Vision and the hypothalamus

Article Outline

• Abstract
• The autonomic nervous system
• Anatomy of the hypothalamus
• Peptides
• Cytokines
• Nitric oxide
• Functions of the hypothalamus
• The hypothalamic-pituitary-adrenal axis
• Hypothalamus and neurodegenerative disorders
  • Alzheimer's disease
  • Huntington's disease
  • Parkinson's disease
• Retinohypothalamic tracts
• Vision and the hypothalamus
  • Cornea
  • Disease—nonocular
  • Intersensory
  • Inflammation
  • Intraocular pressure
  • Lacrimation
  • Metabolism
  • Neurologic syndromes
  • Sleep
• Retinal peptides
• Clinical implications
• Conclusion
• References
• Copyright

Abstract 

For nearly 2 millennia, signs of hypothalamic-related vision disorders have been noticed as illustrated by paintings and drawings of that time of undiagnosed Horner's syndrome. It was not until the 1800s, however, that specific connections between the hypothalamus and the vision system were discovered. With a fuller elaboration of the autonomic nervous system in the early to mid 1900s, many more pathways were discovered. The more recently discovered retinohypothalamic tracts show the extent and influence of light stimulation on hypothalamic function and bodily processes. The hypothalamus maintains its myriad connections via neural pathways, such as with the pituitary and pineal glands; the chemical messengers of the peptides, cytokines, and neurotransmitters; and the nitric oxide mechanism. As a result of these connections, the hypothalamus has involvement in many degenerative diseases. A complete feedback mechanism between the eye and hypothalamus is established by the retinohypothalamic tracts and the ciliary nerves innervating the anterior pole of the eye and the retina. A discussion of hypothalamic-related vision disorders includes neurologic syndromes, the lacrimal system, the retina, and ocular inflammation. Tables and figures have been used to aid in the explanation of the many connections and chemicals controlled by the hypothalamus. The understanding of the functions of the hypothalamus will allow the clinician to gain better insight into the many pathologies associated between the vision system and the hypothalamus. In the future, it may be possible that some ocular disease treatments will be via direct action on hypothalamic function.

Keywords: Hypothalamus, Vision, Peptides, Cytokines, Nitric oxide (NO)

A starting point on when the relationship between the hypothalamus and vision first appeared in the literature is with Horner's syndrome, which occurs when there is a lesion in the sympathetic nervous system innervation between the eye and the hypothalamus.¹ According to the same authors,¹ Horner's syndrome was known approximately 1,800 years ago as illustrated in a funeral portrait. Bernard, in 1852, is credited with the first description of the syndrome, which was later elaborated and popularized by Horner in 1869.²

Discovering the connection between the sympathetic nervous system and the hypothalamus was a slow process. The first description of the hypothalamus was given, approximately 1,800 years ago, by Galen. As investigative techniques into the anatomy of the brain advanced, illustrations of the structure of the hypothalamus were made in drawings by DaVinci in 1508 and, shortly thereafter, by Michelangelo's paintings in the Sistine Chapel.³ The same investigators³ credit Cajal with anatomically locating and describing the hypothalamus in 1894. Swaab⁴ credited Wilhelm His as first describing the hypothalamus as a distinct anatomic structure in 1893.

Bernard began investigations of the sympathetic nervous system (SNS) in 1849.⁵ Primarily through the pioneering efforts of Cannon (beginning in 1914) and Selye (beginning in the 1940s) did the important connections and relationships between the sympathetic nervous system and the hypothalamus become established in the scientific and medical literature.⁶

In the 1940s there were experiments relating vision function to the SNS, with the identification of fibers other than those going to the pupil. One of the earliest reports of SNS innervation to the eye was by Morgan,⁷ with the finding of SNS fibers in the ciliary muscle. In a later report, Morgan⁸ concluded that the SNS action on the ciliary muscle dealt only with the blood supply. During the 1970s there were a series of pharmacologic studies investigating the SNS innervation to the ciliary muscle. The results showed that the SNS not only innervated the vascular supply of the eye but negative accommodation as well.⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶

By the 1980s, specific retinohypothalamic pathways were discovered by Sadun et al.,¹⁷ leading to the elaboration of a much broader role of the hypothalamus in relation to the function of the vision system.¹⁷ The purposes of this report are to describe the hypothalamus anatomically and neurophysiologically, the many interconnections between the hypothalamus and the vision system, the interrelationships among the many functions of the hypothalamus with specific emphasis on vision function, and the optometrist's role in the diagnosis and treatment of hypothalamus-related vision disorders. The current report is but a brief survey of the great wealth of information regarding the hypothalamus. Accordingly, an extensive list of references is given to allow in-depth study when desired.

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The autonomic nervous system 

As a result of research studies in the 1920s, Walter B. Cannon's “fight or flight” theory introduced the autonomic nervous system (ANS) response being mediated by hormones.¹⁸ Two basic elements of Cannon's theory are (1) there is the same response to a variety of stimuli and (2) the response is mediated by hormones. Much of the ANS and the neurotransmitters were unknown at Cannon's time. Although it was Bernard in 1865 who introduced the concept of homeostasis,¹⁹ it was Cannon who built on the concept through his experimentation.

Expanding on Cannon's work, Hans Selye investigated the body's reaction to stress.²⁰ His theory is known as the “General-Adaptation Syndrome” or “Stress Syndrome,” which now included the hypothalamic-hypophyseal-adrenocortical axis. Selye's theory also included elaboration of homeostasis. Later the hypothalamic-hypophyseal-adrenocortical axis became known as the hypothalamic-pituitary-adrenal axis (HPA).

Further understanding of the ANS was described by Neal Miller²¹ with his theory of ANS learning. His theory of psychosomatic illness is based on inappropriate ANS learning. For example, because there is an absence of an odd-error signal for retinal blur, the response to blur may be to either under- or overaccommodate to blurry stimuli.²² With a bias to overaccommodate to a near object, Miller's theory can explain the near-work theory etiology of nearsightedness based on inappropriate ANS learning.²³

A detailed review and modern understanding of the ANS is elaborated by Berntson et al.²⁴ As a result of a series of experiments, they noted that the relationship between the sympathetic and parasympathetic nervous systems can be, as classically described, reciprocal—as one increases in function, the other decreases. However, further experimentation found that they can also act uncoupled—independent of each other as demonstrated by basal heart rate control by the vagus nerve, or co-activity—as one increases the other increases, and vice versa. For example, as demonstrated in salivation, both sympathetic and vagal activities result in salivation. This model may help to explain why some ANS drugs are effective for some patients and not others and the reason that some medications to reduce intraocular pressure (IOP) may instead increase it.

Contemporary models of the ANS greatly expand the earlier hormonal models with the discovery of opiate-receptor binding,²⁵ the first description of brain peptides,²⁶, ²⁷ peptides as neurotransmitters,²⁸ and the role of nitric oxide (NO) in the nervous system.²⁹, ³⁰, ³¹ As described above, there are innumerable connections between the ANS and the hypothalamus, mediated by hormones, peptides, cytokines, and NO. In addition, within the hypothalamus there exists paracrine,^∗ autocrine,^† and juxtacrine^‡ factors, which are nonsynapse, inter- and intracellular means of communication.³²

The ANS is not only under the influence of the nerves that comprise it but hormones, peptides, cytokines, NO, and paracrine, autocrine, and juxtacrine communications as well. This elaborate mechanism results in numerous intraconnection possibilities and innumerous interconnection possibilities with all components of the body's functions.

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Anatomy of the hypothalamus 

The hypothalamus is located in the diencephalon and is approximately in the geometric center of the brain. It is surrounded by several structures: superiorly by the thalamus and the anterior commissure, inferiorly by the optic chiasm and the hypophysis, dorsally by the hypothalamus sulcus, and ventrally by the infundibulum. In relation to the ventricles, the rostal and ventral walls of the third ventricle are formed by the hypothalamus.³³, ³⁴, ³⁵ Illustrations of the hypothalamus are shown in Figure 1, Figure 2.

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• Figure 1 

  The hypothalamus is located close to the geometric center of the brain, just below and anterior to the thalamus, and above the pituitary gland. This central location of the hypothalamus not only allows ready inter-communication with other brain structures, but provides a safe environment during head trauma.¹⁷⁷

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• Figure 2 

  A detailed representation of the hypothalamus showing some of the components and their location within the hypothalamus. Within the hypothalamus there exists paracrine, autocrine, and juxtacrine factors, which are non-synapse, inter- and intra-cellular means of communication.¹⁷⁸

The size of the hypothalamus is approximately 4cm³. The weight of the hypothalamus is approximately 39 to 42g. Table 1 lists the different components of the hypothalamus, with their function(s) and associated peptide(s).

