Biology subjects

Jhou, T. C.

Publications and source records attributed to Jhou, T. C..

3 recordsLinked to original sources

bioRxiv2026

Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats

Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).

genetics↗

bioRxiv2023

Pumping the brakes: Rostromedial tegmental inhibition of compulsive cocaine seeking

Addiction is marked by aberrant decision-making and an inability to suppress inappropriate and often dangerous behaviors. We previously demonstrated that inactivation of the rostromedial tegmental nucleus (RMTg) in rats causes persistent food seeking despite impending aversive footshock, an effect strikingly similar to the punishment resistance observed in people with a history of protracted drug use [1]. Here, we extend these studies to demonstrate chemogenetic silencing of RMTg axonal projections to the ventral tegmental area (VTA) (RMTg{lozenge}VTA pathway) causes rats to endure significantly more footshock to receive cocaine infusions. To further test whether activation of this circuit is sufficient to suppress reward seeking in the absence of an overtly aversive stimulus, we used temporally specific optogenetic stimulation of the RMTg{lozenge}VTA pathway as a "punisher" in place of footshock following lever pressing for either food or cocaine reward. While optical stimulation of the RMTg{lozenge}VTA pathway robustly suppressed lever pressing for food, we found that stimulation of this circuit had only modest effects on suppressing responding for cocaine infusions. Even though optical RMTg{lozenge}VTA stimulation was not particularly effective at reducing ongoing cocaine use, this experience nevertheless had long-lasting consequences, as reinstatement of drug seeking in response to cocaine-associated cues was profoundly suppressed when tested nearly two weeks later. These results suggest the RMTg may serve as a useful target for producing enduring reductions in drug craving, particularly during periods of abstinence from drug use.

neuroscience↗

bioRxiv2018

Cocaine Self-Administration and Time-dependent Decreases in Prelimbic Activity

Cocaine self-administration causes dephosphorylation of proteins in prelimbic (PL) cortex that mediate excitation-transcription coupling, suggesting that cocaine causes decreased activity in PL neurons. Thus, we used in vivo single-unit extracellular recordings in awake, behaving rats to measure activity in PL neurons before, during, and after cocaine self-administration on the first and last session day (range 12-14 days). On the last day, cocaine suppressed 52% of recorded neurons in the PL cortex when compared to a 20 min baseline, significantly more than the 23% of neurons suppressed on the first day of cocaine. There was no change in the percentage of neurons that were excited on the first vs. the last day of self-administration (14% vs. 13%, respectively). To determine whether the tonic inhibitory shift was induced by the behavior or by the drug itself, rats received a final session in which cocaine availability was delayed for the first 30 min or in which cocaine was administered non-contingently in the absence of levers or cues in a subset of rats. These manipulations indicated that cocaine was both necessary and sufficient to induce a downshift in PL neuronal activity. However, this activity decrease was not observed in rats that received only non-contingent cocaine for 12-14 days, indicating that contingency during self-administration training contributes to the cocaine-induced tonic downshift in PL activity. These data suggest that the session-by-session decrease in PL neuronal activity induced by cocaine is a reflection of learned drug-seeking behavior and, hence, reducing this inhibition may lessen cocaine addiction.

neuroscience↗