Christie D. Fowler, PhD
Assistant Professor Department of Neurobiology and Behavior University of California 1232 McGaugh Hall, Irvine CA 92697, USA; E-mail: cdfowler@uci.edu
Historically, the function of the Cerebrospinal fluid (CSF) was considered to be limited to maintenance of extracellular ion concentrations and to serve as a protective ‘cushion’ during cranial impact. However, recent advances have revealed that the CSF provides a rich source of signaling molecules, including growth factors, hormones, proteins, peptides, lipids, glucose, microRNAs, mRNA, and enzymes.1-5 Indeed, primary CSF removed from the brain is sufficient to maintain cortical explants and cells in culture without the presence of other factors,6 clearly demonstrating the extent of micronutrient and growth factor enrichment in this fluid. Several initial studies of CSF function had suggested that signaling factors present in the CSF mediate satiety, circadian rhythms, and locomotor behavior.7,8 In these early studies, reinstatement of feeding behaviour was induced by infusing CSF collected from fasted sheep into the ventricles of satiated sheep,9 and similarly, CSF collected from sleep-deprived goats increased the duration of sleep and decreased locomotor activity when infused into the ventricles of rats.7 These findings indicated that substances present in the CSF can exert a significant influence on motivated behaviors. More recently, Pedrazzoli and colleagues established that the peptide orexin (a.k.a., hypocretin) is increased in the CSF during sleep deprivation.10 In addition to regulating arousal and wakefulness, orexin has been implicated in drug reinforcement, obesity and neurodegenerative diseases, such as Parkinson and Alzheimer’s diseases.11-15 As such altered expression of orexin in the CSF under these physiological conditions could be a mediating factor for the sleep-related effects in the earlier study7 and may also have additional multifaceted effects on physiological function.
In vivo, production of CSF occurs at several choroid plexus sites, including the lateral, third and fourth ventricles, thus creating an independent circulatory system for the brain.3 At each of these sites, the choroid plexus appears to differ in some respects in structure, function, and factors produced/released into the ventricles.16The epithelial cells that comprise the choroid plexus contain extensive basolateral infoldings and microvilli, providing an extensive surface area for transport into the ventricular fluid. These cuboidal epithelial cells exhibit a polarized shape, with differential function ascribed to the apical and basolateral membranes.17 The apical membrane interfaces with the capillaries of the brain and mainly functions to uptake nutrients from the blood, whereas the basolateral membrane provides a removal mechanism for toxins and excess substances from the CSF, in addition to releasing factors into ventricular circulation.17 As such, dysfunction in the transport mechanism of the choroid plexus could potentially alter CSF compositions and compromise brain health.
The potential for CSF-derived factors to impact neural function may be further imparted when one takes into account that the total surface area at the choroid plexus-CSF interface is roughly the same as the entire blood-brain-barrier.16 As CSF is generated, it moves transcellularly and paracellulary among the epithelial cells of the choroid plexus to be released into the ventricular space.16 Since the amount of CSF produced allows for turnover of approximately four times per day in humans,18 the levels of circulating factors has the potential to be continuously regulated to influence neuronal function. It has also been proposed that the apical membrane of the choroid plexus expresses receptors that function as feedback loops to mediate the further release of certain factors into the ventricles,16 and thus the presence of growth factors, neuropeptides, proteins, cytokines and hormones may be regulated in this manner. Indeed, this feature of the choroid plexus has been experimentally exploited to alter growth factor release; genetically displaying growth factor ligands on bacteriophage coats binds the construct to receptors on the choroid plexus cell surface, thus altering further release of the growth factor into the ventricle.19 In addition to factors produced by the epithelial cells of the choroid plexus, the presence of blood vessels in the choroidal stroma allows for the presence of the CSF-blood interface through which factors from the blood may enter the central nervous system through leaky endothelial junctions.
