Optogenetic Activation of a Lateral Hypothalamic-Ventral Tegmental Drive-Reward Pathway

Abstract

Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates.

Effects of GABA and Leptin Receptor‐Expressing Neurons in the Lateral Hypothalamus on Feeding, Locomotion, and Thermogenesis

“…The LH contains a heterogeneous assembly of cell populations, in which gamma‐aminobutyric acid (GABA)ergic neurons predominate . LH GABA neurons are known to mediate multiple behaviors important for body weight regulation, such as promoting consumption of chow and palatable solutions and altering energy expenditure . LH GABA neurons differ in expression of neurochemical markers, such as neurotensin, galanin, and the leptin receptor (LepR).…”

Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight

“…11 , 12 , 13 However, the LH is in fact the most potent self-stimulation center in the brain, and given that hungry/food-restricted rats self-stimulate even more than fed rats, an interaction between the metabolic status and reward may require processing by this brain nucleus, 7 , 14 although it is also possible that stimulation of the median forebrain bundle, which connects the VTA to the NAc and runs through the LH, may contribute to the reinforcing effects of the intracranial self-stimulation studies. 15 The LH is innervated by the hindbrain glucagon-like peptide-1 (GLP-1) neurons and GLP-1 receptors (GLP-1R) are expressed in the LH. 16 A potential reward impact of this communication is largely unexplored.…”

Computer Vision Evidence Supporting Craniometric Alignment of Rat Brain Atlases to Streamline Expert-Guided, First-Order Migration of Hypothalamic Spatial Datasets Related to Behavioral Control

“…The alignment tool we furnish in this study has been created with the needs of the behavioral neuroscientist in mind. We selected 50 μm as the interval that defines levels between PW and S reference spaces that are narrowly in register vs. not in register with one another, because this interval is greater in resolution than the resolution of most probes used for manipulations in the rat, which typically range from 100 to 300 μm in diameter (Zhang et al, 2010 ; Larson et al, 2015 ; Gigante et al, 2016 ). In our experience (e.g., Khan et al, 1999 , 2004 , 2007 ), greater resolution is not required at this time to achieve the practical goals of performing a successful, reproducible intracranial manipulation of neural substrates in this animal model.…”

“…Such manipulations have included ablation or stimulation of brain structures (Sheer, 1961 ; Myers, 1974 ; Thompson, 1978 ), tissue microdissection for biochemical analyses (Palkovits and Brownstein, 1988 ), chemical sampling of brain extracellular space via microdialysis or electrochemistry (Parada et al, 1998 ; also see Carter and Shieh, 2015 ), delineation of neural circuits using tracers (Heimer and Robards, 1981 ; Zaborszky and Heimer, 1989 ; Zaborszky et al, 2006 ), or molecular neurobiological techniques involving antisense, RNA interference, or viral-based vector delivery of various constructs to activate or silence activity in a cell-specific manner (Khan, 2013 ). More recently, such manipulations have also included optogenetic studies in rats (e.g., Gradinaru et al, 2009 ; Witten et al, 2011 ), including studies involving in vivo stimulation of hypothalamic cell bodies, their axonal projections, or their axonal inputs (Larson et al, 2015 ; Gigante et al, 2016 ), a structure that we also focus on in this study. Stereotaxic-based methods to manipulate brain structures to control behavior in the rat have contributed richly to our collective understanding of structure-function relations in the brain.…”