Lateral hypothalamus
| Lateral hypothalamus | |
|---|---|
 Lateral hypothalamus is 'LT', at right, in yellow. | |
| Identifiers | |
| MeSH | D007026 |
| NeuroNames | 426 |
| NeuroLex ID | birnlex_4037 |
| TA98 | A14.1.08.929 |
| FMA | 62030 |
| Anatomical terms of neuroanatomy | |
The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA),
The
Inputs
![[icon]](/File:Wiki_letter_w_cropped.svg){kind=small} |
Outputs
| This section needs expansion with: The list of outputs included here is not a comprehensive list. You can help by adding to it. (July 2015) |
The orexinergic projections from the lateral hypothalamus innervate the entirety of the remainder of the
ascending reticular activating system.[13]
Other output regions include: the
orexin receptor 1 (OX1) receptors physically and functionally join to form the CB1–OX1 receptor heterodimer.[4][9][10] There is substantial anatomical and functional overlap and systemic cross-talk between the endocannabinoid system and orexin system within the central nervous system.[4]
Function
Through the diverse outputs of the orexin system, the orexin neurons in the lateral hypothalamus mediate an array of functions. Two of the most commonly noted functions of orexin peptides in the lateral hypothalamus are the promotion of feeding behavior and arousal (i.e., wakefulness).HPT axis) through other hypothalamic outputs, and regulating visceral functions (e.g., respiration, blood pressure, and urination) via a group of structures in the brain stem, among other functions.[3][5][14]
The
Clinical significance
Narcolepsy is associated with a marked reduction in the number of orexinergic projection neurons from the lateral hypothalamus and very low orexin peptides in cerebrospinal fluid.[17] This has been identified as the mechanism responsible for narcoleptic symptoms.[17]
Evidence suggest that OX1 neurons that synapse onto the
References
- ^ hier-409 at NeuroNames
- ^ ISBN 9780071481274.
Orexinergic projections in the CNS. Orexin neurons with cell bodies in the lateral hypothalamic area (LHA) and posterior hypothalamus (PH) project throughout the brain (excluding the cerebellum) with dense projections to the noradrenergic locus ceruleus (LC), histaminergic tuberomamillary nucleus (TMN), serotonergic raphe nuclei, cholinergic laterodorsal and pedunculopontine nuclei (LDT and PPT), and the dopaminergic ventral tegmental area (VTA). ... Orexin neurons project to and activate monoaminergic and cholinergic neurons involved in the maintenance of a long "awake" period. Lack of orexin produces narcolepsy (Chapter 12). Orexin neurons are regulated by peripheral mediators that carry information about energy balance, including glucose, leptin, and ghrelin. They also receive inputs from limbic structures. Orexin neurons are, therefore, in a position not only to regulate sleep-wake cycles, but also to respond to significant environmental and metabolic signals. Accordingly, orexin plays a role in the regulation of energy homeostasis, reward, and perhaps more generally in emotion.
- ^ PMID 24102345.
Orexin neurons are excitatory, express the vesicular glutamate transporter VGLUT2 (Rosin et al., 2003), and also produce dynorphin ... The analgesic properties of orexin peptides have been well-established ... The involvement of orexin in pain is also supported by clinical observations, which have shown there is an association between changes in the Ox receptors and headaches (see below) (Rainero et al., 2004) and a recent multicentre case-control study revealed that chronic pain is more common in patients with narcolepsy with cataplexy than in the controls ... The orexin system has also been found to effect visceral functions, in addition to its roles in energy homeostasis and endocrine function, mentioned previously. ... orexin excites MCH neurons (van den Pol et al., 2004) and inhibits ventral medial hypothalamic (VMH) glucoreceptors to enhance feeding behaviours (Shiraishi et al., 2000). Moreover, a recent study demonstrated that the area postrema and nucleus of the tractus solitarius (NTS) are necessary for orexin-mediated hyperphagia ... However, i.v. injections of orexin-A have no effect on sympathetic activity (Matsumura et al., 2001), suggesting that the cardiac effects of orexin are mediated centrally. Consistently, microinjections of orexin-A into the rostral ventrolateral medulla (Huang et al., 2010) or rostral ventromedial medulla (Ciriello and de Oliveira, 2003) elicit cardiovascular excitatory responses through the activation of both OX1 and OX2 receptors (Huang et al., 2010).
However, orexin-A signalling in the nucleus ambiguus (NA) (de Oliveira and Ciriello, 2003) and subfornical organ (Smith et al., 2007) has been shown to produce bradycardia responses ... Moreover, activation of OX1 receptors in the dorsal motor nucleus of the vagus results in facilitation of vagal pancreatic efferent nerve activities (Wu et al., 2004), stimulating pancreatic exocrine secretion (Miyasaka et al., 2002). Administration of orexin-A, i.a., increases duodenal secretion in normal fed but not in fasted animals, by an effect that is independent of cholinergic pathways (Flemstrom et al., 2003; Bengtsson et al., 2007). In addition, orexin-A can modify gastrointestinal motility, including gastric emptying, gastric interdigestive motility (Naslund et al., 2002; Ehrstrom et al., 2005a,b2005b; Bulbul et al., 2010), and enteric peristalsis (Satoh et al., 2006), as well as colonic motility ...