It has been proposed that the transport of factors from the choroid plexus into the ventricular CSF may occur via three main routes: (1) transport in the CSF itself as the choroid plexus is permeable for smaller molecules, (2) membrane-bound transport mechanisms on the plasma membrane of choroidal epithelial cells, (3) release from the intracellular compartment as extracellular vesicles20 (Figure 1). In the prior literature, these extracellular vesicles have been referred to as either exosomes or microvesicles, although this terminology inconsistently varies across fields.21 Van der Pol and colleagues propose that the main distinction between the two types of vesicles concerns their size, with exosomes being smaller in diameter than microvesicles when examined from the same cell. However, this distinction is not clearly defined when one considers varying types of cells. For instance, exosomes have been most commonly reported to range from ~50-100 nm in diameter, and microvesicles from between ~20-1000 nm in diameter; as can be seen, these classifications provide a range of overlap.21 Both types of extracellular vesicles can be formed by an outward blebbing of a cell’s plasma mem brane, but exosomes may be additionally formed as intraluminal vesicles within multivesicle endosomes that are then released from the cell as the endosome fuses with the plasma membrane. For the purposes of this review, we will employ the general terminology of extracellular vesicles to refer to both exosomes and microvesicles, and moreover, it should also be noted that this classification is distinct from membrane particles or apoptotic vesicles.21 Many cell types have been shown to release extracellular vesicles via budding of the cell membrane, including epithelial, immune, tumor and stem cells,22,23 and the resulting vesicles differ in content and function. Whereas initial investigations assumed extracellular vesicles contained cellular debris, growing evidence has established that these compartments are enriched with a vast source of signaling molecules that have crucial roles in a number of physiological processes. Release of extracellular vesicles has been shown to occur via Ca2+-, protein kinase C-, or ceramide-dependent mechanisms, and after entry into the CSF, the vesicles may immediately breakdown to dump contents into the fluid or can travel to a distant site to fuse with the membrane of a target cell and transfer genomic material.22,23,24 The method of vesicular packaging for extracellular communication may be preferred for mRNA and miRNAs transport, as exposure to circulating RNAses are limited and long-distance communication may be achieved via cell-specific targeting motifs on the vesicle surface. Importantly, several recent reports have demonstrated that mRNA from microvesicles can become integrated and translated into the proper protein within the target cell,23,24 short-interfering RNA (siRNA) packaged into exosomes can efficiently silence gene expression,25 and epigenetic changes can be induced in target cells via transfer of miRNAs.22 In consideration of these findings, elucidation of the structure and function of these packaged compartments could hold promise as a novel avenue for therapeutic delivery of preloaded vesicles with mRNA, miRNA, siRNA or pharmacological compounds into the central nervous system.
Figure 1: Mechanisms of extracellular transport from the choroid plexus into the cerebrospinal fluid. Factors derived from the choroid plexus may be released into the ventricular space: (A) as exosomes released from intracellular Multivesicle endosomes (MVEs) through exocytosis, (B) via blebbing of the cellular membrane as a microvesicle or exosome, (C) transcellularly and/or paracellulary with release of cerebrospinal fluid, or (D) via membrane-bound transport mechanisms located in the epithelial plasma membrane.
With the exception of hydrocephalus, the CSF has not traditionally been considered a vital regulatory mechanism of and/or implicated in human disease states. However, recent reports are beginning to redefine our understanding of choroid plexus and CSF function as they demonstrate the importance of factors derived from the CSF in maintaining physiological function (Table 1). For instance, growth factors produced by the choroid plexus, such as Insulin-like growth factor 2 (IGF2) and Fibroblast growth factor 2 (FGF2), have been shown to regulate neurogenesis throughout the lifespan.3,6 Further, an elegant study from Sawamoto and colleagues recently demonstrated that the CSF directly interacts with cilia in the subventricular zone to mediate the migration of progenitor cells in the adult brain.26
Table 1: Summary of neuropathology associated with abnormal choroid plexus and CSF.
|
Disease |
Fragile X-Associated Tremor/Ataxia Syndrome | Cerebral Folate Transport Deficiency | Alzheimer’s Disease | Multiple Sclerosis |
AIDS |
| Choroid Plexus Characteristics | Iron accumulation in stroma | Failure to transport FRα along with B-vitamin | Failure to clear amyloid-β (Aβ) plaques | HLA-DR expression | Accumulation of HIV-1 |
| CSF Characteristics | Low iron levels | Low FRα and B-vitamin levels | Accumulation of amyloid-β (Aβ) protein | Increased CD4/CD8 ratio | To be further investigated |
Choroid plexus transport has been implicated as a contributing factor for certain neurodegenerative diseases. For instance, Fragile X-associated tremor/ataxia syndrome (FXTAS) is associated with iron dysregulation in mitochondria.27 Interestingly, post-mortem FXTAS subjects exhibit an accumulation of iron in the stroma of the choroid plexus and decreased amounts of transferrin, ferroportin, and ceruloplasmin, all of which are essential to the transport of iron.27 These findings suggest that abnormal transport of iron within the choroid plexus may contribute to pathophysiology exhibited by FXTAS subjects. Another disorder, cerebral folate transport deficiency, is characterized by a lack of B-vitamin within the brain. The polarized cells of the choroid plexus have been shown to translocate the folate receptor α(FRα) in a unilateral direction from the basolateral to the apical compartments, leading to exocytosis into the CSF and subsequent integration in the brain parenchyma.28 Thus, abnormal transport of substrates involved in the production of B-vitamins may underlie the pathology found in this disorder.
