The lateral hypothalamus as integrator of metabolic and environmental needs: From electrical self-stimulation to opto-genetics
Highlights
► A historical perspective of lateral hypothalamic functions is provided. ► The anatomy, connectivity, and chemistry of the lateral hypothalamic area is reviewed. ► Lateral hypothalamic mechanisms involved in energy homeostasis are discussed. ► The utility of cutting-edge modern methodology is highlighted.
Section snippets
Introduction and historical perspective
The diencephalon first gained attention in the mid 19th century, after the group around the Swiss neurologist, Walter Hess showed that electrical stimulation of different hypothalamic areas in cats elicited a variety of behaviors, including fight, flight, copulation, and voracious eating [1], [2]. The influential discoveries of two hypothalamic areas with opposing effects on food intake and body weight in rats soon followed: a lateral area resulting in eating when electrically stimulated and in
Background of anatomy and chemistry of the lateral hypothalamus
The lateral hypothalamic area or zone is a large and heterogeneous area with several distinct nuclear groups and is one of the most extensively interconnected areas of the hypothalamus, allowing it to receive a vast array of interoceptive and exteroceptive information and to modulate cognitive, skeletal motor, autonomic, and endocrine functions (Fig. 2). The lateral hypothalamic area merges rostrally into the preoptic area and caudally into the ventral tegmental area. It borders medially to the
Role of the lateral hypothalamic area in sensing of the internal milieu
Sensing the internal milieu by the brain, including the availability of nutrients, is fundamental for the orchestration of optimal adaptive responses under given environmental conditions. Although the basomedial hypothalamus and caudal brainstem have been identified as key areas involved in nutrient sensing (as reviewed in [102], [103]), there is accumulating evidence for a similar role of the lateral hypothalamus and other brain areas. There are two ways by which a brain area can sense
Reward seeking
As mentioned in the introduction, one of the hallmarks of the lateral hypothalamus is its support of electrical self-stimulation, but that because of the indiscriminate activation of local neurons and fibers of passage with electrical stimulation, its underlying neurology is far from clear. Recent studies strongly implicate projections of lateral hypothalamic orexin neurons to the midbrain ventral tegmental area in this behavior. Orexin fibers innervate ventral tegmental dopamine neurons [145],
Gut, pancreas, and hepatic functions
Again, electrical stimulation and lesions of the LHA were the first to show changes in gastrointestinal [174], pancreatic [175], hepatic [176], [177], and adipose tissue functions [178], as mediated by the sympathetic and parasympathetic nervous system. However, only the discovery of neuropeptides and other technological advances made it possible to identify the specific pathways and confirm some of these earlier claims.
We demonstrated that local administration of minute amounts of orexin-A
Conclusions and perspective
An exciting new discovery more than 50 years ago showed that electrical stimulation of the lateral hypothalamic area induces feeding and self-stimulation behavior. However, only the continuous progress in neuroanatomical, neurochemical, and genetically-based techniques has allowed us to have at least a glimpse of understanding the neurology behind these phenomena. As could have been suspected 50 years ago, the lateral hypothalamus “does it not alone”; it is the rich connectivity with key
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