Biology subjects

Horan, N. L.

Publications and source records attributed to Horan, N. L..

3 recordsLinked to original sources

bioRxiv2026

Astrocyte molecular rhythm disruption in nucleus accumbens promotes increased binge-like drinking in mice

Alcohol misuse is a leading cause of preventable death worldwide. Chronic alcohol is associated with disrupted circadian rhythms, yet molecular mechanisms linking circadian rhythm dysregulation and alcohol consumption are poorly understood. Current FDA-approved treatments for alcohol use disorder (AUD) do not target molecular rhythms or sleep-wake cycles. Mammalian circadian rhythms are regulated by transcription-translation feedback loops that regulate expression of 'clock genes' (e.g., Arntl encoding for BMAL1). Both human and rodent studies demonstrate associations between clock gene variants and changes in reward-seeking behavior. Evidence suggests astrocytes, non-neuronal brain cells with cell-autonomous rhythms, may regulate both circadian rhythms and reward. In the nucleus accumbens (NAc), a region responsible for modulating alcohol- and reward-related behavior, over 43% of the astrocyte transcriptome is expressed rhythmically. However, no studies to date have investigated roles of NAc astrocyte rhythmicity in regulating alcohol drinking. We used AAV8-Gfap-Cre to functionally ablate molecular rhythms in NAc astrocytes of BMAL1 floxed mice. Two-bottle choice (2BC), drinking-in-the-light (DIL), and drinking-in-the-dark (DID) assessed alcohol drinking. Behavioral assays included locomotor response to novelty, sucrose preference, and social interaction. Disrupting molecular clock function in NAc astrocytes increased binge-like drinking during both DIL and DID paradigms (d = 1.44), but not with any other drinking paradigm or behavior. This study carves out a unique role for astrocytes in controlling the temporal organization of reward circuitry and susceptibility to binge-drinking. Future studies will investigate clock-controlled astrocyte mechanisms, such as glutamate uptake and ATP release, that may underlie binge-like drinking behavior.

neuroscience↗

bioRxiv2025

Cancer-induced Nerve Injury Unveils a Sympathetic-to-Sensory Nerve Axis in Head and Neck Cancer

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, with patients frequently reporting spontaneous, neuropathic-like pain. While sympathetic and sensory nerves have been individually implicated in cancer progression, whether and how these systems interact to drive pain and tumor growth has remained unclear. Here, we integrate prospective human data with reverse-translational mouse models to reveal that cancer-induced nerve injury unveils crosstalk between sympathetic postganglionic neurons and trigeminal sensory afferents in the tumor microenvironment. In patients, circulating norepinephrine (NE) correlated with spontaneous pain and perineural invasion, identifying a potential sympathetic contribution to disease burden. In mice, aggressive non-immunogenic OSCC tumors evoked spontaneous nociceptive behaviors, elevated tumoral NE, and sensory nerve injury marked by ATF3 expression and hyperexcitability. Tumor-associated sensory neurons acquired adrenergic sensitivity through 1-adrenergic receptor plasticity, while sympathetic neurons exhibited plasticity characterized by sprouting, altered gene expression, and heightened excitability, creating a maladaptive feed-forward loop that amplified nociceptive signaling. Disrupting this sympathetic-sensory communication by sympathectomy or selective ablation of TRPV1 sensory fibers reduced tumor growth, sympathetic tone, and spontaneous pain like behaviors, although sensory adrenergic sensitivity persisted. Together, these findings establish that reciprocal sympathetic-sensory plasticity and crosstalk in the tumor may fuel both OSCC progression and neuropathic like pain. Targeting this peripheral neuroplasticity may offer a translational strategy to limit tumor growth and alleviate pain. One Sentence SummaryReciprocal plasticity and crosstalk between sympathetic and sensory nerves drive both tumor progression and neuropathic-like pain in oral squamous cell carcinoma, suggesting peripheral neuroplasticity as a therapeutic target.

neuroscience↗

bioRxiv2022

Paf1 complex subunit Rtf1 stimulates H2B ubiquitylation by interacting with the highly conserved N-terminal helix of Rad6

Histone modifications coupled to transcription elongation play important roles in regulating the accuracy and efficiency of gene expression. The mono-ubiquitylation of a conserved lysine in H2B (K123 in Saccharomyces cerevisiae; K120 in humans) occurs co-transcriptionally and is required for initiating a histone modification cascade on active genes. H2BK123 ubiquitylation (H2BK123ub) requires the RNA polymerase II (RNAPII)-associated Paf1 transcription elongation complex (Paf1C). Through its Histone Modification Domain (HMD), the Rtf1 subunit of Paf1C directly interacts with the ubiquitin conjugase Rad6, leading to the stimulation of H2BK123ub in vivo and in vitro. To understand the molecular mechanisms that target Rad6 to its histone substrate, we identified the site of interaction for the HMD on Rad6. Using in vitro crosslinking followed by mass spectrometry, we localized the primary contact surface for the HMD to the highly conserved N-terminal helix of Rad6. Using a combination of genetic and biochemical experiments, we identified separation-of-function mutations in S. cerevisiae RAD6 that greatly impair H2BK123 ubiquitylation but not other Rad6 functions. Finally, by employing RNA-sequencing as a sensitive approach for comparing mutant phenotypes, we show that mutating either side of the proposed Rad6-HMD interface yields strikingly similar transcriptome profiles that extensively overlap with those of a mutant that lacks the site of ubiquitylation in H2B. Our results fit a model in which a specific interface between a transcription elongation factor and a ubiquitin conjugase guides substrate selection toward a highly conserved chromatin target during active gene expression. Significance StatementTranscription by RNAPII is tightly coordinated with mechanisms that control chromatin structure. Disruption of this interplay leads to deleterious effects on gene expression and genome architecture. Proteins that associate with RNAPII during transcription elongation play an important role in coupling histone modifications to active transcription. Paf1C, a conserved member of the RNAPII active elongation complex, is required for the ubiquitylation of histone H2B, a modification with effects on nucleosome stability and the methylation and acetylation state of chromatin. Here, we provide new insights into how a conserved domain in Paf1C, which we previously showed to be necessary and sufficient for Paf1C-mediated stimulation of H2B ubiquitylation, interacts with the ubiquitin conjugase for H2B thereby guiding its specificity.

molecular biology↗