Biology subjects

Hwang, E.-K.

Publications and source records attributed to Hwang, E.-K..

4 recordsLinked to original sources

bioRxiv2025

Impaired synaptic inhibition and enhanced aversion encoding by lateral habenula neurons during Δ9-tetrahydrocannabinol withdrawal.

The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input to control monoaminergic outflow and is implicated in depression, anxiety, impulsivity, and aversion. Although cannabis withdrawal is associated with negative affect and heightened anxiety, LHb involvement is not established. Here, effects of withdrawal from the psychoactive cannabis constituent {Delta}9-tetrahydrocannabinol ({Delta}9-THC) on LHb neurons were assessed with photometric calcium measurement during fear conditioning and in vitro electrophysiology. LHb calcium signals were larger during footshock, and presentation of a tone paired with footshock in {Delta}9-THC withdrawn rats. Fear-induced freezing to the tone was also larger during {Delta}9-THC withdrawal. Electrophysiology revealed larger LHb excitatory-inhibitory (E-I) ratios during {Delta}9-THC withdrawal, resulting from impaired synaptic GABA release. Moreover, GABA release via optogenetic activation of BF-LHb inputs was impaired during {Delta}9-THC withdrawal, whereas no changes occurred at ventral tegmental area-LHb inputs. Recovery of BF-LHb GABA release and cannabinoid CB1 receptor desensitization were incomplete at 30 days of {Delta}9-THC withdrawal. The data show that LHb responsivity to primary aversive and conditioned stimuli are increased during {Delta}9-THC withdrawal, and that this is likely mediated by altered E-I balance. We propose negative affect experienced during cannabis withdrawal is related to LHb hypersensitivity to aversive stimuli and this facilitates encoding of associated environmental cues.

neuroscience↗

bioRxiv2025

Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and D2 receptor-expressing medium spiny neurons in nucleus accumbens core and shell

A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naive animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions in rats during forced abstinence from extended-access oxycodone self-administration. In early abstinence (prior to incubation), CP-AMPAR levels were low. After 17-33 days of abstinence (when incubation is stably plateaued), CP-AMPAR levels were significantly elevated in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell subregions prevents expression of oxycodone incubation. Then, using transgenic rats, we found CP-AMPAR upregulation on both D1 and D2 receptor-expressing MSN, which contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Overall, our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.

neuroscience↗

bioRxiv2024

Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving

Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca2+-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naive rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of incubated rats normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.

neuroscience↗

bioRxiv2021

Lateral habenula M2 muscarinic receptor control of neuronal activity and cocaine seeking behavior

The lateral habenula (LHb) plays a central role in balancing reward and aversion by opposing the contributions of brain reward nuclei. Using a rat cocaine self-administration model, we previously found that LHb inhibition or non-selective blockade of LHb muscarinic acetylcholine receptors (mAChRs) led to persistent cocaine seeking despite its signaled unavailability. As understanding roles for the LHb and cholinergic signaling in behavioral control is important to psychiatric illness and addiction, we examine how mAChRs act on LHb neurons using in vitro electrophysiology. We find that different groups of LHb neurons are depolarized or hyperpolarized by the cholinergic agonist carbachol (CCh), and that CCh could inhibit GABAergic and glutamatergic synaptic inputs to these cells. Presynaptic CCh effects were reversed by the M2 mAChR (M2R) antagonist AFDX-116, but not by pirenzepine, an M1R antagonist. Contemporaneous measurement of CCh effects on synaptic inhibition and excitation in LHb neurons showed a smaller effect on inhibition, suggesting a net shift in synaptic integration toward greater inhibition by mAChRs. Synaptic currents elicited by light-activation of ventral tegmental area (VTA) axons in the LHb, following channelrhodopsin-2 transfection of VTA, were also inhibited by M2Rs, suggesting the VTA as at least one M2R-sensitive LHb afferent. Finally, Go-NoGo cocaine seeking studies showed that blockade of LHb M2Rs, and not M1Rs, triggered continued cocaine seeking. These data identify LHb M2Rs as a potential control point of LHb function that enables withholding responses for cocaine and define cellular mechanisms through which mAChRs modulate LHb activity.

neuroscience↗