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Kwag, J.

Publications and source records attributed to Kwag, J..

9 recordsLinked to original sources

Egocentric spatial scaffolds organize cortical memory engrams

Episodic memory requires reconstructing the position of the self within a remembered environment, yet whether and how memory engrams incorporate self-referenced spatial information remains unknown. Using activity-dependent engram tagging, longitudinal calcium imaging and optogenetic perturbation in the retrosplenial cortex, we found that cortical memory engrams are enriched for egocentric and boundary-coding neurons that encode self-position relative to environmental boundaries. Longitudinal imaging revealed that future engram neurons are preferentially recruited from a pre-existing spatial scaffold rather than generated de novo during learning. During memory retrieval, scaffold populations underwent coordinated refinement and became transiently reorganized into a scaffold-engram network state whose dynamics tracked memory expression. Silencing scaffold neurons reduced memory expression while preserving recall dynamics, whereas engram silencing abolished recall dynamics while maintaining a stable low-memory state. Together, these findings identify a scaffold-engram architecture through which episodic memories are reconstructed by reinstating the self-referenced spatial representations within remembered space.

neuroscience↗

Retrosplenial PV and SST interneurons shape egocentric spatial precision and stability

Accurate navigation requires egocentric representations of environmental geometry to be continuously updated by self-motion while remaining stable over time. The retrosplenial cortex (RSC) is central to this process, yet how local inhibitory circuits support this balance remains unclear. We show that parvalbumin (PV) and somatostatin (SST) interneurons regulate distinct components of egocentric spatial coding in RSC. PV interneurons are strongly modulated by self-motion and exhibit bearing-aligned synchrony that precedes SST activation, linking movement to egocentric coding precision. In contrast, SST interneurons display weak self-motion modulation but robust boundary-anchored activity with globally coherent dynamics that stabilize representations over time. Optogenetic silencing revealed dissociable effects: PV perturbation degraded egocentric coding precision while SST perturbation disrupted global population organization. Behaviorally, PV silencing impaired initial egocentric orientation while SST silencing preserved initial orientation but impaired its sustained update. These findings identify separable inhibitory mechanisms balancing rapid updating with representational stability during navigation.

neuroscience↗

Memory encoding and retrieval by retrosplenial parvalbumin interneurons is impaired in Alzheimer's disease model mice

Memory deficits in Alzheimers disease (AD) show a strong link with GABAergic interneuron dysfunctions1-7. Ensemble dynamics of GABAergic interneurons are critical in memory encoding and retrieval8-12 but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As retrosplenial cortex (RSC) is a brain area critical for episodic memory13-16 and affected by beta-amyloid accumulation in early AD17-21, we address this question by performing Ca2+ imaging in RSC parvalbumin-expressing (PV) interneurons during a contextual fear memory (CFM) task in healthy control mice and the 5XFAD mouse model of AD. We found that subpopulations of PV interneurons that were responsive to aversive electric foot shocks during contextual fear conditioning (CFC) in the control mice significantly decreased in the 5XFAD mice, indicating a dysfunction in the recruitment of CFM-encoding PV interneurons. In control mice, CFC-responsive PV interneuron ensemble activities were selectively upregulated during the freezing epoch of the CFM retrieval, manifested by CFC-induced synaptic potentiation of PV interneuron-mediated inhibition. However, CFC-induced changes in PV interneuron ensemble dynamics during CFM retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during CFC in control mice mimicked the CFM deficits in 5XFAD mice, while optogenetic activation of PV interneurons during CFC in the 5XFAD mice restored CFM retrieval. These results demonstrate the necessity and sufficiency of CFC-responsive PV interneurons for CFM retrieval and suggest that synaptic dysfunction in CFM-encoding PV interneurons disrupt the inhibitory ensemble dynamics underlying CFM retrieval, subsequently leading to memory deficits in AD.

neuroscience↗

Egocentric vector coding of geometric vertex in the retrosplenial cortex

Neural representation of the environmental features in a self-centered, egocentric manner is important in constructing an egocentric cognitive map that is critical for goal-directed navigation and episodic memory formation1. To create a geometrically detailed egocentric cognitive map, neural representations of edges and vertices of environmental features are needed. While egocentric neural representations of edges, like egocentric boundary vector cells2-6 and border cells exist7, those of vertices are unknown. Here we report that single neurons in the granular retrosplenial cortex (RSC) generate spatial receptive fields exclusively near the vertices of environmental geometries during free exploration, which we termed vertex cells. Each spatial receptive field of vertex cells occurred at a specific orientation and distance relative to the animal, tuned by head direction, indicating an egocentric vector coding of the vertex. The removal of physical boundaries that define the environmental geometry abolished egocentric vector coding vertex cells. Moreover, goal-directed navigation selectively strengthened the egocentric vertex vector coding at the vertex near the goal location. Overall, our results suggest that egocentric vector coding of vertex by granular RSC neurons help to construct a geometrically detailed egocentric cognitive map that guides goal-directed navigation.

neuroscience↗

Retrosplenial cortex is necessary for spatial and non-spatial latent learning in mice

