The Normal Human Adult Hypothalamus Proteomic Landscape: Rise of Neuroproteomics in Biological Psychiatry and Systems Biology
Publication: OMICS: A Journal of Integrative Biology
Volume 25, Issue Number 11
Abstract
The human hypothalamus is central to the regulation of neuroendocrine and neurovegetative systems, as well as modulation of chronobiology and behavioral aspects in human health and disease. Surprisingly, a deep proteomic analysis of the normal human hypothalamic proteome has been missing for such an important organ so far. In this study, we delineated the human hypothalamus proteome using a high-resolution mass spectrometry approach which resulted in the identification of 5349 proteins, while a multiple post-translational modification (PTM) search identified 191 additional proteins, which were missed in the first search. A proteogenomic analysis resulted in the discovery of multiple novel protein-coding regions as we identified proteins from noncoding regions (pseudogenes) and proteins translated from short open reading frames that can be missed using the traditional pipeline of prediction of protein-coding genes as a part of genome annotation. We also identified several PTMs of hypothalamic proteins that may be required for normal hypothalamic functions. Moreover, we observed an enrichment of proteins pertaining to autophagy and adult neurogenesis in the proteome data. We believe that the hypothalamic proteome reported herein would help to decipher the molecular basis for the diverse range of physiological functions attributed to it, as well as its role in neurological and psychiatric diseases. Extensive proteomic profiling of the hypothalamic nuclei would further elaborate on the role and functional characterization of several hypothalamus-specific proteins and pathways to inform future research and clinical discoveries in biological psychiatry, neurology, and system biology.
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References
Ahima RS, and Antwi DA. (2008). Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am 37, 811–823.
Almagro Armenteros JJ, Tsirigos KD, Sonderby CK, et al. (2019). SignalP 5.0 improves signal peptide predictions using deep neural networks. Nat Biotechnol 37, 420–423.
Andersson U, Filipsson K, Abbott CR, et al. (2004). AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem 279, 12005–12008.
Antil N, Kumar M, Behera SK, et al. (2021). Unraveling Toxoplasma gondii GT1 strain virulence and new protein-coding genes with proteogenomic analyses. OMICS 25, 591–604.
Baeza J, Smallegan MJ, and Denu JM. (2016). Mechanisms and dynamics of protein acetylation in mitochondria. Trends Biochem Sci 41, 231–244.
Bains JS, Wamsteeker Cusulin JI, and Inoue W. (2015). Stress-related synaptic plasticity in the hypothalamus. Nat Rev Neurosci 16, 377–388.
Bakos J, Zatkova M, Bacova Z, and Ostatnikova D. (2016). The role of hypothalamic neuropeptides in neurogenesis and neuritogenesis. Neural Plast 2016, 3276383.
Belgardt BF, Husch A, Rother E, et al. (2008). PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab 7, 291–301.
Bernstein HG, Dobrowolny H, Bogerts B, Keilhoff G, and Steiner J. (2019). The hypothalamus and neuropsychiatric disorders: psychiatry meets microscopy. Cell Tissue Res 375, 243–258.
Bernstein HG, Klix M, Dobrowolny H, et al. (2012). A postmortem assessment of mammillary body volume, neuronal number and densities, and fornix volume in subjects with mood disorders. Eur Arch Psychiatry Clin Neurosci 262, 637–646.
Bocci T, Caleo M, Tognazzi S, et al. (2014). Evidence for metaplasticity in the human visual cortex. J Neural Transm (Vienna) 121, 221–231.
Bolborea M, and Dale N. (2013). Hypothalamic tanycytes: potential roles in the control of feeding and energy balance. Trends Neurosci 36, 91–100.
Boone M, and Deen PM. (2008). Physiology and pathophysiology of the vasopressin-regulated renal water reabsorption. Pflugers Arch 456, 1005–1024.
Bora A, Annangudi SP, Millet LJ, et al. (2008). Neuropeptidomics of the supraoptic rat nucleus. J Proteome Res 7, 4992–5003.
Cai D, Zhong M, Wang R, et al. (2006). Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc Natl Acad Sci U S A 103, 1936–1940.