Table 1. Components of the hypothalamus

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Peptides 

Peptides are released and contained in nerves, both sympathetic and cholinergic.³⁶ These authors further propose that future pharmacologic agents will be either peptide inhibitors or stimulators.

The earliest peptide identified was substance P by von Euler and Gaddum³⁷ in 1931. At that time they did not recognize the function of substance P (SP). It was not until Lembeck,³⁸ in 1953, that SP was understood to be a neurotransmitter.

In 1977, Nobel Prize co-laureates described the first hypothalamic peptide, thyroid releasing factor (TRF).²⁶, ²⁷ With 1.0mg of ovine TRF, which Guillemin²⁶ obtained in 1969 from 300,000 sheep hypothalamic fragments, he was able to chemically analyze the newly discovered peptide. His results were similar as to those found by Schally.²⁷

As discussed in the ANS section above, the first description of peptides as neurotransmitters was by Snyder.²⁸ Today there more than 200 peptides⁴; this discussion is limited to the hypothalamic peptides, which are listed in Table 2. The extensive involvement of the hypothalamic peptides in the body's neurophysiology, with emphasis on the vision system, will be a major theme of the remainder of this discussion.

Table 2. Hypothalamic peptides^∗

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Cytokines 

The first cytokine to be identified was interferon³⁹ in 1957, although it was not classified as a cytokine at that time. Baron and Isaacs⁴⁰ and Isaacs⁴¹ reported that interferon is active as an antiviral agent. One of the first articles that made the classification of cytokines identified not only interferon, but interleukin 1 (IL-1) and tumor necrosis factor (TNF).⁴² Cytokines are found in low levels in normal tissue and are activated by tissue stress. This activation may be via pleiotropy (exerting a variety of actions) or redundancy (exerting the same action).⁴³ In both cases, their activation is related to immune function. For example, TNF causes fever by stimulating IL-1 production.⁴⁴ A thorough description of the cytokines' immunologic functions was presented by Delves et al.⁴⁵ In conjunction with NO (see below) the cytokines are involved in fever production and sleep mechanisms.⁴⁶

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Nitric oxide 

Nitric Oxide (NO) is not to be confused with N₂O, nitrous oxide, which was discovered by Joseph Priestly in 1793 and is better known as laughing gas.⁴⁷ It was not until the 1990s that NO was recognized as being a significant regulator of central and peripheral neurotransmission, activation of platelets, and blood flow.³¹ The production of NO is localized by its release from individual cells. At the end of the 1990s, there were about 20,000 reports published on the topic of NO, which were selectively reviewed by Moncada.²⁹ In the review, emphasis was placed on the vasodilation properties, gastrointestinal influence, memory function, production of cerebrospinal fluid, production of neurotransmitters, immunology, and reaction to inflammation. The NO system consists of a large nerve network, which is neither adrenergic nor cholinergic and is known as the nitrergic system.²⁹ Barañano and Snyder⁴⁸ expanded on the roles of NO and added the attribute of neurotransmitter as one of NO's properties.

Another area of investigation of the properties of NO is its role in the placebo effect. Via the release of NO during stress, a physiologic reaction occurs that has been related to the placebo effect.⁴⁹ The hypothalamus is a major center during the reaction of stress with its release of NO.

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Functions of the hypothalamus 

After its initial discovery, the hypothalamus was believed to play a minor or subservient role in nervous system function and regulation. Recent studies report quite the contrary; the hypothalamus is the main component of the sympathetic nervous system, regulates much of the pituitary's activity, and produces many of the nervous system's neurotransmitters and peptides. Emphasizing the important and central role of the hypothalamus in the SNS, Hess⁵⁰ summarized the many functions of the hypothalamus known at that time. Before a discussion about the specific connections between the vision system and the hypothalamus, an update on the understanding of the many functions and connections of the hypothalamus is presented in Table 1, Table 2, Table 3.

Table 3. Hypothalamic connections

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The hypothalamic-pituitary-adrenal axis 

In addition to the innumerable functions and connections illustrated in the tables, the hypothalamus has further wide-ranging physiologic influence via the HPA. The complete literature describing the HPA is encyclopedic and outside the realm of a brief literature review. However, by taking one of its functions, adrenocorticotropic hormone (ACTH) production, a glimpse of the HPA in the relationship between the brain and behavior will be revealed.

ACTH is released by the anterior pituitary gland in response to stimulation from hypothalamic peptides corticotrophin-releasing hormone (CRH), vasopressin (AVP), oxytocin (OT), and angiotensin II (AII), with CRH from the paraventricular nucleus (PVN) being the main stimulus.⁵¹, ⁵² The importance of the role of CRH was emphasized in 1955 by Nobel Prize winners Guillemin²⁶ and Schally.²⁷ They described that CRH increases behavioral activation, stimulates the SNS, and inhibits feeding and sexual behaviors. The involvement in the SNS is extensive, involving both adrenaline and noradrenaline through both their α and β receptors.⁵¹ In the pituitary gland, ACTH is chemically derived from the synthesis of pro-opiomelanocortin (POMC), another hypothalamic peptide, which in turn stimulates production of cortisol, which then inhibits hypothalamic production of CRH.⁵³ In response to stress, the hypothalamus initiates the response for cortisol production, the most prevalent of the glucocorticoids.⁵⁴

The current and future use of cortisol-related pharmaceutical agents can be well illustrated with anecortave acetate, a synthetic analog of cortisol acetate.⁵⁵ The most notable properties of anecortave acetate are its being angiostatic, without having the glucocorticoid receptor–mediated effects typical of corticol.⁵⁶ Currently, there is a clinical trial evaluating the effectiveness of anecortave acetate in arresting the progression of dry age-related macular degeneration in patients who are at risk for progressing to wet age-related macular degeneration. The first phase reporting on the safety of the treatment was completed in 2003.⁵⁷ Interim reports of the success and progress of the clinical trial were reported in 2007.⁵⁸ In a more recent study, Robin et al.⁵⁹ reported the successful use of anecortave acetate in the treatment of steroid-related ocular hypertension (see Figure 3).

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• Figure 3 

  In response to stress, the hypothalamus initiates the response for cortisol production, the most prevalent of the glucocorticoids. This stimulation of the hypothalamus, in response to stress, results in the release of CRH. In response the pituitary gland produces and releases ACTH, which is chemically derived from the synthesis of proopiomelanocortin (POMC), another hypothalamic peptide, which in turn stimulates production of cortisol, by the adrenal glands, which then inhibits hypothalamic production of CRH.

The magnitude of the importance of physiologically proper levels of ACTH, CRH, and cortisol can be understood by their role in the etiology of disease and in the treatment of disease. For example, there is a lack of ACTH in Addison's disease, Alzheimer's disease, Parkinson's disease, and Crohn's disease, and HPA suppression in Cushing's syndrome and post-traumatic stress disorder,⁶⁰, ⁶¹ whereas an increase in ACTH reduces delta brain wave sleep.⁶²

More recent research has explored the role of the HPA in stress. McCann et al.⁶³ reported on the extensive connections involved in CRH release in response to stress with influence on the locus coeruleus, the limbic system, and NO activity. In a comprehensive review, Hauger et al.⁶⁴ described the expansive interconnections and interactions of CRH, ranging from the molecular level, to behavioral responses to stress including memory, learning, early-life stress, panic disorder, depression, and bipolar disorder. Other research suggests that chronic stress results in a learned hypo-response by the HPA.⁶⁵, ⁶⁶ Recent reviews of human psychoimmunology reported on the intimate involvement of the HPA via its links with the ANS, CNS, and behavior.⁶⁷, ⁶⁸

