Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain.

Abstract Mammalian reproduction depends on the coordinated expression of behavior with precisely timed physiological events that are fundamentally different in males and females. An improved understanding of the neuroanatomical relationships between sexually dimorphic parts of the forebrain has contributed to a significant paradigm shift in how functional neural systems are approached experimentally. This review focuses on the organization of interconnected limbic-hypothalamic pathways that participate in the neural control of reproduction and summarizes what is known about the developmental neurobiology of these pathways. Sex steroid hormones such as estrogen and testosterone have much in common with neurotrophins and regulate cell death, neuronal migration, neurogenesis, and neurotransmitter plasticity. In addition, these hormones direct formation of sexually dimorphic circuits by influencing axonal guidance and synaptogenesis. The signaling events underlying the developmental activities of sex steroids involve interactions between nuclear hormone receptors and other transcriptional regulators, as well as interactions at multiple levels with neurotrophin and neurotransmitter signal transduction pathways. INTRODUCTION A principal goal of brain development is to produce the necessary neural architecture for integration of information from the external environment with internal cues that reflect important aspects of an animal's physiological state. This integration allows the elaboration of adaptive behavioral and physiological responses that are essential for an individual's survival, as well as for propagation of the species. From an evolutionary perspective, the most adaptive physiological responses are those that ensure successful reproduction. The long-term consequences of adaptive behavioral profiles that enhance survival are of little significance if an animal lacks the reproductive fitness necessary to pass on its genome. Moreover, the coordination of physiological events with behavior is a prerequisite to successful reproduction. For example, it is of no benefit to a mammalian species if females 0147-006X/02/0721-0507$14.00 507 Annu. Rev. Neurosci. 2002.25:507-536. Downloaded from www.annualreviews.org by SCELC Trial on 10/23/10. For personal use only. 508 SIMERLY display appropriate solicitation behaviors and successfully copulate with conspecific males but have not ovulated. Males have similar requirements for physiological coordination; an individual that has mature sperm and is ready to impregnate a female will not get the chance if he displays agonistic behaviors. Thus, the future of a species often rests with the ability of its members to coordinate behavioral responses with physiological processes in response to sexually relevant cues. This coordination of behavior and physiology must also be reliable, which depends in part on how consistently the neural circuits underlying neuroendocrine integration are constructed and regulated. Mammals reproduce sexually; males and females of a species display distinct patterns of copulatory behaviors and neuroendocrine physiology (Gerall & Givon 1992, Gorski & Jacobson 1981. This array of sex-specific behaviors and physiological responses is so vital to the success of mammalian species that robust developmental mechanisms have evolved to produce distinct yet complimentary neural systems that ensure the coordinated expression of reproductive function in male and female mammals. In this review key aspects of sexually dimorphic neural systems in the rodent forebrain are examined to consider developmental mechanisms that may be responsible for specifying sex-specific aspects of these neural pathways. Although the regions dealt with in detail play major roles in reproduction, it is important to note that significant sexual dimorphisms have been documented throughout the central nervous system, from the cerebral cortex to spinal motor neurons; therefore, the process of sexual differentiation of the brain should be viewed as a widespread series of developmental events with functional significance for diverse behaviors and physiological responses. The central tenet of sexual differentiation is that the brain is bipotential but develops differently in males and females under the influence of sex steroid hormones during the perinatal period. In male rats, secretion of androgen from the differentiated testis produces two perinatal elevations in plasma testosterone, the first of which occurs on day 18 of gestation, and the second at approximately 2 h after birth Sexually Dimorphic Forebrain Pathways The hypothalamus plays a critical role in coordinating expression of reproductive behaviors and physiological responses with environmental cues. Its close anatomical and physiological relationship with the pituitary gland provides an effective means for coordinating diverse homeostatic processes through neuroendocrine regulation of hormone secretion. The hypothalamus also shares strong connections with the limbic region of the forebrain so it can effectively coordinate neuroendocrine responses with sensory cues that regulate motivated behavior. The preoptic region of the hypothalamus was the historical focus of early studies on morphological sex differences, owing in part to its dominant role in the regulation of copulatory behavior and gonadotropin secretion (Gerall & Givon 1992 The modern era of sexual differentiation research was ushered in when Raisman and Field used electron microscopy to identify the first clear sex difference in neuronal connectivity 510 SIMERLY the anteroventral periventricular nucleus (AVPV) of the preoptic region was found to be larger in female rodents, suggesting that sexual dimorphisms may also favor females (Bleier et al. 1982). The demonstration that the AVPV contained a greater number of dopaminergic neurons in females, which can be reduced to that of males by a single injection of testosterone, indicated that sex steroid hormones may actually facilitate loss of neurons in certain regions THE MEDIAL PREOPTIC NUCLEUS The sexually dimorphic nucleus of the preoptic area comprises neurons that are part of the medial preoptic nucleus (MPN), a nucleus known for its dominant role in expression of male sexual behavior Each subdivision of the MPN shows a distinct pattern of connectivity: The MPNm sends its strongest projections to the periventricular zone of the hypothalamus, which is primarily involved in the control of hormone secretion from the anterior pituitary, while the MPNc sends its major projections to other sexually dimorphic forebrain nuclei 511 THE ANTEROVENTRAL PERIVENTRICULAR NUCLEUS (AVPV) Because gonadotropin secretion is perhaps the most significant sex difference in reproductive physiology, some of the earliest studies of sexual differentiation focused on the impact of sex steroid hormones on the phasic secretion of luteinizing hormone (LH), which initiates ovulation in female mammals (see Gerall & Givon 1992 for review). Treatment of ovariectomized adult female rats with estrogen causes a massive surge in LH secretion, yet similar treatments in males fail to induce a similar response. This sexually dimorphic response to hormone treatment can be reversed by castrating male rats at birth, and treatment of neonatal female rats with a single dose of testosterone results in permanent anovulatory sterility. Evidence from a variety of experimental approaches indicates that sex steroids act at the level of the preoptic region during postnatal life to organize the neural pathways controlling preovulatory gonadotropin secretion. The AVPV is a likely site of action because it plays a critical role in controlling the preovulatory LH surge and is sensitive to the developmental actions of sex steroid hormones (see The total number of neurons in the AVPV has not been determined in male and female rats, but cellular markers for dopaminergic neurons and peptidergic neurons According to a recent model for telencephalic projections onto hypothalamic motor regions proposed by FOREBRAIN SEXUAL DIFFERENTIATION 515 understanding sensory integration and control of reproduction seems clear, but the accuracy of its predictions remains to be validated experimentally. The accessory olfactory and ventral subiculoseptal pathways represent the major limbic-hypothalamic pathways impacting reproduction. The posterior nucleus of the amygdala (PA) (see Despite the robust innervation of sexually dimorphic nuclei in the hypothalamus by the BSTp and amgdala (MEApd and PA), neither the periventricular nor the medial zone dimorphic nuclei provide substantial return projections. Instead, feedback appears to be conveyed by the ventral premammillary nucleus (PMv), which Annu. Rev. Neurosci. 2002.25:507-536 However, even sensory influences transmitted to the hypothalamus along monomorphic pathways may contribute to sexually dimorphic responses because the hypothalamic regions innervated are sexually differentiated. For example, the LSv provides strong inputs to both the AVPV and MPNm/c, which may process the afferent multimodal information differently in each sex. Sexually dimorphic pathways such as the accessory olfactory pathway provide more robust sensory inputs to hypothalamic nuclei in males, which indicates that there is greater convergence of this information onto hypothalamic neurons in target nuclei. This convergence is even more profound in target regions with fewer neurons in males, as is the case with the AVPV. Alternatively, descending projections from the LSv appear to be more divergent in males since there are more neurons in target nuclei such as the MPNm/c in males relative to that of females. Although at present it is difficult to confidently predict the functional impact of sexually dimorphic patterns of sensory convergence and divergence on specific reproductive functions, it appears likely that the sexually dimorphic representations of these sensory routes and hypothalamic targets impose a sex-specific bias on information processing at nodal points in these circuits. The emerging appreciation of the sexually dimorphic organization of sensory pathways, and a detailed understanding of the cellular relationships that define the signaling balance encoded in patterns of sensory convergence and divergence onto hypothalamic circuits, is a Annu. Rev. Neurosci. 2002.25:507-536. Downloaded from www.annualreviews.org by SCELC Trial on 10/23/10. For personal use only. FOREBRAIN SEXUAL DIFFERENTIATION 517 prerequisite to an improved understanding of how these pathways function in the control of neuroendocrine physiology and behavior. The recent clarification of anatomical relationships between sexually dimorphic parts of the forebrain and new theoretical proposals on information processing in cortico-hypothalamic pathway