To date, dysfunction of the choroid plexus has been most studied as a mediating factor of Alzheimer’s disease. Postmortem, neural pathology in the Alzheimer’s brain is evidenced by a build-up of amyloid-β (Aβ) plaques and intracellular neurofibrillary degeneration of hyperphosphorylated tau (neurofibrillary tangles).29,30 Under normal circumstances, the Aβ protein is produced by the brain and subsequently becomes cleared through enzymatic degradation, capillary reabsorption, and/or CSF transport through the choroid plexus.29,31 In contrast, pathological accumulation of Aβ plaques and neurofibrillary tangles in the disease state leads to dysfunction of neurons and synapses throughout the brain, most notably those in brain regions involved in memory and cognitive function, such as the hippocampus and cortex.32 As such, recent evidence suggests that the choroid plexus and CSF may play a significant role in the pathology of Alzheimer’s disease.1,31,33 Altered clearance of Aβ by the CSF with aging results in accumulation of Aβ protein, thus promoting the formation of plaques. In late onset Alzheimer’s disease, structural abnormalities of the choroid plexus, which in clude cellular atrophy, calcification and fibrosis, and thickening of the basement membrane,29 are evidenced. These abnormalities are thought to lead to altered synthesis, secretion, clearance and transport of factors between the choroid plexus, cerebrospinal fluid and blood.29 Therefore, in patients with Alzheimer’s disease, choroidal dysfunction prevents adequate clearing of Aβ from the CSF and promotes Aβ accumulation in the brain.29,33 Another possible role for CSF in the pathogenesis of Alzheimer’s disease is through transport of melatonin. The pineal gland directly secretes melatonin into the CSF of the third ventricle,34 or, alternatively, the hormone may enter via leaky endothelial cells of blood vessels in the choroid plexus.35 Interestingly, recent findings suggest that the amount of melatonin in the CSF is negatively correlated with the status of Alzheimer’s disease symptoms.36 Through its actions as an antioxidant it has been proposed that melatonin exerts neuroprotective effects by counteracting oxidative damage.36 In the younger brain, evidence suggests that melatonin administration can result in anti-amyloid and antioxidant effects; however, administration of melatonin to the aged brain has been shown to exert a minimal effect on pre-existing amyloid deposits.37 Thus, as a therapeutic approach, strategies to increase melatonin in the CSF may be of benefit in the early stages of Alzheimer’s disease and/or as a preventative measure based on familial considerations.38
The choroid plexus also functions as a principal mediator of the innate immune response of the central nervous system. Peripheral immune molecules interact with receptors located on choroid plexus cells to initiate the release of proinflammatory molecules, such as interleukins, into the CSF.16 Myeloid progenitors located in the vascularized choroid stroma have also been shown to provide a source of brain macrophages.39,40 Moreover, inflammatory processes mediated by the choroid plexus have been speculated to contribute to the heightened immune response found in multiple sclerosis and encephalitis.41 In addition, the choroid plexus is a main entry point for viruses to infiltrate the brain from the periphery. For instance, the presence of HIV-1 in the choroid plexus has been suggested to occur prior to the onset of Acquired Immune Deficiency Syndrome (AIDS) and immunosuppression,42 and infected CSF or choroid plexusderived macrophages can induce toxic effects on neurons in vitro.43 HIV-1 or other viruses may also be capable of altering the expression of signaling molecules within the epithelial cells of the choroid plexus to permit enhanced entry of the virus into the CSF, a possibility which needs to be more systematically investigated in future studies.
