47 research outputs found
Developmental Programming of Hypothalamic Neural Circuits Integrating Fluid and Energy Homeostasis
No full textDrinking and feeding are coordinated homeostatic events, but our understanding of the development of their converging hypothalamic neural circuits remains rudimentary. Many environmental factors developmentally program neural circuits during critical periods in early postnatal life. Agouti-related peptide (AgRP) neurons are substrates of developmental programming, responding to nutritional cues during a critical period to reach downstream targets. The paraventricular nucleus of the hypothalamus (PVH) receives inputs from both AgRP neurons and the median preoptic nucleus (MEPO) to regulate energy and fluid homeostasis, representing a possible node of integration. We used TRAP2;Ai14 double transgenic mice to show a population of active neurons responding to water deprivation (Thirst-TRAP) overlaps with fast-refeed Fos induction (Hunger-Fos) in the PVH. To determine the age at which MEPO projections reach the PVH, we used DiI axonal labeling as well as Fos-labeling in response to hypertonic saline (HS). Our results indicate neurons in the MEPO project to the PVH and respond to HS by the end of the first week of life, and densities of Fos-labeled nuclei in the PVH do not peak until the second postnatal week, preceding innervation of the PVH by AgRP neurons. Based on these observations, we hypothesized perturbations to fluid homeostasis in neonatal mice may impact the formation of AgRP circuitry with sustained changes in ingestive behavior. Adult male mice exposed to HS treatment daily from postnatal day (P) 5 to P15 (HSPN) displayed significantly increased densities of AgRP axons in the MEPO and PVH, while female HSPN mice experienced a decrease in the MEPO. Short-term high fat diet (HFD) exposure leads to greater water intake in adult HSPN male mice, while long-term HFD leads to a significantly lower body weight gain in HSPN females. Moreover, a dehydration-anorexia challenge results in a sustained anorexic response HSPN males after rehydration, while a fast-refeed challenge results in a sustained decrease in water intake in HSPN males after refeeding. Together, these results suggest a sexually dimorphic effect of early perturbations to fluid homeostasis on the development of feeding circuits, with context-specific consequences for ingestive behavior
Regulation of RNA Editing by Intracellular Acidification
No full textAdenosine deaminases acting on RNA (ADARs) catalyze adenosine-to-inosine (A-to-I) RNA editing to expand the diversity of genomically-encoded transcripts and proteins by hydrolytic deamination of genomically-encoded adenosine residues in metazoan double-stranded RNAs. This RNA processing event is widespread, especially in the human transcriptome, and enables post-transcriptional regulation of many cellular processes. Despite the prevalence and profound biological impact of RNA editing, the mechanisms modulating ADARs and RNA editing are poorly understood. In this work, we compare two different experimental strategies for quantification of A-to-I editing, as well as examine numerous in vitro and in vivo model systems to investigate the modulation of RNA editing
Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain.
No full textAbstract 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
Leptin Grows Up and Gets a Neural Network
No full textStudies seeking a dominant site of action for the hormone leptin have focused on leptin receptor-expressing neuropeptidergic neurons. In this issue, Vong et al. show that leptin regulates energy homeostasis predominantly via a distributed network of GABAergic neurons
Sex‐specific patterns of galanin, cholecystokinin, and substance P expression in neurons of the principal bed nucleus of the stria terminalis are differentially reflected within three efferent preoptic pathways in the juvenile rat
No full textHormonal Regulation of Glutamate Receptor Gene Expression in the Anteroventral Periventricular Nucleus of the Hypothalamus
No full textGlutamate plays an important role in mediating the positive feedback effects of ovarian steroids on gonadotropin secretion, and the preoptic region of the hypothalamus is a likely site of action of glutamate. The anteroventral periventricular nucleus (AVPV) of the preoptic region is an essential part of neural pathways mediating hormonal feedback on gonadotropin secretion, and it appears to provide direct inputs to gonadotropin releasing hormone (GnRH)-containing neurons. Immunohistochemistry andin situhybridization were used in this study to define the distribution and hormonal regulation of glutamate receptor subtypes in the AVPV of juvenile female rats. Neurons that express the NMDAR1 receptor subtype are abundant in the AVPV, as are cells that express AMPA receptor subtypes (GluR1, GluR2, and GluR3 but not GluR4), and the AVPV appears to contain a dense plexus of NMDAR1-immunoreactive presynaptic terminals. However, AVPV neurons do not seem to express detectable levels of kainate receptor (GluR5, GluR6, and GluR7) or metabotropic receptor (mGluR1–6) subtypes. Treatment of ovariectomized juvenile rats with estradiol induced expression of GluR1 mRNA but did not alter levels of GluR2 or GluR3 mRNA. Treatment of estrogen-primed ovariectomized juvenile rats with progesterone caused an initial increase in GluR1 mRNA expression, followed by a small decrease 24 hr after treatment. In contrast, estrogen appears to suppress levels of NMDAR1 mRNA in the AVPV, which remained unchanged after progesterone treatment. Thus, one mechanism whereby ovarian steroids may provide positive feedback to GnRH neurons is by altering the sensitivity of AVPV neurons to glutamatergic activation.</jats:p
Anatomy, Development, and Function of Sexually Dimorphic Neural Circuits in the Mammalian Brain
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