Parvocellular neurones of the hypothalamic paraventricular nucleus (PVN) comprise neurosecretory and non-neurosecretory subpopulations. We labelled neurosecretory neurones with intravenous injection of the retrograde tracer, fluoro-gold, and recorded from fluoro-gold-positive and negative PVN parvocellular neurones in hypothalamic slices. Non-neurosecretory parvocellular neurones generated a low-threshold spike (LTS) and robust T-type Ca2+ current, whereas neurosecretory neurones showed no LTS and a small T-current. LTS neurones were located in non-neurosecretory regions of the PVN, and non-LTS neurones were located in neurosecretory regions of the PVN. These findings indicate that neurosecretory and non-neurosecretory subtypes of parvocellular PVN neurones express distinct membrane electrical properties.

Noradrenergic projections to the hypothalamus play a critical role in the afferent control of oxytocin and vasopressin release. Recent evidence for intrahypothalamic glutamatergic circuits prompted us to test the hypothesis that the excitatory effect of noradrenergic inputs on oxytocin and vasopressin release is mediated in part by local glutamatergic interneurons. The voltage response to norepinephrine (30-300 M) was tested with whole-cell recordings in putative magnocellular neurons of the paraventricular nucleus (PVN) in hypothalamic slices (400 m). Norepinephrine elicited an ␣ 1 receptor-mediated direct depolarization in 23% of the magnocellular neurons tested; however, the most prominent response, seen in 42% of the magnocellular neurons, was an ␣ 1 receptor-mediated increase in the frequency of EPSPs. The norepinephrine-induced increase in EPSPs was blocked by tetrodotoxin and by ionotropic glutamate receptor antagonists, suggesting that norepinephrine excited presynaptic glutamate neurons to cause an increase in spike-mediated transmitter release. The increase in EPSPs also was observed in a surgically isolated PVN preparation (64% of cells) and with microdrop applications of norepinephrine (1 mM, 33% of cells) and glutamate (0.5-1 mM, 28%) in the PVN, indicating that the norepinephrine-sensitive presynaptic glutamate neurons are located within the PVN. Biocytin injection and subsequent immunohistochemical labeling revealed that both oxytocin and vasopressin neurons responded to norepinephrine. Our data indicate that magnocellular neurons of the PVN receive excitatory inputs from intranuclear glutamatergic neurons that express ␣ 1 -adrenoreceptors. These glutamatergic interneurons may serve as an excitatory relay in the afferent noradrenergic control of oxytocin and vasopressin release under certain physiological conditions.

Given the close relationship among neuroendocrine systems, it is likely that there may be common signals that coordinate the acquisition of adult reproductive function with other homeostatic processes. In this review, we focus on central nervous system insulin-like growth factor-1 (IGF-1) as a signal controlling reproductive function, with possible links to somatic growth, particularly during puberty. In vertebrates, the appropriate neurosecretion of the decapeptide gonadotropin-releasing hormone (GnRH) plays a critical role in the progression of puberty. Gonadotropin-releasing hormone is released in pulses from neuroterminals in the median eminence (ME), and each GnRH pulse triggers the production of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These pituitary hormones in turn stimulate the synthesis and release of sex steroids by the gonads. Any factor that affects GnRH or gonadotropin pulsatility is important for puberty and reproductive function and, among these factors, the neurotrophic factor IGF-1 is a strong candidate. Although IGF-1 is most commonly studied as the tertiary peripheral hormone in the somatotropic axis via its synthesis in the liver, IGF-1 is also synthesized in the brain, within neurons and glia. In neuroendocrine brain regions, central IGF-1 plays roles in the regulation of neuroendocrine functions, including direct actions on GnRH neurons. Moreover, GnRH neurons themselves co-express IGF-1 and the IGF-1 receptor, and this expression is developmentally regulated. Here, we examine the role of IGF-1 acting in the hypothalamus as a critical link between reproductive and other neuroendocrine functions.

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Reproductive development in vertebrates is controlled by changes in hypothalamic GnRH neurons and their inputs from other neurons and glia. One factor involved in the regulation of the GnRH system is the neurotrophic factor, IGF-1. To better understand the regulation of GnRH neurons by hypothalamic IGF-1, we quantified levels of IGF-1 mRNA in hypothalamic and preoptic regions containing GnRH cells, studied the effects of IGF-1 on GnRH gene expression, and examined the neuroanatomical relationship between GnRH neurons and hypothalamic IGF-1 in neonatal, peripubertal, and reproductively mature mice. Our results indicated that IGF-1 mRNA levels in the preoptic area and anterior hypothalamus peaked at postnatal day (P) 5, decreased through P20, and then increased through peripubertal and adult development. Second, IGF-1 had stimulatory effects on GnRH gene expression in explanted preoptic area-anterior hypothalamuses of P5 and peripubertal mice, with results varying by sex and duration of treatment. In contrast, IGF-1 had no effect or even inhibited GnRH gene expression in adult P60 mice. Third, GnRH perikarya coexpressed IGF-1, and this increased throughout sexual maturation. Taken together, the results suggest that IGF-1 can modulate GnRH neurons, that the sensitivity of GnRH neurons to IGF-1 changes developmentally, and that GnRH cells coexpress IGF-1.