The involvement of ACTH in the etiology of vision disorders and their treatment has a history of more than 50 years. One of the early publications reported on the use of ACTH in the treatment of cataract, retinitis pigmentosa, uveitis, and retrolental fibroplasias (as labeled in the reference), with success in one case of cataract.⁶⁹ Duke-Elder⁷⁰ reviewed the use of ACTH for a variety of ocular diseases, with a caution of ACTH use in patients with diabetes, hypertension, chronic nephritis, and psychotic states. The diseases treated, with various results, included uveitis, retinal and neural inflammations, central serous retinopathy, optic neuritis, retrobulbar neuritis, retinal perphlebitis, vitreous hemorraghes, kerititis, corneal abscesses, phlyctenular disease, herpes zoster, pannus, episcleritis, scleritis, conjunctivitis, diabetic retinopathy, Coat's disease, central retinal venous thrombosis, retrolental fibroplasia, glaucoma, Sjögren's syndrome, exophthalmic conditions, and neoplasms.⁷⁰ The use of ACTH for scleromalacia had limited results as reported by Anderson and Margolis.⁷¹ Brown and Corner⁷² treated 4 infants who had retrolental fibroplasia with ACTH. The results were that 3 of the 4 infants had normal fundi. In another study, in the same year with 32 infants who had retrolental fibroplasias, the author reported no improvement with ACTH treatment.⁷³ Topical application of cortisone and hydrocortisone were reported to be successful in the treatment of kerato-conjunctivitis sicca in patients with Sjögren's syndrome, but systemic treatment with ACTH showed limited improvement.⁷⁴ A question arose concerning the effects of steroid therapy in causing posterior subcapsular cataracts (PSC). Toogood et al.⁷⁵ reported that in a study of 56 patients receiving corticosteroid therapy, only 3 (5.4%) had PSC. The authors concluded that the corticosteroid therapy was not a causative factor in the development of PSC. In a literature review, Kaiser-Kupfer⁷⁶ cautioned the use of ACTH for retrolental fibroplasias, as these reports were from poorly designed studies. More recently, ACTH as well as peptides and cytokines have been found to be important in lacrimal gland function.⁷⁷

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Hypothalamus and neurodegenerative disorders 

The most comprehensive description of the role of the hypothalamus in degenerative disease was presented by Swaab.⁴, ⁷⁸ An abridged summary is shown in Table 4.

Table 4. Hypothalamus and neurodegenerative disorders⁷⁸

As examples of the nature of the relationship between the hypothalamus and degenerative disease, Alzheimer's disease, Huntington's disease, and Parkinson's disease will be specifically discussed.

Alzheimer's disease 

Alzheimer's disease (AD) is associated with aging and depression, a decrease in vasopressin (VP) and vasoactive intestinal peptide (VIP), and a decrease in melatonin. The decrease in VP and VIP is the result of an impaired response of the peptide-producing cells in the suprachiasmatic nucleus (SCN). Damage to the hypothalamus can produce anterograde amnesia and AD. In AD there is an increase in the volume of the third ventricle whose rostral and ventral walls are formed by the hypothalamus, with an associated atrophy of the hypothalamus. Development of neurofibrillary tangles (NFTs) and congophilic neuritic plaques are found in the hypothalamus in AD.⁴, ⁷⁸

Huntington's disease 

In Huntington's disease (HD) there are changes in the supra optic nuclei (SON) and the PVN resulting in a decrease of VP production. Also, there are changes in the ventromedial nucleus (VMN), tubermamillary nucleus (TMN), and lateral tuberal nucleus (NTL). Associated hypothalamic ANS and endocrine abnormalities include sleep disturbances, weight loss, decrease in β endorphin, and an increase in luteinizing hormone-releasing hormone (LHRH).⁴, ⁷⁸

Parkinson's disease 

In Parkinson's disease (PD) there is a decrease in the hypothalamus of the number of oxytocin neurons associated with Lewy bodies, aggregates of protein deposits inside nerve cells, in the hypothalamic nuclei. There are a number of ANS and endocrine symptoms suggesting hypothalamic involvement: dizziness, salivation, seborrhea, excessive sweating, constipation, sphincter disturbances, dysphagia, orthostatic hypertension, blue mottled skin, low resting skin temperatures, heat intolerance, sleep disorders, depression, impotence, sleep disruption, weight gain or loss, and bulimia. The hypothalamus has an abnormal secretion of prolactin, thyrotropin-stimulating hormone (TSH), growth hormone, and nelanocyte stimulating hormone (MSH) in PD.⁴, ⁷⁸

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Retinohypothalamic tracts 

Beginning in the 1980s, Sadun et al.⁷⁹ began publishing reports of retinohypothalamic pathways. Utilizing a newly developed staining method for human autopsy tissue, nerve fibers between the eye and the brain could now be traced. The result of their investigation was the finding that fibers from the retina projected to the SCN of the hypothalamus. The explanation for the pathway was that it was involved in mediating endogenous circadian rhythms by the SCN's connection to the pineal gland and its production of melatonin. A year later there was the discovery of a second retinohypothalamic pathway that terminated in the PVN of the hypothalamus.⁸⁰ A recent article reported on the importance of the PVN in its regulation of efferent sympathetic nerve outflow.⁸¹ Continuing the investigation of retinohypothalamic pathways, Sadun et al.⁸² reported a third pathway—from the retina to the SON of the hypothalamus. In describing the possible function(s) of this pathway, the authors provided a detailed discussion of the neurophysiologic implications of their findings.

The SCN synthesizes several hormones including VP, which is related to circadian rhythm patterns, the production of melatonin by the pineal gland, and the sleep mechanism.¹⁷ The SON's magnocellular neurons not only synthesize vasopressin but oxytocin and some opioid peptides (see Table 1 for other SON peptides). The primary functions of the SON include nitric oxide synthase injury, fluid and electrolyte homeostasis, and water balance.⁸³, ⁸⁴, ⁸⁵ The magnocellular neurons of the PVN similarly produce vasopressin and oxytocin. The magnocellular and parvocellular neurons of the PVN are involved with a variety of neurotransmitters including somatostatin and enkephalins. The authors concluded with a description of the importance of visual function in relation to neuroendocrine function and neuro-ophthalmic disease in general. The conclusion by the investigators is amplified by the myriad of functions and connections of the hypothalamus that are displayed in Table 1, Table 2, Table 3.

A recent discovery in relation to the RHT is the opsin, melanopsin. Opsins are G-protein–coupled receptors (GPCRs);⁸⁶ the best known is rhodopsin, which was discovered in 1877 by Franz Boll with further elaboration by Willy Kühne in 1879.⁸⁷, ⁸⁸ Later opsins were found in the cones. Expanding on the pioneering work of Wald,⁸⁸ Bowmaker and Dartnall⁸⁹ reported the λmax for rhodopsin was 498nm, with the λmax for red cones at 563nm, green cones at 534nm, and blue cones at 420nm. Adding to our understanding of circadian rhythms and melatonin production is a newly discovered opsin, melanopsin, which is found in the human retina. Retinal cells containing melanopsin project to the SCN via the retinohypothalamic tracts (RHT).⁹⁰, ⁹¹ Melanopsin is also found in melanophores in the iris and the inner brain.⁹² The discovery of melanopsin greatly aids our understanding of the nonvisual aspects of light stimulation in particular and enhances our appreciation of the interaction between the hypothalamus and the vision system in general.

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Vision and the hypothalamus 

In addition to the retinohypothalamic pathways, there are numerous relationships between hypothalamic function and the vision system. The connections are various, including SNS fibers to the choroid, ciliary body, ciliary muscle, and iris; the physical proximity of the hypothalamus to the optic chiasm; the hypothalamic control of intraocular pressure, lacrimation, sleep, peptides, neurotransmitters, NO, and the immune system; and inter-sensory connections. Some of the more common relationships are listed below.

Cornea 

TNF-α, IL-1α, and IL-1β levels are increased post excimer laser photorefractive keratectomy.⁹³, ⁹⁴ SP and calcitonin gene-related peptide (CGRP) aid in corneal wound healing.⁹⁵

Disease—nonocular 

A number of nonocular diseases have ocular manifestations resulting from hypothalamic dysfunction. In Pradi-Willi syndrome, hypopigmentation and strabismus are frequently noted,⁹⁶ pigmentation regulation being a hypothalamic function. There was a reduced critical flicker frequency (CFF) in a patient with hypothalamic pituitary disease.⁹⁷

A correlation was reported between age-related macular degeneration and AD in a study of 1,438 subjects, with no explanation found for the relationship.⁹⁸ A high occurrence of glaucoma was reported in patients with AD by Bayer et al.⁹⁹ and in AD disease and PD by Bayer et al.¹⁰⁰ As mentioned above in the Hypothalamus and Neurodegenerative Disorders section, one pathological factor of AD is a decrease in VP production from the SCN, which is related to the degenerative process of aging.⁴, ⁷⁸ Swaab⁴, ⁷⁸ also reported that damage to the hypothalamus is related to PD.

