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Dopaminergic pathways
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=== Mesocorticolimbic system === [[File:Mesocorticolimbic Circuit.png|thumb|The mesocorticolimbic pathway originates through the VTA and passes through the amygdala, nucleus accumbens, and hippocampus. These functions are relative to memory, emotional regulation, motivation, and reward.]] The [[Mesocorticolimbic circuit|mesocorticolimbic system]] ([[mesocorticolimbic circuit]]) refers to both the [[mesocortical pathway|mesocortical]] and [[mesolimbic pathway|mesolimbic]] pathways.<ref name="projection" /><ref name="MEDRS-quality human review">{{cite journal | vauthors = Doyon WM, Thomas AM, Ostroumov A, Dong Y, Dani JA | title = Potential substrates for nicotine and alcohol interactions: a focus on the mesocorticolimbic dopamine system | journal = Biochemical Pharmacology | volume = 86 | issue = 8 | pages = 1181–93 | date = October 2013 | pmid = 23876345 | pmc = 3800178 | doi = 10.1016/j.bcp.2013.07.007 }}</ref> Both pathways originate at the ventral tegmental area (VTA) which is located in the midbrain. Through separate connections to the prefrontal cortex (mesocortical) and ventral striatum (mesolimbic), the mesocorticolimbic projection has a significant role in learning, motivation, reward, memory and movement.<ref>{{cite journal | vauthors = Yamaguchi T, Wang HL, Li X, Ng TH, Morales M | title = Mesocorticolimbic glutamatergic pathway | journal = The Journal of Neuroscience | volume = 31 | issue = 23 | pages = 8476–90 | date = June 2011 | pmid = 21653852 | pmc = 6623324 | doi = 10.1523/JNEUROSCI.1598-11.2011 }}</ref> Dopamine receptor subtypes, D1 and D2 have been shown to have complementary functions in the mesocorticolimbic projection, facilitating learning in response to both positive and [[negative feedback]].<ref>{{cite journal | vauthors = Verharen JP, Adan RA, Vanderschuren LJ | title = Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making | journal = Neuropsychopharmacology | volume = 44 | issue = 13 | pages = 2195–2204 | date = December 2019 | pmid = 31254972 | pmc = 6897916 | doi = 10.1038/s41386-019-0454-0 }}</ref> Both pathways of the mesocorticolimbic system are associated with [[ADHD]], [[schizophrenia]] and [[addiction]].<ref name="NHM-Cognitive Control">{{cite book|title=Molecular Neuropharmacology: A Foundation for Clinical Neuroscience|vauthors=Malenka RC, Nestler EJ, Hyman SE|publisher=McGraw-Hill Medical|year=2009|isbn=9780071481274|veditors=Sydor A, Brown RY|edition=2nd|location=New York|pages=313–321|chapter=Chapter 13: Higher Cognitive Function and Behavioral Control|quote={{bull}} Executive function, the cognitive control of behavior, depends on the prefrontal cortex, which is highly developed in higher primates and especially humans.<br />{{bull}} Working memory is a short-term, capacity-limited cognitive buffer that stores information and permits its manipulation to guide decision-making and behavior. ...<br /> These diverse inputs and back projections to both cortical and subcortical structures put the prefrontal cortex in a position to exert what is often called “top-down” control or cognitive control of behavior. ... The prefrontal cortex receives inputs not only from other cortical regions, including association cortex, but also, via the thalamus, inputs from subcortical structures subserving emotion and motivation, such as the amygdala (Chapter 14) and ventral striatum (or nucleus accumbens; Chapter 15). ...<br />In conditions in which prepotent responses tend to dominate behavior, such as in drug addiction, where drug cues can elicit drug seeking (Chapter 15), or in attention deficit hyperactivity disorder (ADHD; described below), significant negative consequences can result. ... ADHD can be conceptualized as a disorder of executive function; specifically, ADHD is characterized by reduced ability to exert and maintain cognitive control of behavior. Compared with healthy individuals, those with ADHD have diminished ability to suppress inappropriate prepotent responses to stimuli (impaired response inhibition) and diminished ability to inhibit responses to irrelevant stimuli (impaired interference suppression). ... <!--Inhibitory control brain structures-->Functional neuroimaging in humans demonstrates activation of the prefrontal cortex and caudate nucleus (part of the striatum) in tasks that demand inhibitory control of behavior. ... Early results with structural MRI show thinning of the cerebral cortex in ADHD subjects compared with age-matched controls in prefrontal cortex and posterior parietal cortex, areas involved in working memory and attention.