Ventral Tegmental Area Neurotensin Signaling Links the Lateral Hypothalamus to Locomotor Activity and Striatal Dopamine Efflux in Male Mice

Abstract

Projections from the lateral hypothalamic area (LHA) innervate components of the mesolimbic dopamine (MLDA) system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), to modulate motivation appropriately for physiologic state. Neurotensin (NT)-containing LHA neurons respond to multiple homeostatic challenges and project to the VTA, suggesting that these neurons could link such signals to MLDA function. Indeed, we found that pharmacogenetic activation of LHA NT neurons promoted prolonged DA-dependent locomotor activity and NAc DA efflux, suggesting the importance of VTA neurotransmitter release by LHA NT neurons for the control of MLDA function. Using a microdialysis-mass spectrometry technique that we developed to detect endogenous NT in extracellular fluid in the mouse brain, we found that activation of LHA NT cells acutely increased the extracellular concentration of NT (a known activator of VTA DA cells) in the VTA. In contrast to the prolonged elevation of extracellular NAc DA, however, VTA NT concentrations rapidly returned to baseline. Intra-VTA infusion of NT receptor antagonist abrogated the ability of LHA NT cells to increase extracellular DA in the NAc, demonstrating that VTA NT promotes NAc DA release. Thus, transient LHA-derived NT release in the VTA couples LHA signaling to prolonged changes in DA efflux and MLDA function.

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

“…3D). D1R antagonism blunted LHA Nts-induced locomotor activity in Nts Cre ;NtsR1 ++ mice, consistent with previous studies (Patterson et al, 2015), and also in Nts Cre ;NtsR1 KOKO mice (Fig. 3H, K, p=0.06 for Nts Cre ;NtsR1 KOKO mice).…”

“…Since activation of LHA Nts neurons promotes DA release and D1R-mediated locomotor activity (Patterson et al, 2015), we next investigated whether D1R is necessary for all LHA Nts-induced weight-loss behaviors. Pre-treatment with the D1R antagonist SCH23390 (0.1 mg/kg i.p. )…”

“…The large population of LHA Nts neurons is distinct from orexigenic melanin-concentrating hormone or orexin/hypocretin neurons (Brown et al, 2017), and although some LHA Nts neurons co-express GABA (Jennings et al, 2015; Patterson et al, 2015), they but do not provoke the voracious feeding response that occurs with activation of all LHA GABA neurons (Jennings et al, 2013; Jennings et al, 2015; Navarro et al, 2016; Nieh et al, 2015). Instead, LHA Nts neurons are physiologically activated by signals that suppress feeding, such as dehydration anorexia (Watts and Sanchez-Watts, 2007) or the appetite-suppressing hormone, leptin (Leinninger et al, 2011).…”

“…However, only 15% of LHA Nts neurons mediate leptin action (Brown et al, 2017; Leinninger et al, 2011), yet the overall role of the large population of LHA Nts neurons, and Nts signaling from them, is unclear. Since LHA Nts neurons release Nts to the VTA, where NtsR1-expressing dopamine (DA) neurons have been implicated in coordinating feeding and locomotor activity (Opland et al, 2013; Patterson et al, 2015; Woodworth et al, 2017), LHA Nts neurons might support NtsR1 and/or DA-mediated weight loss behaviors. Indeed, experimental activation of LHA Nts neurons increases DA-dependent locomotor activity (Patterson et al, 2015) but the potential anorectic role of LHA Nts neurons and NtsR1 was not examined.…”

“…Since LHA Nts neurons release Nts to the VTA, where NtsR1-expressing dopamine (DA) neurons have been implicated in coordinating feeding and locomotor activity (Opland et al, 2013; Patterson et al, 2015; Woodworth et al, 2017), LHA Nts neurons might support NtsR1 and/or DA-mediated weight loss behaviors. Indeed, experimental activation of LHA Nts neurons increases DA-dependent locomotor activity (Patterson et al, 2015) but the potential anorectic role of LHA Nts neurons and NtsR1 was not examined. We therefore used chemogenetics to activate LHA Nts neurons in the presence and absence of NtsR1 to determine if they mediate the known anorectic and locomotor effects of Nts, and their potential for stimulating weight loss behaviors.…”