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

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.

The Formation and Function of the VTA Dopamine System

“…Conversely, Dyn decreases firing activity in most NAc medial shell-and basolateral amygdala (BLA)-projecting dopaminergic neurons and in a small part of the NAc lateral shell-projecting dopaminergic neurons in the VTA [117]. Furthermore, LH orexin neurons also project to some mPFCprojecting dopaminergic neurons in the VTA [118]. The optogenetic activation of the inputs from the LH orexin and Dyn neurons to the VTA enhances dopamine release in the NAc core, promoting reward-seeking behaviors.…”

The wake- and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimer’s disease

“…The ORX regulates arousal and wakefulness through modulation of the locus coeruleus 8 . Various studies on experimental animals have shown that the neuropeptide ORX is involved in locomotor activity, attention, cognition, feeding behavior reward, and thermogenesis by regulating prolactin, growth hormones, acetylcholine, and corticosterone levels [8][9][10][11][12] . Liguori et al demonstrated an increase in CSF ORX levels in patients with moderate to severe AD was associated with sleep dysfunction and decline in cognition 13 .…”

Abuse potential assessment of the dual orexin receptor antagonist daridorexant in rats

“…In addition to their location in wake-controlling regions of the brain, OXRs are found in areas of the mesolimbic dopamine system ( Cole et al, 2020 ; Kallo et al, 2022 ; Kawashima et al, 2022 ; Schmeichel et al, 2017 ) where they help to orchestrate the amount of arousal necessary for successfully engaging in highly motivational and rewarding tasks ( de Lecea, 2021 ). For example, in rats, OXR signaling mediates natural or drug-related reward seeking under large effort requirements ( Schmeichel et al, 2018 ) and is required to make cognitive associations of the environmental context to reward reception ( Harris et al, 2005 ).…”