Hypothalamus: Neuroendometabolic Center

Introduction

Enabled by its strategic anatomy, the hypothalamus uniquely serves the interface between the neural and endocrine systems. It is at the same time a part of the brain, an intrinsic component of neural pathways, and an endocrine gland, specially connected to the pituitary gland to form the “master gland” unit of the body. The multiple functions of the hypothalamus ultimately involve regulation of the body’s energy status and the maintenance of homeostasis, or bodily equilibrium. It has been long understood that, to refine this regulation, the hypothalamus responds both to information from the brain and to the levels of the peripheral hormones and body fluids it regulates. Appreciation has grown that the hypothalamus also receives input from the gut and fat stores, in essence closing the loop of metabolic regulation. All these incoming factors are compared with intrinsic setpoints, and outgoing messages are then released to enact modifications that will match the body to the appropriate setpoint. We have reviewed pediatric disorders of the neuroendocrine system, both congenital and acquired, elsewhere ; this chapter focuses on normal anatomy, embryology, and physiology of the hypothalamus.

Anatomy

Despite the importance of the hypothalamus for multiple homeostatic functions, the structure is less than 1% of human brain volume; its various parts total approximately 4 g of the 1200 to 1400 g of an adult human brain and measure less than 4 cm. Many of the borders of the hypothalamus are difficult to distinguish and are semiarbitrary, although magnetic resonance imaging techniques for study of the hypothalamus are improving. The hypothalamus lies at the base of the third ventricle, immediately posterior to the optic chiasm.

Because of its many eminences, the hypothalamus is an irregular structure that roughly forms a diamond. It is composed of four main structures: the tuber cinereum, the median eminence, the infundibulum, and the mammillary bodies. The tuber cinereum lies centrally on the inferior aspect of the hypothalamus. The median eminence, a central swelling located on the tuber cinereum, forms the floor of the third ventricle. The infundibulum is a stalk that connects the median eminence to the posterior lobe of the pituitary, and the mammillary bodies are two round protuberances at the posterior end of the inferior surface of the hypothalamus.

The hypothalamus can be difficult to describe because of its lack of landmarks. Of the many systems devised to divide the hypothalamus into discrete areas, two are particularly helpful. One describes nine zones, determined by their mediolateral and anteroposterior locations ^, ; it is shown in Fig. 139.1 . The second system defines discrete clusters of cell bodies (nuclei) that have characteristic anatomic positions and functions ( Table 139.1 ). Hypothalamic nuclei are not well circumscribed in adult brains. Examination of developing brains, in which cell groups are more discrete, has led to a greater understanding of hypothalamic architecture. Nonetheless, this schema is also semiarbitrary and is divided in many ways, depending on the source.

An area of particular controversy involves reports of sexual structural differences in several hypothalamic nuclei. In both rats and human adults, the sexually dimorphic nucleus of the preoptic area is larger in males than in females. ^, Another preoptic cell group was found to be larger in men. The bed nucleus of the stria terminalis is male predominant, ^, whereas the massa intermedia (interthalamic adhesion) is female predominant. Age-related changes in neuronal health and sex hormone activity can affect these differences. For example, because the cell loss of human senescence in the sexually dimorphic nucleus of the preoptic area follows different time courses in men and women, the magnitude of the structural difference is age dependent. ^, Sexual functional differences have also been shown in the hypothalamus by immunocytochemical staining for various neuronal products (e.g., somatostatin and vasopressin, also known as antidiuretic hormone [ ADH ]) and hormone receptors (e.g., androgen and estrogen receptors) and may also be age dependent. For example, the female dominance of neurokinin B immunoreactivity in the infundibular nucleus does not appear until puberty and progresses into adulthood. Speculation and controversy surround the implications for sexually dimorphic behaviors and psychological phenomena. Most relevant to neonatologists is the debate about imprinting of the brain by androgens in utero and its consequences for therapeutic outcomes in patients with various disorders of sex development, including ambiguous genitalia.

A final anatomic feature that is integral to hypothalamic functioning is blood supply. The hypothalamus communicates with the anterior pituitary gland through a special portal circulation that not only is fenestrated (the exception to the blood-brain barrier) but also transmits information bidirectionally. This feature enhances the ability of the hypothalamus to receive both signals from the general circulation and feedback from the pituitary. Furthermore, the hypothalamohypophysial portal system ensures that high concentrations of hypothalamic factors reach the pituitary, often at concentrations that far surpass those in the general circulation.

Embryology

Early in nervous system development, three primary brain vesicles form from the neural tube: the prosencephalon or forebrain, the mesencephalon or midbrain, and the rhombencephalon or hindbrain. Secondary vesicles then form from the prosencephalon during the fourth to fifth weeks of gestation. The secondary vesicles are termed the telencephalon, or endbrain, and the diencephalon. The telencephalon grows to cover all other brain structures and eventually becomes the cerebral hemispheres. The diencephalon also grows, forming a roof plate and two alar plates. During the sixth embryonic week, neuroblasts in the inferior portion of the alar plates of the diencephalon proliferate, forming the human hypothalamus. ^, Hypothalamic development occurs in two main stages: forebrain induction by early signals before or during gastrulation and then cell type differentiation by ventralizing and rostralizing signals from the axial mesendoderm. Axial mesendoderm induction of hypothalamic development is necessary for eye separation, and its failure causes holoprosencephaly.

Distinct cell groups are easier to distinguish in the fetal hypothalamus than in the adult hypothalamus. The fetal hypothalamic nuclei become recognizable between 6 and 12 weeks of gestation. At this same time, the hypothalamic fiber tracts develop, and many hypothalamic factors become detectable. For example, somatostatin, dopamine, and thyrotropin-releasing hormone are detectable as early as the 10th week of gestation. At 9 to 10 weeks of gestation, little differentiation of the hypothalamic nuclei has occurred. By 24 to 33 weeks, the hypothalamus contains an increased number of better-defined structures and more closely resembles an adult hypothalamus. In the immediate postnatal period, the neonatal hypothalamic cell groups are remarkably similar to those structures in a mature adult.

Information regarding the embryology of the hypothalamohypophysial portal system is limited. Evidence exists that the primary plexus begins to develop as early as 11.5 weeks of gestation. Capillary penetrance of the median eminence is not evident until more than 16 weeks of gestation. Further development throughout gestation is indicated by the greater number of capillary loops and the maturer vasculature present at birth.

Our understanding of hypothalamic embryology has advanced from the morphologic to the genetic level. Development of the hypothalamus and pituitary gland is coordinated through parallel actions of genes expressed in both organs; extrinsic signals activate repertoires of transcription factors in a well-defined spatiotemporal pattern that leads to cellular differentiation into the various cell types that assume the distinct functions of the mature organs. ^{, ,} Some of these genes are summarized in Table 139.2 . ^,

Neurologic Functions

Like other brain centers, the hypothalamus participates in neural pathways by synthesizing and secreting neurotransmitters that are chemical messengers used for synaptic transmission, signaling, and neuromodulation. Different pathways control various functions of the hypothalamus, although for some functions, discrete areas or nuclei are not identifiable as the control centers. Some of the neurotransmitters are summarized in Table 139.3 . For example, several hypothalamic nuclei project to the medulla oblongata to maintain homeostatic functions via the serotonergic system. Other neurotransmitters are also involved in hypothalamic functioning, such as the excitatory amino acids in a pathway connecting to the hippocampus and limbic system, but their actions are less well understood.