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July 4th, 2025
Version: 1
University of California San Francisco
neuroscience
biorxiv

Multimodal sensory overload in dopamine-deficient larval zebrafish leads to paradoxical kinesia

Bose, K.Open in Google Scholar•Guo, S.Open in Google Scholar•Bhardwaj, K.Open in Google Scholar

Paradoxical kinesia, the temporary alleviation of motor deficits by powerful, urgent stimuli in Parkinson\'s disease (PD), remains poorly understood at the neural circuit level. Through chemo-genetic ablation of tyrosine hydroxylase-expressing neurons in larval zebrafish and brain-wide calcium imaging under head-fixed, tail-free conditions, we uncovered a neural mechanism underlying this phenomenon. While catecholamine (CA)-deficient larvae exhibited severe locomotor deficits during free swimming, they showed paradoxical recovery of tail movements during whole-brain neural activity imaging. This locomotor recovery was accompanied by a significantly increased number of active neurons in the midbrain and hindbrain, but with reduced firing rates. Further analyses across 2158 anatomically defined regions allowed us to uncover a subset of regions, genes, and neurotransmitter types. GABAergic neurons were found to primarily account for the hyperactivity in the hindbrain, while glutamatergic neurons accounted for the hyperactivity in the midbrain. Hierarchical clustering of neuronal activity with tail movements revealed distinct motor- and non-motor-associated hyperactive clusters in the hindbrain and midbrain, respectively. We identified the Mesencephalic Locomotor Region (MLR) sandwiched between these domains, with enhanced glutamatergic firing rate and cholinergic activation. Furthermore, we found that Telencephalic corticotropin-releasing factor b (crhb) expressing neurons play a crucial role in mediating stress-response to the tectum, which in turn triggers a cascade of neuronal hyperactivity downstream via MLR. These findings reveal a neural mechanism that links stress-induced sensory processing with motor control systems in the absence of regulatory feedback from catecholaminergic neurons, suggesting a direct, unmodulated pathway that bypasses typical inhibitory controls.

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