PUTATIVE SEX DIFFERENCES IN THE EXCITABILITY OF BETA- ENDORPHIN AND NEUROPEPTIDE-Y-SECRETING NEURONS OF THE ARCUATE NUCLEUS
Authors: Dremencov *Eliyahu , Kominkova Viera , Grinchii Daniil 
Published: February 2025

Abstract

Background
The arcuate nucleus (ARN) of the hypothalamus, located in the proximity to the medial eminence (ME) and third ventriculi (3V; Fig 1) is involved in multiple biological functions, such as feeding, sexual activity, and the regulation of the cardiovascular system. It was reported that leptin increased c- Fos expression in the proopiomelanocortin (POMC)- and decreased it in the neuropeptide-Y (NPY)- positive neurons of the ARN[1], suggesting that it stimulates the former, and inhibits the later.
However, the effect of leptin on the excitability of the individual ARN neurons was not yet examined. The sex differences in the excitability of the ARN neurons were not yet studied as well.

Aims & Objectives
This study aimed at the direct electrophysiological examination of the effect of leptin on the firing activity of ARN neurons in male and female rats in in vivo conditions.

Methods
Wistar rats were anesthetized with urethane and the electrodes were stereotaxically inserted into the ARN (Fig 1). After a spontaneous active neuron was recorded for at least one minute, leptin was administered intravenously, and the firing activity of the same neuron was recorded for two additional minutes.

Results
It was found that approximately half of the ARN neurons had an excitatory, and another half an inhibitory response to the leptin administration (Fig 1). The excitability of the neurons with excitatory response to leptin was not different between the sexes. The average firing rate of the neurons with inhibitory response to leptin in females was however significantly lower, comparing to the males.

Discussion & Conclusion
Based on the previous c-Fos immunohistochemistry study[1], we assume that the neurons with stimulatory response to leptin are ß-endorphin-releasing (BEN) POMC-positive neurons, and these with inhibitory response are NPY-releasing neurons. It was previously reported that the NPY Y1 receptors in females have higher sensitivity, comparing to the males their affinity was greater in females[2]. Y1 receptors might thus be responsible, at least in part, for the sex differences in the excitability of the neurons putatively identified as NPY neurons. Since the ARN are involved in both mood and metabolic and eating disorders, the sex differences in the excitability of the ARN neural circuits may explain the difference in the prevalence of these disorders between the sexes. This work was supported by the Slovak Research and Development Agency (grant APVV-20-0202) and Scientific Grant Agency of Ministry of Education of Slovak Republic and Slovak Academy of Sciences (grant VEGA-2/0057/22).

References
1)Elias, C. F.; Aschkenasi, C.; Lee, C.; Kelly, J.; Ahima, R. S.; Bjorbaek, C.; Flier, J. S.; Saper, C. B.; Elmquist, J. K., Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999, 23, (4), 775-86.
2) Michel, M. C.; Lewejohann, K.; Farke, W.; Bischoff, A.; Feth, F.; Rascher, W., Regulation of NPY/NPY Y1 receptor/G protein system in rat brain cortex. Am J Physiol 1995, 268, (1 Pt 2), R192-200.