The lateral hypothalamus as integrator of metabolic and environmental needs: from electrical self-stimulation to opto-genetics

Abstract

As one of the evolutionary oldest parts of the brain, the diencephalon evolved to harmonize changing environmental conditions with the internal state for survival of the individual and the species. The pioneering work of physiologists and psychologists around the middle of the last century clearly demonstrated that the hypothalamus is crucial for the display of motivated behaviors, culminating in the discovery of electrical self-stimulation behavior and providing the first neurological hint accounting for the concepts of reinforcement and reward. Here we review recent progress in understanding the role of the lateral hypothalamic area in the control of ingestive behavior and the regulation of energy balance. With its vast array of interoceptive and exteroceptive afferent inputs and its equally rich efferent connectivity, the lateral hypothalamic area is in an ideal position to integrate large amounts of information and orchestrate adaptive responses. Most important for energy homeostasis, it receives metabolic state information through both neural and humoral routes and can affect energy assimilation and energy expenditure through direct access to behavioral, autonomic, and endocrine effector pathways. The complex interplays of classical and peptide neurotransmitters such as orexin carrying out these integrative functions are just beginning to be understood. Exciting new techniques allowing selective stimulation or inhibition of specific neuronal phenotypes will greatly facilitate the functional mapping of both input and output pathways.

Fig. 1

Sustained inhibition of self-stimulation by intragastric food but not water load in rats as demonstrated by Hoebel and Teitelbaum ^[7] in 1962. The authors concluded that: “Self-stimulation rate was slowed to about half the normal rate by a stomach load of 18 ml of liquid milk diet. The same amount of water had only a transient effect, suggesting that some consequence of food intake other than taste or stomach distension was responsible for prolonged inhibition ^[7].

Fig. 2

Schematic diagrams showing major inputs (top)and outputs (bottom) of the lateral hypothalamic area on an outline of the rat brain.

Fig. 3

Interactions of lateral hypothalamic neurons with other hypothalamic areas and major behavioral, autonomic, and endocrine output pathways and functions. This highly simplified diagram does not show the relationship with other important hypothalamic nuclei such as the dorsomedial and ventral hypothalamic nuclei. Also not shown are the massive reciprocal connections from cortex and limbic structures to the lateral hypothalamic area. Arrows entering the three nuclei but not contacting individual neurons signifies potential input to all the different neuron types in that area. Abbreviations: AgRP, agouti-related protein; AVP, arginine-vasopressin; CART, cocaine and amphetamine-regulated transcript; CRH, corticotrophin-releasing hormone; DYN, dynorphin; GABA, gamma-aminobutyric acid; Gal, galanin, Glu, glutamate; MCH, melanin-concentrating hormone; NPY, neuropeptide Y; NT, neurotensin; ORX, orexin/hypocretin; OT, oxytocin; POMC, proopio-melanocortin; TRH, Thyrotropin-releasing hormone; LHA, lateral hypothalamic area; PVN, paraventricular nucleus of the hypothalamus; SCN, suprachiasmatic nucleus; 3V, third ventricle.

Fig. 4

Co-existence of orexigenic (galanin) and anorexigenic (neurotensin) neuropeptides in the LHA was demonstrated in colchicine-treated reporter mice with green fluorescent protein expression in galanin neurons (green) and co-staining for neurotensin (red).

Fig. 5

Orexin-1R antagonist administration into the VTA blocks high-fat intake induced by accumbens administration of DAMGO. a: Vehicle or the orexin receptor antagonist SB334867 (15 nmol/side) was injected into the VTA and saline or DAMGO (250 ng) into the nucleus accumbens after overnight access to high-fat chow for pre-satiation. The robust DAMGO-induced feeding response over saline baseline (p<0.001) was almost completely abolished by VTA pretreatment with the orexin receptor antagonist. In animals with either one or both of the bilateral cannula tips not within the VTA, the orexin receptor antagonist was unable to block DAMGO-induced high-fat feeding. Bars that do not share the same letter are significantly different from each other (based on ANOVA, followed by Bonferroni-adjusted multiple comparisons test, p<0.05). b: Verification of orexin receptor antagonist injection sites aimed at the VTA. Striped circles depict animals with both sites within the VTA (n = 11), gray circles depict animals with one or both sites outside the VTA (n = 6), and diamond-filled circles depict animals with unilateral injections (n = 2). Injection sites are superimposed on images from the Paxinos and Watson stereotaxic atlas.