Intersensory 

Fibers in the lateral hypothalamus from both the retina and the olfactory bulb link vision and olfaction.¹⁰¹

Inflammation 

The levels of the hypothalamic cytokines, TNF-α, IL-1β, IL-6, and IL-8, increase in association with autoimmune inflammations such as proliferative vitreoretinopathy (PVR) and uveitis.¹⁰², ¹⁰³ Interleukin-12 (IL-12) induces production of interferon-γ that reduces uveitis inflammation.¹⁰⁴

Intraocular pressure 

CGRP in cornea, uvea, and ciliary body is a vasodilator involved in the blood–aqueous barrier and the elevation of intraocular pressure.¹⁰⁵ Riise and Simonsen¹⁰⁶ reported that there is hypothalamic control of intraocular pressure.

Lacrimation 

Hypothalamus-based peptides, substance P (SP), neuropeptide Y (NPY), CGRP, and VIP are found in the lacrimal sac and nasolacrimal duct.¹⁰⁷

Metabolism 

Via retino-hypothalamic nerve fibers, there is an influence on a number of metabolic functions such as those for calcium, creatinin, cholesterol, and eosinophils.¹⁰⁸

Neurologic syndromes 

Adie's tonic pupil (slow pupillary reflexes) and Argyll Robertson pupil (loss of direct and indirect pupillary reflexes while maintaining the accommodative pupillary reflex) can be caused by a viral infection or syphilis. Viral infections may be associated with hypothalamic dysfunction, whereas the neurosarcoidosis of syphilis causes lesions in the hypothalamus affecting the pupil and accommodation.⁴, ⁷⁸ Horner's syndrome occurs when there is a lesion in the sympathetic nervous system innervation between the eye and the hypothalamus. Wernicke's syndrome, which includes ptosis and slow pupillary reflexes,¹ is associated with periventricular and mamillary lesions to the hypothalamus.⁴, ⁷⁸

Sleep 

There are sleep problems in patients with visual impairment.¹⁰⁹ In retinitis pigmentosa, decreased melatonin production results in sleepiness and lack of sleep quality.¹¹⁰, ¹¹¹ As described above, in the Retinohypothalamic tracts section, fibers from the RHT go to the SCN, which in turn connect to the pineal gland, thereby regulating the production of melatonin.

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Retinal peptides 

Although the emphasis of this report has been on the hypothalamus and its myriad functions, one of the hypothalamic functions is retinal regulation via the retinal peptides. These peptides are most likely involved in the complete feedback loop from the retina to the hypothalamus to the retina. For example, some of the peptides common to the retina and the hypothalamus are SP; VIP; vascular endothelial growth factor, which affects retinal vascularization,¹¹² neurotensin (NT), and NPY. ¹¹³ Accordingly, the future treatment for retinal diseases may very well be peptides or peptide antagonists.

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Clinical implications 

Almost all bodily functions are either directly or indirectly controlled or influenced by the hypothalamus. In this regard, the eye is certainly no exception. A good question for a clinician to ask is where to begin to analyze the relationship between the patient's vision and hypothalamic function? As with the standard clinical routine, the analysis begins during the case history. For example, does that patient complain about tearing, dry eyes, or sleep disturbances? The lacrimal system and corneal healing are both related to peptide levels in the tears. Is the patient taking any medications that may affect hypothalamic function? Most ANS-acting drugs will affect the hypothalamus. One example is drugs affecting the body's water balance, which can affect intraocular pressure. It is important to remember that what happens in one function of the hypothalamus tends to happen in other functions as well. A patient with a complaint of a short reading time, indicating an accommodative infacility, may (1) not have enough sleep; (2) have poor concentration or memory; (3) have a water imbalance; (4) be hungry; (5) have blood sugar level irregularities; or (6) have body temperature regulation problems. In other words, although the clinician's first thought may not be the hypothalamus as an etiologic factor, it should remain high on the list of possibilities when making a diagnosis of common conditions.

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Conclusion 

Much material has been covered with the primary purpose to document the pervasive nature of hypothalamic control and how the control occurs both via nerve pathways; the chemical messengers of the peptides, cytokines, and neurotransmitters; and the NO mechanism. As optometrists become more involved in prescribing or administering oral and injectible medications, it will be essential to be aware of the systemic effects of these drugs as well as what drug–drug interactions may interface with hypothalamic controls.

As primary care providers, optometrists should know about the relation of peptides to pharmaceuticals that are now being produced and marketed. For example, on www.rxlist.com¹¹⁴ 6 of the top 100 prescriptions dispensed are peptide antagonists. Predictably, in the near future more pharmaceutical agents will act to either increase or decrease peptide production.³⁶ Peptides can currently be detected by analysis of the tears.¹¹⁵ Future tests will most likely expand the number of peptides analyzed as well as become a routine clinical test rather than an outside laboratory procedure.

