Biology subjects

Wirthlin, M.

Publications and source records attributed to Wirthlin, M..

5 recordsLinked to original sources

bioRxiv2025

Cross-species consensus atlas of the primate basal ganglia

The basal ganglia (BG) are conserved brain regions essential for motor control, learning, emotion, and cognition, and are implicated in neurological and psychiatric disease. Yet a unified cross-species taxonomy of BG cell types is lacking, limiting translation of BG circuit mechanisms, interpretation of human genetic risk, and development of cell type-targeted tools. We present a multiomic consensus atlas of 1.8 million nuclei from human, macaque, and marmoset spanning eight BG structures. Integrating cross-species gene expression, open chromatin, and spatial profiling enables definition of conserved and divergent cell types. Alignment to existing mouse and human atlases identifies 61 homologous cell types conserved over 80 million years. We identify a STRd D2 StrioMat Hybrid medium spiny neuron (MSN) type with molecular, electrophysiological, and morphological features that clarify hybrid MSN identities. Comparative cis-regulatory analysis reveals conserved sequence grammars that encode cell identity and inform viral targeting strategies, providing a foundational resource for BG evolution, function, and disease.

neuroscience↗

bioRxiv2022

Convergent gene expression highlights shared vocal motor microcircuitry in songbirds and humans

Vocal learning is a skilled motor behavior observed in several mammalian and avian species and is critical for human speech. While convergent gene expression patterns have highlighted similar primary motor and striatal pathways for vocal imitation in songbirds and humans, the extent of molecular and circuit convergence remains unresolved. Here we profiled the four principal song nuclei of the zebra finch (HVC, LMAN, RA, Area X) and their surrounding brain regions using RNA-Seq and compared them with specialized markers we identified for human speech brain regions. Expanding previous work, both songbird RA and HVC exhibited convergent specialized gene expression of [~]350 genes with human laryngeal sensorimotor cortex. The songbird HVCRA intratelencephalic (IT) neurons were the predominant cell type that was convergent with human, specifically layer 2/3 IT neurons, while the songbird RA extratelencephalic (ET) projection neurons exhibited convergent expression with human layer 5 ET projection neurons. The molecular specializations of both songbird LMAN and human Brocas area were more unique to each species. These findings demonstrate the extent of convergent molecular specializations in distantly related species for vocal imitation and emphasize important evolutionary constraints for this complex trait. One-Sentence SummaryOur data provide hundreds of candidate genes to study the molecular basis and evolution of song and speech across species.

neuroscience↗

bioRxiv2021

Machine learning sequence prioritization for cell type-specific enhancer design

Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations, enabling characterization of their roles in behavior and in disease states. Available approaches for engineering targeted technologies for new neuron subtypes are low-yield, involving intensive transgenic strain or virus screening. Here, we introduce SNAIL (Specific Nuclear-Anchored Independent Labeling), a new virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and using them to make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV) neurons. Furthermore, we show that nuclear isolation using SNAIL in wild type mice is sufficient to capture characteristic open chromatin features of PV neurons in the cortex, striatum, and external globus pallidus. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.

genomics↗

bioRxiv2020

Transcriptional Diversity of Medium Spiny Neurons in the Primate Striatum

The striatum is the interface between dopamine reward signals and cortico-basal ganglia circuits that mediate diverse behavioral functions. Medium spiny neurons (MSNs) constitute the vast majority of striatal neurons and are traditionally classified as direct- or indirect-pathway neurons. However, that traditional model does not explain the anatomical and functional diversity of MSNs. Here, we defined molecularly distinct MSN types in the primate striatum, including (1) dorsal striatum MSN types associated with striosome and matrix compartments, (2) ventral striatum types associated with the nucleus accumbens shell and olfactory tubercle, and (3) an MSN-like type restricted to -opioid receptor rich islands in the ventral striatum. These results lay the foundation for achieving cell type-specific transgenesis in the primate striatum and provide a blueprint for investigating circuit-specific processing.

neuroscience↗

bioRxiv2018

Disentangling the origins of confidence in speeded perceptual judgments through multimodal imaging

The human capacity to compute the likelihood that a decision is correct - known as metacognition - has proven difficult to study in isolation as it usually co-occurs with decision-making. Here, we isolated post-decisional from decisional contributions to metacognition by combining a novel paradigm with multimodal imaging. Healthy volunteers reported their confidence in the accuracy of decisions they made or decisions they observed. We found better metacognitive performance for committed vs. observed decisions, indicating that committing to a decision informs confidence. Relying on concurrent electroencephalography and hemodynamic recordings, we found a common correlate of confidence following committed and observed decisions in the inferior frontal gyrus, and a dissociation in the anterior prefrontal cortex and anterior insula. We discuss these results in light of decisional and post-decisional accounts of confidence, and propose a generative model of confidence in which metacognitive performance naturally improves when evidence accumulation is constrained upon committing a decision.

neuroscience↗