Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding

Abstract

Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.

Melanocortin receptor 3 and 4 mRNA expression in the adult female Syrian hamster brain

“…Studies have identified the involvement of MC3Rs and MC4Rs in reward circuits. Antagonists acting on MC3Rs and MC4Rs result in alterations in reward behaviors and locomotor activity (de Vrind et al, 2021;Dunigan et al, 2021a). A reward is derived from sex behaviors and regions such as the NAc, CPu, and the VTA are involved in the reward circuit.…”

A critical update on the leptin‐melanocortin system

“…Abundant expression of Lepr‐b was also detected in other brain regions such as the cerebellum, multiple thalamic nuclei, the cortex, hippocampus, and the ventral tegmental area (VTA) (Bjørbæk et al, 1998; Elmquist et al, 1998; Figlewicz et al, 2003; Mercer, Hoggard, Williams, Lawrence, Hannah, Morgan, et al, 1996; Mercer, Hoggard, Williams, Lawrence, Hannah, & Trayhurn, 1996). Highlighting the contribution of such extrahypothalamic neurons in energy homeostasis, recent reports have identified neuronal populations in the cerebellum regulating satiation (Low et al, 2021), neuronal circuits including the thalamus being partly involved in leptin's anorexigenic effects (Zhang et al, 2020), and LEPR‐expressing neurons in the VTA and substantia nigra involved in food reward, energy intake, and locomotion (de Vrind et al, 2021; Fernandes et al, 2015; Hommel et al, 2006).…”

Constitutive and conditional gene knockout mice for the study of intervertebral disc degeneration: Current status, decision considerations, and future possibilities

“…This gene is expressed in a variety of tissues, such as the hypothalamus, IVDs, cartilage, and bone. 122 , 123 , 124 , 125 , 126 What's more, it is an important marker of stem cells derived from the periosteum, mesenchymal stem cells and notochord derived cells, and has the characteristics of stem cells. It has been suggested that Lepr ‐expressing cells can differentiate into chondrocytes, fibroblasts, osteoblasts, and adipose cells.…”

“…The leptin receptor ( Lepr ) gene belongs to the obesity gene family, which encodes leptin receptor that recognizes and transports leptin. This gene is expressed in a variety of tissues, such as the hypothalamus, IVDs, cartilage, and bone 122–126 . What's more, it is an important marker of stem cells derived from the periosteum, mesenchymal stem cells and notochord derived cells, and has the characteristics of stem cells.…”