No abstract

Neurosteroids play an important role in the development of the cerebellum. In particular, estradiol and progesterone appear capable of inducing increases in dendritic spine density during development, and there is evidence that both are synthesized de novo in the cerebellum during critical developmental periods. In normal neonates and adults, there are few differences in the cerebellum between the sexes and most studies indicate that hormone and receptor levels also do not differ significantly during development. However, the sexes do differ significantly in risk of neuropsychological diseases associated with cerebellar pathology, and in animal models there are noticeable sex differences in the response to insult and genetic mutation. In both humans and animals, males tend to fare worse. Boys are more at risk for autism and Attention Deficit Hyperactivity Disorder than girls, and schizophrenia manifests at an earlier age in men. In rats males fare worse than females after perinatal exposure to polychlorinated biphenyls, and male mice heterozygous for the staggerer and reeler mutation show a more severe phenotype. Although very recent evidence suggests that differences in neurosteroid levels between the sexes in diseased animals may play a role in generating different disease phenotypes, the reason this hormonal difference occurs in diseased but not normal animals is currently unknown.

Prostaglandins are lipid-derived molecules that mediate the generation of fever in the central nervous system. In addition to their proinflammatory role, prostaglandins also impact neuronal development and synaptic plasticity, sometimes in a sex-specific manner. The cerebellum has a high expression of prostaglandin receptors during development, but the role that these molecules play during normal cerebellar maturation is unknown. We demonstrate here that disrupting prostaglandin synthesis with cyclo-oxygenase inhibitors during a time-sensitive window in early postnatal life alters cerebellar Purkinje cell development in rats, resulting in initially increased dendritic growth in both sexes. We show that this results in later cerebellar atrophy in males only, resulting in a sex-specific loss of cerebellar volume. Further, although performance in motor tasks is spared, social interaction and the sensory threshold are altered in males developmentally exposed to cyclo-oxygenase inhibitors. This work demonstrates a previously unknown role for prostaglandins in cerebellar development and emphasizes the role that the cerebellum plays outside motor tasks, in cognitive and sensory domains that may help to explain its connection to complex neurodevelopmental disorders such as autism.

Gonadal steroids organize the developing brain during a perinatal sensitive period and exert enduring consequences for adult behavior. In male rodents, testicular androgens are aromatized in neurons to estrogens and initiate multiple distinct cellular processes that ultimately determine the masculine phenotype. Within specific brain regions, overall cell number and dendritic morphology are principle targets of hormonal organization. Recent advances have been made in elucidating the cellular mechanisms by which the neurological underpinnings of sexually dimorphic physiology and behavior are determined. These include estradiol-mediated prostaglandin synthesis, presynaptic release of glutamate, postsynaptic changes in glutamate receptors and changes in cell adhesion molecules. Sex differences in cell death are mediated by hormonal modulation of survival and death factors such as TNFα and Bcl-2/BAX. Sexual differentiationThe term "sexual differentiation" refers to a series of events that begins with sex determination by the SRY gene on the Y chromosome which programs the bipotential gonad to become a testis, followed by hormonally mediated cascades that direct the formation of the reproductive tract, genitalia, secondary sex characteristics and ultimately, the brain (reviewed in [1]). Production of testicular hormones during development coordinately organizes the brain and behavior in a process described by the Organizational/Activational Hypothesis of sexual differentiation [2]. This simple tenet articulates the complex notion that steroid hormones act on the developing brain to permanently organize it in a manner that directs the actions of adult hormones. Testosterone from the male testis masculinizes the brain during a perinatal sensitive period and as a result, the adult male brain is sensitive to the sex-behavior inducing effects of testosterone. Successful masculinization is evident in an adult male's mounting, intromission and ejaculatory behavior with a sexually receptive female. The opposite of masculinization is feminization, an organizational process that occurs by default when there is insufficient gonadal steroid exposure during the critical period. Successful feminization is evident in

Background: Sydenham's chorea (SC), the neurologic manifestation of rheumatic fever, remains the most prevalent form of chorea in children. Suggested treatments of chorea in SC include prophylactic penicillin, symptomatic (antipsychotic and anticonvulsant) medications, and immunomodulatory therapy (steroids, intravenous immunoglobulin (IVIG), and plasma exchange). In this manuscript, we undertook a systematic review of the published literature to examine the data supporting these therapeutic recommendations.Methods: A search of PubMed, Embase, Psychinfo, and clinicaltrials.gov was conducted for publications pertaining to the treatment of SC/rheumatic chorea from 1956 to 2016.Results: Penicillin prophylaxis appears to reduce the likelihood of further cardiac complications and the recurrence rate of chorea. Data on symptomatic therapy for chorea are limited to individual case reports or series and rare comparison studies. The efficacy of steroid use is supported by a single placebo-controlled study and several case series. Information on other immunomodulatory therapies such as IVIG and plasmapheresis are limited to a small number of reports and a single comparison study.Discussion: Treatment decisions in SC are currently based on the treating physician's clinical experience, the desire to avoid side effects, and the existence of only limited scientific evidence. Based on a review of the available literature, chorea often improves with symptomatic therapy and immunotherapy tends to be reserved for those who fail to respond. Steroids are beneficial; however, data using IVIG and plasmapheresis are very limited. Larger, well-controlled studies, using standardized assessment scales, are required if therapeutic decisions for SC are to be based on meaningful information.