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References 

1. In:  Miller NR,  Newman NJ,  Biousse V, et al. editor. Walsh & Hoyt's clinical neuro-ophthalmology: The essentials. 2^nd ed. Philadelphia: Lippincott, Williams & Wilkins; 2007;
   • View In Article
2. Amonoo-Kuofi HS. Horner's syndrome revisited: With an update of the central pathway. Clin Anat. 1999;12(5):345–361
   • View In Article
   • MEDLINE
   • CrossRef
3. Lechan RM, Toni R. Functional anatomy of the hypothalamus and pituitary. Available at: www.Endotext.com. Last accessed November 6, 2008.
   • View In Article
4. Swaab DF. The human hypothalamus: Basic and clinical aspects. Part I: Nuclei of the human hypothalamus. Amsterdam: Elsevier; 2003;
   • View In Article
5. Alquier T, Kahn BB. Peripheral signals set the tone for central regulation of metabolism. Endocrinology. 2004;145(9):4022–4024
   • View In Article
   • MEDLINE
   • CrossRef
6. McEwen BS, Lasley EN. Stress and emotional connection. The end of stress as we know it. Washington, D.C.: Joseph Henry Press; 2002;
   • View In Article
7. Morgan MW. The nervous control of accommodation. Am J Optom. 1944;21:87–93
   • View In Article
8. Morgan MW. A new theory for the control of accommodation. Am J Optom. 1946;23:99–110
   • View In Article
9. Kasai T, Unno M, Fujii K, et al. Dynamic characteristics of human eye accommodation system. Proceedings of Osaka University. Japan. 1971;No. 1014:569–586
   • View In Article
10. Hurwitz BS, Davidowitz J, Chin NB, et al. The effects of the sympathetic nervous system on accommodation. I. Beta sympathetic nervous system. Arch Ophthalmol. 1972;87:668–674
    • View In Article
    • MEDLINE
11. Garner LF, Brown B, Baker R, et al. The effect of phenylephrine hydrochloride on the resting point of accommodation. Invest Ophthalmol Vis Sci. 1983;24(4):393–395
    • View In Article
    • MEDLINE
12. Gilmartin B, Hogan RE, Thompson SM. The effect of timolol maleate on tonic accommodation, tonic convergence, and pupil diameter. Invest Ophthalmol Vis Sci. 1984;25(6):763–770
    • View In Article
    • MEDLINE
13. Gilmartin B, Hogan RE. The relationship between tonic accommodation and ciliary muscle innervation. Invest Ophthalmol Vis Sci. 1985;26(7):1024–1028
    • View In Article
    • MEDLINE
14. Stephens KG. Effect of sympathetic nervous system of accommodation. Am J Optometry. 1985;62(6):402–406
    • View In Article
15. Mordi JA, Lyle WM, Mousa GY. Effect of phenylephrine on accommodation. Am J Optometry. 1986;63(4):294–297
    • View In Article
16. Bullimore MA, Gilmartin B. Tonic accommodation, cognitive demand, and ciliary muscle innervation. Am J Optometry. 1987;64(1):45–50
    • View In Article
17. Lubkin V, Bezai P, Sadun AA. The eye as a metronome of the body. Surv Ophthalmol. 2002;47(1):17–26
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (548 KB)
    • CrossRef
18. Cannon WB. The wisdom of the body. Rev. ed. New York: W.W. Norton; 1939;
    • View In Article
19. Bernard C. An introduction to the study of experimental medicine. New York: Dover Publications (Reprint edition); 1957;
    • View In Article
20. Selye H. Stress and disease. Science. 1955;122(3171):625–631
    • View In Article
    • MEDLINE
21. Miller NE. The learning of visceral and glandular responses. Science. 1969;163:434–445
    • View In Article
    • MEDLINE
22. Stark L, Takahashi Y. Absence of an odd-error signal mechanism in human accommodation. IEEE Transactions in Bio-Medical Engineering. 1965;12(3-4):138–146
    • View In Article
23. Miller NE. Neal E. Miller: Selected papers. New York: Aldine-Atherton; 1971;
    • View In Article
24. Berntson GG, Cacioppo JT, Quigley KS. Autonomic determinism: The modes of autonomic control, the doctrine of autonomic space, and the laws of autonomic constraint. Physiological Rev. 1991;98(4):459–487
    • View In Article
25. Pert CB, Snyder SH. Properties of opiate-receptor binding in rat brain. Proc Natl Acad Sci. 1973;70(8):2243–2247
    • View In Article
26. Guillemin R. Peptides in the brain. The new endocrinology of the neuron. Nobel Lecture December 8, 1977. 1977;Available at: http://nobelprize.org/nobelfoundation/publications/lectures/index.html. Last accessed December 17, 2009.
    • View In Article
27. Schally AV. Aspects of hypothalamic regulation of the pituitary gland with major emphasis on its implications for the control of reproductive processes. Nobel Lecture. December 8, 1977;
    • View In Article
28. Snyder SH. Brain peptides as neurotransmitters. Science. 1980;209(4460):976–983
    • View In Article
    • MEDLINE
29. Moncada S. Nitric oxide: Discovery and impact on clinical medicine. J Royal Soc Med. 1999;92:164–169
    • View In Article
30. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992;6:3051–3064
    • View In Article
    • MEDLINE
31. Moncada S, Palmer RM, Higgs EA. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43(2):109–142
    • View In Article
    • MEDLINE
32. Denef C. Paracrinicity: The story of 30 years of cellular pituitary crosstalk. J Neuroendocrinol. 2008;20(1):1–70
    • View In Article
    • CrossRef
33. Netter F. The Ciba collection of medical illustrations, Volume I, nervous system. New York: Ciba; 1964;
    • View In Article
34. In:  Schmidt RF editors. Fundamentals of neurophysiology. 3rd Revised Edition. New York: Springer-Verlag; 1985;
    • View In Article
35. Strandring S. Gray's anatomy: the anatomical basis of clinical practice. 39^th ed.. London: Churchill Livingstone; 2004;
    • View In Article
36. Brain SD, Cox HM. Neuropeptides and their receptors: Innovative science providing novel therapeutic targets. Br J Pharmacol. 2006;147:S202–S211
    • View In Article
    • CrossRef
37. von Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol. 1931;72:74–87
    • View In Article
    • MEDLINE
38. Lembeck F. Central transmission of afferent impulses. III. Incidence and significance of the substance P in the dorsal roots of the spinal cord. Naunyn Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie. 1953;219(3):197–213
    • View In Article
39. Isaacs A, Lindenmann J. Virus interference: the interferon. Proc Royal Soc London. 1957;B 147:258
    • View In Article
40. Baron S, Isaacs A. Absence of interferon in lungs from fatal cases of influenza. Br Med J. 1962;January 6:18-20
    • View In Article
41. Isaacs A. Antiviral action of interferon. Br Med J. 1962;August 11: 353–5
    • View In Article
42. Sehgal P, Walther Z, Tamm I. Rapid enhancement of β₂-interferon/B-cell differentiation factor BSF-2 gene expression in human fibroblasts by diacycglycerols and the calcium ionophore A23187. Proc Natl Acad Sci USA. 1987;84:3663–3667
    • View In Article
43. Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: Actions and mechanisms of action. Physiol Rev. 1999;79:1–71
    • View In Article
    • MEDLINE
44. Simon HB. Hyperthermia. N Engl J Med. 1993;329:483–487
    • View In Article
    • MEDLINE
    • CrossRef
45. Delves PJ, Roitt IM, Martin SJ, et al. Roitt's essential immunology. Malden, MA: Blackwell Publishing; 2006;
    • View In Article
46. Kreuger JM, Majde JA. Microbial products and cytokines in sleep and fever regulation. Crit Rev Immunol. 1994;14(304):355–379
    • View In Article
    • MEDLINE
47. Cameron E, May P. Nitrous oxide—Laughing gas. School of Chemistry, University of Bristol, 2008. Available at: www.chm.bris.ac.uk/motm/n2o/n2oj.htm. Last accessed December 17, 2009.
    • View In Article
48. Barañano DE, Snyder SH. Neurol roles of heme oxygenase: Contrast to nitric oxide synthase. Proc Natl Acad Sci. 2001;98(20):10996–11002
    • View In Article
49. Stefano GB, Friccione GL, Slingsby BT, et al. The placebo effect and relaxation response: Neural processes and their coupling to constitutive nitric oxide. Brain Res Rev. 2001;35:1–19
    • View In Article
    • MEDLINE
    • CrossRef
50. Hess W. The central control of the activity of the internal organs. Nobel Prize in Physiology or Medicine 1949, Nobel Lecture, December 12, 1949. Available at: http://nobelprize.org/nobelfoundation/publications/lectures/index.html. Last accessed December 17, 2009.
    • View In Article
51. Assenmacher I, Szafarczyk A, Alonso G, et al. In:  Ganong WF,  Dallman MF,  Roberts JL editor. The hypothalamic-pituitary-adrenal axis revisited. Ann NY Acad Sci. Physiology of neural pathways affecting CRH secretion. Volume 512:New York: The New York Academy of Sciences; 1987;p. 149–161
