Hypothalamus H. Ruth Clemo, Ph.D.

OBJECTIVES

1. To know the three rostro-caudal regions of the hypothalamus and their principal nuclei 2. To know the principal afferent (neural inputs) and efferent (outputs) connections of the hypothalamus, and their potential role in its autonomic (visceromotor) and neuroendocrine function. 3. To appreciate that the hypothalamus is an integral part of the limbic system, sharing numerous limbic pathways discussed in a prior lecture, and facilitating the visceromotor (autonomic) aspects of emotion and other behaviors.

I. INTRODUCTION

The hypothalamus is a small ventral portion of the diencephalon which functions to promote homeostasis via its connections with (1) the limbic system, (2) the brainstem and spinal cord (visceral and somatic connections) and (3) the pituitary gland. It is associated with emotional, autonomic, and endocrine functions.

A. Neural/Endocrine Function -The hypothalamus is the highest CNS component of the autonomic nervous system, and governs the most complex of viscero-endocrine responses.The nervous and endocrine systems work together to orchestrate autonomic (visceral) components of complex human behaviors through autonomic and limbic connections of the hypothalamus and its intimate vascular and neural association with the pituitary gland (hypophysis).

B. Autonomic Role - CNS autonomic integration is organized in a hierarchy. Simple reflexes (e.g. bladder contraction) integrated in the spinal cord; more complex reflexes (e.g. respiration, blood pressure) in the medulla; pupillary reflexes in midbrain. The most complex visceral activities (e.g. maintenance of body temperature, metabolic rate, feeding, reproductive) are integrated in the hypothalamus, and govern central autonomic mechanisms.

C. Hypothalamus Monitors Blood Chemistry and Osmolarity - The hypothalamus is among the most highly vascularized regions of the brain, with fenestrated capillaries allowing for an exchange of substances into the brain (circumventing the blood-brain barrier). Examples: 1. Cells in the supraoptic nucleus act as "osmoreceptors," monitoring osmolarity of the blood, releasing vasopressin (ADH) as required for conservation of body water. 2. "Glucoreceptors" in the ventromedial nucleus (satiety center) monitor blood glucose levels, affecting appetite control. 3. Receptors for circulating hormones produced by pituitary target glands (e.g. estrogen, progesterone, corticosteroids, glucocorticoids, thyroxin), facilitate feedback modulation for release of releasing factors into the hypothalamo- hypophyseal portal system. II. ANATOMICAL RELATIONSHIPS

Ventrally, it consists of the tuber cinereum and mammillary bodies; bounded rostrally by the anterior commissure, lamina terminalis, and optic chiasm; dorsally by the hypothalamic sulcus and thalamus; laterally, by the subthalamus. The hypothalamus surrounds the ventral portion of the third ventricle.

The infundibulum (pituitary stalk) connects the tuber cinereum (containing median eminence) to the pituitary gland. Its vascular connections link the median eminence with the anterior lobe and carry releasing factors to affect endocrine control. Neural connections from the anterior region (supraoptic/paravent. nuclei) project (via hypoth.- hypophyseal tract) to posterior lobe control release of vasopressin (ADH) and oxyocin from the neurohypophysis.

From: Haymaker et al, The Hypothalamus

III. REGIONS OF THE HYPOTHALAMUS

The hypothalamus has been divided into three regions from rostral to caudal:

A. Anterior Region - most rostral region, above and rostral to the optic chiasm; contains the preoptic area which is contiguous rostrally (under the anterior commissure) with the basal forebrain. Some of its principal nuclei include: preoptic nuclei, suprachiasmatic nucleus, supraoptic and paraventricular nuclei, sexually dimorphic area. B. Tuberal Region - middle region, above the tuber cinereum (infundibulum). Some of its principal nuclei include: the dorsomedial and ventromedial hypothalamic nuclei, lateral hypothalamic area, and arcuate nucleus (within median eminence). C. Posterior Region - most caudal region. It contains the posterior hypothalamic area and the mammillary complex.

