Mouse Study Maps Ketamine Hallucination Circuits

A new study in mice has pinpointed specific brain circuits that become dysregulated during S-ketamine-induced hallucination-like states. Published in the journal Nature, the research dissects how the drug separates perception from action, a core feature of psychotic disorders.

Researchers combined an auditory discrimination task with AI-based analysis of mouse behavior to quantify false threat responses and behavioral disorganization caused by S-ketamine. Control tests ruled out explanations like anhedonia, anesthesia, or basic hearing problems. The team then used advanced imaging and manipulation techniques to trace the circuit malfunctions.

Two Pathways, Two Problems

The investigation revealed two distinct neural pathways converging on the tail region of the striatum (TS), each responsible for a different aspect of the disrupted state. One pathway, from the basolateral amygdala to the caudal striatum (BLA→TS), normally supports salience-weighted perceptual decisions. When S-ketamine aberrantly recruited this circuit, it promoted auditory false alarms-mice reacted to sounds that were not true threats.

In contrast, a separate pathway from the medial prefrontal cortex to the caudal striatum (mPFC→TS) primarily shaped behavioral expression. Dysregulation here did not cause false perceptions but instead generated disorganized, chaotic action patterns. The study identified the TS as a critical integrative node linking perceptual evaluation to behavioral output.

A Shift in Network State

At the broader network level, S-ketamine caused a profound shift in how the tail striatum operated. Normal TS activity is sparse and shows high contrast between signals. Under the drug's influence, this state changed to one of high-frequency, low-amplitude activity where brain cells were diffusely coupled. The authors state this is "consistent with reduced integrative precision." Inputs from the auditory cortex to the TS were not broadly suppressed.

Chemogenetic experiments in drug-naive mice confirmed the roles of these circuits. Manipulating the BLA→TS pathway influenced perceptual decisions, while manipulating the mPFC→TS pathway altered behavioral organization.

A Potential Pharmacological Intervention

The research also explored a potential mitigation strategy. The scientists administered dexmedetomidine, a sedative, alongside S-ketamine. This co-administration did not simply suppress overall brain activity. Instead, it restored pathway-level temporal dynamics and reorganized the network coupling in the TS back toward a normal state.

The study's authors conclude that their findings "define a circuit framework for NMDAR-antagonist-induced hallucination-like states." They also provide a mechanistic rationale for dexmedetomidine-mediated mitigation of S-ketamine-associated perceptual and behavioral disruption. All data and analysis code from the study are publicly available.