Biology subjects

Liu, Q.-s.

Publications and source records attributed to Liu, Q.-s..

5 recordsLinked to original sources

bioRxiv2024

Different Emotional States Engage Distinct Descending Pathways from the Prefrontal Cortex

Effective emotional processing, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA) and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, the functional specialization of the mPFC[->]BLA and mPFC[->]NAc pathways in representing affective states remains unclear. We found that while overall firing patterns appeared consistent across emotional states, deeper analysis revealed distinct variabilities. Specifically, mPFC[->]BLA neurons, especially "center-ON" neurons, exhibited heightened activity during behaviors classically associated with anxiety-like states, suggesting their involvement in aversive behavioral regulation. Conversely, mPFC[->]NAc neurons were more active during exploratory and approach-related behaviors, implicating them in the processing of positively valenced behavioral states. Notably, mPFC[->]NAc neurons showed significant pattern decorrelation during social interactions, suggesting a pivotal role in processing social preference. Additionally, repeated win/loss outcomes in the tube test produced distinct hierarchy-dependent behavioral changes and elevated corticosterone levels in loser mice, supporting the biological relevance of these behaviorally defined states. Together, these findings reveal pathway-specific representations of affect-related behavioral states in mPFC circuits and provide a framework for understanding how prefrontal outputs organize adaptive behavior across environmental contexts.

neuroscience↗

bioRxiv2024

Dissociable dorsal medial prefrontal cortex ensembles are necessary for cocaine seeking and fear conditioning in mice

The dmPFC plays a dual role in modulating drug seeking and fear-related behaviors. Learned associations between cues and drug seeking are encoded by a specific ensemble of neurons. This study explored the stability of a dmPFC cocaine seeking ensemble over two weeks and its influence on persistent cocaine seeking and fear memory retrieval. In the first series of experiments, we trained TetTag mice in cocaine self-administration and tagged strongly activated neurons with EGFP during the initial day 7 cocaine seeking session. Subsequently, a follow-up seeking test was conducted two weeks later to examine ensemble reactivation between two seeking sessions via c-Fos immunostaining. In the second series of experiments, we co-injected viruses expressing TRE-cre and a cre-dependent inhibitory PSAM-GlyR into the dmPFC of male and female c-fos-tTA mice to enable "tagging" of cocaine seeking ensemble or cued fear ensemble neurons with an inhibitory chemogenetic receptors. Then we investigated their contribution to subsequent cocaine seeking and fear recall during inhibition of the tagged ensemble by administering uPSEM792s (0.3 mg/kg), a selective ligand for PSAM-GlyR. In both sexes, there was a positive association between the persistence of cocaine seeking and the proportion of reactivated EGFP+ neurons within the dmPFC. More importantly, inhibition of the cocaine seeking ensemble suppressed cocaine seeking, but not recall of fear memory, while inhibition of the fear ensemble reduced conditioned freezing but not cocaine seeking. The results demonstrate that cocaine and fear recall ensembles in the dmPFC are stable, but largely exclusive from one another.

neuroscience↗

bioRxiv2023

Neuropathic pain has sex-specific effects on oxycodone seeking and drug-seeking ensembles in the dorsomedial prefrontal cortex

