Estrogen Selectively Regulates Spine Density within the Dendritic Arbor of Rat Ventromedial Hypothalamic Neurons

Abstract

Estrogen acts in the hypothalamic ventromedial nucleus (VMH) to promote female sexual behavior. One potential mechanism through which estrogen may facilitate this behavior is by reconfiguring synaptic connections within the VMH. Estrogen treatment increases the number of synapses and dendritic spines in the VMH, but how this remodeling occurs within the context of the local, behaviorally relevant microcircuitry is unknown. The goal of this study was to localize estrogen-induced changes in spine density within the VMH and relate these to dendritic morphology and the presence of nuclear estrogen receptor. The hypothalami from ovariectomized rats, treated with either vehicle or estradiol, were lightly fixed, and VMH neurons were iontophoretically filled with Lucifer yellow. Confocal microscopy was used to examine neuronal morphology. Estrogen treatment increased dendritic spine density by 48% in the ventrolateral VMH but had no effect on spine density in the dorsal VMH. The primary dendrites of VMH neurons were differentially affected by estrogen. Estrogen treatment increased spine density twofold on the short primary dendrites but did not affect spine density on long primary dendrites. Immunocytochemical staining showed that none of the filled neurons expressed estrogen receptor-␣. Thus, although the effect of estrogen on spine density is localized to a VMH subdivision where estrogen receptor is expressed, estrogen treatment induces spines on neurons that lack estrogen receptor. Taken together, our results suggest that the effect of estrogen on ventrolateral VMH spines is selective within the dendritic arbor of a neuron and may be mediated by an indirect, possibly transynaptic, mechanism.

Hypothalamic progesterone receptor-A mediates gonadotropin surges, self priming and receptivity in estrogen-primed female mice

“…In VMN subdivision containing densely packed clusters of neurons known to display EB-induced spines (Frankfurt et al 1990, Calizo & Flanagan-Cato 2000, PR-B predominance was detected for both mRNA and protein.…”

Membrane-Initiated Estradiol Signaling Induces Spinogenesis Required for Female Sexual Receptivity

“…Estradiol-stimulated spinogenesis has been well documented in multiple brain areas (Matsumoto and Arai, 1981;Gould et al, 1990;Woolley and McEwen, 1992;Calizo and Flanagan-Cato, 2000). The increase in spine density in the hippocampus has been shown to affect hippocampus-dependent working memory (Daniel and Dohanich, 2001;Williams, 2001, 2004).…”

“…Underlying these actions, estradiol has the ability to regulate plasticity by affecting dendritic structure, particularly spinogenesis. Although the actions of estradiol on dendritic spines were initially described in the hypothalamus, they have been extensively characterized in the hippocampus (Matsumoto and Arai, 1981;Frankfurt et al, 1990;Gould et al, 1990;Woolley and McEwen, 1992;Calizo and Flanagan-Cato, 2000). In regions associated with the regulation of reproduction in females, such as the ventromedial nucleus (VMH) and the arcuate nucleus (ARH) of the hypothalamus, estradiol increases spine density, suggesting a relationship between these events that has never been tested (Matsumoto and Arai, 1981;Garcia-Segura et al, 1986;Calizo and Flanagan-Cato, 2000).…”

“…Although the actions of estradiol on dendritic spines were initially described in the hypothalamus, they have been extensively characterized in the hippocampus (Matsumoto and Arai, 1981;Frankfurt et al, 1990;Gould et al, 1990;Woolley and McEwen, 1992;Calizo and Flanagan-Cato, 2000). In regions associated with the regulation of reproduction in females, such as the ventromedial nucleus (VMH) and the arcuate nucleus (ARH) of the hypothalamus, estradiol increases spine density, suggesting a relationship between these events that has never been tested (Matsumoto and Arai, 1981;Garcia-Segura et al, 1986;Calizo and Flanagan-Cato, 2000). In the ARH, the increase of spines was assumed to mediate estrogen positive feedback, which regulates luteinizing hormone release and ovulation (Matsumoto and Arai, 1981;Parducz et al, 2002Parducz et al, , 2006Csakvari et al, 2007Csakvari et al, , 2008Naftolin et al, 2007).…”

Coupling of Neuronal Nitric Oxide Synthase to NMDA Receptors via Postsynaptic Density-95 Depends on Estrogen and Contributes to the Central Control of Adult Female Reproduction

“…In particular, they have been shown to play a key role in the cyclic increases in dendritic spine density and synaptogenesis in the rat hippocampus throughout the estrous cycle (Woolley and McEwen, 1992). Like-wise, estrogen treatment in gonadectomized female rats controls dynamic changes in spine density in the hippocampus (Gould et al, 1990) and hypothalamus (Calizo and Flanagan-Cato, 2000). These findings raise the possibility that, in addition to neuronal connectivity remodeling, the short-term variations in circulating levels of estrogens that occur during the reproductive cycle may result in ongoing, cyclic fluctuation in protein-protein interactions at the postsynaptic density, thereby constituting a potential mechanism for their control of NO production within the brain (Weiner et al, 1994;Pu et al, 1996).…”