Elsevier

Physiology & Behavior

Volume 89, Issue 4, 30 November 2006, Pages 490-500
Physiology & Behavior

Hindbrain catecholamine neurons control multiple glucoregulatory responses

https://doi.org/10.1016/j.physbeh.2006.05.036Get rights and content

Abstract

Reduced brain glucose availability evokes an integrated constellation of responses that protect and restore the brain's glucose supply. These include increased food intake, adrenal medullary secretion, corticosterone secretion and suppression of estrous cycles. Our research has focused on mechanisms and neural circuitry underlying these systemic glucoregulatory responses. Using microinjection techniques, we found that localized glucoprivation of hindbrain but not hypothalamic sites, elicited key glucoregulatory responses, indicating that glucoreceptor cells controlling these responses are located in the hindbrain. Selective destruction of hindbrain catecholamine neurons using the retrogradely transported immunotoxin, anti-dopamine beta-hydroxylase conjugated to saporin (DSAP), revealed that spinally-projecting epinephrine (E) or norepinephrine (NE) neurons are required for the adrenal medullary response to glucoprivation, while E/NE neurons with hypothalamic projections are required for feeding, corticosterone and reproductive responses. We also found that E/NE neurons are required for both consummatory and appetitive phases of glucoprivic feeding, suggesting that multilevel collateral projections of these neurons coordinate various components of the behavioral response. Epinephrine or NE neurons co-expressing neuropeptide Y (NPY) may be the neuronal phenotype required for glucoprivic feeding: they increase NPY mRNA expression in response to glucoprivation and are nearly eliminated by DSAP injections that abolish glucoprivic feeding. In contrast, lesion of arcuate nucleus NPY neurons, using the toxin, NPY–saporin, does not impair glucoprivic feeding or hyperglycemic responses. Thus, hindbrain E/NE neurons orchestrate multiple concurrent glucoregulatory responses. Specific catecholamine phenotypes may mediate the individual components of the overall response. Glucoreceptive control of these neurons resides within the hindbrain.

Section snippets

Anti-dopamine β-hydroxylase saporin (DSAP) selectively lesions brain NE and E neurons

Anti-dopamine β-hydroxylase conjugated to saporin, which we refer to as DSAP, is an immunotoxin that can be used to selectively destroy NE and E neurons [13], [14], [15], [16]. It consists of a monoclonal antibody against dopamine β-hydroxylase (DBH), conjugated to the ribosomal toxin, saporin (SAP). The DSAP molecule is selectively internalized by E and NE neurons due to their unique expression of the catecholamine biosynthetic enzyme, DBH, which is exposed to the extracellular space during

DSAP-induced selective destruction of hindbrain catecholamine neurons abolishes specific glucoregulatory responses

In our initial studies [18], we found that PVH injections of DSAP abolished the feeding response to systemic glucoprivation induced by 2-deoxy-glucose (2DG), a glycolytic inhibitor [25] (Fig. 4), but did not impair the adrenal medullary hyperglycemic response to 2DG. The feeding deficit was highly selective, leaving deprivation-induced feeding and feeding in response to beta mercaptoacetate (MA)-induced lipoprivation intact. Injection into the spinal cord did not impair glucoprivic feeding, but

Hindbrain catecholamine neurons are necessary for the consummatory component of glucoprivic feeding

Appetitive behaviors and consummatory responses are distinct but closely integrated components of ingestion [26], [27]. Appetitive responses include complex motivated behaviors involved in searching for and ingesting food. Consummatory responses include reflexes necessary for accepting, chewing and swallowing food once it is in the mouth. Results from experiments using decerebrate rats [28] have shown that the forebrain is not required for glucoprivation-induced enhancement of consummatory

Hindbrain catecholamine neurons are functionally specialized

The fact that PVH DSAP injections impair or abolish glucoregulatory feeding, reproductive, adrenal medullary and corticosterone responses does not necessarily suggest that the same neurons mediate all of these responses, since functionally distinct neurons may have overlapping terminal beds and therefore be simultaneously lesioned by the DSAP injection. Moreover, the fact that PVH DSAP injections impair these responses does not necessarily indicate that catecholamine terminals in the PVH and

Hindbrain NPY neurons participate in glucoregulatory responses

One way to explore the division of labor between different populations of hindbrain catecholamine neurons is to isolate the functions of specific catecholamine subphenotypes, many of which have been identified already on the basis of co-expressed peptides and membrane receptors. We have made some progress in this regard by investigating the contribution to glucoprivic feeding of hindbrain catecholamine neurons that co-express NPY. Several lines of evidence suggest that NPY neurons are important

Glucoreceptor cells controlling systemic glucoregulatory responses are located in the hindbrain

Receptor cells that detect glucose deficit and elicit systemic glucoregulatory responses are either the catecholamine neurons themselves or are located in close proximity to them within the hindbrain. The most compelling evidence for this is the following: firstly, glucoprivic feeding and adrenal medullary responses are retained in decerebrate rats [28], [54]; secondly, acute cerebral aqueduct occlusion blocks both feeding and adrenal medullary responses to lateral ventricular but not 4th

Role of glucoprivation in the patterning of “daily meals”

There is no question that glucoprivation, when present, is a powerful stimulatory control of food intake. It can be activated despite large adipose stores. It can be activated even during periods of sustained and strongly suppressed food intake caused by chronic administration of exogenous leptin [85] and is not reduced under these conditions. Such demonstrations indicate the primacy of the brain's glucose requirement, as compared to body fat stores, as a control of appetite. Moreover, studies

Summary

Although catecholamine neuron participation in the control of food intake and autonomic and neuroendocrine responses has long been suspected, results of DSAP lesions have made it clear that hindbrain catecholamine neurons play specific and essential roles in eliciting a variety of responses to glucose deficit. The influence of these neurons extends across all levels of the neuroaxis to orchestrate responses of multiple complex systems. The degree to which individual hindbrain catecholamine

Acknowledgements

This work was supported by PHS grants R01 DK 40498 and NS 4552004 and by the Juvenile Diabetes Research Foundation International and the American Diabetes Association.

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