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Biology subjects

Lee, W.-C.

Publications and source records attributed to Lee, W.-C..

3 recordsLinked to original sources

Developmental maturation of frontal cortical circuits impacts decision-making

In humans, frontal cortical circuits mature in parallel with the development of higher cognitive functions over the course of 15-20 years. In mice, behavior and brain structure change rapidly until reaching sexual maturity ([~]8 weeks of age). In contrast, the degree to which frontal cortices and the behaviors they support continue to develop in mice after this period is unclear. Here, we uncover age-related changes in the acquisition and execution of a probabilistic reward reinforcement task. Both young and old mice complete a similar number of trials per session, but 16-30-week-old mice obtain higher reward rates than younger mice. The older mice adjust their behavior more readily after failing to receive a reward, suggesting that age-dependent changes to circuits relevant to forming action-outcome associations, such as those in frontal associative cortices (FACs). Indeed, we identified cell-type and input-specific refinements of FAC circuits over the first 24 weeks of age, including protracted reductions in excitatory drive and increases in inhibition onto pyramidal cells. Dampening inhibitory activity in FAC alters behavior in a manner that counteracts the age-related differences. Together, these reveal an extended period of synaptic maturation in FAC that directly impacts age-related changes in decision-making.

neuroscience↗

Ventral pallidum GABA and glutamate neurons drive approach and avoidance through distinct modulation of VTA cell types

The ventral pallidum (VP) contains GABA and glutamate (Glut) neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the cell-type-specific mechanisms by which VP projections to VTA drive behavior. Here, we found that both VP GABA and Glut neurons were activated during approach to reward or delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine (DA) and glutamate neurons. Remarkably, this cell-type-specific recruitment was behavior-contingent such that VTA recruitment was inhibited when evoked by the subjects own action. Conversely, VP Glut neurons activated VTA GABA, as well as DA and Glut neurons, despite driving aversion. However, VP Glut neurons evoked DA in reward-associated ventromedial nucleus accumbens (NAc), but reduced DA in aversion-associated dorsomedial NAc. These findings show how heterogeneous VP cell types can engage VTA cell types to shape approach and avoidance behaviors. HIGHLIGHTSO_LIVP GABA and Glut neurons are activated by approach to reward and aversive stimuli C_LIO_LIVP GABA and Glut neurons oppositely affect VTA GABA, both activate VTA DA and Glut C_LIO_LIVP Glut neurons activate DA release in ventral NAc but inhibit DA from dorsal NAc C_LIO_LIVTA DA responses to VP GABA activity are inhibited by the subjects own action C_LI

neuroscience↗

Genomic and TCR Repertoire Intratumor Heterogeneity of Small-cell Lung Cancer and its Impact on Survival

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC.

genomics↗