Latent learning occurs when associations are formed between stimuli in the absence of explicit reinforcement. Traditionally, latent learning in rodents has been associated with the creation internal models of space. However, increasing evidence points to roles of internal models also in non-spatial decision making. Whether the same brain structures and processes support the creation of spatially-anchored or non-spatial internal models via latent learning, is an open question. To address this question, we developed a novel operant box task that allows to test spatial and non-spatial versions of a flavour-based sensory preconditioning paradigm. We probed the role of the retrosplenial cortex, a brain area associated with spatial cognition and subjective value representation, in this task using precise, closed-loop optogenetic silencing during different task phases. We show that the retrosplenial cortex is necessary for both spatial and non-spatial latent learning in mice. We further demonstrate that the requirement of retrosplenial cortex is limited to the preconditioning phase of the task. Our results provide insight into the specific role of the retrosplenial cortex in latent learning, demonstrate that latent learning plays a general part in the creation of internal models, independent of spatial anchors, and provide a novel avenue for studying model-based decision making.

neuroscience↗

In vivo direct imaging of neuronal activity at high temporo-spatial resolution

There has been a longstanding demand for noninvasive neuroimaging methods capable of detecting neuronal activity at both high temporal and spatial resolution. Here, we propose a novel method that enables Direct Imaging of Neuronal Activity for functional MRI (termed DIANA-fMRI) that can dynamically image spiking activity in milliseconds precision, while retaining the original benefit of high spatial resolution of MRI. DIANA-fMRI was demonstrated through in vivo mice brain imaging at 9.4 T applying electrical whisker-pad stimulation, directly imaging the spiking activity as well as capturing its sequential propagation along the thalamocortical pathway, as further confirmed through in vivo spike recording and optogenetics. DIANA-fMRI will open up new avenues in brain science by providing a deeper understanding of the brains functional organization including neural networks.

neuroscience↗

Distinct roles of parvalbumin and somatostatin interneurons in the synchronization of spike-times in the neocortex

Synchronization of precise spike-times across multiple neurons carries information about sensory stimuli. Inhibitory interneurons are suggested to promote this synchronization, but it is unclear whether distinct interneuron subtypes provide different contributions. To test this, we examined single-unit recordings from barrel cortex in vivo and used optogenetics to determine the contribution of two classes of inhibitory interneurons: parvalbumin (PV)- and somatostatin (SST)-positive interneurons to spike-timing synchronization across cortical layers. We found that PV interneurons preferentially promote the synchronization of spike-times when instantaneous firing-rates are low (<12 Hz), whereas SST interneurons preferentially promote the synchronization of spike-times when instantaneous firing-rates are high (>12 Hz). Furthermore, using a computational model, we demonstrate that these effects can be explained by PV and SST interneurons having preferential contribution to feedforward and feedback inhibition, respectively. Our findings demonstrate that distinct subtypes of inhibitory interneurons have frequency-selective roles in spatio-temporal synchronization of precise spike-times.

neuroscience↗

Neocortical inhibitory interneuron subtypes display distinct responses to synchrony and rate of inputs

Populations of neurons in the neocortex can carry information with both the synchrony and the rate of their spikes. However, it is unknown whether distinct subtypes of neurons in the cortical microcircuit are more sensitive to information carried by synchrony versus rate. Here, we address this question using patterned optical stimulation in slices of barrel cortex from transgenic mouse lines labelling distinct interneuron populations: fast-spiking parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. We use optical stimulation of channelrhodopsin-2 (ChR2) expressing excitatory neurons in layer 2/3 in order to encode a random 1-bit signal in either the synchrony or rate of activity in presynaptic cells. We then examine the mutual information between this 1-bit signal and the voltage and spiking responses in PV+ and SST+ interneurons. Generally, we find that both interneuron types carry more information than GFP negative (GFP-) control cells. More specifically, we find that for a synchrony encoding, PV+ interneurons carry more information in the first 5 milliseconds, while both interneuron subtypes carry more information than negative controls in their later response. We also find that for a rate encoding, SST+ interneurons carry more information than either PV+ or negative controls after several milliseconds. These data demonstrate that inhibitory interneuron subtypes in the neocortex have distinct responses to information carried by synchrony versus rates of spiking.

neuroscience↗

Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomers in vivo

Abnormal accumulation of amyloid {beta} oligomers (A{beta}O) is a hallmark of Alzheimers disease (AD), which leads to learning and memory deficits. Hippocampal theta oscillations that are critical in spatial navigation, learning and memory are impaired in AD. Since GABAergic interneurons, such as somatostatin-positive (SST+) and parvalbumin-positive (PV+) interneurons, are believed to play key roles in the hippocampal oscillogenesis, we asked whether A{beta}O selectively impairs these SST+ and PV+ interneurons. To selectively manipulate SST+ or PV+ interneuron activity in mice with A{beta}O pathology in vivo, we co-injected A{beta}O and adeno-associated virus (AAV) for expressing floxed channelrhodopsin-2 (ChR2) into the hippocampus of SST-Cre or PV-Cre mice. Local field potential (LFP) recordings in vivo in these A{beta}O-injected mice showed a reduction in the peak power of theta oscillations and desynchronization of spikes from CA1 pyramidal neurons relative to theta oscillations compared to those in control mice. Optogenetic-activation of SST+ but not PV+ interneurons in A{beta}O-injected mice fully restored the peak power of theta oscillations and resynchronized the theta spike phases to a level observed in control mice. In vitro whole-cell voltage-clamp recordings in CA1 pyramidal neurons in hippocampal slices treated with A{beta}O revealed that short-term plasticity of SST+ interneuron inhibitory inputs to CA1 pyramidal neurons at theta frequency were selectively disrupted while that of PV+ interneuron inputs were unaffected. Together, our results suggest that dysfunction in inputs from SST+ interneurons to CA1 pyramidal neurons may underlie the impairment of theta oscillations observed in A{beta}O-injected mice in vivo. Our findings identify SST+ interneurons as a target for restoring theta-frequency oscillations in early AD.

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