Richard B. Simerly

Projections of the sexually dimorphic anteroventral periventricular nucleus in the female rat

The anteroventral periventricular nucleus of the hypothalamus (AVPV) is a sexually dimorphic nucleus in the preoptic region that appears to be a nodal point in forebrain circuits, mediating hormonal feedback on gonadotropin secretion. The results of anterograde transport experiments indicate that the AVPV sends ascending projections to the ventral part of the lateral septal nucleus, the parastrial nucleus, and the region adjacent to the vascular organ of the lamina terminalis (OVLT) that contains a subpopulation of gonadotropin releasing hormone (GnRH)‐containing neurons. The majority of projections from the AVPV pass caudally through the periventricular zone of the hypothalamus and form dense terminal fields in the periventricular nuclei, parvicellular parts of the paraventricular nucleus, and in the arcuate nucleus. Inputs to medial zone nuclei are more limited, with substantial projections to only the medial preoptic and dorsomedial nuclei. The AVPV sends few projections to the caudal brainstem, but terminals were observed reliably in the periaqueductal gray and medial part of the nucleus of the solitary tract. Anterograde double‐labeling experiments demonstrate terminals derived from neurons in the AVPV in close apposition to GnRH‐containing neurons in the preoptic region, and to dopaminergic neurons in the arcuate nucleus. Thus, the organization of projections from the AVPV in female rats suggests that neurons in this nucleus may influence the secretion of luteinizing hormone and prolactin through direct projections to GnRH neurons and tuberoinfundibular dopaminergic neurons. J. Comp. Neurol. 384:142‐164, 1997.

Anatomy, Development, and Function of Sexually Dimorphic Neural Circuits in the Mammalian Brain

Publisher Summary This chapter discusses the anatomy, development, and function of sexually dimorphic neural circuits in the mammalian brain. If structural sex differences promote as well as prevent sex differences in behavior and other centrally regulated functions in rodents, this may be true for human brains as well. Human brains show sex differences in the volume of several brain structures, including the anterior commissure, the left planum temporale, and several nuclei in the hypothalamus and BST. In addition, several neurotransmitter systems are sexually dimorphic. Although these differences are typically associated with differences in behavior, these sex differences may also normalize behavior in males and females. The effects of stroke support the possibility that similar functions indeed have a sexually dimorphic neural basis. Stroke affects language abilities differently in males than it does in females. Frontal lesions cause aphasias more frequently in females than in males, whereas the opposite is true for temporal lesions.

Organization and regulation of sexually dimorphic neuroendocrine pathways

Reproduction depends on the co-ordinated expression of stereotypical behaviors and precisely timed physiological events, yet the neurobiological mechanisms underlying the integration of sensory and hormonal information that is crucial to this process have remained difficult to define. A variety of experimental approaches has provided compelling evidence that the anteroventral periventricular nucleus (AVPV) of the preoptic region plays a particularly important role in the neural control of gonadotropin secretion. It is larger in female rats, contains high densities of neurons that express receptors for ovarian steroid hormones and appears to provide direct projections to gonadotropin releasing hormone neurons in the hypothalamus. Moreover, it receives inputs from a variety of distinct sensory systems known to influence secretion of luteinizing hormone from the anterior pituitary. Thus, the AVPV appears to represent an important nodal point in sexually dimorphic forebrain circuits for the integration of sensory and hormonal information that influence reproduction. Examples of neurohumoral integration at the level of functional neural systems, individual neurons in the AVPV, or at the molecular level have been identified which provide new insight into how the hypothalamus co-ordinates expression of sex specific reproductive behaviors with gonadotropin secretion.

Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice

The Scar/WAVE family of scaffolding proteins organize molecular networks that relay signals from the GTPase Rac to the actin cytoskeleton. The WAVE-1 isoform is a brain-specific protein expressed in variety of areas including the regions of the hippocampus and the Purkinje cells of the cerebellum. Targeted disruption of the WAVE-1 gene generated mice with reduced anxiety, sensorimotor retardation, and deficits in hippocampal-dependent learning and memory. These sensorimotor and cognitive deficits are analogous to the symptoms of patients with 3p-syndrome mental retardation who are haploinsufficient for WRP/MEGAP, a component of the WAVE-1 signaling network. Thus WAVE-1 is required for normal neural functioning.

Hormonal Regulation of Glutamate Receptor Gene Expression in the Anteroventral Periventricular Nucleus of the Hypothalamus

Glutamate 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 and in situ hybridization 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.

Neurons in the principal nucleus of the bed nuclei of the stria terminalis provide a sexually dimorphic GABAergic input to the anteroventral periventricular nucleus of the hypothalamus.

Neurons of the principal nucleus of the bed nuclei of the stria terminalis (BSTp) process pheromonal and viscerosensory stimuli associated with reproduction and relay this information to preoptic and hypothalamic cell groups that regulate reproductive function. The anteroventral periventricular nucleus of the hypothalamus (AVPV), a nucleus involved in the regulation of gonadotropin secretory patterns, receives dense projections from BSTp neurons in males but not in females. By injecting the anterograde tracer, Phaseolus vulgaris leucoagglutinin (PHAL), into the BSTp of rats and immunohistochemically colocalizing the GABA synthetic enzyme, GAD65, to PHAL-immunoreactive fibers in the AVPV, we tested the hypothesis that these sex-specific projections arise from BSTp neurons that synthesize the inhibitory neurotransmitter GABA. Although dense GAD65-immunoreactive fiber terminals were observed in both the male and female AVPV, higher numbers of GAD65-labeled terminals were found in the male, and those localized to PHAL-immunoreactive fibers were seen almost exclusively in males. Treatment of newborn females with testosterone or neonatal orchidectomy of males reversed these sex differences, while GAD65-immunoreactivity in the AVPV was not altered in response to exogenous hormone treatments administered to peripubertal animals. Our results suggest that projections from BSTp neurons constitute a stable, sex-specific GABAergic input to the AVPV that is patterned permanently by perinatal hormone exposure.

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

Neurons in the principal bed nucleus of the stria terminalis (BSTp) integrate hormonal and sensory information associated with reproduction and transmit this information to hypothalamic nuclei that regulate neuroendocrine and behavioral functions. The neuropeptides galanin (GAL), cholecystokinin (CCK), and substance P (SP) are highly expressed in BSTp neurons and are differentially regulated by sex steroids. The current experiments investigated whether developmental or peripubertal hormone‐mediated changes in GAL, CCK, and SP expression are reflected within efferent pathways to the preoptic structures that regulate gonadotropin secretion and sexual behavior. Anterograde labeling of projections from the BSTp of male and female juvenile rats combined with immunohistochemical labeling of GAL‐, CCK‐, and SP‐containing fibers in the anteroventral periventricular preoptic nucleus (AVPV) and the central and medial divisions of the medial preoptic nucleus (MPNc, MPNm, respectively) revealed unique sex differences in each region. In the AVPV, Phaseolus vulgaris leucoagglutinin‐labeled fibers were seen at a greater density in males than in females, and higher percentages of these fibers contained GAL in males than in females. In contrast, fibers projecting from the BSTp to the MPNc were more likely to contain SP in females than in males. Treatment of gonadectomized, peripubertal males and females with exogenous testosterone and estradiol did not alter the densities of GAL‐, CCK‐, or SP‐containing fibers in any of the three brain areas examined. Collectively, these results suggest that patterns of neuropeptide expression in BSTp projections are established during development, resulting in a distinct, stable, and sex‐specific chemoarchitectural profile for each projection pathway. J. Comp. Neurol. 465:551–559, 2003.