In general terms, within each of these regions, the peri-ventricular zone (adjacent to third ventricle) has more clustered groups of neurons (therefore designated "nuclei"), whereas in the lateral zone (lateral to the fornix) cells are more diffuse because they are separated by the many fiber systems that traverse this zone (therefore designated "areas"; e.g.. lateral hypothalamic area).

From: House, Pansky & Siegel

IV. PRINCIPAL NUCLEI OF THE HYPOTHALAMUS AND THEIR FUNCTION:

There are a number of hypothalamic nuclei whose function has been fairly well established.

Supraoptic and Paraventricular Nuclei - neurons produce oxytocin and vasopressin (ADH) which are transported through the axons of the hypothalamo-hypophyseal tract to be stored or released from the posterior lobe of the pituitary (neurohypophysis).

Suprachiasmatic Nucleus - lies immediately above the optic chiasm; thought to be responsible for circadian rhymicity ("biological clock"); it receives retinal input.

Sexually Dimorphic Area - This "nucleus" (third interstitial nucleus of the anterior hypothalamus, INAH3) is three times larger in males than females suggesting the existence of specific morphological differences between the brains of men and women..

A Systematic Approach to Neuroscience. (From House, Pansky and Siegel - based on Netter)

Ventromedial Nucleus - the "satiety center"; its neurons have glucoreceptors; when its constituent neurons are excited it turns off appetite (satiated); the adjacent lateral hypothalamic area contains a reciprocal "appetite center". Lesions of the VMH result in hypothalamic obesity.

Arcuate Nucleus - principal cell group of the median eminence immediately above the infundibulum (pituitary stalk); within this nucleus hypothalamic "releasing factors" are released into the capillaries of the hypothalamo-hypophyseal portal system and travel to the anterior lobe of the pituitary (adenohypophysis).

Mammillary Complex (esp. medial mammillary nucleus) - receives input from the hippocampus via the fornix, and gives rise to the mammillothalamic tract; (part of the classic Papez circuit), and is therefore thought to play some role in memory (but this function is not yet proven); in Korsakoff's amnestic syndrome (B1 thiamin deficiency in alcoholics) there are petechial hemorrhages in the medial mammillary nuclei that are thought to be partially responsible for the anterograde amnesia.

SUMMARY OF PRINCIPAL NUCLEI OF THE HYPOTHALAMUS

Region Medial area Lateral area Anterior Medial Preoptic Area & Supraoptic nuc Lateral preoptic nucleus Paraventricular & Anterior nucleus Lateral nucleus Suprachiasmatic nucleus

Tuberal Dorsomedial nucleus Lateral nucleus Ventromedial nucleus Lateral tuberal nuclei Arcuate nucleus

Posterior Mammillary body Lateral nucleus Posterior nucleus

V. AFFERENT CONNECTIONS

A. Fornix - originates in the hippocampus and terminates largely in the mammillary complex (see also limbic system handout).

As the fornix approaches the ant. commissure, it divides into a precommissural bundle (to basal forebrain, including the septum and preoptic area) and a larger postcommissural bundle (which gives off fibers to anterior nucleus of the thalamus, lateral hypothalamus, and medial mammillary nucleus), and courses caudally to the midbrain tegmentum (including paramedian midbrain reticular formation, i.e.. limbic midbrain area).

B. Stria Terminalis and Ansa Peduncularis (amygdalo-hypothalamic fibers) – from amygdala to hypothalamus, both systems contain both amygdalofugal and amygdalopetal fibers, so there is continual bidirectional conversation going on between the amygdala and hypothalamus; emotional effects on hypothalamic function (eg. feeding/ appetite, reproduction)

From: Noback and Demarest, The Human Nervous System

C. Medial Forebrain Bundle - ascending and descending fibers which interconnect the septum, preoptic area, hypothalamus, and the paramedian midbrain tegmentum. The MFB traverses the lateral hypothalamic area, and contains the several neurotransmitter pathways that traffic through the hypothalamus in route to higher levels. These include noradrenergic (dorsal and ventral NE bundles), dopaminergic (mesolimbic and mesocortical) and serotonergic fiber system. (see also CNS transmitter lecture outline).