Calvo SE, Clauser KR, and Mootha VK. (2016). MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res 44, D1251–D1257.
Chattrjee O, Patil K, Sahu A, et al. (2016). An overview of the oxytocin-oxytocin receptor signaling network. J Cell Commun Signal 10, 355–360.
Chen G, and Cheng MF. (2007). Inhibition of lesion-induced neurogenesis impaired behavioral recovery in adult ring doves. Behav Brain Res 177, 358–363.
Cheng MF. (2013). Hypothalamic neurogenesis in the adult brain. Front Neuroendocrinol 34, 167–178.
Chiang CK, Mehta N, Patel A, et al. (2014). The proteomic landscape of the suprachiasmatic nucleus clock reveals large-scale coordination of key biological processes. PLoS Genet 10, e1004695.
Chin C. (2007). Identification of novel metabolic proteins released by insulin signaling of the rat hypothalmus using liquid chromatography-mass spectrometry (LC-MS). J Korean Neurosurg Soc 42, 470–474.
Choudhary C, Kumar C, Gnad F, et al. (2009). Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840.
Claret M, Smith MA, Batterham RL, et al. (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 117, 2325–2336.
Colgrave ML, Xi L, Lehnert SA, et al. (2011). Neuropeptide profiling of the bovine hypothalamus: thermal stabilization is an effective tool in inhibiting post-mortem degradation. Proteomics 11, 1264–1276.
Conrad K, Roggenbuck D, Reinhold D, and Dorner T. (2010). Profiling of rheumatoid arthritis associated autoantibodies. Autoimmun Rev 9, 431–435.
Contreras C, Nogueiras R, Dieguez C, Medina-Gomez G, and Lopez M. (2016). Hypothalamus and thermogenesis: heating the BAT, browning the WAT. Mol Cell Endocrinol 438, 107–115.
Cykowski MD, Takei H, Schulz PE, Appel SH, and Powell SZ. (2014). TDP-43 pathology in the basal forebrain and hypothalamus of patients with amyotrophic lateral sclerosis. Acta Neuropathol Commun 2, 171.
Dagamajalu S, Rex DAB, Philem PD, Rainey JK, and Keshava Prasad TS. (2021). A network map of apelin-mediated signaling. J Cell Commun Signal (online ahead of print).
Demirev AV, Song HL, Cho MH, et al. (2019). V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function. Neurobiol Dis 129, 182–194.
Deolankar SC, Patil AH, Rex DAB, Subba P, Mahadevan A, and Prasad TSK. (2021). Mapping post-translational modifications in brain regions in alzheimer's disease using proteomics data mining. OMICS 25, 525–536.
Dhaliwal J, Trinkle-Mulcahy L, and Lagace DC. (2017). Autophagy and adult neurogenesis: discoveries made half a century ago yet in their infancy of being connected. Brain Plast 3, 99–110.
Dietrich MO, and Horvath TL. (2013). Hypothalamic control of energy balance: insights into the role of synaptic plasticity. Trends Neurosci 36, 65–73.
Elias JE, Haas W, Faherty BK, and Gygi SP. (2005). Comparative evaluation of mass spectrometry platforms used in large-scale proteomics investigations. Nat Methods 2, 667–675.
Evans J, Sumners C, Moore J, et al. (2002). Characterization of mitotic neurons derived from adult rat hypothalamus and brain stem. J Neurophysiol 87, 1076–1085.
Faigle W, Cruciani C, Wolski W, et al. (2019). Brain citrullination patterns and T cell reactivity of cerebrospinal fluid-derived CD4(+) T cells in multiple sclerosis. Front Immunol 10, 540.
Frith MC, Forrest AR, Nourbakhsh E, et al. (2006). The abundance of short proteins in the mammalian proteome. PLoS Genet 2, e52.
Fronczek R, van Geest S, Frolich M, et al. (2012). Hypocretin (orexin) loss in Alzheimer's disease. Neurobiol Aging 33, 1642–1650.
