The sympathetic nervous system is predominantly controlled by the right side of the brain (focused upon the insular cortex), while the left side predominantly controls the parasympathetic nervous system.[4] The cerebral cortex in rodents shows
lateral specialization in its regulation of immunity with immunosuppression being controlled by the right hemisphere, and immunopotention by the left one.[9][13] Humans show similar lateral specialized control of the immune system from the evidence of
strokes,[14] surgery to control
epilepsy,[15] and the application of
TMS.[16]
Brainstem
The higher brain top down control of physiology is mediated by the sympathetic and parasympathetic nervous systems in the brainstem,[1][2][3][4] and the hypothalamus.[1][17][18] The sympathetic nervous system arises in brainstem nuclei that project down into intermediolateral columns of
thoracolumbar spinal cord neurons in
spinal segments T1âL2. The parasympathetic nervous system in the motor nuclei of
cranial nerves III, VII, IX, (control over the pupil and salivary glands) and X (vagus âmany functions including immunity) and sacral spinal segments (gastrointestinal and urogenital systems).[12] Another control occurs through top down control by the medial areas of the
prefrontal cortex.[1][17][18] upon the
hypothalamus which has a nonnerve control of the body through
hormonal secretions of the
pituitary.
Immunity
The brain controls immunity both indirectly through HPA
glucocorticoid secretions from the pituitary, and by various direct innervations.[19]
Antibodies. There is sympathetic innervation of the
thymus gland.[20] Sympathetic control exists over
antibody production,[21] and the modulation of
cytokine concentrations.[22]
Cellular immunity. An intact sympathetic nervous system is required to maintain full cellular immunoregulation as denervated mice do not produce and activate, for example,
splenic suppressor T cells, or
thymicNKT cells.[23]
Organ inflammation. Sympathetic innervation of various organs[19] contacts macrophages and dendritic cells and can increase local inflammation including the kidney[24] gut,[25] the skin,[26] and the
synovial joints[27]
Antiinflammation. The vagus nerve carries a parasympathetic
cholinergic antiinflammatory pathway that reduces
proinflammatory cytokines such as
TNF by spleen
macrophages in the
red pulp and the
marginal zone and so the activation of
inflammation.[28][29] This control is in part controlled by direct innervation of body organs such as the spleen.[30] However, the existence of the parasympathetic antiinflammatory nerve pathway is controversial with one reviewer stating: âthere is no evidence for an anti-inflammatory role of the efferent vagus nerve that is independent of the sympathetic nervous system.â[31]
Metabolism
The
liver receives both sympathetic and parasympathetic nervous system innervation.[32]
Insulin. Vagal innervation of the
pancreas controls the release of insulin release from its
beta cells (and this is inhibited by norepinephrine released under sympathetic control from the
splanchnic nerve).[35]
Thyroid hormones can control glucose production via the hypothalamus and its sympathetic and parasympathetic innervation of the liver.[36]
The brains of animals can anticipatorily learn to control cell level physiology such as immunity through
Pavlovian conditioning. In this conditioning, a neutral
stimulussaccharin is paired in a drink with an agent,
cyclophosphamide, that produces an unconditioned response (
immunosuppression). After learning this pairing, the taste of saccharin by itself through neural top down control created immunosuppression, as a new conditioned response.[42] This work was originally done on rats, however, the same conditioning can also occur in humans.[43] The conditioned response happens in the brain with the ventromedial nucleus of the hypothalamus providing the output pathway to the immune system, the amygdala, the input of visceral information, and the insular cortex acquires and creates the conditioned response.[5]
The production of different components of the immune system can be controlled as conditioned responses:
^
abCritchley, H. D. (2005). "Neural mechanisms of autonomic, affective, and cognitive integration". The Journal of Comparative Neurology. 493 (1): 154â166.
doi:
10.1002/cne.20749.
PMID16254997.
S2CID32616395.
^
abVan Eden, C. G.; Buijs, R. M. (2000). "Functional neuroanatomy of the prefrontal cortex: autonomic interactions". Cognition, emotion and autonomic responses: The integrative role of the prefrontal cortex and limbic structures. Progress in Brain Research. Vol. 126. pp. 49â62.
doi:
10.1016/S0079-6123(00)26006-8.
ISBN9780444503329.
PMID11105639.
