Correct combination
Case 162
【Discussion】
A bain cell owns dendrites and an axon. It gets varios information from other brain cells through dendrites. It gives an information to other brain cells through an axon. The strength of information is dependent on volume of electric signals. An axon is devided to various branches. A branche can grow longer and make a new synapse and connect to a dendrite from other brain cell (1). The electric signal convey in the synapse is conducted by flow of chemical transmitters. The rapid excitory chemical tranmitter is glutamate and the rapid inhibitory one is γ-amino butyric acid (GABA). Both glutamate and GABA are amino acids created in mitochodria of pre-synapse neurone (dendrite and axon) with assistance of glia cells who are adjacent to neurone. Glia cells create glutamin which are precursors of glutamate and GABA via TCA cycle supplied by glucose (2, 3). Then, the excitory and inhibitory brain function is basically dependent on glutamate and GABA, respectively. However, it is known that there are other chemical transmitters such as dopamine, noradrenalin, serotonin and acetylcholine and so on(4 – 7). Unlike glutamate and GABA, these chemical transmitters are produced in specific regions; dopamine in substantia nigra and ventral tegmental area (VTA); noradrenaline in Locus ceruleus: serotonin in Raphe nucleus.
Pain and thermal signals arise from the receptors of free nerve ending of the skin and enter the posterior horn of the spinal cord as the first neurone. The first neurone transmits the signals to the second neuron via the synapse at the gelatin substance which situates at the posterior horn of the spinal cord. Then, these signals ascend via lateral spinothalamic tract and enter the thalamus (VPL: ventral posterior lateral nucleus). The second neuron transmit the signals to the third neuron via the synapse which situates at VPL nucleus. Eventually, these signals reach the sensory cortex at central posterior area (Brodman 1, 2, 3a, 3b) of the parietal lobe. Thereafter, brain perceives pain and thermal sensation. The chemical transmitter of pain is glutamate.
In mouse studies, mice whose sciatic nerves were injured (a model of chronic pain), were reported to be less tolerant or more sensitive to pain and heat sensation than not only healthy mice but also mice who were siatic-nerve-injured and voluntary excersized mice. It is believed that there is a negative neurone pathway that amygdala (BLA) and prefrontal cortx (mPFC) via glutamate route repress nucleus accumbens (NAc) which function motivation and reward (6, 7). Another negative neurone pathway is that lateral huberna (Lhb) which is controled by raphe nucleus (serotonin decrease) activates retromedial tegmental area (RMTg) via glutamate and then, RMTg suppress function of lateral ventral tegmenta area (VTA) via GAVA (5). Namely, pain experience (hippocampus), pain related fear (amygdala) and negative thoughts (prefrontal cortex) repress function of motivation and rewarding (NAc), leading to strengthen glutamate pathway of thalamus and sensory cortex. Further, anxiety and depression (induced by serotonine decrease in raphe nucleus) activate a neuron pathway of Lhb to RMTg, inducing to repress dopamine passageway via GABA (2 – 4).
Exercise stimulates brain function, especially via acetyl choligenic (Ach; acetyl choline) and monoamine transmitter of noradrenaline and dopamine. Lateral dorsal tegmental area (LDT) activates VTA via Ach which initiates to fire dopamine travelling pathway. VTA stimulates NAc deeply related to motivation and rewarding. NAc stimulate dopamine pathway of the whole cerebrum including prefrontal cortex (positive, disappearing anxiety) and sensory (pain and temperature) cortex at central posterior area, inducing alleviation of pain. Further, another positive pathway is that locus ceruleus (LC) via noradrenaline stimulate amygdala (pleasure nucleus) which followed by activation of prefronatal cortex via glutamate, and sirmultaneously stimulating NAc via a limbic pathway. It eventually strengthens the activity of mesocortico-limbic circuit, inducing allevation of pain.
The thalamus is not merely a station of these sensory routes. It is believed that thalmus make these signals weaken or stenghen and transmit to the sensory area. In other words, these signals can be accomodated in the thalamus. Thalamus is one of the members of limbic system. The degree of pain whether weakened or strengthened can be affected by signals from limbic system.
Limbic structure compose of hippocampus, hypothalamus, thalamus, nucleus accumbence, fornix, cingulate gyrus, amygdala and olfactory cortex. Each component has a specific function and connect together. They own several chemotransmitter routes inside; GABA route, glutamate route, dopamine route, noradrenalin route, serotonin route, acetylcholine route and so on. Their functions initiate, strengthen, soothe, weaken and disappear under control of electric activity. Electric activity is also affected by quality and quantity of chemotransmitter. In other words, brain function is subject to the flowing volume of chemotransmitter in each route.
【Summary】
Brain activity indicates flow of electric signal and the strength of brain activity is equal to electric activity via dendrites and axon. Dendrites and branches of axon connect with synapse. Learning, solving a question and making a new idea might create a new connection between a dendrite and a branch of axon. Various chemical transmitters travel at the synapse. Of these, glutamate and GABA which are produced with assitance of the brain cell and glia cells are conventional chemical transmitters; glutamate, excitory transmitter: GABA, inhibitory transmitter. Meanwhile, dopamine, noradrenaline and acethyl choline are specific transmitters and produced in specific sites.
There are conventional two routes in our brain: glutamate excitory route and GABA inhibitory route. Dopamine, noradrenaline and acethyl choline are used for other exitory routes, competitive to glutamate excitory route. Namely, in the patients with chronic pain, conventional glutamate pathway is stengthened by fear center in amygdala, inducing less motivation and less rewarding in nucleus accumbence. Eventually, pain pathway of glutamete running to sensory cortex is strengthened. Meanwhile, in the patients with chronic pain plus exercise, exercise induces activation of acetylcholine and noradrenaline. Ach is a chemical transmtter of motor neurone and parasympathetic neurone and noradrenaline is a transmitter of sympathetic neurone. Ach from LDT stimulate dopamine pathway: secretion from VTA and activate nucleus accumbens. Nadrenaline from locus ceruleus activate pleasure nucleus of amygdala which also stimulates positive center of prefrontal cortex.
NAc: nucleus accumbens, GABA: γ-amino butyric acid, Lhb: lateral hubenula, RMTg: retromedial tegmental area, VTA: ventral tegmenta area, LDT: lateral dorsal tegmental area, LC: locus ceruleus, orex LHA: lateral hypothalamic area, RN: raphe nucleus, SNc: substantia nigra compact
【References】
1.Ford CP. Control of extracellular dopamine at dendrite and axon terminals. J Neurosci. 2010 19; 30: 6975–6983.
2.Bak LK, et al. The glutamate/GABA–glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer". J. Neurochem. 2006; 98 : 641–53
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4.Kam K, et al. "Excitatory synaptic transmission persists independently of the glutamate–glutamine cycle". J. Neurosci. 2007; 27 (34): 192–200.
5.Jhou, TC, et al. The rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, selectively encodes aversive stimuli and promotes behavioral inhibition. Neuron. 2009; 61: 786–800.
6.Antonio A, et al. "Behavioral Functions of the Mesolimbic Dopaminergic System: an Affective Neuroethological Perspective". Brain Research Reviews. 2017; 56 : 283–321.
7.Katsuya Kami, et al. Activation of mesolimbic reward system via laterodorsal tegmental nucleus and hypothalamus in exercise-induced hypoalgesia. Scientific Reports volume 8, Article number: 11540 (2018)
2019.9.18