    • View In Article
52. Negro-Vilar A, Johnston C, Spinedi E, et al. In:  Ganong WF,  Dallman MF,  Roberts JL editor. The hypothalamic-pituitary-adrenal axis revisited. Ann NY Acad Sci. Physiological role of peptides and amines on the regulation of ACTH secretion. Volume 512:New York: The New York Academy of Sciences; 1987;p. 218–236
    • View In Article
53. Thompson RC, Seasholtz AF, Douglass JO, et al. In:  Ganong WF,  Dallman MF,  Roberts JL editor. The hypothalamic-pituitary-adrenal axis revisited. Ann NY Acad Sci. The rat corticotropin-releasing hormone gene. Volume 512:New York: The New York Academy of Sciences; 1987;p. 1–11
    • View In Article
54. Barnes PJ. Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci. 1998;94:557–572
    • View In Article
55. Augustin AJ, D'Amico DJ, Mieler WF, et al. Safety of posterior juxtascleral depot administration of the angiostatic cortisone anecortave acetate for treatment of subfoveal chroidal neovascularization in patients with age-related macular degeneration. Graefe's Arch Clin Exp Ophthalmol. 2005;243:9–12
    • View In Article
    • MEDLINE
    • CrossRef
56. Dahlin DC, Rahimy MH. Pharmacokinetics and metabolism of anecortave acetate in animals and humans. Surv Ophthalmol. 2007;52(Suppl 1):S49–S61
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (494 KB)
    • CrossRef
57. Russell SR, Hudson HL, Jerdan JA. Anecortave acetate for the treatment of exudative age-related macular degeneration—A review of clinical outcomes. Surv Ophthalmol. 2007;52(Suppl 1):S79–S90
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (699 KB)
    • CrossRef
58. Clark AF. Introduction. Surv Ophthalmol. 2007;52(Suppl 1):S1–S2
    • View In Article
    • Full Text
    • Full-Text PDF (50 KB)
    • CrossRef
59. Robin AL, Suan EP, Sjaarda RN, et al. Arch Ophthalmol. 2009;127(2):173–178
    • View In Article
    • CrossRef
60. De Souza EB, Whitehouse PJ, Price DL, et al. In:  Ganong WF, Dallman ,  Roberts JL editor. The hypothalamic-pituitary-adrenal axis revisited. Ann NY Acad Sci. Abnormalities in corticotrophin-releasing hormone (CRH) in Alzheimer's disease and other human disorders. Volume 512:New York: The New York Academy of Sciences; 1987;p. 237–247
    • View In Article
61. Yehuda R, Golier JA, Halligan SL, et al. The ACTH response to desamethasone in PTSD. Am J Psychiatry. 2004;161:1397–1403
    • View In Article
    • MEDLINE
    • CrossRef
62. Bjartell A, Ekman R, Sundler F, et al. In:  Ganong WF,  Dallman MF,  Roberts JL editor. The hypothalamic-pituitary-adrenal axis revisited. Ann NY Acad Sci. Delta sleep-inducing peptide-like immunoreactivity in pituitary ACTH/MSH and adrenal medullary cells. Volume 512:New York: The New York Academy of Sciences; 1987;p. 476–479
    • View In Article
63. McCann SM, Antunes-Rodrigues J, Franci CR, et al. Role of the hypothalamic pituitary adrenal axis in the control of the response to stress and infection. Brazilian Journal of Medical and Biological Research. 2000;33:1121–1131
    • View In Article
64. Hauger RL, Risbrough V, Brauns O, et al. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: New molecular targets. CNS & Neurological Disorders – Drug Targets. 2006;5(4):453–479
    • View In Article
65. Ostrander MM, Ulrich-Lai YM, Choi DC, et al. Hypoactivity of the hypothalamic-pituitary-adrenocortical axis during recovery from chronic variable stress. Endocrinology. 2006;147(4):2008–2017
    • View In Article
    • MEDLINE
    • CrossRef
66. Lucin KM, Sanders VM, Jones TB, et al. Impaired antibody synthesis after spinal cord injury is level-dependent and is due to sympathetic nervous system dysregulation. Exp Neurol. 2007;207(1):75–84
    • View In Article
    • CrossRef
67. Sternberg EM. Neural regulation of innate immunity: A coordinated nonspecific host response to pathogens. Nat Rev Immunol. 2006;64(4):318–328
    • View In Article
68. Irwin MR. Human psychoneuroimmunolgy: 20 years of discovery. Brain, Behavior, and Immunity. 2008;22:129–139
    • View In Article
    • CrossRef
69. Town AE, Rakoff AE. Relationship of endocrines to cataract. Trans Am Ophthalmol Soc. 1950;48:313–330
    • View In Article
    • MEDLINE
70. Duke-Elder S. The clinical value of cortisone and ACTH in ocular disease. Br J Ophthalmol. 1951;35:637–671
    • View In Article
    • MEDLINE
    • CrossRef
71. Anderson B, Margolis G. Scleromalacia: Clinical and pathologic study of a case with consideration of differential diagnosis, relationship of collagen disease, and effect of ACTH and cortisone therapy. Trans Am Ophthalmol Soc. 1951;49:235–265
    • View In Article
    • MEDLINE
72. Brown CA, Corner B. Retrolental fibroplasias: Early development and the effect of ACTH in treatment. Br J Ophthalmol. 1952;36:281–302
    • View In Article
    • MEDLINE
    • CrossRef
73. Appelbaum A. Retrolental fibroplasias: Blindness in infants of low weight at birth. California Med. 1952;77(4):259–265
    • View In Article
74. Thompson M, Eadie S. Kerato-conjunctivitis sicca and rheumatoid arthritis. Ann Rheumatism. 1956;15:21–25
    • View In Article
75. Toogood JH, Dyson C, Thompson CA, et al. Posterior subcapsular cataracts as a complication of adrenocortical steroid therapy. Can Med Assoc J. 1962;86:52–56
    • View In Article
    • MEDLINE
76. Kaiser-Kupfer MI. Clinical research methodology in ophthalmology. Trans Am Ophthalmol Soc. 1980;78:896-46
    • View In Article
77. Zoukhri D. Effect of inflammation of lacrimal gland function. Exp Eye Res. 2006;82(5):885–898
    • View In Article
    • MEDLINE
    • CrossRef
78. Swaab DF. The human hypothalamus: Basic and clinical aspects. Part II: Neuropathology of the human hypothalamus and adjacent structures. Amsterdam: Elsevier; 2003;
    • View In Article
79. Sadun AA, Schaechter JD, Smith LE. A retinohypothalamic pathway: Light mediation of circadian rhythms. Brain Res. 1984;302(2):371–377
    • View In Article
    • MEDLINE
    • CrossRef
80. Schaechter JD, Sadun AA. A second hypothalamic nucleus receiving retinal input in man: The paraventricular nucleus. Brain Res. 1985;340(2):243–250
    • View In Article
    • MEDLINE
    • CrossRef
81. Kenney MJ, Weiss ML, Haywood JR. The paraventricular nucleus: An important component of the central neurocircuitry regulating sympathetic nerve outflow. Acta Physiologica Scand. 2003;177(1):7–15
    • View In Article
82. Sadun AA, Johnson BM, Schaechter J. Neuroanatomy of the human visual system: Part III: Three retinal projections to the hypothalamus. Neuro-ophthalmology. 1986;6(6):371–376
    • View In Article
83. In:  Kastin AJ editors. Handbook of biologically active peptides. Burlington, MA: Academic Press; 2006;
    • View In Article
84. Lumme A, Vanhatalo S, Sadeniemi M, et al. Expression of nitric oxide synthase in hypothalamic nuclei following axonal injury or colchinine treatment. Exp Neurol. 1997;144(2):248–257
    • View In Article
    • MEDLINE
    • CrossRef
85. Hypothalmus. Available at www.neuroanatomy.wisc.edu/coursebook/neuro2(2).pdfLast accessed December 17, 2009
    • View In Article
86. Terakita A. The opsins. Genome Biology. 2005;6(3):213/1–213/9
    • View In Article
87. Wald G, Brown PK. The synthesis of rhodopsin from retinene. Proc Natl Acad Sci. 1950;36:84–92
    • View In Article
88. Wald G. The molecular basis of visual excitation. Nobel Lecture, December 12, 1967. Available at: http://nobelprize.org/nobelfoundation/publications/lectures/index.html. Last accessed December 17, 2009.
    • View In Article
89. Bowmaker JK, Dartnall HJA. Visual pigments of rods and cones in a human retina. J Physiol. 1980;298:501–511
    • View In Article
    • MEDLINE
90. Provencio I, Rodriguez IR, Jiang G, et al. A novel human opsin in the inner retina. J Neurosci. 2000;20(2):600–605
    • View In Article
91. Hannibal J, Hindersson P, Knudsen SM, et al. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci. 2002;22:RC191 1–7
    • View In Article
92. Provencio I, Jiang G, De Grip WJ, et al. Melanopsin: An opsin in melanophores, brain, and eye. Proc Natl Acad Sci. 1998;95:240–245
    • View In Article
93. Vesaluoma M, Teppo A-N, Grönhagen-Riska C, et al. Increased release of tumour necrosis factor-α in human tear fluid after excimer lazer induced corneal wound. Br J Ophthalmol. 1997;81:145–149
    • View In Article
    • MEDLINE
