Biology subjects

Jo, Y. S.

Publications and source records attributed to Jo, Y. S..

6 recordsLinked to original sources

bioRxiv2026

A self-limiting orexin-habenula circuit for stress resilience

Resilience requires neural systems that mobilise active coping during stress while limiting its persistence to preserve homeostasis under sustained challenge1-4. Here we identify a self-limiting orexin-habenula circuit in which lateral hypothalamic orexin neurons engage aromatic L-amino acid decarboxylase-expressing D-neurons (encoded by Ddc) in the lateral habenula via orexin receptor type 2 (OX2R)5-7. Activation of this pathway increased nucleus accumbens dopamine and promoted active coping and positive valence. Optotagging revealed rapid stress-evoked recruitment followed by post-stress suppression. In lateral habenula neurons, orexin peptides exerted dissociable effects: orexin-A engaged an OX2R-dependent inhibitory programme superimposed on a parallel inward current, whereas orexin-B did not reproduce this inhibitory profile and instead exerted a distinct membrane effect. Chronic stress disrupted this buffering system through coordinated inflammatory activation, promoter methylation and erosion of D-neuron identity and orexin responsiveness. Restoring orexin-A reversed behavioural and molecular deficits through OX2R-dependent suppression of nuclear factor kappa B signalling, preservation of Tet2 expression, and demethylation-linked maintenance of the Ddc programme. Together, these findings define a self-limiting orexin-habenula resilience circuit that enables adaptive coping while constraining stress-induced vulnerability.

neuroscience↗

bioRxiv2024

Encoding opposing valences through frequency-dependent transmitter switching in single peptidergic neurons

Peptidergic neurons often co-express fast transmitters and neuropeptides in separate vesicles with distinct release properties. However, the release dynamics of each transmitter in various contexts have not been fully understood in behaving animals. Here, we demonstrate that calcitonin gene-related peptide (CGRP) neurons in the external lateral subdivision of the parabrachial nucleus (CGRPPBel) encode opposing valence via differential release, rather than corelease, of glutamate and neuropeptides, according to firing rate. Glutamate is released preferentially at lower firing rates with minimal release at higher firing rates, whereas neuropeptides are released at higher firing rates, resulting in frequency-dependent switching of transmitters. Aversive stimuli evoke high frequency responses with accompanying neuropeptide release to encode negative valence, whereas appetitive stimuli evoke low frequency responses with glutamate release to encode positive valence. Our study reveals a previously unknown capability of single CGRPPBel neurons to bidirectionally encode valence via frequency-dependent differential release of transmitters in vivo.

neuroscience↗

bioRxiv2024

A dopamine-dependent mechanism for reward-induced modification of fear memories

How positive and negative affective stimuli interact in the brain to influence behavioral outcomes remains poorly understood. Here, we show that recall of a positive reward-associated conditioned stimulus (CSRew+) can prevent or reverse fear generalization in mice. Modification of generalized fear by recall of a CSRew+ is dependent on the midbrain dopamine system and the regulation of discriminatory threat encoding by the central amygdala (CeA). Precisely timed, transient elevations in dopamine and activation of dopamine D2 receptors in the CeA are necessary to reverse threat generalization and non-discriminatory threat encoding in the CeA. Recall of a positive association is also effective at enhancing the extinction of a conditioned threat response in a dopamine dependent manner. These data demonstrate that recall of a positive experience can be an effective means to suppress generalized fear and show that dopamine projections to the CeA are an important neural substrate for this phenomenon.

neuroscience↗

bioRxiv2024

Parabrachial CGRP neurons modulates conditioned active defensive behavior under a naturalistic threat

Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, activation of CGRP neurons can trigger either freezing or fleeing defensive behavior, depending on the circumstances. However, the majority of previous findings have reported that CGRP neurons modulate only freezing behavior. Thus, the present study examined the role of CGRP neurons in active defensive behavior, using a predator-like robot programmed to chase mice in fear conditioning. Our electrophysiological results showed that CGRP neurons encoded the intensity of various unconditioned stimuli (US) through different firing durations and amplitudes. Optogenetic and behavioral results revealed that activation of CGRP neurons in the presence of the chasing robot intensified fear memory and significantly elevated conditioned fleeing behavior during recall of an aversive memory. Animals with inactivated CGRP neurons exhibited significantly low levels of fleeing behavior even when the robot was set to be more threatening during conditioning. Our findings expand the known role of CGRP neurons in the PBN as a crucial part of the brains alarm system, showing they can regulate not only passive but also active defensive behaviors.

neuroscience↗

bioRxiv2021

Intrinsic regulators of the action potential waveform control dopamine release to shape behavior

Despite the widely known role of dopamine in reinforcement learning, how the patterns of dopamine release that are critical to the acquisition, performance, and extinction of conditioned responses are generated is poorly resolved. Here, we demonstrate that the coordinated actions of two ion channels, Kv4.3 and BKCa1.1, control the pattern of dopamine neuron firing and dopamine release on different time scales to regulate separate phases of reinforced behavior in mice. Inactivation of Kv4.3 in VTA dopamine neurons increases ex vivo pacemaker activity and excitability that is associated with increased in vivo ramping dynamics prior to lever press in a learned instrumental response paradigm. Loss of Kv4.3 enhances performance of the learned response and facilitates extinction. In contrast, loss of BKCa1.1 increases burst firing and phasic dopamine release that enhances learning of an instrumental response. Inactivation of BKCa1.1 enhances extinction burst lever pressing in early extinction training that is associated with increased reward prediction error signals. These data demonstrate that temporally distinct patterns of dopamine release are governed by the intrinsic regulators of the cell to shape behavior. TeaserWe show that ion channels in midbrain dopamine neurons are critical for patterning action potential firing at the cell body and governing neurotransmitter release to regulate reinforcement learning.

neuroscience↗

bioRxiv2020

A midbrain dynorphin circuit promotes threat generalization

Discrimination between predictive and non-predictive threat stimuli decrease as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identified several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted U relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.

neuroscience↗