Review
Development of the ventromedial nucleus of the hypothalamus

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Abstract

The ventromedial nucleus of the hypothalamus (VMH) is important in the regulation of female sexual behavior, feeding, energy balance, and cardiovascular function. It is a highly conserved nucleus across species and a good model for studying neuronal organization into nuclei. Expression of various transcription factors, receptors, and neurotransmitters are important for the development of this nucleus and for mapping the position of identified cells within the nucleus. The VMH is subdivided into regions, all of which may project to specific locations to carry out various functions. For example, the ventrolateral quadrant contains a subset of neurons that highly express estrogen receptors. These neurons specifically are involved in the lordosis response pathway through projections to other estrogen receptor containing regions. In development, neurons that form the VMH generate from the proliferative zone surrounding the third ventricle. Neurons then migrate along radial glial fibers to final positions within the nucleus. Migration and positioning of neurons is an important step in setting up connections to and from the VMH and hence in its function. As compared to other developing brain regions, cell death may play a minor role in sculpting the VMH. We review the processes involved in forming a functional nuclear group and some of the factors known to be involved particularly focusing on the positioning of identified neurons within the VMH.

Introduction

There are two major organizational schemes for neurons in the vertebrate central nervous system: layers (e.g., cerebral cortex) and nuclei (e.g., diencephalon). There is a growing understanding of cortical development, and a number of the molecules that play roles in this process have been identified [60], [94], [107], [108], [124], however, significantly less is known about the development of nuclear groups [100], [114], [157], [164]. The proposed “protomap” for cortical regions involves newborn cells arising from proliferative zones surrounding the lateral ventricles and developing into cortical layers [136], [137]. In the hypothalamus, particular regions along the third ventricle give rise to cells forming specific subdivisions [4].

Progress in delineating broad compartments (e.g., prosomeres) within the forebrain has emerged from experiments describing the distribution of transcriptional regulating genes [144] and other factors that either mediate [54], [57], or induce [47] ventral forebrain organization. Prosomeres are transverse domains defined by certain morphological and molecular similarities. Such compartments may indicate groups with shared cell histories and common influences [134]. Apparent boundaries for compartments of these cell groups may be delineated by the presence of cell-dense zones surrounded by cell-poor zones [26], and comprised of fiber bundles [156] or selective molecular environments [161]. Numerous studies suggest that these regions of cell density also modulate selected functions such as circadian rhythms by the suprachiasmatic nucleus [148], or stress responses by the paraventricular nucleus [86]. Understanding how cells position themselves into a nucleus that regulates particular physiological functions or behaviors has been hindered by the complexity of the processes involved [164].

The development of a hypothalamic nuclear group begins with neurogenesis in the proliferative zone of the third ventricle. This requires divisions that yield progenitor cells, followed by divisions that yield terminally mitotic cells that exit the proliferative zone surrounding the third ventricle to take up residence in the hypothalamus. While evidence suggests that cell fate information may be imparted during neurogenesis in the cortex [113], this is less established for hypothalamic structures. In one study, the development of estrogen receptor-containing neurons was found to proceed autonomously following the transplantation of fetal hypothalamic tissue into different environments [131]. Although an anatomical technique was used to evaluate estrogen receptors (autoradiography), the tissue was evaluated more for the presence of estrogen binding than for the formation of particular nuclear groups. Nonetheless, the data are consistent with an early determination of cell fate. Following a final mitotic event, a cell must migrate (or not) to a destination among potential hypothalamic destinations to join particular cell groups. Finally, as a fully differentiated neuron, axons are projected to other sites in the CNS and synaptic input is received from other sites, thereby facilitating specific functions or behaviors. This review follows the development of the ventromedial nucleus of the hypothalamus (VMH, sometimes referred to as VMN) as the nucleus emerges from an undifferentiated cell mass.

The VMH is a medial hypothalamic cell group that sits close to the base of the diencephalon, adjacent to the third ventricle above the median eminence and pituitary complex. It is a bilateral cell group that has an elliptical shape, stretching more laterally in rodents as it extends rostral to caudal (Fig. 1A). The VMH is first clearly defined as a nuclear group between E15 and E17 in the mouse [167] (Fig. 1B). Its cytoarchitecture is strongly defined by the surrounding cell-poor, fiber-rich, zone. The cell-poor zone is rich in dendritic processes [31], [117], providing an extensive receptive surface for fibers of the stria terminalis [68]. Within the VMH, subnuclear groups have been delineated based on fiber projections and cell types, including dorsomedial, central, ventrolateral, and anterior zones [22], [149], [175]. A basal subnucleus in the ventrolateral region, designated the tuberal nucleus, also can be delineated based on neuronal birthdates and cell phenotype [4], [22], [180].