Central spindle self-organization and cytokinesis in artificially activated sea urchin eggs

Author Posting. © Marine Biological Laboratory, 2016. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 230, no.2 (2016): 85-95.The ability of microtubules of the mitotic apparatus to control the positioning and initiation of the cleavage furrow during cytokinesis was first established from studies on early echinoderm embryos. However, the identity of the microtubule population that imparts cytokinetic signaling is unclear. The two main––and not necessarily mutually exclusive–– candidates are the central spindle and the astral rays. In the present study, we examined cytokinesis in ammonia-activated sea urchin eggs, which lack paternally derived centrosomes and undergo mitosis mediated by unusual anastral, bipolar mini-spindles. Live cell imaging and immunolabeling for microtubules and the centralspindlin constituent and kinesin-related protein, MKLP1, demonstrated that furrowing in ammonia-activated eggs was associated with aligned arrays of centralspindlin-linked, opposed bundles of antiparallel microtubules. These autonomous, zipper- like arrays were not associated with a mitotic apparatus, but did possess characteristics similar to the central spindle region of control, fertilized embryos. Our results highlight the self-organizing nature of the central spindle region and its ability to induce cytokinesis-like furrowing, even in the absence of a complete mitotic apparatus.This research was supported by student/faculty summer research grants from the Dickinson College Research and Development Committee to JHH; Laura and Arthur Colwin Summer Research Fellowships from the MBL to JHH and CBS; a National Science Foundation Major Research Instrumentation grant to JHH (MRI-0320606); and a NSF collaborative research grant to JHH (MCB-1412688) and to CBS (MCB- 1412734)

Early life programming and neurodevelopmental disorders.

For more than a century, clinical investigators have focused on early life as a source of adult psychopathology. Early theories about psychic conflict and toxic parenting have been replaced by more recent formulations of complex interactions of genes and environment. Although the hypothesized mechanisms have evolved, a central notion remains: early life is a period of unique sensitivity during which experience confers enduring effects. The mechanisms for these effects remain almost as much a mystery today as they were a century ago. Recent studies suggest that maternal diet can program offspring growth and metabolic pathways, altering lifelong susceptibility to diabetes and obesity. If maternal psychosocial experience has similar programming effects on the developing offspring, one might expect a comparable contribution to neurodevelopmental disorders, including affective disorders, schizophrenia, autism, and eating disorders. Due to their early onset, prevalence, and chronicity, some of these disorders, such as depression and schizophrenia, are among the highest causes of disability worldwide according to the World Health Organization 2002 report. Consideration of the early life programming and transcriptional regulation in adult exposures supports a critical need to understand epigenetic mechanisms as a critical determinant in disease predisposition. Incorporating the latest insight gained from clinical and epidemiological studies with potential epigenetic mechanisms from basic research, the following review summarizes findings from a workshop on Early Life Programming and Neurodevelopmental Disorders held at the University of Pennsylvania in 2009

A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits

We tested the hypothesis that genes encoded on the sex chromosomes play a direct role in sexual differentiation of brain and behavior. We used mice in which the testis-determining gene (Sry) was moved from the Y chromosome to an autosome (by deletion of Sry from the Y and subsequent insertion of an Sry transgene onto an autosome), so that the determination of testis development occurred independently of the complement of X or Y chromosomes. We compared XX and XY mice with ovaries (females) and XX and XY mice with testes (males). These comparisons allowed us to assess the effect of sex chromosome complement (XX vs XY) independent of gonadal status (testes vs ovaries) on sexually dimorphic neural and behavioral phenotypes. The phenotypes included measures of male copulatory behavior, social exploration behavior, and sexually dimorphic neuroanatomical structures in the septum, hypothalamus, and lumbar spinal cord. Most of the sexually dimorphic phenotypes correlated with the presence of ovaries or testes and therefore reflect the hormonal output of the gonads. We found, however, that both male and female mice with XY sex chromosomes were more masculine than XX mice in the density of vasopressin-immunoreactive fibers in the lateral septum. Moreover, two male groups differing only in the form of their Sry gene showed differences in behavior. The results show that sex chromosome genes contribute directly to the development of a sex difference in the brain

Reversible Disassembly of the Actin Cytoskeleton Improves the Survival Rate and Developmental Competence of Cryopreserved Mouse Oocytes

Effective cryopreservation of oocytes is critically needed in many areas of human reproductive medicine and basic science, such as stem cell research. Currently, oocyte cryopreservation has a low success rate. The goal of this study was to understand the mechanisms associated with oocyte cryopreservation through biophysical means using a mouse model. Specifically, we experimentally investigated the biomechanical properties of the ooplasm prior and after cryopreservation as well as the consequences of reversible dismantling of the F-actin network in mouse oocytes prior to freezing. The study was complemented with the evaluation of post-thaw developmental competence of oocytes after in vitro fertilization. Our results show that the freezing-thawing process markedly alters the physiological viscoelastic properties of the actin cytoskeleton. The reversible depolymerization of the F-actin network prior to freezing preserves normal ooplasm viscoelastic properties, results in high post-thaw survival and significantly improves developmental competence. These findings provide new information on the biophysical characteristics of mammalian oocytes, identify a pathophysiological mechanism underlying cryodamage and suggest a novel cryopreservation method