Neurons of the mediobasal hypothalamus act to control the endocrine system. By secreting factors into the median eminence that are carried to the anterior pituitary gland, these neurons regulate hormone release form the thyroid, ovary, testis and adrenal gland. Many different neurotransmitters are present in the mediobasal hypothalamus, several of them were first discovered in this important brain area. Neuronal communication to these neuroendocrine neurons is therefore critical in conveying information from the rest of the brain to this final common pathway regulating hormonal balances. Of the dozens of neurotransmitters found here, two amino acid transmitters, glutamate and GABA, appear to be responsible for almost all actual synaptic activity, and when their receptors are blocked, synaptic activity is generally eliminated. A number of hypothalamic peptides have been shown to play a very important role in endocrine regulation. The general scientific point addressed here is that neuroactive peptides in the mediobasal hypothalamus act primarily to modulate the activity of the amino acid neurotransmitters. Dr. van den Pol will study a new hypothalamic peptide neurotransmitter called hypocretin, which increases neuronal activity. Hypocretin is synthesized only by neurons in the dorsolateral hypothalamus and perifornical area, a part of the brain intimately involved in the regulation of body weight and energy balance. Nerve cells that make hypocretin send long axons to the mediobasal hypothalamus, suggesting they may signal this brain region. Dr. Van den Pol's laboratory will use rat brain slices in vitro and synaptically coupled cultures to study the mediobasal hypothalamic cells that are influenced by this new transmitter and its mechanism of action. To accomplish this, they will use digital imaging and electrophysiology. To test the hypothesis that hypocretin acts by modulating GABA and glutamate neurons of the arcuate neurons, other transmitter actions will be blocked and the effect of hypocretin on GABA and glutamate mediated electrical activity will be determined. They will also investigate if hypocretin's mechanism of action involves intracellular calcium. Results obtained from these studies could contribute to elucidate the role of hypocretin in feeding, maintenance of weight and body temperature and in the regulation of the endocrine and autonomic nervous system. It will also advance our knowledge on how neurotransmitters work.
