Deep brain stimulation of medial forebrain bundle modulates the noradrenergic activity and feedforward circuitry in rodent depression model

Deep Brain Stimulation (DBS) of the superolateral medial forebrain bundle (MFB) has shown promising long-term anti-depressant effects in treatment-resistant depression patients, although its mechanisms are not clear. The study explores mfb-DBS mediated modulation of central noradrenaline (NA) transmission in a rodent depression model. Flinders Sensitive Line (FSL) rats, an experimental depression model, were used to examine the noradrenergic fibers' spatial distribution and myelination traversing the mfb. In vivo NA release in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC) was monitored with fiber photometry during unilateral mfb-DBS across diverse stimulation parameters. Stimulation induced changes in the parvalbumin-mediated feedforward microcircuitry and neuron activation were identified. Moreover, the activation of the ascending projected (A1, A2, A6) NA cell groups was quantified by c-fos staining, and the animals’ affective state monitored by ultrasonic vocalization recordings. Medial forebrain bundle NA fibers were predominantly unmyelinated and located in the medial quadrate. Stimulation increased mPFC NA release across both groups, but notably higher release was measured in the FSLs NAC. The depressive model also demonstrated more positive affective vocalizations post-DBS. The A1/ A2 cell groups in the FSLs had reduced activity, yet were reactivated by DBS, while the A6 group was highly active in both groups, albeit with a reduced neuron density in the depressive model. DBS normalized parvalbumin interneuron activity in the FSL rats. The study emphasizes the potential therapeutic role of MFB DBS in modulating NA system, providing insights into its anti-depressant mechanisms of action in major depression.