    • CrossRef
94. Tuominen I, Vesaluoma M, Teppo A-N, et al. Soluble Fas and Fas ligand in human tear fluid after photorefractive keratectomy. Br J Ophthalmol. 1999;83:360–363
    • View In Article
95. Yamada M, Ogata M, Kawai M, et al. Substance P and its metabolites in normal human tears. Invest Ophthalmol Vis Sci. 2002;43(8):2622–2625
    • View In Article
    • MEDLINE
96. Creel DJ, Bendel CM, Wiesner GL, et al. Abnormalities of the central visual pathways in Parder-Willi syndrome associated with hypopigmentation. N Engl J Med. 1986;314:1606–1609
    • View In Article
    • MEDLINE
    • CrossRef
97. Daley MI, Cook D. Impaired visual flicker discrimination with hypothalamic pituitary disease. Arch Neurol. 1983;40:643–644
    • View In Article
    • MEDLINE
98. Klaver CCW, Ott A, Hofman A, et al. Is age-related maculopathy associated with Alzheimer's disease?: The Rotterdam Study. Am J Epidemol. 1999;150(9):963–968
    • View In Article
99. Bayer AU, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzeimer's disease. Eur Neurol. 2002;47(3):165–168
    • View In Article
    • MEDLINE
    • CrossRef
100. Bayer AU, Keller ON, Ferrari F, et al. Association of glaucoma with neurogenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease. Am J Ophthalmol. 2002;133(1):135–137
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (82 KB)
     • CrossRef
101. Cooper HM, Parvopassu F, Herbin M, et al. Neuroanatomical pathways linking vision and olfaction in mammals. Psychoneuroendocrinology. 1994;19(5-7):623–639
     • View In Article
     • MEDLINE
     • CrossRef
102. Kauffmann DJH, van Meurs JC, Mertens DAE, et al. Cytokines in vitreous humor: Interleukin-6 is elevated in proliferative viteroretinopathy. Invest Ophthalmol Vis Sci. 1994;35(3):900–906
     • View In Article
     • MEDLINE
103. Ooi KG-J, Galatowicz G, Calder VL, et al. Cytokines and chemokines in uveitis—Is there a correlation with clinical phenotype?. Clin Med Res. 2006;4(4):294–309
     • View In Article
     • MEDLINE
     • CrossRef
104. Tarrant TK, Silver PB, Wahlsten JL, et al. Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon γ, nitric oxide, and apoptosis. J Exp Med. 1999;189(2):219–230
     • View In Article
     • MEDLINE
     • CrossRef
105. Stone RA, McGlinn AM. Calcitonin gene-related peptide immunoreactive nerves in human and rhesus monkey eyes. Invest Ophthalmol Vis Sci. 1988;29(2):305–310
     • View In Article
     • MEDLINE
106. Riise D, Simonsen SE. Intraocular pressure in unilateral optic nerve lesion. Acta Ophthalmologica. 1969;47(3):750–756
     • View In Article
     • MEDLINE
107. Paulsen F, Hallmann U, Paulsen J, et al. Innervation of the cavernous body of the human efferent tear ducts and function in tear outflow mechanism. J Anat. 2000;197:177–187
     • View In Article
108. Dieckhues VB. The influence of eyesight on organ and metabolic function in man and animal. Hippokrates. 1974;45(4):433–449
     • View In Article
     • MEDLINE
109. Vervloed MPJ, Hoevenaars E, Maas A. Behavioral treatment of sleep problems in a child with a visual impairment. J Vis Impair Blindness. 2003;97:28–37
     • View In Article
110. Ionescu D, Driver HS, Heon E, et al. Sleep and daytime sleepiness in retinitis pigmentosa patients. J Sleep Res. 2001;10:329–335
     • View In Article
     • MEDLINE
     • CrossRef
111. Gordo MA, Recio J, Sánchez-Barceló EJ. Decreased sleep quality in patients suffering from retinitis pigmentosa. J Sleep Res. 2001;10:159–164
     • View In Article
     • MEDLINE
     • CrossRef
112. Gebarowska D, Stitt AW, Gardiner TA, et al. Synthetic peptides interacting with the 67-kd laminin receptor can reduce retinal ischemia and inhibit hypoxia-induced retinal neovascularization. Am J Pathol. 2002;160(1):307–313
     • View In Article
     • Abstract
     • Full Text
     • Full-Text PDF (1556 KB)
     • CrossRef
113. Tornqvist K, Ehinger B. Peptide immunoreactive neurons in the human retina. Invest Ophthalmol Vis Sci. 1988;29(5):680–686
     • View In Article
     • MEDLINE
114. Available at: www.rxlist.com. Last accessed December 17, 2009.
     • View In Article
115. Grus FH, Podust VN, Bruns K, et al. SELDI-TOF-MS Proteinchip array profiling of tears from patients with dry eye. Invest Ophthalmol Vis Sci. 2005;46(3):863–876
     • View In Article
     • MEDLINE
     • CrossRef
116. Available at: www.biology-online.org/dictionary/Paracrine. Last accessed December 17, 2009.
     • View In Article
117. Dinan TG, Scott LV. Anatomy of melancholia: Focus on hypothalamic-pituitary-adrenal axis overactivity and the role of vasopressin. J Anat. 2005;207:259–264
     • View In Article
     • MEDLINE
     • CrossRef
118. Potter E, Behan DP, Linton EA, et al. The central distribution of a corticotrophin-releasing factor (CRF)-binding protein predicts multiple sites and modes of interaction with CRF. Proc Natl Acad Sci. 1992;89:4192–4196
     • View In Article
119. Henriksen G, Willoch F. Imaging of opioid receptors in the central nervous system. Brain. 2008;131:1171–1196
     • View In Article
     • CrossRef
120. Clark KA, Shin AC, Sirivelu MP, et al. Systemic administration of leptin decreases plasma corticosterone levels. Brain Res. 2008;1195:89–95
     • View In Article
     • CrossRef
121. Available at: http://braininfo.rprc.washington.edu/. Last accessed December 17, 2009.
     • View In Article
122. Curristin SM, Cao A, Stewart WB, et al. Disrupted synaptic development in the hypoxic newborn brain. Proc Natl Acad Sci. 2002;99(24):15729–15734
     • View In Article
123. Nadler JV, Tu B, Timofeeva O, et al. Neuropeptide Y in the recurrent mossy fiber pathway. Peptides. 2007;28(2):357–364
     • View In Article
     • MEDLINE
     • CrossRef
124. Coveñas R, Martin F, Belda M, et al. Mapping of neurokinin-like immunoreactivity in the human brainstem. BMC Neuroscience. 2003;4:3–15
     • View In Article
     • MEDLINE
     • CrossRef
125. Crocker A, España RA, Papadopoulou M, et al. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology. 2005;65(8):1184–1188
     • View In Article
     • CrossRef
126. Qin L, He J, Hanes RN, et al. J Neuroinflammation. 2008;5:10–26
     • View In Article
     • CrossRef
127. Taheri S, Hafizi S. The orexins/hypocretins: Hypothalamic peptides linked to sleep and appetite. Psychol Med. 2002;32:955–958
     • View In Article
     • MEDLINE
     • CrossRef
128. Kar S, Slowikowski SPM, Westaway D, et al. Interactions between β-amyloid and central cholinergic neurons: Implications for Alzheimer's disease. J Psychiatry Neurosci. 2004;29(6):427–441
     • View In Article
     • MEDLINE
129. Simantov R, Kuhar MJ, Uhl GR, et al. Opioid peptide enkephalin: Immunohistochemical mapping in rat nervous system. Proc Natl Acad Sci. 1977;74(5):2167–2171
     • View In Article
130. Denton DA, McKinley MJ, Weisinger RS. Hypothalamic integration of body fluid regulation. Proc Natl Acad Sci. 1996;93:7397–7404
     • View In Article
131. Pelletier G, Desy L. Localization of ACTH in the human hypothalamus. Cell Tiss Res. 1979;196(3):525–530
     • View In Article
132. Available at: www.neuroanatomy.wisc.edu/coursebook/neuro2(2).pdf. Last accessed December 17, 2009.
     • View In Article
133. Lightman SL. The neuroendocrine paraventricular hypothalamus: Receptors, signal transduction, mRNA and neurosecretion. J Exp Biol. 1988;139:31–49
     • View In Article
     • MEDLINE
134. De Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: Hypothalamus-specific peptides with neuroexicitatory activity. Proc Natl Acad Sci. 1998;95:322–327
     • View In Article
135. Rechtshaffen A, Siegel J. Sleep and dreaming. In:  Kandel ER,  Schwartz JH,  Jessel TM editor. Principles of neuroscience. Fourth ed. New York: McGraw-Hill; 2000;p. 936–947
     • View In Article
136. Elmquist JK, Ahima RS, Elias CF, et al. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci. 1998;95:741–746
     • View In Article
137. Saarela S, Reiter RJ. Function of melatonin in thermoregulatory processes. Life Sci. 1994;54(5):295–311
     • View In Article
     • MEDLINE
     • CrossRef
138. Hofman MA, Fliers E, Goudsmit E, et al. Morphometric analysis of the suprachiasmatic and paraventricular nuclei in the human brain: Sex differences and age-dependent changes. J Anat. 1988;160:127–143
     • View In Article
     • MEDLINE
