Biology subjects

Newman, C. E.

Publications and source records attributed to Newman, C. E..

4 recordsLinked to original sources

bioRxiv2026

A conserved population of genetically defined striatal neurons gates opioid reward

A longstanding paradox in striatal circuit architecture is that opioid reward depends on -opioid receptors ({micro}ORs) in nucleus accumbens medium spiny neurons (MSNs), yet {micro}OR function is not explained by the canonical D1/direct and D2/indirect pathway organization. Here, we identify a rare MSN population marked by Chst9 that exhibits exceptionally high expression of the {micro}OR and is conserved across species. Notably, Chst9-MSNs comprise a specialized indirect pathway striatal neuron subtype that is molecularly and spatially distinct from canonical striatal populations. Opioids robustly silence Chst9-MSNs, and selective deletion of Oprm1 from this population abolishes fentanyl-conditioned place preference. These findings establish Chst9-MSNs as a critical substrate for opioid reward and define a new cellular framework for therapies targeting opioid use disorder.

neuroscience↗

bioRxiv2026

Multimodal characterization of transcriptionally defined ventral tegmental area dopamine neurons

Ventral tegmental area (VTA) dopamine (DA) neurons are highly implicated in reward learning, motivated behaviors, and substance use disorders. DA neurons in the VTA are traditionally characterized by expression of genes involved in DA synthesis, release, or reuptake, such as tyrosine hydroxylase (encoded by the Th gene), which is the rate-limiting step in DA synthesis. However, recent transcriptomic studies have revealed substantial cellular heterogeneity within the VTA, including multiple subtypes of VTA DA neurons. Using single nucleus RNA sequencing, we previously identified two transcriptionally distinct Th+ subpopulations: a DA/glutamate/GABA Combinatorial neuron marked by Slc26a7 and a DA-only neuron marked by Gch1. However, the functional properties of these distinct DA neuron classes remain unknown. Here, we developed an AAV-based strategy enabling cell-type-specific access to these populations and performed comparative transcriptional, electrophysiological, and anatomical analyses, providing the first functional characterization of these transcriptionally-defined DA neuron subtypes. Whole-cell recordings revealed similar baseline membrane properties but a divergence in intrinsic excitability and latency to fire action potentials after current input. Anatomical mapping revealed overlapping but biased projection patterns, and Combinatorial neurons, but not DA-only neurons, were selectively recruited following experience with cocaine. Together, these findings reveal functional specialization among transcriptionally-defined VTA DA neuron subpopulations, dissociating DA-specific from multi-neurotransmitter properties and refining our understanding of VTA heterogeneity.

neuroscience↗

bioRxiv2025

Morphine regulates astrocyte transcriptional dynamics in the ventral tegmental area by stimulation of glucocorticoid signaling

Opioids are potent analgesics often prescribed for the treatment of chronic pain, a condition affecting millions worldwide. Although pain states increase vulnerability to opioid use disorders, the neural mechanisms underlying this interaction remain incompletely understood. The ventral tegmental area (VTA) is a key site for opioid actions, and emerging evidence suggests that pain states and opioid experience both induce transcriptional, molecular, and circuit adaptations in the VTA that contribute to motivated behaviors. However, the transcriptional responses of distinct VTA cell types to each of these factors (alone or in combination) have not been identified. Here, we employed single-nucleus RNA sequencing to comprehensively define transcriptional alterations in the rat VTA to acute morphine administration in a chronic inflammatory pain model. We report that morphine induces gene expression changes primarily in glial cells and dopamine neurons, with minimal effects in other neuronal cell types. Surprisingly, VTA astrocytes and oligodendrocytes exhibited the most robust transcriptional responses to opioid exposure, despite lacking detectable opioid receptor expression. Among the most highly regulated glial genes was Fkbp5, which encodes a co-chaperone protein that acts in concert with heat shock proteins to modulate stress responses. Using pharmacological and CRISPR-based approaches in rat glial cells and human astrocytes, we demonstrate that regulation of Fkbp5 is mediated indirectly through glucocorticoid signaling rather than direct opioid receptor activation. These findings reveal that glial cells within reward circuits undergo profound transcriptional reprogramming in response to opioids through indirect, stress-hormone mediated mechanisms, highlighting a previously unappreciated non-neuronal contribution to opioid-induced neural adaptations.

neuroscience↗

bioRxiv2024

Reelin marks cocaine-activated striatal ensembles, promotes neuronal excitability, and regulates cocaine reward

Drugs of abuse activate defined neuronal ensembles in brain reward structures such as the nucleus accumbens (NAc), which are thought to promote the enduring synaptic, circuit, and behavioral consequences of drug exposure. While the molecular and cellular effects arising from experience with drugs like cocaine are increasingly well understood, the mechanisms that sculpt NAc ensemble participation are largely unknown. Here, we leveraged unbiased single-nucleus transcriptional profiling to identify expression of the secreted glycoprotein Reelin (encoded by the Reln gene) as a marker of cocaine-activated neuronal ensembles within the rat NAc. Multiplexed in situ detection confirmed selective expression of the immediate early gene Fos in Reln+ neurons after cocaine experience, and also revealed enrichment of Reln mRNA in Drd1+ medium spiny neurons (MSNs) in both the rat and human brain. Using a novel CRISPR interference strategy enabling selective Reln knockdown in the adult NAc, we observed altered expression of genes linked to calcium signaling, emergence of a transcriptional trajectory consistent with loss of cocaine sensitivity, and a striking decrease in MSN intrinsic excitability. At the behavioral level, loss of Reln prevented cocaine locomotor sensitization, abolished cocaine place preference memory, and decreased cocaine self-administration behavior. Together, these results identify Reelin as a critical mechanistic link between ensemble participation and cocaine-induced behavioral adaptations.

neuroscience↗