Rust, A. | bioRxiv Science

bioRxiv2026

Developmental Chlorpyrifos Exposure Disrupts Tectal Circuit Formation and Behavior in Xenopus laevis

Developmental exposure to organophosphate pesticides has been associated with adverse neurodevelopmental outcomes, but the circuit-level mechanisms underlying these effects remain poorly understood. Here, we examined how low-level chlorpyrifos (CPF) exposure affects neural circuit maturation and behavior in Xenopus laevis tadpoles. Tadpoles were exposed to 1 {micro}M CPF from developmental stage 42 to stage 49, spanning a critical period of synaptogenesis and circuit refinement. CPF-exposed tadpoles displayed abnormal schooling behavior, characterized primarily by impaired body-axis alignment despite preserved group aggregation, as well as altered spontaneous swimming marked by reduced looping and increased seizure-like activity. Whole-cell recordings from tectal neurons revealed persistent reductions in inhibitory synaptic drive, consistent with altered excitation-inhibition balance. Although acute CPF exposure transiently increased intrinsic excitability of tectal neurons as well as baseline swimming activity, this effect was not maintained after chronic exposure. Morphological analysis of GFP-labeled tectal neurons revealed altered dendritic branching distribution despite no change in total dendritic length or branch number. Together, these findings suggest that developmental CPF exposure disrupts tectal circuit maturation, leading to abnormal neural connectivity and maladaptive behavioral outcomes relevant to neurodevelopmental dysfunction.

neuroscience↗

bioRxiv2023

Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice

Dystonia is common, debilitating, often medically refractory, and difficult to diagnose. The gold standard for both clinical and mouse model dystonia evaluation is subjective assessment, ideally by expert consensus. However, this subjectivity makes translational quantification of clinically-relevant dystonia metrics across species nearly impossible. Many mouse models of genetic dystonias display abnormal striatal cholinergic interneuron excitation, but few display subjectively dystonic features. Therefore, whether striatal cholinergic interneuron pathology causes dystonia remains unknown. To address these critical limitations, we first demonstrate that objectively quantifiable leg adduction variability correlates with leg dystonia severity in people. We then show that chemogenetic excitation of striatal cholinergic interneurons in mice causes comparable leg adduction variability in mice. This clinically-relevant dystonic behavior in mice does not occur with acute excitation, but rather develops after 14 days of ongoing striatal cholinergic interneuron excitation. This requirement for prolonged excitation recapitulates the clinically observed phenomena of a delay between an inciting brain injury and subsequent dystonia manifestation and demonstrates a causative link between chronic striatal cholinergic interneuron excitation and clinically-relevant dystonic behavior in mice. Therefore, these results support targeting striatal ChIs for dystonia drug development and suggests early treatment in the window following injury but prior to dystonia onset. One Sentence SummaryChronic excitation of dorsal striatal cholinergic interneuron causes clinically-relevant dystonic phenotypes in mice

neuroscience↗