The VMH has been implicated in a broad array of homeostatic and behavioral functions, including affective, ingestive and sexual behaviors [22]. Conventionally, the arcuate nucleus has become the primary site for studies of weight regulation and feeding behavior; however, disruptions of the VMH can also lead to obesity in adulthood [105]. As we learn more of the molecular nature of cells within the VMH, and of signaling molecules inside and outside of the nucleus, we are gaining a greater appreciation for specific cell types and molecules in the VMH that may play role(s) in regulating feeding behavior or energy balance [129]. For a more thorough review of hypothalamic pathways involved in feeding behavior see [45]. The VMH is also important for the regulation of female sexual behavior. In particular, the lordosis response is dependent upon neurons in the ventrolateral VMH, specifically those that express estrogen receptors. Electrolytic lesions that involve ventrolateral VMH neurons containing steroid hormone receptors (e.g., estrogen and progesterone receptors) inhibit lordosis behavior in both rats [46], and cats [99]. The important complementary result—activation of behavior following steroid hormone implantation directly to the VMH—has also been shown [146]. Cardiovascular function can also be regulated by the VMH; stimulation of neurons within the VMH can cause a change in blood pressure and/or heart rate [72]. The VMH also has a role in the pain pathway. Electrical stimulation of the VMH induces analgesia in rodents [32], [44], [140] and disruptions of the VMH cause hyperalgesia in rats [122]. A proposed mechanism for this effect includes the binding of prostaglandin E2 to its EP1 receptor, stimulating an analgesic pathway [74]. The remainder of this review focuses on the structural and neurochemical development of the VMH rather than in adulthood.

The VMH has been thought of as a collection of heterogenous cell types, some of which have been identified. The identification of populations of neurons has been a focus for several studies. One recent study [152] used laser-capture microdissection to isolate a set of genes that is enriched in the VMH relative to surrounding areas. Ongoing studies will help identify various genes expressed in different subsections of the VMH. The discovery of the gene steroidogenic factor-1 (SF-1) [66], [73], [79] as a gene expressed selectively within the VMH, has ushered in a new way of thinking about the structure, function, and development of this important hypothalamic cell group. This review will discuss the developmental processes leading to a functional VMH and will categorize molecular factors related to its development through neurogenesis, migration, differentiation, and connectivity.

Section snippets

Cell identities

Cell identity is an important characteristic of brain organization. Phenotypically identified cells in the hypothalamus during development can be found in patterns or domains that can be seen across vertebrate species [134], [135]. The VMH contains neurons and fibers that can be grouped by specific cell types into subnuclear regions (e.g., dorsomedial, central, and ventrolateral). Factors expressed in cells of the VMH may be potential candidates for developmental signals or cues that can aid in

Neurogenesis

The process of developing a functional nucleus begins with the “birth” or terminal mitosis of neurons that populate the region. Based on [3H]thymidine incorporation studies, cells in the VMH derive primarily from precursors in the proliferative zone surrounding the lower portion of the third ventricle dorsal to the arcuate nucleus [4]. Neurons that populate the VMH are born between E10 and E15 in mice, E13 to E17 in rats, and around E30 in the primate [153], [169], [174]. Despite having been

Migration

Following neuronal divisions along the proliferative zone, cells must migrate to form the VMH. BrdU studies in the mouse have shown that cells of the VMH may undergo final mitotic divisions as early as E10, while the earliest sign of cytoarchitectonic boundaries are not seen until E16 and E17. Using Nissl stains, the VMH begins to appear as a distinct oval shaped collection of cells on either side of the third ventricle around E18 and E19 in rats [28], [76], E16 and E17 in mice [151], [167],

Programmed cell death

In the developing brain, programmed cell death plays a major role in the organization of brain structures [56]. Almost 10 years ago it was realized that there may be significantly more cell death during normal development than previously appreciated [15]. Subsequent experiments revealed significant cell death in regions of the hypothalamus that are sexually dimorphic [6], [37], [111]. Sex differences in cell death have emerged as a central component of many theories of brain sexual

Connections

The major afferent connections to the VMH include the preoptic area, thalamic and epithalamic areas, amygdala, and dorsal midbrain including the medial central gray [22], [49]. The major efferent connections from the VMH are to the amygdala, medial preoptic area, anterior hypothalamus, bed nucleus of the stria terminalis (BST), central gray, zona incerta, and the peripeduncular nucleus [149] (Fig. 8). These projections have been examined in the adult mouse, rat, and guinea pig; however, not

Conclusion

There is a wealth of information regarding the structure and function of various hypothalamic nuclei; however, there is much less known about their development and factors that may be involved. The VMH provides a model for hypothalamic development and for gaining insight regarding the mechanisms and factors that are involved in the development of a cell group. The VMH appears as a well defined cell group just days before birth in the rodent, and reaching this stage requires the proliferation,

Acknowledgments

The authors thank Dr. Simon McArthur for his critical reading of this manuscript. We thank Michelle Edelmann and Dr. Andrew Vendel for help in creating figures. We thank current and former members of the Tobet and Parker labs for helping produce data that form the basis for hypotheses contained in this review. This work was supported by NIH Grants MH 57748, MH61376 (S.A.T.) and DK54480 (K.L.P.).

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