Functional Interaction Between GABAergic Neurons in the Ventral Tegmental Area and Serotonergic Neurons in the Dorsal Raphe Nucleus

Sheikh Mizanur Rahaman; Srikanta Chowdhury; Yasutaka Mukai; Daisuke Ono; Hiroshi Yamaguchi; Akihiro Yamanaka

doi:10.3389/fnins.2022.877054

Functional Interaction Between GABAergic Neurons in the Ventral Tegmental Area and Serotonergic Neurons in the Dorsal Raphe Nucleus

Front Neurosci. 2022 May 19:16:877054. doi: 10.3389/fnins.2022.877054. eCollection 2022.

Authors

Sheikh Mizanur Rahaman^{1

2}, Srikanta Chowdhury^{1

2

3}, Yasutaka Mukai^{1

2}, Daisuke Ono^{1

2}, Hiroshi Yamaguchi^{1

2}, Akihiro Yamanaka^{1

2}

Affiliations

¹ Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
² Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, United States.

Abstract

GABAergic neurons in the ventral tegmental area (VTA) have brain-wide projections and are involved in multiple behavioral and physiological functions. Here, we revealed the responsiveness of Gad67+ neurons in VTA (VTA_Gad67+) to various neurotransmitters involved in the regulation of sleep/wakefulness by slice patch clamp recording. Among the substances tested, a cholinergic agonist activated, but serotonin, dopamine and histamine inhibited these neurons. Dense VTA_Gad67+ neuronal projections were observed in brain areas regulating sleep/wakefulness, including the central amygdala (CeA), dorsal raphe nucleus (DRN), and locus coeruleus (LC). Using a combination of electrophysiology and optogenetic studies, we showed that VTA_Gad67+ neurons inhibited all neurons recorded in the DRN, but did not inhibit randomly recorded neurons in the CeA and LC. Further examination revealed that the serotonergic neurons in the DRN (DRN_5-HT) were monosynaptically innervated and inhibited by VTA_Gad67+ neurons. All recorded DRN_5-HT neurons received inhibitory input from VTA_Gad67+ neurons, while only one quarter of them received inhibitory input from local GABAergic neurons. Gad67+ neurons in the DRN (DRN_Gad67+) also received monosynaptic inhibitory input from VTA_Gad67+ neurons. Taken together, we found that VTA_Gad67+ neurons were integrated in many inputs, and their output inhibits DRN_5-HT neurons, which may regulate physiological functions including sleep/wakefulness.

Keywords: GABA; electrophysiology; optogenetics; raphe nucleus; serotonin; ventral tegmental area.