The presence of orexin-A and its receptors has been shown in human kidneys and urine ... These findings are supported by results from physiological studies, which demonstrated that orexin-A is involved in the pelvic-urethral reflex (Peng et al., 2008) and the micturition reflex - ^ PMID 24391536.
Direct CB1-HcrtR1 interaction was first proposed in 2003 (Hilairet et al., 2003). Indeed, a 100-fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed ... In this study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1 heteromer compared with the HcrtR1-HcrtR1 homomer was reported (Ward et al., 2011b). These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact. ... The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction.
• Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2
• Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
• Figure 3: Schematic of brain pathways involved in food intake - ^ S2CID 7239191.
With regard to gastrointestinal functions, orexin-A acts centrally to regulate gastrointestinal functions such as gastric and pancreatic secretion, and gastrointestinal motility. ... Little is, however, known about a role of central orexin in visceral sensation. ... These results suggest for the first time that orexin-A specifically acts centrally in the brain to enhance antinociceptive response to colonic distension. We would furthermore suggest that endogenous orexin-A indeed mediates the antinociceptive effect of morphine on visceral sensation through the orexin 1 receptors. All these evidence might indicate that brain orexin plays a role in the pathophysiology of functional gastrointestinal disorders such as irritable bowel syndrome because visceral hypersensitivity of the gut is considered to play a vital role in the diseases.
- ^ PMID 25250003.
Orexins promote both arousal and feeding (Sweet et al., 1999). ... Orexin-A also influences body temperature. In fact, an ICV administration of orexin-A induces an increase in firing rate of the sympathetic nerves to BAT, accompanied with a rise in BAT and colonic temperatures (Monda et al., 2001).
- ^ PMID 25610411.
CB1 is present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons in the gastrointestinal tract (Massa et al., 2005). Activation of CB1 is shown to modulate nutrient processing, such as gastric secretion, gastric emptying, and intestinal motility. ... CB1 is shown to co-localize with the food intake inhibiting neuropeptide, corticotrophin-releasing hormone, in the paraventricular nucleus of the hypothalamus, and with the two orexigenic peptides, melanin-concentrating hormone in the lateral hypothalamus and with pre-pro-orexin in the ventromedial hypothalamus (Inui, 1999; Horvath, 2003). CB1 knockout (KO) mice showed higher levels of CRH mRNA, suggesting that hypothalamic EC receptors are involved in energy balance and may be able to mediate food intake (Cota et al., 2003). ... The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved (Viveros et al., 2008).
- ^ ISBN 9781592599509. Retrieved 19 July 2015.
- ^ PMID 24834023.
OX1–CB1 dimerization was suggested to strongly potentiate orexin receptor signaling, but a likely explanation for the signal potentiation is, instead, offered by the ability of OX1 receptor signaling to produce 2-arachidonoyl glycerol, a CB1 receptor ligand, and a subsequent co-signaling of the receptors (Haj-Dahmane and Shen, 2005; Turunen et al., 2012; Jäntti et al., 2013). However, this does not preclude dimerization.
- ^ PMID 24530395.
Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors. ... In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors.
- PMID 26169110.
- ^ Wright A. "Limbic System: Amygdala". In Byrne JH (ed.). Homeostasis and Higher Brain Function. Neuroscience Online. University of Texas Health Science Center at Houston.
- ISBN 9780071481274.
The RAS is a complex structure consisting of several different circuits including the four monoaminergic pathways ... The norepinephrine pathway originates from the locus ceruleus (LC) and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the brainstem as well; the dopaminergic neurons originate in ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brain stem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells. ... Orexin neurons are located in the lateral hypothalamus. They are organized in a widely projecting manner, much like the monoamines (Chapter 6), and innervate all of the components of the ARAS. They excite the REM-off monoaminergic neurons during wakefulness and the PT cholinergic neurons during REM sleep. They are inhibited by the VLPO neurons during NREM sleep.
- PMID 24574958.
In this review we focus on the role of orexin in cardio-respiratory functions and its potential link to hypertension. ... the central chemoreflex may be a causal link to the increased SNA and ABP in SHRs. Modulation of the orexin system could be a potential target in treating some forms of hypertension.
- PMID 25685481.
- PMID 26096126.
Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. We tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R following intracisternal (i.c.) WIN55,212–2 (15μg/rat) in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response
- ^ ISBN 9780071481274.
Most cases of narcolepsy in humans are not linked to mutations in the genes encoding orexin peptides or receptors, but are associated with significantly reduced, often undetectable, levels of orexin in cerebrospinal fluid and brain tissues. Together, the linkage of narcolepsy with HLA alleles, its peak and trough incidence among those born in March and September, respectively (suggesting an environmental influence during the fetal or perinatal period), and the loss of orexin neurons raise the interesting possibility that narcolepsy may be caused by an autoimmune mediated destruction of these neurons in analogy with the autoimmune destruction of insulin-secreting β-islet cells in type I diabetes. A search for small-molecule agonists at orexin receptors is underway and could lead to a treatment for narcolepsy.