Fukuda M, Gotoh Y, Tachibana T, et al. (1995). Induction of neurite outgrowth by MAP kinase in PC12 cells. Oncogene 11, 239–244.
Gaspar JM, Mendes NF, Correa-da-Silva F, et al. (2018). Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity. Brain Behav Immun 73, 550–561.
Gaspar JM, and Velloso LA. (2018). Hypoxia inducible factor as a central regulator of metabolism—implications for the development of obesity. Front Neurosci 12, 813.
Goold RG, and Gordon-Weeks PR. (2005). The MAP kinase pathway is upstream of the activation of GSK3beta that enables it to phosphorylate MAP1B and contributes to the stimulation of axon growth. Mol Cell Neurosci 28, 524–534.
Gorges M, Vercruysse P, Muller HP, et al. (2017). Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 88, 1033–1041.
Hatcher NG, Atkins N Jr., Annangudi SP, et al. (2008). Mass spectrometry-based discovery of circadian peptides. Proc Natl Acad Sci U S A 105, 12527–12532.
Hattori H, and Kanfer JN. (1985). Synaptosomal phospholipase D potential role in providing choline for acetylcholine synthesis. J Neurochem 45, 1578–1584.
Honda M, Eriksson KS, Zhang S, et al. (2009). IGFBP3 colocalizes with and regulates hypocretin (orexin). PLoS One 4, e4254.
Humeau Y, Vitale N, Chasserot-Golaz S, et al. (2001). A role for phospholipase D1 in neurotransmitter release. Proc Natl Acad Sci U S A 98, 15300–15305.
Hus-Citharel A, Bodineau L, Frugiere A, Joubert F, Bouby N, and Llorens-Cortes C. (2014). Apelin counteracts vasopressin-induced water reabsorption via cross talk between apelin and vasopressin receptor signaling pathways in the rat collecting duct. Endocrinology 155, 4483–4493.
Iannitelli A, Quartini A, Tirassa P, and Bersani G. (2017). Schizophrenia and neurogenesis: a stem cell approach. Neurosci Biobehav Rev 80, 414–442.
Iqbal J, Elmquist JK, Ross LR, Ackermann MR, and Jacobson CD. (1995). Postnatal neurogenesis of the hypothalamic paraventricular and supraoptic nuclei in the Brazilian opossum brain. Brain Res Dev Brain Res 85, 151–160.
Iqbal J, Li W, Ullah K, et al. (2013). Study of rat hypothalamic proteome by HPLC/ESI ion trap and HPLC/ESI-Q-TOF MS. Proteomics 13, 2455–2468.
Itakura E, and Mizushima N. (2010). Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6, 764–776.
Jiang Z, Cui Y, Wang L, Zhao Y, Yan S, and Chang X. (2013). Investigating citrullinated proteins in tumour cell lines. World J Surg Oncol 11, 260.
Jin Z, Fu Z, Yang J, Troncosco J, Everett AD, and Van Eyk JE. (2013). Identification and characterization of citrulline-modified brain proteins by combining HCD and CID fragmentation. Proteomics 13, 2682–2691.
Jones CB, Lulic T, Bailey AZ, et al. (2016). Metaplasticity in human primary somatosensory cortex: effects on physiology and tactile perception. J Neurophysiol 115, 2681–2691.
Kanaho Y, Funakoshi Y, and Hasegawa H. (2009). Phospholipase D signalling and its involvement in neurite outgrowth. Biochim Biophys Acta 1791, 898–904.
Kanfer JN, Hattori H, and Orihel D. (1986). Reduced phospholipase D activity in brain tissue samples from Alzheimer's disease patients. Ann Neurol 20, 265–267.
Kanfer JN, Singh IN, Pettegrew JW, McCartney DG, and Sorrentino G. (1996). Phospholipid metabolism in Alzheimer's disease and in a human cholinergic cell. J Lipid Mediat Cell Signal 14, 361–363.
Kaushik S, Rodriguez-Navarro JA, Arias E, et al. (2011). Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 14, 173–183.
Kim MS, Pinto SM, Getnet D, et al. (2014). A draft map of the human proteome. Nature 509, 575–581.
