Agouti-Related Protein Containing Nerve Terminals Innervate Thyrotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus*

Gene expression for agouti-related protein (AGRP), an endogenous antagonist of melanocortin receptors, has been localized to the hypothalamic arcuate nucleus, where it colocalizes with neuropeptide Y (NPY). Having reported that the NPY innervation of hypophysiotropic TRH neurons in the hypothalamic paraventricular nucleus (PVN) originates primarily from NPY-producing neurons in the arcuate nucleus, here we examined the possibility that TRH neurons in the PVN are similarly innervated by AGRP nerve terminals. Using immunohistochemistry, AGRP-containing cell bodies were found almost exclusively in the arcuate nucleus, but their projections were distributed widely in the hypothalamus, most conspicuously in the paraventricular (PVN), arcuate and dorsomedial nuclei, and the posterior hypothalamic area. Ablation of the arcuate nucleus by the neonatal administration of monosodium glutamate obliterated nearly all AGRP-immunoreactivity in the hypothalamus. In the PVN, double-labeling light and electron microscopic immunohistochemistry revealed that TRH neurons receive dense innervation by AGRP nerve terminals, with the frequent occurrence of axosomatic and axodendritic synapses (mainly of the symmetrical type). These findings provide morphological basis to hypothesize a role for AGRP in the arcuato-paraventricular pathway, in the down-regulation of the hypothalamic-pituitary-thyroid axis, which occurs as an adaptive response to starvation.