^RamıÌRez-Amaya, V.; Bermudez-Rattoni, F. (1999). "Conditioned Enhancement of Antibody Production is Disrupted by Insular Cortex and Amygdala but Not Hippocampal Lesions". Brain, Behavior, and Immunity. 13 (1): 46â60.
doi:
10.1006/brbi.1998.0547.
PMID10371677.
S2CID20527835.
^Ohira, H.; Isowa, T.; Nomura, M.; Ichikawa, N.; Kimura, K.; Miyakoshi, M.; Iidaka, T.; Fukuyama, S.; Nakajima, T.; Yamada, J. (2008). "Imaging brain and immune association accompanying cognitive appraisal of an acute stressor". NeuroImage. 39 (1): 500â514.
doi:
10.1016/j.neuroimage.2007.08.017.
PMID17913515.
S2CID26357564.
^
abVlajkoviÄ, S.; NikoliÄ, V.; NikoliÄ, A.; MilanoviÄ, S.; JankoviÄ, B. D. (1994). "Asymmetrical modulation of immune reactivity in left- and right-biased rats after ipsilateral ablation of the prefrontal, parietal and occipital brain neocortex". The International Journal of Neuroscience. 78 (1â2): 123â134.
doi:
10.3109/00207459408986051.
PMID7829286.
^Koch, H. J.; Uyanik, G.; Bogdahn, U.; Ickenstein, G. W. (2006). "Relation between Laterality and Immune Response after Acute Cerebral Ischemia". Neuroimmunomodulation. 13 (1): 8â12.
doi:
10.1159/000092108.
PMID16612132.
S2CID21581127.
^Meador, K. J.; Loring, D. W.; Ray, P. G.; Helman, S. W.; Vazquez, B. R.; Neveu, P. J. (2004). "Role of cerebral lateralization in control of immune processes in humans". Annals of Neurology. 55 (6): 840â844.
doi:
10.1002/ana.20105.
PMID15174018.
S2CID25106845.
^Clow, A.; Lambert, S.; Evans, P.; Hucklebridge, F.; Higuchi, K. (2003). "An investigation into asymmetrical cortical regulation of salivary S-IgA in conscious man using transcranial magnetic stimulation". International Journal of Psychophysiology. 47 (1): 57â64.
doi:
10.1016/S0167-8760(02)00093-4.
PMID12543446.
^Trotter, R. N.; Stornetta, R. L.; Guyenet, P. G.; Roberts, M. R. (2007). "Transneuronal mapping of the CNS network controlling sympathetic outflow to the rat thymus". Autonomic Neuroscience. 131 (1â2): 9â20.
doi:
10.1016/j.autneu.2006.06.001.
PMID16843070.
S2CID25595673.
^Besedovsky, H. O.; Del Rey, A.; Sorkin, E.; Da Prada, M.; Keller, H. H. (1979). "Immunoregulation mediated by the sympathetic nervous system". Cellular Immunology. 48 (2): 346â355.
doi:
10.1016/0008-8749(79)90129-1.
PMID389444.
^Li, X.; Taylor, S.; Zegarelli, B.; Shen, S.; O'Rourke, J.; Cone, R. E. (2004). "The induction of splenic suppressor T cells through an immune-privileged site requires an intact sympathetic nervous system". Journal of Neuroimmunology. 153 (1â2): 40â49.
doi:
10.1016/j.jneuroim.2004.04.008.
PMID15265662.
S2CID41872803.
^Exton, M. S.; Schult, M.; Donath, S.; Strubel, T.; Bode, U.; Del Rey, A.; Westermann, J.; Schedlowski, M. (1999). "Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation". The American Journal of Physiology. 276 (6 Pt 2): R1710âR1717.
doi:
10.1152/ajpregu.1999.276.6.R1710.
PMID10362751.
^Wang, P. Y. T.; Caspi, L.; Lam, C. K. L.; Chari, M.; Li, X.; Light, P. E.; Gutierrez-Juarez, R.; Ang, M.; Schwartz, G. J.; Lam, T. K. T. (2008). "Upper intestinal lipids trigger a gutâbrainâliver axis to regulate glucose production". Nature. 452 (7190): 1012â1016.
Bibcode:
2008Natur.452.1012W.
doi:
10.1038/nature06852.
PMID18401341.
S2CID4425358.
^Engeland, W. (2007). "Functional Innervation of the Adrenal Cortex by the Splanchnic Nerve". Hormone and Metabolic Research. 30 (6/07): 311â314.
doi:
10.1055/s-2007-978890.
