Behavioral Decoding Reveals Cortical Endocannabinoid Potentiation during Δ⁹-THC Impairment

Area of Science:

• Neuroscience
• Behavioral Science
• Pharmacology

Background:

• The precise mechanisms by which delta-9-tetrahydrocannabinol (THC) affects natural behaviors are not fully understood.
• Investigating the neural underpinnings of THC-induced behavioral changes is crucial for understanding its effects.

Purpose of the Study:

• To elucidate how THC impairs natural behaviors in mice.
• To identify specific neural circuits and molecular pathways involved in THC-induced motor deficits.

Main Methods:

• Development of a video-monitored behavioral platform utilizing machine learning classifiers to analyze natural mouse behaviors.
• Infusion of THC into the medial prefrontal cortex (mPFC) and assessment of its effects on walking kinematics.
• Measurement of mPFC GABAergic activity and excitatory/inhibitory (E/I) balance.
• Closed-loop optogenetic stimulation of mPFC GABAergic neurons to investigate motor impairment.
• Measurement of endocannabinoid (eCB) release and CB1 receptor (CB1R) activity.

Main Results:

• THC infusion into the mPFC disrupted walking kinematics, indicative of impairment.
• THC increased mPFC GABAergic activity before walk initiation, altering the E/I balance.
• Optogenetic stimulation mimicking THC's effects exacerbated motor impairments.
• THC induced a transient potentiation of mPFC eCB release, linked to movement and CB1R-mediated synaptic inhibition.

Conclusions:

• THC modifies the mPFC E/I balance towards excitation through dynamic changes in eCB release.
• These neurochemical alterations induced by THC are directly responsible for behavioral impairments.