The impact of sex, variable stimulation mode and parameters on mfb-DBS evoked dopamine release dynamics in a rodent depression model.

Background: Superolateral medial forebrain bundle (mfb) DBS has shown rapid and lasting antidepressant effects in treatment-resistant depression (TRD). Diverse stimulation parameters recruit the unmyelinated dopaminergic (DA) or the other myelinated mfb projections differently and with variable effects on the reward circuitry. Prior studies have demonstrated acute differences in DA release across depressive and healthy models with varying pulse widths (PWs).

Objective: To evaluate the effects of diverse mfb-DBS parameters (frequency/ PW) on tonic and phasic DA release and tonic DA activity during behavior tests, examining sex differences and unilateral versus bilateral DBS across depression-like (FSL) and control (SD) models.

Methods: Fiber Photometry was used to monitor DA activity evoked by unilateral and bilateral mfb stimulation under different conditions, including during behavioral tasks, and across the experimental models.

Results: i.) mfb-DBS increased DA release across parameters in both models, with high frequency leading to synchronized peak release and larger increments; ii.) FSL animals exhibited sustained DA responses compared to the healthy controls, especially in males, at the latest phase of the DBS interval; iii.) SDs showed larger tonic activity changes pre- and post-DBS; and iv.) FSL females displayed more DA transients in anxiety-inducing behavioral context.

Limitations: The study did not examine phenotypic changes nor assess the contribution of each fiber type to the neurotransmitter release, leaving open whether unilateral DBS replicates the effects of bilateral stimulation.

Conclusion: The results deepen the understanding of mechanisms and dynamics of DA release following mfb-DBS in a rodent model of depression.