Pyramidal cell dynamics of psychedelic head twitches in mice
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Introduction
Psychedelic drugs exert their effects primarily via activation of serotonin 5-HT2A receptors, yet how this translates from receptor-level engagement to systems-level brain dynamics remains incompletely understood. In rodents, stereotypical shaking behaviour such as head twitches provides a robust and selective readout of 5-HT2A receptor activation, but its underlying neurophysiology is unresolved. Here, we combined behavioural, physiological, and cell-type-specific imaging approaches to bridge this gap, asking how 5-HT2A receptor activation shapes cortical dynamics across levels of organisation. Methods We employed the selective 5-HT2A agonist 25CN-NBOH across a series of complementary in vivo mouse paradigms. Behavioural assays quantified head-twitch responses, including their dose-dependence, temporal dynamics, and adaptation under repeated or closely spaced administration. In parallel, systemic physiological effects were assessed using non-invasive measurements of heart rate, respiration, and neck-arterial blood flow under controlled temperature conditions. Finally, we applied cell-type-specific voltage imaging in awake mice, targeting layer 2/3 pyramidal neurons of the motor cortex, to resolve neuronal and haemodynamic activity associated with psychedelic-induced shaking behaviour. Results 25CN-NBOH induced robust head-twitch responses with rapid onset and characteristic decay dynamics, showing both short-term tachyphylaxis and subchronic tolerance. Beyond behaviour, 5-HT2A receptor activation produced consistent changes in cardiovascular and respiratory parameters, including increased heart rate and altered neck arterial blood flow in a temperature-dependent manner. At the cortical level, shaking behaviour was associated with distinct patterns of neuronal activity, including high-frequency oscillations preceding events and slower oscillatory components overlapping with behaviour. These dynamics reflected activity in pyramidal neurons alongside concurrent haemodynamic signals, linking cellular and vascular responses. Discussion Together, these findings delineate a multi-level organisation of 5-HT2A receptor function spanning neuronal and vascular domains, rather than acting solely at the level of synaptic signalling. The head-twitch response is associated with distinct cortical dynamics, including activity in pyramidal neurons as well as haemodynamic changes, linking a well-established behavioural readout to measurable circuit-level processes. This integrated perspective has implications not only for animal physiology but also for the interpretation of haemodynamic signals in psychedelic neuroimaging, which are likely shaped by both neuronal and vascular contributions. Media & dissemination: Front. Pharmacol. | JOP | IJMS | Breaking convention Funding: European Commission (Horizon 2020, MSCA – original project outline) | Beckley Foundation Institution: Laboratory for Neuronal Circuit Dynamics, Department of Brain Sciences, Imperial College London (UK) How to cite: Buchborn T (2026). Pyramidal cell dynamics of psychedelic head twitches. psyborn.com/psychedelic-head-twitch-dynamics.
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