Estrogen modulates the sexually dimorphic synaptic connectivity of the ventromedial nucleus

Abstract

Neurons in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl) display a remarkable estrogen-dependent functional and structural plasticity, which is likely to be mediated, in part at least, by neuronal afferents. The present study was designed to determine whether the number of synapses per neuron and the size of individual synapses in the VMNvl vary across the estrus cycle and, also, whether they differ between the sexes. To accomplish this, the VMNvl of adult female rats at proestrus or diestrus day 1 and of age-matched male rats was analyzed using electron microscopy. We found that a single VMNvl neuron receives around 7,000 synapses during diestrus and approximately 10,000 during proestrus. This estrus cycle-related variation is accounted for by increases in the number of all types of synapses. In males, the number of synapses received by each VMNvl neuron is similar to that of diestrus rats (approximately 7,500). However, in males the number of axodendritic and axospinous synapses is smaller than in proestrus rats, whereas the number of axosomatic synapses is higher than in diestrus rats. In addition, we found that the size of the postsynaptic densities of axospinous and axosomatic synapses is consistently larger in males than in females. Our results show that the synaptic organization of the VMNvl is sexually dimorphic, with females having more dendritic synapses and males more somatic synapses. They also show that the synaptic plasticity induced by estrogen in the VMNvl is characterized by changes in the number, but not the size, of the synapses.

Sex Steroid Hormones Regulate the Expression of Growth-associated Protein 43, Microtubule-associated Protein 2, Synapsin 1 and Actin in the Ventromedial Nucleus of the Hypothalamus

“…The overall cross-sectional area of the VMNvl was higher in proestrus than in all the other phases of the estrous cycle. These results are in agreement with previous morphometric studies showing an increase in the VMNvl volume both along the estrous cycle (Madeira et al 2001;Sá and Madeira 2005a) and also after estradiol benzoate and progesterone administration to ovariectomized rats (Carrer and Aoki 1982;Sá et al 2009). …”

“…This finding suggests that the number of axon terminals available for the establishment of synapses upon VMNvl neurons also vary across the estrous cycle. This possibility is in keeping with data from earlier morphometric studies showing that the volume of the VMN neuropil, where axon terminals are located, increase when the concentration of estradiol augments, both along the estrous cycle (Madeira et al 2001;Sá and Madeira 2005a) and in response to exogenous administration to ovariectomized rats (Carrer and Aoki 1982;Sá et al 2009). …”

“…The fluctuation in the extent of the malefemale differences results, partially at least, from the variations over the estrous cycle in the volume of the neuronal cell bodies and in the size of the dendritic trees of VMN neurons, which are both greater in proestrus than in diestrus rats (Madeira et al 2001). Identical estrous cyclerelated variations were observed in the dendritic spine density (Frankfurt et al 1990;Madeira et al 2001) and in the density and total number of dendritic and spine synapses (Sá and Madeira 2005a). The ebb and flow of spines and synapses over the estrous cycle reflect estrogeninduced plasticity since the administration of estrogens to ovariectomized rats provokes identical adjustments in the morphology of VMN neurons, namely in the dendritic spine density (Matsumoto and Arai 1986;Miller and Aoki 1991) and in number of spine and dendritic synapses (Sá et al 2009), alterations that do not occur under the influence of progesterone (Sá et al 2009).…”

The neural basis of sex differences in sexual behavior: A quantitative meta-analysis

“…Taken together, it may be inferred that the hypothalamus acts more autonomously and dissociatedly from other sexual processing-regions during visual sexual stimulation in women than in men. Such sex-specific hypothalamic autarchy may rest upon sex differences in the morphology and connectivity of this structure (Byne, 1998; Hines, 2010; Ibanez et al, 2001; Kilpatrick et al, 2006; Lenz and McCarthy, 2010; Makris et al, 2013; Pérez et al, 1990; Sá and Madeira, 2005; Wang et al, 2014). Furthermore, given its neuroanatomical specificity relating to sexual orientation and functional relevance for encoding sexual preferences (Balthazart, 2016; Bao and Swaab, 2011; LeVay, 2011; Poeppl et al, 2016), the sex differences in hypothalamus activation during sexual stimulation might well be represent the neural correlate of behavioral findings pointing to a less distinct sexual orientation in women (Bailey, 2009).…”

Cellular Prion Protein and Sexual Dimorphic Areas in Rodents. Correlates with Alzheimer Disease

“…The ventromedial nucleus of the hypothalamus is also considered to be sexually dimorphic, oestrogen dependant, having marked plasticity and a greater synaptic density in men than in women [10].…”