The functional architecture of dehydration-anorexia

Abstract

The anorexia that accompanies the drinking of hypertonic saline (DE-anorexia) is a critical adaptive behavioral mechanism that helps protect the integrity of fluid compartments during extended periods of cellular dehydration. Feeding is rapidly reinstated once drinking water is made available again. The relative simplicity and reproducibility of these behaviors makes DE-anorexia a very useful model for investigating how the various neural networks that control ingestive behaviors first suppress and then reinstate feeding. We show that DE-anorexia develops primarily because the mechanisms that terminate ongoing meals are upregulated in such a way as to significantly reduce meal size. At the same time however, signals generated by the ensuing negative energy balance appropriately activate neural mechanisms that can increase food intake. But as the output from these two competing processes is integrated, the net result is an increasing reduction of nocturnal food intake, despite the fact that spontaneous meals are initiated with the same frequency as in control animals. Furthermore, hypothalamic NPY injections also stimulate feeding in DE-anorexic animals with the same latency as controls, but again meals are prematurely terminated. Comparing Fos expression patterns across the brain following 2-deoxyglucose administration to control and DE-anorexic animals implicates neurons in the descending part of the parvicellular paraventricular nucleus of the hypothalamus and the lateral hypothalamic areas as key components of the networks that control DE-anorexia. Finally, DE-anorexia generates multiple inhibitory processes to suppress feeding. These are differentially disengaged once drinking water is reinstated. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.

Figure 1

A schematic representation of the functional networks that interact to control ingestive behaviors. A key feature of this model is the presence of stimulatory and inhibitory networks in the hypothalamus that are regulated by multiple inputs, including those that encode post-ingestive signals from the gastrointestinal tract. The outputs of the stimulatory and inhibitory networks are integrated to control the downstream motor control circuits. (Adapted from [5])

Figure 2

Anorexia can be expressed First, as an adaptive response that helps animals confront an imposed challenge or stressor. These responses can result from stimuli that are internally or externally generated. Dehydration anorexia is an example of a adaptive response that results from internally generated signals. Second, anorexia can develop as a response to pathological conditions, either as a primary or a secondary indication. (Adapted from [8])

Figure 3

The correlation between plasma osmolality and cumulative nocturnal food intake in individual rats given 2.5% hypertonic saline to drink for between 1 and 5 days. The gray rectangle shows the target range of plasma osmolalities for experiments reported in the papers discussed in this review. (Adapted from data from [11,13])

Figure 4

A schematic representation of the functional networks that interact to generate dehydration anorexia. Stimulatory (1) and inhibitory networks (2) are both upregulated by the effects of increasing plasma osmolality and signals from the gastrointestinal tract. At the same time the activity of other regulatory inputs is maintained (3), but their impact on hypothalamic neurons in the parvicellular paraventricular nucleus of the hypothalamus and the lateral hypothalamic areas, as well as their downstream targets is blunted (4). Anorexia is the net outcome of the altered processing that occurs within the key control networks in the hypothalamus and elsewhere.

Figure 5

A schematic representation of the functional networks that interact to generate feeding in dehydrated-anorexic animals after the return of water. Our results suggest a two stage process. First, signals generated by drinking water act within the integration process (5) to quickly stimulate feeding, perhaps by disinhibiting signals from the stimulatory networks. A second, slower process appears to normalize meal patterns as plasma osmolality drops to control values. The networks then return to the state illustrated in Figure 1 (see text for details).