Kim SC, Sprung R, Chen Y, et al. (2006). Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23, 607–618.
Kirsch P, Esslinger C, Chen Q, et al. (2005). Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 25, 11489–11493.
Klein J, Chalifa V, Liscovitch M, and Loffelholz K. (1995). Role of phospholipase D activation in nervous system physiology and pathophysiology. J Neurochem 65, 1445–1455.
Knepper MA, Kwon TH, and Nielsen S. (2015). Molecular physiology of water balance. N Engl J Med 372, 1349–1358.
Kobayashi M, and Kanfer JN. (1987). Phosphatidylethanol formation via transphosphatidylation by rat brain synaptosomal phospholipase D. J Neurochem 48, 1597–1603.
Kobayashi M, McCartney DG, and Kanfer JN. (1988). Developmental changes and regional distribution of phospholipase D and base exchange enzyme activities in rat brain. Neurochem Res 13, 771–776.
Koizumi K. (1996). The role of the hypothalamus in neuroendocrinology. In: Comprehensive Human Physiology. Greger, Rainer, Windhors, and Uwe, eds. Springer: Berlin, Heidelberg, 379–401.
Kokoeva MV, Yin H, and Flier JS. (2005). Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679–683.
Komatsu M, Waguri S, Ueno T, et al. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169, 425–434.
Koopmans F, van Nierop P, Andres-Alonso M, et al. (2019). SynGO: an evidence-based, expert-curated knowledge base for the synapse. Neuron 103, 217.e4–234.e4.
LaCrosse AL, and Olive MF. (2013). Neuropeptide systems and schizophrenia. CNS Neurol Disord Drug Targets 12, 619–632.
Lee CY, Wang D, Wilhelm M, et al. (2018). Mining the human tissue proteome for protein citrullination. Mol Cell Proteomics 17, 1378–1391.
Lee DA, Bedont JL, Pak T, et al. (2012). Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci 15, 700–702.
Lemaire JJ, Nezzar H, Sakka L, et al. (2013). Maps of the adult human hypothalamus. Surg Neurol Int 4, S156–S163.
Lester DS, and Bramham CR. (1993). Persistent, membrane-associated protein kinase C: from model membranes to synaptic long-term potentiation. Cell Signal 5, 695–708.
Levy BH, and Tasker JG. (2012). Synaptic regulation of the hypothalamic-pituitary-adrenal axis and its modulation by glucocorticoids and stress. Front Cell Neurosci 6, 24.
Lledo PM, Alonso M, and Grubb MS. (2006). Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7, 179–193.
Lockie SH, Stark R, Mequinion M, et al. (2018). Glucose availability predicts the feeding response to ghrelin in male mice, an effect dependent on AMPK in AgRP neurons. Endocrinology 159, 3605–3614.
Lopez M, Varela L, Vazquez MJ, et al. (2010). Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16, 1001–1008.
Mackowiak SD, Zauber H, Bielow C, et al. (2015). Extensive identification and analysis of conserved small ORFs in animals. Genome Biol 16, 179.
Maggi R, Zasso J, and Conti L. (2014). Neurodevelopmental origin and adult neurogenesis of the neuroendocrine hypothalamus. Front Cell Neurosci 8, 440.
Matsuzaki K, Katakura M, Sugimoto N, Hara T, Hashimoto M, and Shido O. (2017). Neural progenitor cell proliferation in the hypothalamus is involved in acquired heat tolerance in long-term heat-acclimated rats. PLoS One 12, e0178787.
Mehrpour M, Esclatine A, Beau I, and Codogno P. (2010). Overview of macroautophagy regulation in mammalian cells. Cell Res 20, 748–762.
Meley D, Bauvy C, Houben-Weerts JH, et al. (2006). AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281, 34870–34879.
Migaud M, Butrille L, and Batailler M. (2015). Seasonal regulation of structural plasticity and neurogenesis in the adult mammalian brain: focus on the sheep hypothalamus. Front Neuroendocrinol 37, 146–157.
Minokoshi Y, Alquier T, Furukawa N, et al. (2004). AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574.