Finally, given the close proximity of CSF to brain regions implicated in substance abuse, such as the habenula, hippocampus, and interpeduncular nucleus,44,45 signaling molecules in the CSF could potentially regulate the neural processes underlying the addictive state. Interestingly, nicotine has been shown to mediate the function of the choroid plexus.46,47 Transthyretin, the plasma thyroid hormone transport protein, is produced by the choroid plexus and acts to transport thyoxine across the blood-brain barrier,48 and nicotine administration has been found to increase the synthesis and release of transthyretin into the CSF.47 Further, prenatal exposure to nicotine has also been correlated with an increased incidence of pathological features of the fourth ventricle choroid plexus and premature death.46 However, further investigations will be critical to ascertain whether extracellular factors from the choroid plexus/CSF are important mechanisms that mediate the development and maintenance of drug dependence. “If established, these findings have the potential to redefine our understanding of novel signaling mechanisms within the brain and in doing so, could provide a foundation for more efficacious therapeutic approaches Table 1.”
Our current understanding of the function of the choroid plexus and CSF has begun to be transformed, and as such, the emerging importance of these signaling mechanisms must now be recognized as putative essential mediators of brain function. Extracellularsignaling factors have been shown to integrate in and modulate function of neurons within the brain and thus, have the potential to both maintain normal homeostatic function and/or contribute to pathological disease states. Moreover, CSFderived factors also hold the potential to serve as biomarkers of disease. As the field progresses, the vital function of factors derived from the choroid plexus will likely continue to emerge, and these advances may then provide a foundation for novel approaches to treat neuropathology in humans.
The authors have no conflicts of interest to disclose.
This work was supported by grants from the NIH National Institute on Drug Abuse (DA039658&DA032543 to C.D.F.).
1. Potter R, Patterson BW, Elbert DL, et al. Increased in vivo amyloid-beta42 production, exchange, and loss in presenilin mutation carriers. Science translational medicine. 2013; 5: 189ra177. doi: 10.1126/scitranslmed.3005615
2. Parada C, Gato A, Bueno D. Mammalian embryonic cerebrospinal fluid proteome has greater apolipoprotein and enzyme pattern complexity than the avian proteome. Journal of proteome research. 2005; 4: 2420-2428. doi: 10.1021/pr050213t
3. Lehtinen MK, Walsh CA. Neurogenesis at the brain-cerebrospinal fluid interface. Annual review of cell and developmental biology. 2011; 27: 653-679. doi: 10.1146/annurev-cellbio-092910-154026
4. Weber JA, Baxter DH, Zhang S, et al. The microRNA spectrum in 12 body fluids. Clinical chemistry. 2010; 56: 1733-1741. doi: 10.1373/clinchem.2010.147405
5. Burgos KL, Javaherian A, Bomprezzi R, et al. Identification of extracellular miRNA in human cerebrospinal fluid by nextgeneration sequencing. Rna. 2013; 19: 712-722. doi: 10.1261/ rna.036863.112
6. Lehtinen MK, Zappaterra MW, Chen X, et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 2011; 69: 893-905. doi: 10.1016/j.neuron.2011.01.023
7. Fencl V, Koski G, Pappenheimer JR. Factors in cerebrospinal fluid from goats that affect sleep and activity in rats. The Journal of physiology. 1971; 216: 565-589. doi: 10.1113/jphysiol.1971. sp009541
8. Pappenheimer JR, Fencl V, Karnovsky ML, Koski G. Peptides in cerebrospinal fluid and their relation to sleep and activity. Research publications – Association for Research in Nervous and Mental Disease. 1974; 53: 201-210.
