Social behaviors such as courtship, parenting, and aggression depend primarily on two factors: a social signal to trigger the behavior, and a hormonal milieu that facilitates or permits it. Gonadal steroids may alter the valence or perceived context of the signal so that the same pheromone, vocalization, or visual display may elicit very different responses depending on the receiver's plasma hormone level. The neural processes underlying this phenomenon, however, are not well understood. Here, we describe how hormones modulate neural responses to social signals in female white-throated sparrows listening to recordings of male song. While manipulating levels of the ovarian steroid estradiol, we mapped and quantified sound-induced expression of the immediate early gene egr-1 in nine brain regions that constitute a social behavior network in vertebrates. In most regions of interest, hearing male song induced more expression than hearing tones or silence, and this selectivity for song was seen only in birds with estradiol levels typical of the breeding season. In females with regressed ovaries and no exogenous estradiol, neural responses were selective for song over tones only in the lateral portion of the ventromedial hypothalamus, not in the rest of the network. Because the effects of hormone treatment on neural responses are not identical in each region, the overall pattern of activation across the network changes with estradiol level and thus with season and breeding context. Our results demonstrate a possible mechanism by which gonadal steroids may alter the processing of social signals and affect social decision-making.

HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction.

Sex steroids facilitate dramatic changes in behavioral responses to sociosexual signals and are increasingly implicated in the sensory processing of those signals. Our previous work demonstrated that in female white-throated sparrows, which are seasonal breeders, genomic responses in the auditory forebrain are selective for conspecific song over frequency-matched tones only when plasma estradiol (E2) reaches breeding levels. Here, we sought to map this E2-dependent selectivity in the best-studied area of the auditory forebrain, the caudomedial nidopallium (NCM). Nonbreeding females with low endogenous levels of E2 were treated with E2 or a placebo and exposed to conspecific song, tones, or no sound playback. Immunoreactive protein product of the immediate early gene zenk (egr-1) was then quantified within seven distinct subregions, or domains, of NCM. We report three main findings: (1) regardless of hormone treatment, the zenk response is significantly higher in dorsal than in ventral NCM, and higher in medial than in lateral NCM; (2) E2-dependent selectivity of the response is limited to the rostral and medial domains of NCM; in the more caudal domains, song induces more zenk expression than tones regardless of hormone treatment; (3) even when no sound stimuli were presented, E2 treatment significantly increased zenk expression in the rostral, but not the caudal, domains of NCM. Together, the latter two findings suggest that E2-dependent plasticity in NCM is concentrated in rostral NCM, which is hodologically and neurochemically distinct from caudal NCM. Activity in rostral NCM may therefore be seasonally regulated in this species.

A growing body of evidence suggests that gonadal steroids such as estradiol (E2) alter neural responses not only in brain regions associated with reproductive behavior, but also in sensory areas. Because catecholamine systems are involved in sensory processing and selective attention, and because they are sensitive to E2 in many species, they may mediate the neural effects of E2 in sensory areas. Here, we tested the effects of E2 on catecholaminergic innervation, synthesis, and activity in the auditory system of white-throated sparrows, a seasonally breeding songbird in which E2 promotes selective auditory responses to song. Non-breeding females with regressed ovaries were held on a winter-like photoperiod and implanted with silastic capsules containing either no hormone or E2. In one hemisphere of the brain, we used immunohistochemistry to quantify fibers immunoreactive for tyrosine hydroxylase or dopamine beta-hydroxylase in the auditory forebrain, thalamus, and midbrain. E2 treatment increased catecholaminergic innervation in the same areas of the auditory system in which E2 promotes selectivity for song. In the contralateral hemisphere, we quantified dopamine, norepinephrine and their metabolites in tissue punches using HPLC. Norepinephrine increased in the auditory forebrain, but not the midbrain, after E2 treatment. We found evidence of interhemispheric differences, both in immunoreactivity and catecholamine content did not depend on E2 treatment. Overall, our results show that increases in plasma E2 typical of the breeding season enhance catecholaminergic innervation and synthesis in some parts of the auditory system, raising the possibility that catecholamines play a role in E2-dependent auditory plasticity in songbirds.

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