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Background/aims: Kisspeptin is the major excitatory regulator of gonadotropin-releasing hormone (GnRH) neurons and is responsible for basal GnRH/LH release and the GnRH/LH surge. Although it is widely assumed, based on mutations in kisspeptin and Kiss1R, that kisspeptin acts to sustain basal GnRH neuronal activity, there have been no studies to investigate whether endogenous basal kisspeptin tone plays a direct role in basal spontaneous GnRH neuronal excitability. It is also of interest to examine possible interactions between endogenous kisspeptin tone and other neuropeptides that have direct effects on GnRH neurons, such as neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART), since the activity of all these neuropeptides changes during states of negative energy balance., Methods: Loose cell-attached and whole-cell current patch-clamp recordings were made from GnRH-GFP neurons in hypothalamic slices from female and male rats., Results: Kisspeptin activated GnRH neurons in a concentration-dependent manner with an EC50 of 3.32 ± 0.02 nM. Surprisingly, a kisspeptin antagonist, Peptide 347, suppressed spontaneous activity in GnRH neurons, demonstrating the essential nature of the endogenous kisspeptin tone. Furthermore, inhibition of endogenous kisspeptin tone blocked the direct activation of GnRH cells that occurs in response to antagonism of NPY Y5 receptor or by CART., Conclusions: Our electrophysiology studies suggest that basal endogenous kisspeptin tone is not only essential for spontaneous GnRH neuronal firing, but it is also required for the net excitatory effects of other neuropeptides, such as CART or NPY antagonism, on GnRH neurons. Therefore, endogenous kisspeptin tone could serve as the linchpin in GnRH activation or inhibition., (© 2014 S. Karger AG, Basel.)

The perinatal environment plays an important role in programming many aspects of physiology and behavior including metabolism, body weight set point, energy balance regulation and predisposition to mental health-related disorders such as anxiety, depression and attention deficit hyperactivity disorder. Maternal health and nutritional status heavily influence the early environment and have a long-term impact on critical central pathways, including the melanocortinergic, serotonergic system and dopaminergic systems. Evidence from a variety of animal models including rodents and nonhuman primates indicates that exposure to maternal high-fat diet (HFD) consumption programs offspring for increased risk of adult obesity. Hyperphagia and increased preference for fatty and sugary foods are implicated as mechanisms for the increased obesity risk. The effects of maternal HFD consumption on energy expenditure are unclear, and future studies need to address the impact of perinatal HFD exposure on this important component of energy balance regulation. Recent evidence from animal models also indicates that maternal HFD consumption increases the risk of offspring developing mental health-related disorders such as anxiety. Potential mechanisms for perinatal HFD programming of neural pathways include circulating factors, such as hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines. As maternal HFD consumption and obesity are common and rapidly increasing, we speculate that future generations will be at increased risk for both metabolic and mental health disorders. Thus, it is critical that future studies identify therapeutic strategies that are effective at preventing maternal HFD-induced malprogramming., (Copyright © 2010 S. Karger AG, Basel.)

Neuropeptide Y (NPY) displays diverse modes of action in the CNS including the modulation of feeding behavior, gonadotropin releasing hormone release, and stress responses. Many of the above physiological actions have been at least partially attributed to actions of NPY on the NPY Y5 receptor subtype. We utilized an antibody directed against the NPY Y5 receptor to characterize the distribution of this receptor in the rat brain. Using Western blot analysis, this antibody recognized a single major band at approximately 57 kD. To further verify the specificity of the antibody, animals were treated for 5 days with antisense oligonucleotides for the Y5 receptor. The antisense treatment significantly reduced food intake and body weight. Furthermore, the Y5 antibody detected a significant decrease in Y5 receptor protein. Y5-like immunoreactivity (-ir) was observed throughout the hypothalamus, thalamus, hippocampus and cortex. Double-label immunofluorescence demonstrated that Y5-ir was colocalized with the following neuronal phenotypes in the hypothalamus, gonadotropin-releasing hormone, neurophysins, corticotropin-releasing hormone, and gamma-amino butyric acid. In addition, functional interactions were demonstrated by the presence of close appositions of NPY fibers with Y5-ir expressing cells. The wide distribution of the Y5 receptor-ir, as well as the colocalization within specific neuronal populations, agrees with the distribution of the Y5 receptor mRNA and the known physiological roles of the NPY/Y5 system. The role of the NPY/Y5 receptor system as a mediator between signals of peripheral energy availability and reproductive neuroendocrine function is discussed., (Copyright 2001 S. Karger AG, Basel)

Brain angiotensin II (AII) receptors play a role in the regulation of luteinizing hormone release. This action is thought to involve luteinizing hormone-releasing hormone containing neurons in the preoptic-anterior hypothalamic (POAH) area of the brain. Previous studies have demonstrated a discrete locus of AII receptor binding sites and responsiveness within the POAH to microinjections of AII in the adult female rat, corresponding to the ventral portion of the bed nucleus of the stria terminalis (BSTV). To further characterize the age- and sex-dependent AII receptor binding in the BSTV and other brain regions, in vitro receptor autoradiography using 125I-sarcosine1, isoleucine8 AII (125I-SI AII) was performed on 2-, 4- and 10-week-old female and male rat brains. Rats of both sexes displayed an age-dependent increase in 125I-SI AII binding in the BSTV, as well as in the suprachiasmatic nucleus (SCh). There was no detectable difference in binding within the BSTV between the female and male of any age group. Prepubertal ovariectomy did not impair the expression of 125I-SI AII binding in the BSTV or the SCh of adult female rats. The developmental expression of AII receptors in the BSTV and SCh may therefore play a role in sexual maturation and regulation of sexual function in the rat.

In vitro receptor autoradiography, using the radiolabeled angiotensin II (Ang II) antagonist 125I-sar1,ile8 Ang II (125I-SI Ang II; 250 pM) in the absence or presence of 1 microM Ang II, was used to identify Ang II receptor binding sites in the preoptic-anterior hypothalamic (POAH) brain region of cycling female rats. A nucleus within this region, lateral to the organum vasculosum of the lamina terminalis and ventral to the anterior commissure, displayed a discrete locus of 125I-SI Ang II binding sites (385 fmol/g tissue). This nucleus, which corresponds to the area of the POAH from which Ang II is most effective at eliciting luteinizing hormone release, has been identified as the ventral portion of the bed nucleus of the stria terminalis (BSTV) by the rat brain atlas of Paxinos and Watson. The selective nonpeptidic Ang II alpha receptor antagonist Dup 753 completely inhibited the binding of 125I-SI Ang II to the BSTV and other hypothalamic nuclei, suggesting that these receptors are of the Ang II alpha subtype.