9. Martin FH, Seoane JR, Baile CA. Feeding in satiated sheep elicited by intraventricular injections of CSF from fasted sheep. Life sciences. 1973; 13: 177-184.doi: 10.1016/0024-3205(73)90193-8
10. Pedrazzoli M, D’Almeida V, Martins PJ, et al. Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation. Brain research. 2004; 995: 1-6. doi: 10.1016/j. brainres.2003.09.032
11. Hollander JA, Pham D, Fowler CD, Kenny PJ. Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. Frontiers in behavioral neuroscience. 2012; 6: 47. doi: 10.3389/ fnbeh.2012.00047
12. Cason AM, Aston-Jones G. Role of orexin/hypocretin in conditioned sucrose-seeking in female rats. Neuropharmacology. 2014; 86: 97-102. doi: 10.1016/j.neuropharm.2014.07.007
13. Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA. Sleep disorders, obesity, and aging: the role of orexin. Ageing research reviews. 2015; 20: 63-73. doi: 10.1016/j. arr.2014.11.001
14. Fronczek R, Overeem S, Lee SY, et al. Hypocretin (orexin) loss and sleep disturbances in Parkinson’s Disease. Brain : a journal of neurology. 2008; 131: e88. doi: 10.1093/brain/ awm222
15. Fronczek R, van Geest S, Frölich M, et al. Hypocretin (orexin) loss in Alzheimer’s disease. Neurobiology of aging. 2012; 33: 1642-1650. doi: 10.1016/j.neurobiolaging.2011.03.014
16. Johanson CE, Duncan JA, Stopa EG, Baird A. Enhanced prospects for drug delivery and brain targeting by the choroid plexus-CSF route. Pharmaceutical research. 2005; 22: 1011- 1037. doi: 10.1007/s11095-005-6039-0
17. Lun M, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus–cerebrospinal fluid system. Nature reviews. Neuroscience. 2015; 16: 445-457. doi: 10.1038/ nrn3921
18. Brown PD, Davies SL, Speake T, Millar ID. Molecular mechanisms of cerebrospinal fluid production. Neuroscience. 2004; 129: 957-970. doi: 10.1016/j.neuroscience.2004.07.003
19. Larocca D, Burg MA, Jensen-Pergakes K, Ravey EP, Gonzalez AM, Baird A. Evolving phage vectors for cell targeted gene delivery. Current pharmaceutical biotechnology. 2002; 3: 45- 57. doi: 10.2174/1389201023378490
20. Strazielle N, Ghersi-Egea JF. Physiology of blood-brain interfaces in relation to brain disposition of small compounds and macromolecules. Molecular pharmaceutics. 2013; 10, 1473- 1491. doi: 10.1021/mp300518e
21. van der Pol E, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacological reviews. 2012; 64: 676-705. doi: 10.1124/pr.112.005983
22. Turturici G, Tinnirello R, Sconzo G, Geraci F. Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. American journal of Physiology Cell physiology. 2014; 306: C621-C633. doi: 10.1152/ ajpcell.00228.2013
23. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010; 285: 17442- 17452. doi: 10.1074/jbc.M110.107821
24. Cai J, Han Y, Ren H, et al. Extracellular vesicle-mediated transfer of donor genomic DNA to recipient cells is a novel mechanism for genetic influence between cells. Journal of molecular cell biology. 2013; 5: 227-238. doi: 10.1093/jmcb/ mjt011
25. Alvarez-Erviti L, Seow Y, Yin HF, Betts C, Lakhal S, Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature biotechnology. 2011; 29: 341- 345. doi: 10.1038/nbt.1807
26. Sawamoto K, Wichterle H, Gonzalez-Perez O, et al. New neurons follow the flow of cerebrospinal fluid in the adult brain. Science. 2006; 311: 629-632. doi: 10.1126/science.1119133
27. Ariza J, Steward C, Rueckert F, et al. Dysregulated iron me- tabolism in the choroid plexus in fragile X-associated tremor/ ataxia syndrome. Brain research. 2015; 1598: 88-96. doi: 10.1016/j.brainres.2014.11.058
28. Grapp M, Wrede A, Schweizer M, et al. Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma. Nature communications. 2013; 4: 2123. doi: 10.1038/ ncomms3123
29. Serot JM, Zmudka J, Jouanny P. A possible role for CSF turnover and choroid plexus in the pathogenesis of late onset Alzheimer’s disease. Journal of Alzheimer’s disease: JAD. 2012; 30: 17-26. doi: 10.3233/JAD-2012-111964
30. Buendia I, Egea J, Parada E, et al. The Melatonin-N,NDibenzyl(N-methyl)amine hybrid ITH91/IQM157 affords neuroprotection in an in vitro alzheimer’s model via hemo-oxygenase-1 induction. ACS chemical neuroscience. 2015; 6(2): 288-296. doi: 10.1021/cn5002073
31. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature medicine. 2006; 12: 856-861. doi: 10.1038/nm1438
32. Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology. 2014; 71: 505-508. doi: 10.1001/jamaneurol.2013.5847
33. Krzyzanowska A, Carro E. Pathological alteration in the choroid plexus of Alzheimer’s disease: implication for new therapy approaches. Frontiers in pharmacology. 2012; 3: 75. doi: 10.3389/fphar.2012.00075
34. Tricoire H, Malpaux B, Moller M. Cellular lining of the sheep pineal recess studied by light-, transmission-, and scanning electron microscopy: morphologic indications for a direct secretion of melatonin from the pineal gland to the cerebrospinal fluid. The Journal of comparative neurology. 2003; 456: 39-47. doi: 10.1002/cne.10477
35. Anton-Tay F, Wurtman RJ. Regional uptake of 3H-melatonin from blood or cerebrospinal fluid by rat brain. Nature. 1969; 221: 474-475. doi: 10.1038/221474a0
36. Tan DX, Manchester LC, Sanchez-Barcelo E, Mediavilla MD, Reiter RJ. Significance of high levels of endogenous melatonin in Mammalian cerebrospinal fluid and in the central nervous system. Current neuropharmacology. 2010; 8: 162-167. doi: 10.2174/157015910792246182
37. He H, Dong W, Huang F. Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease. Current neuropharmacology. 2010; 8: 211-217. doi: 10.2174/157015910792246137
38. Masilamoni JG, Jesudason EP, Dhandayuthapani S, et al. The neuroprotective role of melatonin against amyloid beta peptide injected mice. Free radical research. 2008; 42: 661-673. doi: 10.1080/10715760802277388
39. Matyszak MK, Lawson LJ, Perry VH, Gordon S. Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens. Journal of neuroimmunology. 1992; 40: 173-181. doi: 10.1016/0165- 5728(92)90131-4
40. Nataf S, Strazielle N, Hatterer E, Mouchiroud G, Belin MF, Ghersi-Egea JF. Rat choroid plexuses contain myeloid progenitors capable of differentiation toward macrophage or dendritic cell phenotypes. Glia. 2006; 54: 160-171. doi: 10.1002/ glia.20373
41. Vercellino M, Votta B, Condello C, et al. Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study. Journal of neuroimmunology. 2008; 199: 133-141. doi: 10.1016/j.jneuroim.2008.04.035
42. Petito CK. Human immunodeficiency virus type 1 compartmentalization in the central nervous system. Journal of neurovirology. 2004; 10(Suppl 1): 21-24.doi: 10.1080/753312748
43. Meeker RB, Boles JC, Bragg DC, Robertson K, Hall C. Development of neuronal sensitivity to toxins in cerebrospinal fluid from HIV-type 1-infected individuals. AIDS research and human retroviruses. 2004; 20: 1072-1078. doi: 10.1089/ aid.2004.20.1072
44. Belujon P, Grace AA. Hippocampus, amygdala, and stress: interacting systems that affect susceptibility to addiction. Annals of the New York Academy of Sciences. 2011; 1216: 114-121. doi: 10.1111/j.1749-6632.2010.05896.x
45. Fowler CD, Lu Q, Johnson PM, Marks MJ, Kenny PJ. Habenular alpha5 nicotinic receptor subunit signalling controls nicotine intake. Nature. 2011; 471: 597-601. doi: 10.1038/nature09797
46. LavezziAM, Matturri L, Del Corno G, Johanson CE. Vulnerability of fourth ventricle choroid plexus in sudden unexplained fetal and infant death syndromes related to smoking mothers. International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience. 2013; 31: 319-327. doi: 10.1016/j.ijdevneu.2013.04.006
47. Li MD, Kane JK, Matta SG, Blaner WS, Sharp BM. Nicotine enhances the biosynthesis and secretion of transthyretin from the choroid plexus in rats: implications for beta-amyloid formation. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2000; 20: 1318-1323.doi: 10.1523/JNEUROSCI.20-04-01318.2000
48. Schreiber G, Aldred AR, Jaworowski A, Nilsson C, Achen MG, Segal MB. Thyroxine transport from blood to brain via transthyretin synthesis in choroid plexus. Am J Physiol. 1990; 258: R338-R345. doi: 10.1152/ajpregu.1990.258.2.R338
© 2014-2024 I Openventio Publisher is licensed by Creative Commons Attribution, unless otherwise indicated.
