlying neural substrates of associative fear memory was limited due to the difficulties in direct examination of extinction-induced changes of specific synapses that encode an auditory fear memory. Using dual-eGRASP (enhanced Green Fluorescent Protein Reconstitution Across Synaptic Partners), we found that synapses between engram cells or synaptic engram showed a significantly larger spine morphology at auditory cortex (AC) to lateral amygdala (LA) projections after auditory fear conditioning. Fear extinction reversed the enhanced synaptic engram spines while re-conditioning with the same tone and shock restored the size of the synaptic engram. Taken together, we suggest that the synaptic engram may represent a different state of fear memory. One Sentence SummaryAssociative fear memory enlarged the spine morphology of synapses between engram neurons in the amygdala, which was diminished by memory extinction and restored by re-conditioning, suggesting that connections between engram cells represent a different state of fear memory.

neuroscience↗

bioRxiv2020

Further evidence that CP-AMPARs are critically involved in synaptic tag and capture at hippocampal CA1 synapses

The synaptic tag and capture (STC) hypothesis provides an important theoretical basis for understanding the synaptic basis of associative learning. We recently provided pharmacological evidence that calcium-permeable AMPA receptors (CP-AMPARs) are a crucial component of this process. Here we have investigated two predictions that arise on the basis of CP-AMPARs serving as a trigger of the STC effect. Firstly, we compared the effects of the order in which we delivered a strong theta burst stimulation (TBS) protocol (75 pulses) and a weak TBS protocol (15 pulses) to two independent inputs. We only observed a significant STC effect when the strong preceded the weak TBS. Second, we found that pausing stimulation following either the sTBS or the wTBS for [~]20 min largely eliminates the STC effect. These observations are exactly as predicted for a process that is triggered by the synaptic insertion of CP-AMPARs and provide a framework for establishing the underlying molecular mechanism.

neuroscience↗

bioRxiv2020

PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus

Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance ({gamma}). Here we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involved purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA was activated, resulted in LTP that was associated with a transient increase in {gamma} (LTP{gamma}). This {gamma} increase was due to the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII was necessary and sufficient for LTPN whilst PKA was additionally required for LTP{gamma}. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.

neuroscience↗