A molecular and spinal circuit basis for the functional segregation of itch and pain.

Recent advances reveal an extensive cellular diversity within the dorsal horn. How this complexity processes distinct sensations, like itch and pain, remains a fundamental question. We discovered hidden within a population of neurons expressing the gastrin-releasing peptide receptor (Grpr+), thought to be itch-specific, are highly homologous yet functionally distinct subtypes distinguished by expression of Tachykinin-1 (Tac1).

Combining Machine Learning and Multiplexed, Profiling to Engineer Cell Type and Behavioral Specificity.

A promising strategy for the precise control of neural circuits is to use -regulatory enhancers to drive transgene expression in specific cells. However, enhancer discovery faces key challenges: low success rates, species-specific differences in activity, challenges with multiplexing adeno-associated viruses (AAVs), and the lack of spatial detail from single-cell sequencing. In order to accelerate enhancer discovery for the dorsal spinal cord-a region critical for pain and itch processing-we developed an end-to-end platform, ESCargoT (), combining machine learning (ML)-guided enhancer prioritization, modular AAV assembly, and multiplexed, screening.

Spatial, transcriptomic, and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition.

Key mechanisms underlying chronic pain occur within the dorsal horn. Genome-wide association studies (GWASs) have identified genetic variants predisposed to chronic pain. However, most of these variants lie within regulatory non-coding regions that have not been linked to spinal cord biology.

Mechanical Allodynia Circuitry in the Dorsal Horn Is Defined by the Nature of the Injury.

The spinal dorsal horn is a major site for the induction and maintenance of mechanical allodynia, but the circuitry that underlies this clinically important form of pain remains unclear. The studies presented here provide strong evidence that the neural circuits conveying mechanical allodynia in the dorsal horn differ by the nature of the injury. Calretinin (CR) neurons in lamina II inner convey mechanical allodynia induced by inflammatory injuries, while protein kinase C gamma (PKCγ) neurons at the lamina II/III border convey mechanical allodynia induced by neuropathic injuries.

Polyamine Antagonist Therapies Inhibit Neuroblastoma Initiation and Progression.

Purpose: Deregulated MYC drives oncogenesis in many tissues yet direct pharmacologic inhibition has proven difficult. MYC coordinately regulates polyamine homeostasis as these essential cations support MYC functions, and drugs that antagonize polyamine sufficiency have synthetic-lethal interactions with MYC Neuroblastoma is a lethal tumor in which the MYC homologue MYCN, and ODC1, the rate-limiting enzyme in polyamine synthesis, are frequently deregulated so we tested optimized polyamine depletion regimens for activity against neuroblastoma.

Experimental Design: We used complementary transgenic and xenograft-bearing neuroblastoma models to assess polyamine antagonists.