The ventral NE bundle from cell groups A5, A7 in the lateral pontine reticular formation gives rise to a substantial noradrenergic input into hypothalamic nuclei.

Medial Forebrain Bundle

NE cell Groups A5,A7

D. Retinohypothalamic Fibers - direct retinal fibers via the optic nerve are given off from the optic chiasm to the hypothalamus (suprachiasmatic and supraoptic nuclei); account for influence of light on hypothalamo-pituitary functions. Suprachiasmatic nucleus - known to be involved in circadian rhythmicity.

E. Mammillary Peduncle - GVA and SVA (taste) fibers carrying visceral afferent information essential to hypothalamic coordination of autonomic function (e.g. feeding and appetite, ascend from the solitary nucleus travel with the medial lemniscus, and then in the midbrain form a separate system called the mammillary peduncle to terminate in the mammillary complex and other hypothalamic nuclei.

V. EFFERENT CONNECTIONS:

A. Mammillothalamic Tract - from mammillary body to the anterior nucleus of the thalamus (part of Papez circuit).

Principal mammillary fasciculus arises as a single bundle from the medial mammillary nucleus, passes dorsally for a very short distance, and then divides into two tracts: the mammillothalamic tract, and the mammillotegmental tract which turns caudally to terminate in brainstem reticular formation and possibly parasympathetic autonomic nuclei.

From: House, Pansky & Siegel: A Systematic Approach to Neuroscience

B. Dorsal Longitudinal Fasciculus - fibers from the hypothalamus descend through the periaqueductal gray (PAG) of the midbrain and periventricular gray of pons/medulla to terminate in brainstem parasympathetic autonomic nuclei (e.g. Edinger-Westphal, salivatory, dorsal vagal nuclei). Some of its fibers reach as far caudally as the spinal cord, terminating in the intermediolateral cell column continuing sympathetic preganglionic neurons facilitating direct influence over the autonomic nervous system.

From: Niewenhuys, The Human Central Nervous System

From: House, Pansky, and Siegel, A Systematic Approach to Neuroscience

C. Hypothalamo-hypophyseal Tract - arises from the supraoptic and paraventricular nuclei; courses ventrally through the pituitary stalk to terminate in the neurohypophysis (posterior lobe of the pituitary gland), which acts as a storage and release center for neurohormones (vasopressin and oxytocin) produced in the neurons of the supraoptic and paraventricular nuclei.

From: Noback and Demarest, The Human Nervous System D. "Vascular" Efferents (Neuroendocrine Outputs) - hypothalamic neurons produce releasing factors which are transported through short intrinsic intra-hypothalamic axons to the arcuate nucleus of the median eminence which contains the capillaries of origin of the hypothalamo-hypophyseal portal system through which it directs the release of adenohypophyseal hormones (anterior lobe). The hypothalamus contains neurons which synthesize releasing factors for all the anterior lobe hormones (ACTH, FSH, LH, STH, TSH) except prolactin for which it produces an inhibiting factor (thought to be dopamine).

Table 1: From Kingsley, Concise Text of Neuroscience 1996 Nucleus Releasing Hormones Supraoptic Oxytocin, vasopressin Paraventricular Oxytocin, vasopressin, CRH Preoptic, GnRH, FSH-RH, LH-RH Septal GnRH, FSH-RH, LH-RH Arcuate GnRH, GHRH, PRIH, FSH-RH, LH-RH, STH-RH, PIF (DA) Periventricular TRH, GHIH

Table 2 CRH Corticotropin releasing hormone (ACTH) GnRH Gonadotropin releasing hormone (FSH, LH) TRH Thyrotropin releasing hormone (TSH) GHRH Growth hormone releasing hormone (STH) Prolactin release inhibiting hormone (prolactin) PRIH (dopamine?)

Short intrinsic axons carry releasing factors to the arcuate nucleus (within the median eminence, ie. tuber cinereum) where substances are released into the hypothalamo-hypophyseal portal system.