Approximately 50 million Americans suffer from chronic pain, and opioids are commonly prescribed for such individuals. Unfortunately, nearly a quarter of chronic pain patients have reported misusing their prescription. We are investigating the effect of chronic pain on drug-seeking behavior at the neuronal level. Repeated drug-seeking is associated with reactivation of an ensemble of neurons sparsely scattered throughout the dorsomedial prefrontal cortex (dmPFC). Prior research has demonstrated that chronic pain increases intrinsic excitability of dmPFC neurons, which may increase the likelihood of reactivation during drug seeking. We tested the hypothesis that chronic pain would increase oxycodone seeking behavior, and that the pain state would differentially increase intrinsic excitability in dmPFC drug seeking ensemble neurons. TetTag mice self-administered intravenous oxycodone. After 7 days of forced abstinence, a drug seeking session (extinction conditions) was performed and the ensemble was tagged. Mice received spared nerve injury (SNI) to induce chronic pain during the period between a first and second seeking session, and we measured persistence of seeking between the two sessions to determine if the SNI exacerbated seeking. Following the second seeking session we performed electrophysiology on individual neurons within the dmPFC to assess intrinsic excitability of the drug-seeking ensemble and non-ensemble neurons. We found significant sex differences in the effect of SNI on oxycodone seeking and electrophysiology, such that the induction of chronic pain could modulate seeking behavior in mice that have previously self-administered oxycodone prior to injury. HighlightsO_LIOxycodone seeking was higher in females following SNI that came after the 10-day SA timeline. C_LIO_LIAn increase in intrinsic excitability was detected among non-ensemble neurons from female mice that received SNI, and this correlated with an increase in seeking behavior. C_LI

pharmacology and toxicology↗

bioRxiv2022

Genetic Disruption of System xc- Mediated Glutamate Release from Astrocytes Increases Negative-Outcome Behaviors While Preserving Basic Brain Function in Rat

The impact of CNS disorders is exacerbated by the difficulty in developing safe, effective glutamatergic therapeutics. Synaptic glutamate transmission is vital for neural physiology throughout the brain, which contributes to the vast therapeutic potential and safety risk of glutamatergic therapeutics. Here, we created a genetically modified rat (MSxc) to survey the range of brain functions impacted by the loss of glutamate release from astrocytes involving system xc- (Sxc). Eliminating Sxc activity was not lethal and did not alter growth patterns, activity states, novel object recognition or performance of other simple tasks. In contrast, MSxc rats differed from WT in Pavlovian Conditioned Approach and cocaine self-administration/reinstatement paradigms. Both WT and MSxc rats readily learned that a cue predicted food delivery during Pavlovian Conditioned Approach training. However, WT rats were more likely to approach the food tray (i.e., goal tracking) whereas MSxc rats were more likely to approach the food-predicted cue (i.e., sign tracking) even when this behavior was punished. In the self-administration/reinstatement paradigm, MSxc rats had higher levels of cocaine-primed drug seeking in the absence of altered extinction or cocaine self-administration. These data demonstrate that Sxc-mediated glutamate release from astrocytes regulates non-reinforced and negative-outcome behaviors without altering simple learning or other forms of basic brain function.

neuroscience↗

bioRxiv2022

Epac2 in midbrain dopamine neurons contributes to cocaine reinforcement via facilitation of dopamine release

Repeated exposure to drugs of abuse results in an upregulation of cAMP signaling in the mesolimbic dopamine system, a molecular adaptation thought to be critically involved in the development of drug dependence. Exchange protein directly activated by cAMP (Epac2) is a major cAMP effector abundantly expressed in the brain. However, it remains unknown whether Epac2 contributes to cocaine reinforcement. Here, we report that Epac2 in the mesolimbic dopamine system promotes cocaine reinforcement via enhancement of dopamine release. Conditional knockout of Epac2 from midbrain dopamine neurons (Epac2-cKO) and the selective Epac2 inhibitor ESI-05 decreased cocaine self-administration in mice under both fixed-ratio and progressive-ratio reinforcement schedules and across a broad range of cocaine doses. In addition, Epac2-cKO led to reduced evoked dopamine release, whereas Epac2 agonism robustly enhanced dopamine release in the nucleus accumbens in vitro. This mechanism is central to the behavioral effects of Epac2 disruption, as chemogenetic activation of ventral tegmental area (VTA) dopamine neurons increased dopamine release and reversed the impairment of cocaine self-administration in Epac2-cKO mice. Conversely, chemogenetic inhibition of VTA dopamine neurons reduced dopamine release and cocaine self-administration in wild-type mice. Epac2-mediated enhancement of dopamine release may therefore represent a novel and powerful mechanism that contributes to cocaine reinforcement.

neuroscience↗