An ultra low frequency spike timing dependent plasticity based approach for reducing alcohol drinking

Area of Science:

• Neuroscience
• Addiction Research
• Neuromodulation

Background:

• Alcohol use disorder (AUD) is a chronic brain condition affecting one-third of adults, with high relapse rates and significant societal costs.
• Chronic alcohol use disrupts dopamine receptor 1 (D1) and dopamine receptor 2 (D2) medium spiny neuron (MSN) signaling in the dorsal medial striatum (DMS).
• Current AUD treatments have limited success, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To investigate an electrical stimulation approach using ultra-low frequency (ULF) spike-timing-dependent plasticity (STDP) to correct DMS D1/D2 MSN signaling imbalances in AUD.
• To evaluate the efficacy of this neuromodulation technique in reducing alcohol consumption in mouse models of AUD.
• To assess whether the intervention causes undesired affective behaviors.

Main Methods:

• Utilized ultra-low frequency (ULF) electrical stimulation with spike-timing-dependent plasticity (STDP) in mouse models of AUD.
• Targeted stimulation of D1-MSN afferents into the globus pallidus interna (GPi) and anterior cingulate cortex (ACC) glutamatergic projections to the DMS.
• Employed a time-locked stimulation sequence to modulate DMS D1/D2 MSN signaling.

Main Results:

• The GPi/ACC ULF-STDP intervention selectively decreased hyperactivity in DMS D1-MSNs.
• This reduction in D1-MSN hyperactivity led to significantly decreased alcohol consumption in the mouse models.
• The electrical stimulation approach did not evoke undesired affective behaviors, unlike genetic methods.

Conclusions:

• ULF-STDP electrical stimulation offers a promising, non-genetic method for cell-type-specific neuromodulation in treating severe AUD.
• This approach effectively rebalances DMS D1/D2 MSN signaling, reducing alcohol intake.
• The findings pave the way for developing clinically applicable neuromodulation tools for AUD treatment.