Lateral hypothalamic orexin glucose-inhibited neurons may regulate reward-based feeding by modulating glutamate transmission in the ventral tegmental area

Abstract

Glucose inhibits ∼60% of lateral hypothalamic (LH) orexin neurons. Fasting increases the activation of LH orexin glucose-inhibited (GI) neurons in low glucose. Increases in spontaneous glutamate excitatory postsynaptic currents (sEPSCs) onto putative VTA DA neurons in low glucose are orexin dependent (Sheng et al., 2014). VTA DA neurons modulate reward-based feeding. We tested the hypothesis that increased activation of LH orexin-GI neurons in low glucose increases glutamate signaling onto VTA DA neurons and contributes to reward-based feeding in food restricted animals. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents on putative VTA DA neurons were measured using whole cell voltage clamp recording in horizontal brain slices containing the LH and VTA. Decreased glucose increased the NMDA receptor current for at least one hour after returning glucose to basal levels (P < 0.05; N = 8). The increased current was blocked by an orexin 1 receptor antagonist (P < 0.05; N = 5). Low glucose caused a similar persistent enhancement of AMPA receptor currents (P < 0.05; N = 7). An overnight fast increased the AMPA/NMDA receptor current ratio, an in vivo index of glutamate plasticity, on putative VTA DA neurons. Conditioned place preference (CPP) for palatable food was measured during LH dialysis with glucose. CPP score was negatively correlated with increasing LH glucose (P < 0.05; N = 20). These data suggest that increased activation of LH orexin-GI neurons in low glucose after weight loss, leads to enhanced glutamate signaling on VTA DA neurons, increases the drive to eat rewarding food, and may contribute to weight regain.

Introduction to the Special Issue: “Making orexin-based therapies for addiction a reality: What are the steps from here?”

“…These data parallel those from the addiction field showing greater effects of low-dose SB in rats that exhibit higher addiction like behaviors (Fragale et al, 2019;James et al, 2018a;Moorman et al, 2017), and together indicate that low doses of orexin receptor antagonists may be effective at reducing craving for drugs of abuse or highly salient food (e.g high fat, high sugar), without affecting normal eating and weight maintenance. Teegala et al (2018) extend evidence implicating orexin in homeostatic feeding by showing that signaling at Ox1R mediates increased NMDA current amplitude in ventral tegmental area under low glucose conditions. The authors also show that increasing glucose concentration in lateral hypothalamus is sufficient to reduce conditioned place preference for palatable food in weight-restricted rats, indicating that the glucose sensing mechanism of orexin neurons (the majority of which are inhibited by glucose) could be a therapeutic target for aberrant food seeking behaviors.…”

Ventromedial hypothalamus glucose‐inhibited neurones: A role in glucose and energy homeostasis?

“…These cellular effects translate into alterations in reward‐based feeding behaviour. Accordingly, increasing LH glucose in rats that were weight restricted to 85% of their initial body weight decreased the desire to seek a palatable food reward in a standard CPP paradigm . These are the first data linking changes in brain glucose with feeding behaviour and suggesting a role for glucose‐sensing neurones.…”

“…Increased activity of LH orexin neurones in low glucose activates VTA dopamine neurones . This indirect activation of VTA DA neurones is associated with increased NMDA and AMPA receptor current amplitude after 1 hour in low glucose, which persists for at least 1 hour after glucose is returned to baseline . The effect of low glucose on NMDA current amplitude is blocked by an orexin 1 receptor antagonist, suggesting that exposure to low glucose induces orexin‐dependent glutamate plasticity.…”

Electroacupuncture Enhances Neuroplasticity by Regulating the Orexin A-Mediated cAMP/PKA/CREB Signaling Pathway in Senescence-Accelerated Mouse Prone 8 (SAMP8) Mice

“…Glutamate, as a major excitatory amino acid neurotransmitter in the hypothalamus, has been shown to regulate wakefulness and support orexin neurons [37,38]. Glutamate agonists induce excitatory postsynaptic currents in orexin neurons, and this action can be blocked by specific glutamate receptor antagonists [39]. The glutamate level in the hippocampus is closely related to learning and memory, as neuron metabolism and structure can be disrupted by excitotoxicity [40].…”