Prelimbic cortical stimulation disrupts fear memory consolidation through ventral hippocampal dopamine D₂ receptors

Background and Purpose: Anxiety disorders pose one of the biggest threats to mental health worldwide, yet current therapeutics have been mostly ineffective due to issues with relapse, efficacy and toxicity of the medications. Deep brain stimulation (DBS) is a promising therapy for treatment-resistant psychiatric disorders including anxiety, but very little is known about the effects of deep brain stimulation on fear memories. Experimental Approach: In this study, we employed a standard tone-footshock fear conditioning paradigm and modified plus maze discriminative avoidance task to probe the effects of prelimbic cortex deep brain stimulation on various stages of memory. Key Results: We identified memory consolidation stage as a critical time point to disrupt fear memory via prelimbic cortex deep brain stimulation. The observed disruption was partially modulated by the inactivation of the ventral hippocampus and the transient changes in ventral hippocampus dopamine (D₂) receptors expression upon prelimbic cortex deep brain stimulation. We also observed wide-scale changes of various neurotransmitters and their metabolites in ventral hippocampus, confirming its important role in response to prelimbic cortex deep brain stimulation. Conclusion and Implications: These findings highlight the molecular mechanism in the ventral hippocampus in response to prelimbic cortex stimulation and may have translational value, indicating that targeting the prelimbic cortex in the memory consolidation stage via non-invasive neuromodulation techniques may be a feasible therapeutic strategy against anxiety disorders.