Mo B, Callegari E, Telefont M, and Renner KJ. (2006). Proteomic analysis of the ventromedial nucleus of the hypothalamus (pars lateralis) in the female rat. Proteomics 6, 6066–6074.
Mohanty V, Pinto SM, Subbannayya Y, et al. (2020). Digging deeper for the eye proteome in vitreous substructures: a high-resolution proteome map of the normal human vitreous base. OMICS 24, 379–389.
Muller-Dahlhaus F, and Ziemann U. (2015). Metaplasticity in human cortex. Neuroscientist 21, 185–202.
Neumann ID, and Landgraf R. (2012). Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35, 649–659.
Newson MJ, Roberts EM, Pope GR, Lolait SJ, and O'Carroll AM. (2009). The effects of apelin on hypothalamic-pituitary-adrenal axis neuroendocrine function are mediated through corticotrophin-releasing factor- and vasopressin-dependent mechanisms. J Endocrinol 202, 123–129.
Ni Z, Gunraj C, Kailey P, Cash RF, and Chen R. (2014). Heterosynaptic modulation of motor cortical plasticity in human. J Neurosci 34, 7314–7321.
Nicholas AP, King JL, Sambandam T, et al. (2003). Immunohistochemical localization of citrullinated proteins in adult rat brain. J Comp Neurol 459, 251–266.
Nishida Y, Arakawa S, Fujitani K, et al. (2009). Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461, 654–658.
Niwa A, Nishibori M, Hamasaki S, et al. (2016). Voluntary exercise induces neurogenesis in the hypothalamus and ependymal lining of the third ventricle. Brain Struct Funct 221, 1653–1666.
Oh TS, Cho H, Cho JH, Yu SW, and Kim EK. (2016). Hypothalamic AMPK-induced autophagy increases food intake by regulating NPY and POMC expression. Autophagy 12, 2009–2025.
Oyama M, Kozuka-Hata H, Suzuki Y, Semba K, Yamamoto T, and Sugano S. (2007). Diversity of translation start sites may define increased complexity of the human short ORFeome. Mol Cell Proteomics 6, 1000–1006.
Palollathil A, Aravind A, Vijayakumar M, et al. (2021). Omics data mining for multiPTMs in oral cancer: cellular proteome and secretome of chronic tobacco-treated oral keratinocytes. OMICS 25, 450–462.
Park SY, Ma W, Yoon SN, Kang MJ, and Han JS. (2015). Phospholipase D1 increases Bcl-2 expression during neuronal differentiation of rat neural stem cells. Mol Neurobiol 51, 1089–1102.
Park SY, Yoon SN, Kang MJ, Lee Y, Jung SJ, and Han JS. (2017). Hippocalcin promotes neuronal differentiation and inhibits astrocytic differentiation in neural stem cells. Stem Cell Reports 8, 95–111.
Patil AH, Datta KK, Behera SK, et al. (2018). Dissecting candida pathobiology: post-translational modifications on the Candida tropicalis proteome. OMICS 22, 544–552.
Pedroso AP, Watanabe RL, Albuquerque KT, et al. (2012). Proteomic profiling of the rat hypothalamus. Proteome Sci 10, 26.
Pencea V, Bingaman KD, Wiegand SJ, and Luskin MB. (2001). Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21, 6706–6717.
Pierce AA, and Xu AW. (2010). De novo neurogenesis in adult hypothalamus as a compensatory mechanism to regulate energy balance. J Neurosci 30, 723–730.
Pritzker LB, Nguyen TA, and Moscarello MA. (1999). The developmental expression and activity of peptidylarginine deiminase in the mouse. Neurosci Lett 266, 161–164.
Pueyo JI, Magny EG, and Couso JP. (2016). New peptides under the s(ORF)ace of the genome. Trends Biochem Sci 41, 665–678.
Quan W, Kim HK, Moon EY, et al. (2012). Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153, 1817–1826.
Rankin SL, Partlow GD, McCurdy RD, Giles ED, and Fisher KR. (2003). Postnatal neurogenesis in the vasopressin and oxytocin-containing nucleus of the pig hypothalamus. Brain Res 971, 189–196.
