Browsing by Subject "Sex differences"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    mGluR5 Structural Plasticity in the Nucleus Accumbens: Characterization, Mechanism, and Sex Differences
    (2017-10) Gross, Kellie S
    The group I metabotropic glutamate receptors, mGluR1 and mGluR5, are important modulators of neuronal signaling and plasticity. One specific way that group I mGluRs appear to influence excitatory neurotransmission is through the remodeling of neuronal structure by inducing changes to dendritic spines. However, group I mGluR spine remodeling has only been studied in an extremely limited number of regions and cell types, leaving the contribution of this mechanism to plasticity in many systems unknown. Group I mGluRs, especially mGluR5, have been associated with the synaptic plasticity in the reward circuitry of the brain that is believed to underlie addiction. Structural changes in this circuitry, particularly in the nucleus accumbens (NAc) are strongly correlated with the development and maintenance of addiction. Yet a potential relationship between mGluR5 signaling and spine plasticity in the NAc has not been directly studied. Here, the effects of mGluR5 signaling on spine plasticity in medium spiny neurons of the NAc are characterized, with particular attention on the sex differences and hormonal regulation of these effects. Activation of mGluR5 signaling is found to decrease spine density in the NAc with sex differences in subregion specificity. Additionally, primary gonadal hormones are found to trigger mGluR5 signaling to produce structural modulation in the NAc, with previous evidence implicating mGluR5 in estradiol-induced spine changes in this region in females, and research here finding a similar, novel role for androgen signaling in males. The mechanisms of mGluR5-mediated spine plasticity are also explored. Endocannabinoid signaling was found to be required for mGluR5-induced spine decreases in the male NAc, and spine changes were found to be correlated with a change in NAc F-actin content. Collectively, these results indicate that mGluR5 signaling results in structural plasticity in a region that is critical to reward in a sex-dependent manner, suggesting that the activity of this receptor might contribute differently to both natural and pathological motivated behavior in males and females.
  • Thumbnail Image
    Item
    Preclinical Models of Dystrophic Cardiomyopathy and Therapies for the Dystrophic Heart
    (2019-08) Meyers, Tatyana
    Muscular dystrophies are a diverse group of genetic diseases characterized by progressive muscle weakness and deterioration with wide variability in severity and affected muscle groups. Some of the more devastating muscular dystrophies result from the absence of components of the dystrophin-glycoprotein complex (DGC). Disruption of the DGC compromises sarcolemmal integrity in striated muscle, leading to increased myocyte injury and death. These forms of muscular dystrophy often feature both skeletal muscle wasting and marked cardiomyopathy. The most common of these muscular dystrophies is Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene that result in the loss of this large membrane-stabilizing protein. DMD features a childhood onset and leads to premature death at ages ranging from the teens into the 30’s, often from cardiorespiratory failure. DMD is an X-linked disorder, and is usually inherited from carrier mothers who also face a high risk of cardiomyopathy. Sarcoglycanopathies are a rarer group of autosomal recessive Limb Girdle muscular dystrophies (LGMD) that arise from mutations in the sarcoglycan genes, sometimes leading to an aggressive Duchenne-like disease course in patients of both sexes. The heterotetrameric sarcoglycan complex is a key component of the DGC, and its loss induces significant myocyte pathology that can trigger childhood disease onset and premature death. Muscles and hearts devoid of the sarcolgycan complex display hallmark dystrophic pathology, including muscle wasting, loss of ambulation, and a high incidence of lethal dilated cardiomyopathy. The work presented here is driven by efforts to quantify the susceptibility of dystrophic hearts to acute injury caused by increased cardiac workload, and to understand the contribution of angiotensin signaling to dystrophic heart injury. It describes the following key findings: 1) angiotensin receptor blockers (ARBs) can markedly reduce acute injury in dystrophin-null and sarcoglycan-null mouse hearts; 2) female mouse hearts lacking the sarcoglycan complex are significantly protected compared to male hearts, and do not derive the same benefit from ARBs; and 3) mosaic expression of dystrophin in the heart results in elevated vulnerability to injury that is modulated by factors besides dystrophin levels. This work suggests that angiotensin signaling plays an exaggerated role in dystrophic heart injury through mechanisms that may be sex-dependent, and that earlier and more consistent use of angiotensin-blocking therapies has the potential to limit dystrophic cardiomyopathy. Furthermore, it reveals that dystrophic hearts may continue to show significant vulnerability in the context of gene therapies that restore partial dystrophin expression.
  • Thumbnail Image
    Item
    Sex differences and the role of estrogen, estrous cycle, and DRG neurons in a mouse model of cancer pain
    (2014-04) Triemstra, Jennifer Lynn
    While conflicting views exist in the literature regarding sex differences in cancer pain, recent studies show that women are more likely to experience greater cancer pain than men. Transient receptor potential (TRP) are considered critical receptors in tumor-induced peripheral sensitization while cycling sex steroid hormones are considered critical factors in sex-dependent differences in cancer pain. Whether sex differences in cancer pain are due to estrogens affect on TRP receptors has yet to be determined. Utilizing a mouse model of bone cancer, we compared tumor-induced mechanical allodynia and thermal (heat and cold) hyperalgesia in intact, gonadectomized, and estradiol-replaced males and females. Tumor-induced changes in TRP and estrogen receptor mRNA levels were assessed. We also examined the anti-nociceptive effects of a topical application of a TRPM8 agonist (menthol) and subcutaneous injected TRPV1 antagonist on tumor-induced nociception. We found no sex differences in tumor-induced mechanical allodynia, but, there was greater mechanical allodynia in females during proestrus/estrus than during diestrus. Estradiol replacement in gonadectomized females increased tumor-induced mechanical allodynia, but decreased allodynia in gonadectomized males. Collectively, females were more sensitive to tumor-induced cold hyperalgesia than males. Tumor-induced cold sensitivity was increased in all gonadectomized animals regardless of estradiol replacement. GPR30 mRNA was greater in females during diestrus than proestrus/estrus. TRPV1 mRNA was lower in diestrus females but greater during proestrus/estrus. Estradiol replacement had in inverse effect on TRPV1 mRNA expression in gonadectomized females, but had no effect in gonadectomized males. TRPM8 mRNA was greater in females than males, while TRPA1 mRNA was greater in males than in females. The TRPV1 antagonist induced antinociception in proestrus/estrus females, but this effect was reduced in estradiol replaced gonadectomized males. Menthol-induced antinociception was reduced in gonadectomized females, but restored with estradiol replacement. These findings suggest that estrogen mediates sex differences in tumor-induced mechanical allodynia and cold hyperalgesia, TRP expression, menthol-induced antinociception as well as TRPV1 antagonist antinociception. Collectively, this verifies that estrogen is, in part, responsible for contrasting sensitivity of males and females to cancer pain.
  • Thumbnail Image
    Item
    Sex Differences in Abilities and in Achievement
    (1967) Ario, Marion W
    It is the purpose of this longitudinal study to examine the problems of sex differences in ability and achievement. It is also hoped that the longitudinal aspect of this study will help clarify whether or not changes in these sex differences or lack of sex differences do occur during this period of adolescence.