The white-throated sparrow (Zonotrichia albicollis) represents a powerful model in behavioral neuroendocrinology because it occurs in two plumage morphs that differ with respect to steroid-dependent social behaviors. Birds of the white-striped (WS) morph engage in more territorial aggression than do birds of the tan-striped (TS) morph, and the TS birds engage in more parenting behavior. This behavioral polymorphism is caused by a chromosomal inversion that has captured many genes, including estrogen receptor alpha (ERα). In this study, we tested the hypothesis that morph differences in aggression might be explained by differential sensitivity to estradiol (E2). We administered E2 non-invasively to non-breeding white-throated sparrows and quantified aggression toward a conspecific 10 min later. E2 administration rapidly increased aggression in WS birds but not TS birds, consistent with our hypothesis that differential sensitivity to E2 may at least partially explain morph differences in aggression. To query the site of E2 action in the brain, we administered E2 and quantified Egr-1 expression in brain regions in which expression of ERα is known to differ between the morphs. E2 treatment decreased Egr-1 immunoreactivity in nucleus taeniae of the amygdala, but this effect did not depend on morph. Overall, our results support a role for differential effects of E2 on aggression in the two morphs, but more research will be needed to determine the neuroanatomical site of action.
Like human language, song in songbirds is learned during an early sensitive period and is facilitated by motivation to seek out social interactions with vocalizing adults. Songbirds are therefore powerful models with which to understand the neural underpinnings of vocal learning. Social motivation and early social orienting are thought to be mediated by the oxytocin system; however, the developmental trajectory of oxytocin receptors in songbirds, particularly as it relates to song learning, is currently unknown. This gap in knowledge has hindered the development of songbirds as a model of the role of social orienting in vocal learning. In this study, we used quantitative PCR to measure oxytocin receptor expression during the sensitive period of song learning in zebra finches (Taeniopygia guttata). We focused on brain regions important for social motivation, attachment, song recognition, and song learning. We detected expression in these regions in both sexes from posthatch day 5 to adulthood, encompassing the entire period of song learning. In this species, only males sing; we found that in regions implicated in song learning specifically, oxytocin receptor mRNA expression was higher in males than females. These sex differences were largest during the developmental phase when males attend to and memorize tutor song, suggesting a functional role of expression in learning. Our results show that oxytocin receptors are expressed in relevant brain regions during song learning, and thus provide a foundation for developing the zebra finch as a model for understanding the mechanisms underlying the role of social motivation in vocal development.
Emerging evidence suggests that enlarged perivascular spaces (ePVS) may be a clinically significant neuroimaging marker of global cognitive function related to cerebral small vessel disease (cSVD). We tested this possibility by assessing the relationship between ePVS and both a standardized measure of global cognitive function, the Montreal Cognitive Assessment (MoCA), and an established marker of cSVD, white matter hyperintensity volume (WMH) volume. One hundred and eleven community-dwelling older adults (56–86) underwent neuroimaging and MoCA testing. Quantification of region-specific ePVS burden was performed using a previously validated visual rating method and WMH volumes were computed using the standard ADNI pipeline. Separate linear regression models were run with ePVS as a predictor of MoCA scores and whole brain WMH volume. Results indicated a negative association between MoCA scores and both total ePVS counts (P ≤ 0.001) and centrum semiovale ePVS counts (P ≤ 0.001), after controlling for other relevant cSVD variables. Further, WMH volumes were positively associated with total ePVS (P = 0.010), basal ganglia ePVS (P ≤ 0.001), and centrum semiovale ePVS (P = 0.027). Our results suggest that ePVS burden, particularly in the centrum semiovale, may be a clinically significant neuroimaging marker of global cognitive dysfunction related to cSVD.
Background: Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the etiology of ePVS remains unknown. Here we tested the possibility that baseline cerebrovascular dysfunction, as measured by an MRI measure of cerebrovascular reactivity (CVR), contributes to the later development of ePVS.<break><break>Methods: A total of 79 cognitively normal, older adults (46 women, age range 60-84) were recruited to undergo MRI scanning at baseline and 50 participants returned for a follow-up scan approximately 2.5 years later. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. CVR, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon-dioxide inhalation while acquiring blood oxygen-level dependent (BOLD) MR images.<break><break>Results: Low baseline CVR values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (coefficient estimate (SE) = -15.87 (3.92), p < 0.001, 95% confidence interval [CI] -23.68 to -8.05). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (cSVD) (coefficient estimate (SE) = -15.03 (4.00), p < 0.001, CI -23.02 to -7.05) and neuroimaging markers of cSVD (coefficient estimate (SE) = -13.99 (4.02), p < 0.001, CI -22.03 to -5.95).<break><break>Conclusions: Our results demonstrate that low baseline CVR is a risk factor for later development of ePVS. MRI-based CVR may represent a promising biomarker of cSVD.
BackgroundCerebral small vessel disease (cSVD) is characterized by several in‐vivo neuroimaging biomarkers including enlarged perivascular spaces (ePVS). PVS are fluid‐filled spaces that play a role in the glymphatic system’s removal of brain waste. Arterial pulsatility drives waste removal through the PVS. Thus, arterial stiffness, a common feature of brain aging, may lead to waste accumulation and perivascular space enlargement.MethodWe explored the relationship between arterial stiffness and ePVS counts in 80 cognitively normal older adults ranging in age from 60‐85. Participants were scanned on a 3T Siemens Prisma scanner with a 64‐channel head coil. Arterial stiffness was assessed using cerebrovascular reactivity (CVR), a measure of the ability of cerebrovasculature to dilate in response to hypoxia. Blood‐oxygen‐level‐dependent contrast imaging (BOLD) functional magnetic resonance imaging (fMRI) was used in conjunction with blocked administration of hypercapnic gas. CVR was computed in specific regions by dividing change in BOLD signal by change in end‐tidal CO2. All ePVS counts were performed on T1 MPRAGE and T2 FLAIR images while blinded to participant demographics and under the direction of a neuroradiologist. ePVS were defined as regions of hypointensity less than 3mm in diameter on T1 imaging and were distinguished from mimics by absence of T2 FLAIR hyperintensity. ePVS were individually and manually counted in a single, representative slice in the axial plane of the basal ganglia (BGePVS), centrum semiovale, hippocampus, and midbrain.ResultRegression analyses controlling for age, sex, intracranial volume, and education demonstrated a significant, negative relationship between cross‐sectional whole brain CVR and BGePVS (β =‐0.338, P = 0.003). Moreover, CVR in the left basal ganglia was negatively related to BGePVS in the left basal ganglia (β = ‐0.401, P < 0.001), and CVR in the right basal ganglia was negatively related to BGePVS in the right basal ganglia (β = ‐0.444, P < 0.001).ConclusionOur findings indicate a regional relationship between lower CVR and BGePVS burden, suggesting BGePVS are related to arterial stiffness. Longitudinal studies are required to address causality. Future work should compare other potential mechanisms of perivascular space enlargement to strengthen the hypothesis that arterial stiffness leads to ePVS.
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