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.

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The lordosis reflex is a hormone-dependent behavior displayed by female rats during mating. This study used the transneuronal tracer pseudorabies virus (PRV) to investigate the CNS network that controls the lumbar epaxial muscles that produce this posture. After PRV was injected into lumbar epaxial muscles, the time course analysis of CNS viral infection showed progressively more PRV-labeled neurons in higher brain structures after longer survival times. In particular, the medullary reticular formation, periaqueductal gray (PAG), and ventromedial nucleus of the hypothalamus (VMN) were sequentially labeled with PRV, which supports the proposed hierarchical network of lordosis control. Closer inspection of the PRV-immunoreactive neurons in the PAG revealed a marked preponderance of spheroid neurons, rather than fusiform or triangular morphologies. Furthermore, PRV-immunoreactive neurons were concentrated in the ventrolateral column, rather than the dorsal, dorsolateral, or lateral columns of the PAG. Localization of the PRV-labeled neurons in the VMN indicated that the majority were located in the ventrolateral subdivision, although some were also in other subdivisions of the VMN. As expected, labeled cells also were found in areas traditionally associated with sympathetic outflow to blood vessels and motor pathways, including the intermediolateral nucleus of the spinal cord, the paraventricular hypothalamic nucleus, the red nucleus, and the motor cortex. These results suggest that the various brain regions along the neuraxis previously implicated in the lordosis reflex are indeed serially connected.

Neurons of the ventromedial hypothalamic nucleus (VMH) that project to the periaqueductal gray (PAG) form a crucial segment of the motor pathway that produces the lordosis posture, the hallmark of female rat sexual behavior. One suggested mechanism through which estrogen facilitates lordosis is by remodeling synaptic connectivity within the VMH. For instance, estrogen alters VMH dendritic spine density. Little is known, however, about the local VMH microcircuitry governing lordosis nor how estrogen alters synaptic connectivity within this local circuit to facilitate sexual behavior. The goal of this study was to define better the neuron types within the VMH microcircuitry and to examine whether estrogen alters synaptic connectivity, as measured by dendritic spine density, on VMH projection neurons. A retrograde tracer was injected into the PAG of ovariectomized rats treated with vehicle or estradiol. Retrogradely labeled VMH neurons were filled with Lucifer yellow, then immunostained for estrogen receptor-alpha (ER alpha). VMH neurons that project to the PAG had more dendrites than functionally unidentified neurons. Additionally, VMH projection neurons could be subdivided into those located within the cluster of ER alpha-containing neurons and those medial to the cluster. Estrogen decreased spine density by 57% on the long primary dendrites of VMH projection neurons located within the ER alpha cluster but not on projection neurons medial to the cluster. Only 4% of the VMH projection neurons expressed ER alpha. These results suggest that estrogen may facilitate sexual behavior by decreasing spines selectively, via an indirect mechanism, on a subset of VMH neurons that project to the PAG.

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Female sexual behavior in rodents, typified by the lordosis posture, is hormone-dependent and sex-specific. Ovarian hormones control this behavior via receptors in the hypothalamic ventromedial nucleus (VMH). This review considers the sex differences in the morphology, neurochemistry and neural circuitry of the VMH to gain insights into the mechanisms that control lordosis. The VMH is larger in males compared with females, due to more synaptic connections. Another sex difference is the responsiveness to estradiol, with males exhibiting muted, and in some cases reverse, effects compared with females. The lack of lordosis in males may be explained by differences in synaptic organization or estrogen responsiveness, or both, in the VMH. However, given that damage to other brain regions unmasks lordosis behavior in males, a male-typical VMH is unlikely the main factor that prevents lordosis. In females, key questions remain regarding the mechanisms whereby ovarian hormones modulate VMH function to promote lordosis.

Mineralocorticoids, such as deoxycorticosterone acetate (DOCA), and angiotensin II (AngII) act synergistically in the brain to elicit salt appetite. Glucocorticoids, such as dexamethasone (DEX), also may enhance the behavioral effects of DOCA and AngII. However, the brain regions involved in these behavioral interactions have not been elucidated. This study tested the hypothesis that DEX potentiates the effects of DOCA on AngII binding, especially at the AT1 receptor. We confirmed that DEX potentiated the effects of DOCA on salt appetite. Concomitantly, steroid-specific and region-specific changes in AT1 binding were noted. Specifically, in the hypothalamic paraventricular nucleus, treatment with DEX or DOCA + DEX increased AT1 binding. In the subfornical organ (SFO) and area postrema, there was an increase in AT1 binding when both steroids were combined, but not when given individually. However, there was no change in AT2 binding in any brain region studied and no change in AT1 or AT2 binding to either receptor subtype in the pituitary. The results indicate that DOCA and DEX may increase the sensitivity of the brain to the behavioral and physiological actions of AngII by upregulating AT1 receptors in the SFO and area postrema.