}}</ref><ref name="ADHD 2008 paper">{{cite journal | vauthors = Engert V, Pruessner JC | title = Dopaminergic and noradrenergic contributions to functionality in ADHD: the role of methylphenidate | journal = Current Neuropharmacology | volume = 6 | issue = 4 | pages = 322–8 | date = December 2008 | pmid = 19587853 | pmc = 2701285 | doi = 10.2174/157015908787386069 }}</ref><ref name=":0">{{cite journal | vauthors = Dreyer JL | title = New insights into the roles of microRNAs in drug addiction and neuroplasticity | journal = Genome Medicine | volume = 2 | issue = 12 | pages = 92 | date = December 2010 | pmid = 21205279 | pmc = 3025434 | doi = 10.1186/gm213 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Robison AJ, Nestler EJ | title = Transcriptional and epigenetic mechanisms of addiction | journal = Nature Reviews. Neuroscience | volume = 12 | issue = 11 | pages = 623–37 | date = October 2011 | pmid = 21989194 | pmc = 3272277 | doi = 10.1038/nrn3111 }}</ref> ==== Mesocortical pathway ==== The [[mesocortical pathway]] projects from the ventral tegmental area to the prefrontal cortex ([[Ventral tegmental area|VTA]] → [[Prefrontal cortex]]). This pathway is involved in cognition and the regulation of [[executive function]]s (e.g., attention, working memory, [[inhibitory control]], planning, etc.) This intricate neural circuit serves as a crucial communication route within the brain, facilitating the transmission of dopamine, a neurotransmitter associated with reward, motivation, and cognitive control.<ref>{{Cite journal |last=Keyser |first=J. De |date=1990 |title=The mesoneocortical dopamine neuron system |url=https://doi.org/10.1212/WNL.40.11.1660 |journal=Neurology |volume=40 |issue=11 |pages=1660–1662|doi=10.1212/WNL.40.11.1660 |pmid=2234421 |s2cid=12241566 |url-access=subscription }}</ref> The prefrontal cortex, being a central hub for executive functions, relies on the input from the mesocortical pathway to modulate and fine-tune cognitive processes essential for goal-directed behavior and decision-making.<ref>{{Cite journal |last1=Floresco |first1=Stan B. |last2=Magyar |first2=Orsolya |date=2006 |title=Mesocortical dopamine modulation of executive functions: beyond working memory |url=https://doi.org/10.1007/s00213-006-0404-5 |journal=Psychopharmacology |volume=188 |issue=4 |pages=567–585 |doi=10.1007/s00213-006-0404-5 |pmid=16670842 |s2cid=24568869 |via=SpringerLink|url-access=subscription }}</ref> Dysregulation of the neurons in this pathway has been connected to ADHD.<ref name="ADHD 2008 paper" /> ==== Mesolimbic pathway ==== Referred to as the reward pathway, [[mesolimbic pathway]] projects from the ventral tegmental area to the ventral striatum (VTA → [[Ventral striatum]] [<nowiki/>[[nucleus accumbens]] and [[olfactory tubercle]]]).<ref name=":0" /> When a reward is anticipated, the firing rate of dopamine neurons in the mesolimbic pathway increases.<ref name=":1">{{cite journal | vauthors = Salamone JD, Correa M | title = The mysterious motivational functions of mesolimbic dopamine | journal = Neuron | volume = 76 | issue = 3 | pages = 470–85 | date = November 2012 | pmid = 23141060 | pmc = 4450094 | doi = 10.1016/j.neuron.2012.10.021 }}</ref> The mesolimbic pathway is involved with [[incentive salience]], [[motivation]], reinforcement learning, fear and other cognitive processes.<ref name="NHM pathways" /><ref name="ADHD 2008 paper" /><ref>{{cite journal | vauthors = Pezze MA, Feldon J | title = Mesolimbic dopaminergic pathways in fear conditioning | journal = Progress in Neurobiology | volume = 74 | issue = 5 | pages = 301–20 | date = December 2004 | pmid = 15582224 | doi = 10.1016/j.pneurobio.2004.09.004 | s2cid = 36091832 }}</ref> In animal studies, depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g., the number of lever presses for nicotine or time searching for food).<ref name=":1" /> Research is ongoing to determine the role of the mesolimbic pathway in the perception of pleasure.<ref name="Pleasure system">{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Pleasure systems in the brain | journal = Neuron | volume = 86 | issue = 3 | pages = 646–64 | date = May 2015 | pmid = 25950633 | pmc = 4425246 | doi = 10.1016/j.neuron.2015.02.018 | quote = To summarize: the emerging realization that many diverse pleasures share overlapping brain substrates; better neuroimaging maps for encoding human pleasure in orbitofrontal cortex; identification of hotspots and separable brain mechanisms for generating ‘liking’ and ‘wanting’ for the same reward; identification of larger keyboard patterns of generators for desire and dread within NAc, with multiple modes of function; and the realization that dopamine and most ‘pleasure electrode’ candidates for brain hedonic generators probably did not cause much pleasure after all. }}</ref><ref>{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Neuroscience of affect: brain mechanisms of pleasure and displeasure | journal = Current Opinion in Neurobiology | volume = 23 | issue = 3 | pages = 294–303 | date = June 2013 | pmid = 23375169 | pmc = 3644539 | doi = 10.1016/j.conb.2013.01.017 }}</ref><ref>{{Cite book| vauthors = Nestler EJ |url=https://www.worldcat.org/oclc/1191071328|title=Molecular neuropharmacology a foundation for clinical neuroscience|date=2020|others=Paul J. Kenny, Scott J. Russo, Anne, MD Schaefer|isbn=978-1-260-45691-2|edition=Fourth |location=New York|oclc=1191071328}}</ref><ref>{{cite journal | vauthors = Berridge KC, Kringelbach ML | title = Pleasure systems in the brain | journal = Neuron | volume = 86 | issue = 3 | pages = 646–64 | date = May 2015 | pmid = 25950633 | pmc = 4425246 | doi = 10.1016/j.neuron.2015.02.018 }}</ref> [[File:Nigrostriatal Pathway.png|thumb|The nigrostriatal pathway is involved in behaviors relating to movement and motivation.]]
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