Rappsilber J, Ishihama Y, and Mann M. (2003). Stop and go extraction tips for matrix-assisted laser desorption/ionization, nanoelectrospray, and LC/MS sample pretreatment in proteomics. Anal Chem 75, 663–670.
Ray LB, and Sturgill TW. (1987). Rapid stimulation by insulin of a serine/threonine kinase in 3T3-L1 adipocytes that phosphorylates microtubule-associated protein 2 in vitro. Proc Natl Acad Sci U S A 84, 1502–1506.
Rex DAB, Arun Kumar ST, Rai AB, Kotimoole CN, Modi PK, and Prasad TSK. (2021). Novel post-translational modifications and molecular substrates in glioma identified by bioinformatics. OMICS 25, 463–473.
Roh E, Song DK, and Kim MS. (2016). Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp Mol Med 48, e216.
Rojczyk-Golebiewska E, Palasz A, and Wiaderkiewicz R. (2014). Hypothalamic subependymal niche: a novel site of the adult neurogenesis. Cell Mol Neurobiol 34, 631–642.
Ryan KK, Li B, Grayson BE, Matter EK, Woods SC, and Seeley RJ. (2011). A role for central nervous system PPAR-gamma in the regulation of energy balance. Nat Med 17, 623–626.
Saghatelian A, and Couso JP. (2015). Discovery and characterization of smORF-encoded bioactive polypeptides. Nat Chem Biol 11, 909–916.
Sarina, Yagi Y, Nakano O, et al. (2013). Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways. Brain Res 1490, 61–71.
Sarruf DA, Yu F, Nguyen HT, et al. (2009). Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150, 707–712.
Satoh J, Kino Y, Yamamoto Y, et al. (2014). PLD3 is accumulated on neuritic plaques in Alzheimer's disease brains. Alzheimers Res Ther 6, 70.
Schwanhausser B, Busse D, Li N, et al. (2011). Global quantification of mammalian gene expression control. Nature 473, 337–342.
Shen Y, Xu L, and Foster DA. (2001). Role for phospholipase D in receptor-mediated endocytosis. Mol Cell Biol 21, 595–602.
Slavoff SA, Mitchell AJ, Schwaid AG, et al. (2013). Peptidomic discovery of short open reading frame-encoded peptides in human cells. Nat Chem Biol 9, 59–64.
Smith SM, and Vale WW. (2006). The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8, 383–395.
Sousa-Ferreira L, Alvaro AR, Aveleira C, et al. (2011). Proliferative hypothalamic neurospheres express NPY, AGRP, POMC, CART and Orexin-A and differentiate to functional neurons. PLoS One 6, e19745.
Sousa-Ferreira L, de Almeida LP, and Cavadas C. (2014). Role of hypothalamic neurogenesis in feeding regulation. Trends Endocrinol Metab 25, 80–88.
St-Amand J, Yoshioka M, Tanaka K, and Nishida Y. (2011). Transcriptome-wide identification of preferentially expressed genes in the hypothalamus and pituitary gland. Front Endocrinol (Lausanne) 2, 111.
Stelzhammer V, Amess B, Martins-de-Souza D, et al. (2012). Analysis of the rat hypothalamus proteome by data-independent label-free LC-MS/MS. Proteomics 12, 3386–3392.
Taheri S, Murphy K, Cohen M, et al. (2002). The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochem Biophys Res Commun 291, 1208–1212.
Tapias A, and Wang ZQ. (2017). Lysine acetylation and deacetylation in brain development and neuropathies. Genomics Proteomics Bioinformatics 15, 19–36.
Timper K, and Bruning JC. (2017). Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis Model Mech 10, 679–689.
Toni R, Malaguti A, Benfenati F, and Martini L. (2004). The human hypothalamus: a morpho-functional perspective. J Endocrinol Invest 27, 73–94.
van Beers JJ, Schwarte CM, Stammen-Vogelzangs J, Oosterink E, Bozic B, and Pruijn GJ. (2013). The rheumatoid arthritis synovial fluid citrullinome reveals novel citrullinated epitopes in apolipoprotein E, myeloid nuclear differentiation antigen, and beta-actin. Arthritis Rheum 65, 69–80.