PMID9694555.
^Dibona, G. F. (2000). "Neural control of the kidney: Functionally specific renal sympathetic nerve fibers". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 279 (5): R1517âR1524.
doi:
10.1152/ajpregu.2000.279.5.r1517.
PMID11049831.
S2CID8795875.
^Denton, K. M.; Luff, S. E.; Shweta, A.; Anderson, W. P. (2004). "Differential Neural Control of Glomerular Ultrafiltration". Clinical and Experimental Pharmacology and Physiology. 31 (5â6): 380â386.
doi:
10.1111/j.1440-1681.2004.04002.x.
PMID15191417.
S2CID31128522.
^Oberbeck, R.; Kromm, A.; Exton, M. S.; Schade, U.; Schedlowski, M. (2003). "Pavlovian conditioning of endotoxin-tolerance in rats". Brain, Behavior, and Immunity. 17 (1): 20â27.
doi:
10.1016/S0889-1591(02)00031-4.
PMID12615046.
S2CID26029221.
^Pacheco-LĂłpez, G.; Niemi, M. -B.; Kou, W.; HĂ€rting, M.; Del Rey, A.; Besedovsky, H. O.; Schedlowski, M. (2004). "Behavioural endocrine immune-conditioned response is induced by taste and superantigen pairing". Neuroscience. 129 (3): 555â562.
doi:
10.1016/j.neuroscience.2004.08.033.
PMID15541877.
S2CID25300739.
^Exton, M. S.; Von Hörsten, S.; Schult, M.; Vöge, J.; Strubel, T.; Donath, S.; SteinmĂŒller, C.; Seeliger, H.; Nagel, E.; Westermann, J. R.; Schedlowski, M. (1998). "Behaviorally conditioned immunosuppression using cyclosporine A: Central nervous system reduces IL-2 production via splenic innervation". Journal of Neuroimmunology. 88 (1â2): 182â191.
doi:
10.1016/S0165-5728(98)00122-2.
PMID9688340.
S2CID20921504.
^Von Hörsten, S.; Exton, M. S.; Schult, M.; Nagel, E.; Stalp, M.; Schweitzer, G.; Vöge, J.; Del Rey, A.; Schedlowski, M.; Westermann, J. R. (1998). "Behaviorally conditioned effects of Cyclosporine a on the immune system of rats: Specific alterations of blood leukocyte numbers and decrease of granulocyte function". Journal of Neuroimmunology. 85 (2): 193â201.
doi:
10.1016/S0165-5728(98)00011-3.
PMID9630168.
S2CID36315130.
^Exton, M. S.; Von Hörsten, S.; Strubel, T.; Donath, S.; Schedlowski, M.; Westermann, J. (2000). "Conditioned alterations of specific blood leukocyte subsets are reconditionable". Neuroimmunomodulation. 7 (2): 106â114.
doi:
10.1159/000026428.
PMID10686521.
S2CID44539812.
^Exton, M. S.; Bull, D. F.; King, M. G.; Husband, A. J. (1995). "Behavioral conditioning of endotoxin-induced plasma iron alterations". Pharmacology Biochemistry and Behavior. 50 (4): 675â679.
doi:
10.1016/0091-3057(94)00353-X.
PMID7617718.
S2CID24150355.
^Stockhorst, U.; SteingrĂŒber, H. J.; Scherbaum, W. A. (2000). "Classically conditioned responses following repeated insulin and glucose administration in humans". Behavioural Brain Research. 110 (1â2): 143â159.
doi:
10.1016/S0166-4328(99)00192-8.
PMID10802311.
S2CID11190637.
^
abStockhorst, U.; Mahl, N.; Krueger, M.; Huenig, A.; Schottenfeldnaor, Y.; Huebinger, A.; Berresheim, H.; Steingrueber, H.; Scherbaum, W. (2004). "Classical conditioning and conditionability of insulin and glucose effects in healthy humans". Physiology & Behavior. 81 (3): 375â388.
doi:
10.1016/j.physbeh.2003.12.019.
PMID15135009.
S2CID2498317.
^Fehm-Wolfsdorf, G.; Gnadler, M.; Kern, W.; Klosterhalfen, W.; Kerner, W. (1993). "Classically conditioned changes of blood glucose level in humans". Physiology & Behavior. 54 (1): 155â160.
doi:
10.1016/0031-9384(93)90058-N.
PMID8327595.
S2CID35578093.