Organization and regulation of sexually dimorphic neuroendocrine pathways
Introduction
The expression of sexually dimorphic reproductive behaviors is so widespread in the animal world that they must have profound adaptive significance. Accompanying such behaviors are specialized physiological functions such as ejaculation and ovulation that are essential for sexual reproduction. Anatomical evidence is now available that is beginning to define the functional neural circuits underlying complex sexually dimorphic behaviors associated with copulation 24, 21, 43, 44. In the present article, the organization of neural pathways that integrate sensory and hormonal information impacting sexually dimorphic patterns of gonadotropin secretion will be discussed.
The phasic secretion of luteinizing hormone (LH) from the pituitary gland is perhaps the most significant sex difference in endocrine physiology. In female rats, plasma levels of estradiol increase during the estrous cycle and lead to a massive surge in LH secretion on the afternoon of proestrus ([7]). Treatment of ovariectomized adult female rats with exogenous estradiol causes afternoon surges in LH release, yet treatment of gonadectomized male rats fails to cause a similar response. This sexually dimorphic response to hormone treatment can be reversed by castrating male rats at birth. A male rat that is orchidectomized on the day of birth shows a surge in LH secretion following estradiol treatment and can support ovulation in a transplanted ovary 2, 16. Copulatory behavior is also sexually dimorphic and complete expression of these behaviors is dependent on levels of circulating steroid hormones in adults. Thus, male copulatory behavior is dependent on adequate levels of circulating testosterone and ovarian steroid hormones co-ordinate the expression of lordosis with ovulation in females, thereby promoting the likelihood that fertilization will result from copulation. This array of co-ordinated sex specific behaviors and physiological responses are so vital to the success of mammalian species that complex neurobiological mechanisms have evolved to produce functional neural systems that are different in male and female rats.
For reproduction to proceed properly, the expression of behavioral responses must be co-ordinated with the physiological events that result in pregnancy. Therefore, neural pathways underlying copulatory behaviors must be interfaced with pathways that control hormone secretion. Anatomical evidence collected largely during the last decade demonstrates that there is a system of interconnected sexually dimorphic nuclei in the mammalian forebrain that mediates neural control of reproduction ([33]). In general, these nuclei are larger in male animals and provide more intense inputs to other regions in males. For example, the central part of the medial preoptic nucleus is larger in male rats and appears to provide stronger inputs to other sexually dimorphic nuclei such as the principal nucleus of the bed nuclei of the strict terminalis (BST) ([37]).
Several of the sexually dimorphic nuclei that comprise this sexually dimorphic neural system can be viewed as nodal points since they appear to be essential for expression of specific functions. The medial preoptic nucleus (MPN) lies at the heart of sexually dimorphic circuitry and has been shown to be essential for normal copulatory responses in male rats [15]. In addition, the MPN appears to exert an inhibitory influence on female copulatory behavior and has bidirectional connections with the ventromedial nucleus of the hypothalamus (VMH), which represents a nodal point in the circuits controlling lordosis responses in female rats [24]. Similarly, the medial part of the MPN sends a massive projection to the anteroventral periventricular nucleus of the preoptic region (AVPV) ([37]), which has been shown to play a critical role in the transducing hormonal feedback on gonadotropin secretion [47]. Such interconnections between functionally distinct nodal points in the sexually dimorphic circuit provides for a considerable degree of integration between neural systems subserving sexually dimorphic functions. Moreover, several parts of this circuit receive common sensory inputs and impact common effector systems.
Reproductive neural pathways can be viewed as essentially consisting of sensory and motor components, with intrahypothalamic integrative circuits interposed between the sensory and motor parts of the circuit. The motor neurons of ovulation are those that contain gonadotropin releasing hormone (GnRH). The activity of these neurons is influenced by visceral sensory information ascending from the brainstem via adrenergic pathways, as well as by other sensory modalities such as olfaction. Of particular importance to reproduction are pheromonal cues relayed from the vomeronasal organ centrally by the accessory olfactory bulb [41]. This olfactory information is transmitted to the hypothalamus primarily by two sexually dimorphic nuclei, the medial nucleus of the amygdala and principal nucleus of the BST (BSTp) [29]. This direct pathway may be complemented by processed olfactory information sent to the hypothalamus from the posterior nucleus of the amygdala [6]. Other primary sensory pathways, such as those transmitting visual, auditory and somatosensory information, appear to reach the sexually dimorphic circuit by way of the ventral subiculum and ventral part of the lateral septum [36]. Reproduction in rodents is also highly dependent on circadian influences thought to be relayed to the hypothalamus by the suprachiasmatic nucleus. This nucleus sends its major projection to the sub-paraventricular zone of the hypothalamus. Through the widespread projections of neurons in the sub-paraventricular zone this sensory information diverges to influence a wide variety of behaviors and physiological responses ([40]). One notable exception to this pattern is the AVPV, which appears to receive a direct and sexually dimorphic input from the suprachiasmatic nucleus 45, 42. Intrahypothalamic connections between nodal points in sexually dimorphic circuits represent anatomical substrates for communication and integration of various sensory modalities with behavioral and neuroendocrine effector systems.
Section snippets
Estrogen feedback and GnRH neurons
Although hormonal feedback controls GnRH secretion this action does not appear to be direct since GnRH containing neurons do not express receptors for estrogen (ER). Previously, Shivers et al. [27]demonstrated that GnRH immunoreactive neurons in the preoptic region did not bind exogenous estradiol. Recently, the observations were confirmed by using a combined immunohistochemical/in situ hybridization protocol [46]to simultaneously visualize ER immunoreactive nuclei and GnRH mRNA containing
The AVPV and neuroendocrine integration
The AVPV represents a unique part of sexually dimorphic forebrain circuits. It plays an essential role in mediating hormonal feedback on gonadotropin secretion [47], contains high densities of neurons that express receptors for estrogen and progesterone [34]and implants of antiestrogens into the AVPV cause significant changes in LH secretion [23]. The results of a recent antero-grade examination of the projections of the AVPV [14]support its proposed functional role. The majority of projections
Conclusion
The neurobiological mechanisms underlying integration of hormonal and sensory information in neuroendocrine systems will undoubtedly prove to be exceedingly complex. However, the use of multiple labeling anatomical methods is clarifying the detailed organization of sexually dimorphic pathways involved in mediating reproductive function. Similarly, the application of histochemical techniques that afford cellular resolution to analysis of gene expression events is providing new insight into
Acknowledgements
The generous gifts of H222 antisera (Abbott Laboratories) and the GnRH cDNA (Dr J. Adelman) are gratefully acknowledged. Research in the author’s laboratory is supported by NIH grants NS26723, MH49236 and RR00163.
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