Biology subjects

Hagihara, K. M.

Publications and source records attributed to Hagihara, K. M..

6 recordsLinked to original sources

bioRxiv2026

Deleting learning-induced dendritic spines disrupts the memory they encode

Long-term memory is widely thought to depend on activity-dependent synaptic plasticity and the structural remodeling that accompanies it, yet direct causal evidence that this remodeling is required for memory storage has been lacking. A case in point is the formation of dendritic spines: new spines appear following learning, but whether they constitute a physical substrate of memory remains unresolved. To address this, we developed the New Spine Elimination Tool (NSET), a chemical-genetic strategy, that ablates dendritic spines formed within a defined window of synaptic plasticity. NSET combines inducible expression of a degradable form of the actin-binding protein Drebrin with ligand-triggered proteasomal degradation. Because mainly nascent spines incorporate the degradable proteins into their cytoskeleton, ligand application eliminates them while sparing pre-existing ones. In hippocampal slice cultures, NSET eliminated recently formed spines without altering overall spine density or affecting pre-existing spines. Applied in vivo in the mouse basolateral amygdala, selective removal of learning-induced spines disrupted auditory fear memory, whereas consolidated memories and the capacity for new learning remained intact. These findings provide direct causal evidence that newly formed dendritic spines are required for long-term memory storage.

neuroscience↗

bioRxiv2026

Topographic structure and function of locus coeruleus norepinephrine neurons

Norepinephrine (NE) is released throughout most of the central nervous system by neurons in the locus coeruleus (LC). We found a relationship between the morphologies, gene expression, and activity of LC-NE neurons in mice. Axonal projections of individual neurons were extensive but largely confined to subsets of brain regions. Axonal projections and graded gene expression correlated with locations of cell bodies in LC. In a behavioral task requiring ongoing learning from actions, neurons in dorsal LC projecting to the cerebral cortex were excited when mice made a different choice from the previous one and by reward prediction errors, a signal driving learning. Background activity of neurons in ventral LC was higher when mice ignored stimuli indicating potential reward availability. These observations reveal a topographically organized structure and function of a neurotransmitter system and show that it contains learning signals for flexible behavior.

neuroscience↗

bioRxiv2025

Glutamate indicators with increased sensitivity and tailored deactivation rates

Identifying the input-output operations of neurons requires measurements of synaptic transmission simultaneously at many of a neurons thousands of inputs in the intact brain. To facilitate this goal, we engineered and screened 3365 variants of the fluorescent protein glutamate indicator iGluSnFR3 in neuron culture, and selected variants in the mouse visual cortex. Two variants have high sensitivity, fast activation (< 2 ms) and deactivation times tailored for recording large populations of synapses (iGluSnFR4s, 153 ms) or rapid dynamics (iGluSnFR4f, 26 ms). By imaging action-potential evoked signals on axons and visually-evoked signals on dendritic spines, we show that iGluSnFR4s/4f primarily detect local synaptic glutamate with single-vesicle sensitivity. The indicators detect a wide range of naturalistic synaptic transmission, including in the vibrissal cortex layer 4 and in hippocampal CA1 dendrites. iGluSnFR4 increases the sensitivity and scale (4s) or speed (4f) of tracking information flow in neural networks in vivo.

neuroscience↗

bioRxiv2024

Bidirectional valence coding in amygdala intercalated clusters:A neural substrate for the opponent-process theory of motivation

Processing emotionally meaningful stimuli and eliciting appropriate valence-specific behavior in response is a critical brain function for survival. Thus, how positive and negative valence are represented in neural circuits and how corresponding neural substrates interact to cooperatively select appropriate behavioral output are fundamental questions. In previous work, we identified that two amygdala intercalated clusters show opposite response selectivity to fear- and anxiety-inducing stimuli - negative valence (Hagihara et al. 2021). Here, we further show that the two clusters also exhibit distinctly different representations of stimuli with positive valence, demonstrating a broader role of the amygdala intercalated system beyond fear and anxiety. Together with the mutually inhibitory connectivity between the two clusters, our findings suggest that they serve as an ideal neural substrate for the integrated processing of valence for the selection of behavioral output.

neuroscience↗

bioRxiv2021

Developmental stage-specific patterned activity contributes to callosal axon projections

The developing neocortex exhibits spontaneous network activity with various synchrony levels, which has been implicated in the formation of cortical circuits. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. However, what sort of and when activity is indispensable are not known. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that network activity contributes to callosal axon projections in the mouse visual cortex during a "critical period": restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo Ca2+ imaging revealed that the projections could be established even without fully restoring highly synchronous activity. Overall, our findings suggest that the spontaneous network activity is selectively required during a critical developmental time window for the formation of long-range axonal projections in the cortex. (150)

neuroscience↗

bioRxiv2019

Long-range interhemispheric projection neurons show biased response properties and fine-scale local subnetworks in mouse visual cortex

Integration of information processed separately in distributed brain regions is essential for brain functions. This integration is enabled by long-range projection neurons, and further, concerted interactions between long-range projections and local microcircuits are crucial. It is not well known, however, how this interaction is implemented in cortical circuits. Here, to decipher this logic, using callosal projection neurons (CPNs) as a model of long-range projections, we found that CPNs exhibited distinct response properties and fine-scale local connectivity patterns. In vivo 2-photon calcium imaging revealed that CPNs showed a higher ipsilateral eye (with respect to their somata) preference, and that CPN pairs showed stronger signal/noise correlation than random pairs. Slice recordings showed CPNs were preferentially connected to CPNs, demonstrating the existence of projection target-dependent fine-scale subnetworks. Collectively, our results suggest that long-range projection target predicts response properties and local connectivity of cortical projection neurons.

neuroscience↗