Neurotensin Receptor-1 Identifies a Subset of Ventral Tegmental Dopamine Neurons that Coordinates Energy Balance

Abstract

SUMMARY Dopamine (DA) neurons in the ventral tegmental area (VTA) are heterogeneous and differentially regulate ingestive and locomotor behaviors that impact energy balance. Identification of which VTA DA neurons mediate behaviors that limit weight gain has been hindered, however, by the lack of molecular markers to distinguish VTA DA populations. Here, we identified a specific subset of VTA DA neurons that express neurotensin receptor-1 (NtsR1) and preferentially comprise mesolimbic, but not mesocortical, DA neurons. Genetically targeted ablation of VTA NtsR1 neurons uncouples motivated feeding and physical activity, biasing behavior toward energy expenditure and protecting mice from age-related and diet-induced weight gain. VTA NtsR1 neurons thus represent a molecularly-defined subset of DA neurons that are essential for the coordination of energy balance. Modulation of VTA NtsR1 neurons may therefore be useful to promote behaviors that prevent the development of obesity.

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

“…Since both NtsR1 and NtsR2 are expressed in the VTA (Fig. 1E and (Woodworth et al, 2017), we used this region to verify that Nts Cre ;NtsR1 KOKO mice specifically lack Ntsr1 gene expression, without any compensatory increase in Ntsr2 (Fig. 1F).…”

“…LHA Nts neurons release Nts to target regions including the VTA, where VTA NtsR1 neurons contain DA (Brown et al, 2017; Patterson et al, 2015; Woodworth et al, 2017). Since VTA DA signaling modifies the motivation to work for food rewards (e.g.…”

“…Altogether, we cannot rule out a contribution of NtsR1 in drinking behavior, though it does not appear to be essential for it. Nts may still contribute to locomotor and drinking behaviors via NtsR2, which is predominantly expressed by astrocytes in the VTA (Woodworth et al, 2017)). Alternately, signals other than Nts that are released from LHA Nts neurons might mediate drinking and locomotor activity.…”

“…At 8–12 weeks of age, male Nts Cre ;++ and Nts Cre :NtsR1 KOKO mice underwent stereotaxic surgery (as described in Woodworth et al, 2017), and were injected bilaterally with either 300 uL of AAV-hM3Dq-mCherry or AAV-ChR-mCherry (UNC vector core) into the LHA (AP: −1.34, ML: - 1.05, DV: −5.2) per the mouse brain atlas of Paxinos and Watson. Analysis began 1–2 weeks after recovery.…”

“…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.…”