Elsevier

Physiology & Behavior

Volume 104, Issue 1, 25 July 2011, Pages 29-39
Physiology & Behavior

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

https://doi.org/10.1016/j.physbeh.2011.04.051Get rights and content

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.

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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