New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens

Abstract

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action.

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

“…In the temporal analysis of neurotransmitter release during DBS, we observed a characteristic two-peak pattern for NA release, both during and immediately post-stimulation across all the stimulation parameters. This pattern differs markedly from our previously reported release pro le of DA mediated by mfb-DBS [21,34].…”

Altered neural activity in the mesoaccumbens pathway underlies impaired social reward processing inShank3-deficient rats

“…To record from VTA-GABA neurons we used a combination of rAAV-hVGAT1-Cre-WPRE-hGH polyA 60 (biohippo, Cat no# PT-0346) and AAV9-CAG-FLEX-GCaMP6m 54 (Addgene 100841). To record from DA release in the NAc, we used a GRAB sensor AAV9-hSyn-DA2m (DA4.4) 58 (WZ Biosciences). To activate VTA-GABA neurons in WT rats, we used a combination of rAAV-hVGAT1-Cre-WPRE-hGH polyA (biohippo) and AAV9-Ef1a-DIO-hChR2(E123T/T159C)-EYFP 57 (Addgene, 35509).…”

“…All the viruses used in this study has been previously employed by several other groups [54][55][56][57][58][59][60] . To record from VTA-DA neurons, we used a combination of AAV9.rTH.PI.Cre.SV40 56,59 (Addgene 107788) and AAV9-CAG-FLEX-GCaMP6m.WPRE.SV40 54 (Addgene 100841).…”