Van Drunen R, and Eckel-Mahan K. (2021). Circadian rhythms of the hypothalamus: from function to physiology. Clocks Sleep 3, 189–226.
Varela L, Suyama S, Huang Y, et al. (2017). Endothelial HIF-1alpha enables hypothalamic glucose uptake to drive POMC neurons. Diabetes 66, 1511–1520.
Vercruysse P, Vieau D, Blum D, Petersen A, and Dupuis L. (2018). Hypothalamic alterations in neurodegenerative diseases and their relation to abnormal energy metabolism. Front Mol Neurosci 11, 2.
Vitale N, Caumont AS, Chasserot-Golaz S, et al. (2001). Phospholipase D1: a key factor for the exocytotic machinery in neuroendocrine cells. EMBO J 20, 2424–2434.
Walaas SI, Perdahl-Wallace E, Winblad B, and Greengard P. (1989). Protein phosphorylation systems in postmortem human brain. J Mol Neurosci 1, 105–116.
Wei LC, Shi M, Chen LW, Cao R, Zhang P, and Chan YS. (2002). Nestin-containing cells express glial fibrillary acidic protein in the proliferative regions of central nervous system of postnatal developing and adult mice. Brain Res Dev Brain Res 139, 9–17.
Xi Y, Dhaliwal JS, Ceizar M, Vaculik M, Kumar KL, and Lagace DC. (2016). Knockout of Atg5 delays the maturation and reduces the survival of adult-generated neurons in the hippocampus. Cell Death Dis 7, e2127.
Xu Y, Tamamaki N, Noda T, et al. (2005). Neurogenesis in the ependymal layer of the adult rat 3rd ventricle. Exp Neurol 192, 251–264.
Yazdankhah M, Farioli-Vecchioli S, Tonchev AB, Stoykova A, and Cecconi F. (2014). The autophagy regulators Ambra1 and Beclin 1 are required for adult neurogenesis in the brain subventricular zone. Cell Death Dis 5, e1403.
Yoo S, and Blackshaw S. (2018). Regulation and function of neurogenesis in the adult mammalian hypothalamus. Prog Neurobiol 170, 53–66.
Yoon MS, Yon C, Park SY, et al. (2005). Role of phospholipase D1 in neurite outgrowth of neural stem cells. Biochem Biophys Res Commun 329, 804–811.
Yu G, Wang LG, Han Y, and He QY. (2012). clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287.
Yulyaningsih E, Rudenko IA, Valdearcos M, et al. (2017). Acute lesioning and rapid repair of hypothalamic neurons outside the blood-brain barrier. Cell Rep 19, 2257–2271.
Zhang G, Li J, Purkayastha S, et al. (2013). Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature 497, 211–216.
Zhang H, Zhang G, Gonzalez FJ, Park SM, and Cai D. (2011). Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation. PLoS Biol 9, e1001112.
Zhang N, Fu Z, Linke S, et al. (2010). The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab 11, 364–378.
Zhang Z, Tang J, Di R, et al. (2019). Integrated hypothalamic transcriptome profiling reveals the reproductive roles of mRNAs and miRNAs in sheep. Front Genet 10, 1296.
Zhao ZD, Yang WZ, Gao C, et al. (2017). A hypothalamic circuit that controls body temperature. Proc Natl Acad Sci U S A 114, 2042–2047.
Zink CF, Stein JL, Kempf L, Hakimi S, and Meyer-Lindenberg A. (2010). Vasopressin modulates medial prefrontal cortex-amygdala circuitry during emotion processing in humans. J Neurosci 30, 7017–7022.
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OMICS: A Journal of Integrative Biology
Volume 25 • Issue Number 11 • November 2021
Pages: 693 - 710
PubMed: 34714154
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Copyright 2021, Mary Ann Liebert, Inc., publishers.
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Published online: 8 November 2021
Published in print: November 2021
Published ahead of print: 29 October 2021
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