Characterization of orexin input to dopamine neurons of the ventral tegmental area projecting to the medial prefrontal cortex and shell of nucleus accumbens

Imre Kalló,Zsolt Liposits,Azar Omrani,Roger A H Adan,Frank J Meye,Han De Jong

doi:10.1007/s00429-021-02449-8

Abstract

Orexin neurons are involved in homeostatic regulatory processes, including arousal and feeding, and provide a major input from the hypothalamus to the ventral tegmental area (VTA) of the midbrain. VTA neurons are a central hub processing reward and motivation and target the medial prefrontal cortex (mPFC) and the shell part of nucleus accumbens (NAcs). We investigated whether subpopulations of dopamine (DA) neurons in the VTA projecting either to the mPFC or the medial division of shell part of nucleus accumbens (mNAcs) receive differential input from orexin neurons and whether orexin exerts differential electrophysiological effects upon these cells. VTA neurons projecting to the mPFC or the mNAcs were traced retrogradely by Cav2-Cre virus and identified by expression of yellow fluorescent protein (YFP). Immunocytochemical analysis showed that a higher proportion of all orexin-innervated DA neurons projected to the mNAcs (34.5%) than to the mPFC (5.2%). Of all sampled VTA neurons projecting either to the mPFC or mNAcs, the dopaminergic (68.3 vs. 79.6%) and orexin-innervated DA neurons (68.9 vs. 64.4%) represented the major phenotype. Whole-cell current clamp recordings were obtained from fluorescently labeled neurons in slices during baseline periods and bath application of orexin A. Orexin similarly increased the firing rate of VTA dopamine neurons projecting to mNAcs (1.99 ± 0.61 Hz to 2.53 ± 0.72 Hz) and mPFC (0.40 ± 0.22 Hz to 1.45 ± 0.56 Hz). Thus, the hypothalamic orexin system targets mNAcs and to a lesser extent mPFC-projecting dopaminergic neurons of the VTA and exerts facilitatory effects on both clusters of dopamine neurons.

Highlights

Loss of orexin signaling results in narcolepsy and increased orexin signaling has been implicated in arousal, feeding and addiction (Horvath and Gao 2005; Baimel and Borgland 2017; James et al 2017)
To visualize ventral tegmental area (VTA) neurons projecting to the medial prefrontal cortex (mPFC) and/or to mNAcs, a dual vector strategy was used (Boender et al 2014)
The highest number of them appeared in the parabrachial pigmented (PBP), but they were substantially present in the IF by both the mNAcs and mPFC injections

Summary

Introduction

Loss of orexin ( known as hypocretin) (de Lecea et al 1998; Sakurai et al 1998) signaling results in narcolepsy and increased orexin signaling has been implicated in arousal, feeding and addiction (Horvath and Gao 2005; Baimel and Borgland 2017; James et al 2017). Via orexin 1 and 2 receptors (Trivedi et al 1998; Sakurai et al 1998), excite VTA dopamine neurons (Korotkova et al 2003; Vittoz et al 2008). Orexin increases the firing rate of VTA dopamine neurons projecting the NAc, but not to the basolateral amygdala (Baimel et al 2017). VTA dopamine neurons projecting to the NAc and to the mPFC are activated by orexin and implicated in the arousal (España et al 2001; Vittoz and Berridge 2006; Vittoz et al 2008). It has not been explored whether the orexin innervation of VTA dopamine neurons projecting to the mPFC differs from those projecting to the shell part of the NAc (NAcs)

Methods

Results

Conclusion