139. Kramer KM, Yoshida S, Papademetriou E, et al. The organizational effects of oxytocin on the central expression of estrogen receptor α and oxytocin in adulthood. BMC Neurosci. 2007;8:71–78
     • View In Article
     • CrossRef
140. Sakai K, Agassandian K, Morimoto S, et al. Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest. 2007;117(4):1088–1095
     • View In Article
     • MEDLINE
     • CrossRef
141. Hammock EAD, Young LJ. Oxytocin, vasopressin and pair bondings: Implications for autism. Philos Trans Royal Soc. 2006;361:2187–2198
     • View In Article
142. Trottier S, Chotard C, Traiffort E, et al. Co-localization of histamine with GABA but not with galanin in the human tuberomamillary nucleus. Brain Res. 2002;939(91-2):52–64
     • View In Article
     • MEDLINE
     • CrossRef
143. Levin B. Orexins: neuropeptides for all seasons and functions. Am J Physiol Regul Integr Comp Physiol. 2006;291:R885–R888
     • View In Article
     • MEDLINE
     • CrossRef
144. Bear MF, Conners BW, Paradiso MA. Neuroscience: Exploring the brain. ed3.. Philadelphia: Lippincott, Williams and Wilkins; 2006;
     • View In Article
145. Brothers L. Biological perspectives on empathy. Am J Psychiatry. 1989;146(1):10–19
     • View In Article
     • MEDLINE
146. Myagkov AV, Danilov GE, Fatykhov IR. The correcting influence of the locus coeruleus on ophthalmic hypertension of hypothalamic origin. Neurosci Behav Physiol. 2004;34(1):97–100
     • View In Article
     • MEDLINE
     • CrossRef
147. American College of Obstericians and Gynecologists (ACOG) Committee on Technical Bulletins. American College of Obstetricians and Gynecologists Technical Bulletin 1989;134:1-5.
     • View In Article
148. Yamada K, Yamamoto H, Nakagawa Y, et al. Etiology of idiopathic scoliosis. Clin Orthop. 1984;184:50–57
     • View In Article
149. Greidanus RBvW, Jolles J, De Wied D. Hypothalamic neuropeptides and memory. Acta Neurochirugica. 1985;75(1-4):99–105
     • View In Article
150. Koroshetz WJ, McKee AC. Case records of the Massachusetts General Hospital: Case 39-1988: A 76-old man with confusion, agitation, and a gait disorder. N Engl J Med. 1988;319(13):849–860
     • View In Article
     • MEDLINE
     • CrossRef
151. D'Amore PA, Klagsbrun M. Endothelial cell mitogens derived from retina and hypothalamus: Biochemical and biological similarities. J Cell Biol. 1984;99:1545–1549
     • View In Article
152. Seckl J, Dunger D. Postoperative diabetes insipidus. Br Med J. 1989;298(6665):2–3
     • View In Article
153. Byrd JA. Controversy in scoliosis treatment – symposium: Current theories on the etiology of idiopathic scolisis. Clin Orthopaed Related Res. 1988;229:114–119
     • View In Article
154. Werntz DA. Cerebral hemispheric activity and autonomic nervous function. Dissertation Abstracts International. 1981;DAI V42(06), SECB, PP2255
     • View In Article
155. Gribenski A. Sensory interactions: Hearing and vision. J de Psychologie Normale et Pathologique. 1978;75(2):147–171
     • View In Article
156. Zhu JN, Yung WH, Chow BKC, et al. The cerebellar-hypothalamic circuits: Potential pathways underlying cerebellar involvement in somatic-visceral integration. Brain Res Rev. 2006;52(1):93–106
     • View In Article
     • MEDLINE
     • CrossRef
157. Smeets PAM, deGraaf C, Stafleu A, et al. Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories. Am J Clin Nutr. 2005;82:1011–1016
     • View In Article
     • MEDLINE
158. Witta J, Palkovits M, Rosenberger J, et al. Distribution of nociceptin/orphannin FQ in adult human brain. Brain Res. 2004;997(1):24–29
     • View In Article
     • MEDLINE
     • CrossRef
159. Hollwich F, Dieckhues B, Schrameyer B. Die Wirkung des natürlichen und künstlichen Lichtes über das Auge den Hormon- und Stoffwechsel-haushalt des Menschen. Klinische Monatblatter für Augenheilkunde. 1877;171(1):98–104
     • View In Article
160. Aizman O, Uhlén P, Lal M, et al. Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc Natl Acad Sci. 2001;98(23):13420–13424
     • View In Article
161. Slominski A, Wortsman J, Kohn L, et al. Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin. J Invest Dermatol. 2002;119(6):1449–1455
     • View In Article
     • MEDLINE
     • CrossRef
162. Poole CJM, Lightman SL. Inhibition of vasopressin secretion during migraine. J Neurol Neurosurg Psychiatry. 1988;51:1441–1444
     • View In Article
     • MEDLINE
     • CrossRef
163. Spinazzi R, Andreis PG, Rossi GP, et al. Orexins in the regulation of the hypothalamic-pituitary-adrenal axis. Pharmacol Rev. 2006;58(1):46–57
     • View In Article
     • MEDLINE
     • CrossRef
164. Bannister R. Autonomic disorders. Curr Opin Neurol. 1988;1(4):511–513
     • View In Article
165. Eckland D, Lightman S. The hypothalamus. Curr Opin Neurol. 1988;1(4):527–532
     • View In Article
166. Ling H, Vamvakas S, Busch G, et al. Suppressing role of transforming growth factor-beta 1 on cathepsin activity in cultured kidney tubule cells. Am J Physiol Renal Physiol. 1995;269:F911–F917
     • View In Article
167. Molavi DW. Hypothalomus and autonomic nervous system. The Washington University School of Medicine. Available at: http://thalamus.wustl.edu/course/hypoANS.html. Last accessed December 17, 2009.
     • View In Article
168. Öngür D, Price JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex. 2000;10(3):206–219
     • View In Article
169. Pizzi J, Holden JE. Lateral hypothalamus modifies pain through a substance P connection with the periaqueductal gray. Presented at the Midwest Nursing Research Society, Cincinnati, April 1-4, 2005.
     • View In Article
170. Paulson DF, Wiebe HR, Hammond CB. Hypothalamic and pituitary function in hypogonadotropic hypogonadism. Urology. 1975;6(3):333–336
     • View In Article
     • Abstract
     • Full-Text PDF (398 KB)
     • CrossRef
171. Kaiser UB, Sabbagh E, Katzenellenbogen RA, et al. A mechanism for the differential regulation of gonadotropin subunit gene expression by gonadotropin-releasing hormone. Proc Natl Acad Sci. 1995;92:12280–12284
     • View In Article
172. Delmas A, Leone M, Rousseau S, et al. Clinical review: Vasopressin and terlipressin in septic shock. Crit Care. 2005;9(2):212–222
     • View In Article
     • CrossRef
173. Bissonette B, Sessler DI, LaFlamme P. Intraoperative temperature monitoring sites in infants and children and the effect of inspired gas warming on esophageal temperature. Anesth Analg. 1989;69:(30):192–6
     • View In Article
174. Komisaruk BR, Whipple B, Crawford A, et al. Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by the vagus nerves. Brain Res. 2004;1024(1-2):77–88
     • View In Article
     • MEDLINE
     • CrossRef
175. Berger J. Why do circadian biorhythms age?. J Appl Biomed. 2003;1:77–84
     • View In Article
176. Wartofsky L, Martin D, Earll JM. Alterations in thyroid iodine release and the peripheral metabolism of thyroxine during acute falciparum malaria in man. J Clin Invest. 1972;51:2215–2232
     • View In Article
     • MEDLINE
     • CrossRef
177. The brain. Available at: www.emc.maricopa.edu/./BIOBK/brain_3.gif. Last accessed December 17, 2009.
     • View In Article
178. Hormone control: the hypothalomus. Available at: http://www.psycheducation.org/emotion/hypothalamus.htm. Last accessed December 17, 2009.
     • View In Article

• ∗ Paracrine. “Of or relating to a hormone or to a secretion released by (endocrine) cells into the adjacent cells or surrounding tissue rather than into the bloodstream.”¹¹⁶
• † “In 1980, Sporn and Todaro introduced the concept of autocrine control, an autocrine factor being a substance released by the cell and affecting the cell of origin itself. They showed that cells that had been transformed by an oncogene in culture no longer required serum supplements because they themselves produced or overproduced the essential growth factors.”³²
• ‡ “Juxtacrine communication provides a mechanism of strict spatial control of activation of one cell type by another, in contrast with paracrine control in which the factor acts in the fluid phase within an action radius determined by its diffusion gradient. The active domain of a juxtacrine polypeptide can be cleaved from the cell surface by regulated proteolysis which will, if needed, abolish spatial specificity and which, in turn, will optimize diversity of communication but, by spreading, the signal could also be the start of disregulation.”³²