Medium spiny neuron
|Medium spiny neuron|
|Function||Inhibitory projection neuron|
|Presynaptic connections||Dopaminergic: VTA, SNc
Glutamatergic: PFC, hippocampus, amygdala, thalamus, other
|Postsynaptic connections||Other basal ganglia structures|
|NeuroLex ID||Medium Spiny Neuron|
Medium spiny neurons (MSNs), also known as spiny projection neurons, are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes (characteristic types): D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.
Direct pathway MSNs excite their ultimate basal ganglia output structure (e.g., the thalamus) and promote associated behaviors; these neurons express D1-type dopamine receptors, adenosine A1 receptors, dynorphin peptides, and substance P peptides. Indirect pathway MSNs inhibit their output structure and in turn inhibit associated behaviors; these neurons express D2-type dopamine receptors, adenosine A2A receptors (A2A), DRD2–A2A heterotetramers, and enkephalin. Both types express glutamate receptors (NMDAR and AMPAR), cholinergic receptors (M1 and M4) and CB1 receptors are expressed on the somatodendritic area of both MSN types. A subpopulation of MSNs contain both D1-type and D2-type receptors, with approximately 40% of striatal MSNs expressing both DRD1 and DRD2 mRNA. In the nucleus accumbens (NAcc), these mixed-type MSNs that contain both D1-type and D2-type receptors are mostly contained in the NAcc shell.
The dorsal striatal MSNs play a key role in initiating and controlling movements of the body, limbs, and eyes. The ventral striatal MSNs play a key role in motivation, reward, reinforcement, and aversion. Dorsal and ventral medium spiny neuron subtypes (i.e., direct D1-type and indirect D2-type) are identical phenotypes, but their output connections differ.
Appearance and location
The medium spiny neurons are medium-sized neurons (~15 microns in diameter, ~12-13 microns in the mouse) with large and extensive dendritic trees (~500 microns in diameter). Striatal direct pathway MSNs (dMSNs) project directly to the globus pallidus internal (GPi) and substantia nigra pars reticulata (SNr) whereas striatal indirect pathway MSNs (iMSNs) ultimately project to these two structures via an intermediate connection to the globus pallidus external (GPe) and ventral pallidum (VP). The GPe and VP send a GABAergic projection to the subthalamic nucleus, which then sends glutamatergic projections to the GPi and SNr. Both the GPi and SNr send inhibitory projections to nuclei within the thalamus.
MSNs are inhibitory GABAergic neurons, but the effect of direct MSNs (dMSNs) and indirect MSNs (iMSNs) on their ultimate output structures differs: dMSNs excite, while iMSNs inhibit, their basal ganglia output structures (e.g., the thalamus). Within the basal ganglia, there are several complex circuits of neuronal loops all of which include medium spiny neurons.
The cortical, thalamic, and brain-stem inputs that arrive at the medium spiny neurons show a vast divergence in that each incoming axon forms contacts with many spiny neurons and each spiny neuron receives a vast amount of input from different incoming axons. Since these inputs are glutamatergic they exhibit an excitatory influence on the inhibitory medium spiny neurons.
There are also interneurons in the striatum which regulate the excitability of the medium spiny neurons. The synaptic connections between a particular GABAergic interneuron, the parvalbumin expressing fast-spiking interneuron, and spiny neurons are close to the spiny neurons' soma, or cell body. Recall that excitatory postsynaptic potentials caused by glutamatergic inputs at the dendrites of the spiny neurons only cause an action potential when the depolarization wave is strong enough upon entering the cell soma. Since the fast-spiking interneurons influence is located so closely to this critical gate between the dendrites and the soma, they can readily regulate the generation of an action potential. Additionally, other types of GABAergic interneurons make connections with the spiny neurons. These include interneurons that express tyrosine hydroxylase and neuropeptide Y.
Dorsal striatal MSNs
The direct pathway of movement within the basal ganglia makes excitatory inputs coming from e.g. the cortex cause a net excitation of upper motor neurons in the motor areas of the cortex. In the direct pathway, the medium spiny neurons project to the internal division of the globus pallidus which in turn sends axons to the substantia nigra pars reticulata (SNr) and the ventroanterior and ventrolateral thalamus (VTh). The SNr projects to the deep layer of the superior colliculus thus controlling fast eye movements (saccades). The VTh projects to upper motor neurons in the primary motor cortex (precentral gyrus).
Neurons in the globus pallidus are also inhibitory, thus inhibiting the excitatory neurons in the SNr and VTh. But in contrast to the medium spiny neurons, globus pallidus neurons are tonically active when not activated. Thus in the absence of cortical stimulation, SNr and VTh neurons are tonically inhibited thus preventing involuntary spontaneous movements.
Once the medium spiny neurons receive sufficient excitatory cortical input, they are excited and fire a burst of inhibitory action potentials to globus pallidus neurons. These tonically active neurons are then inhibited, causing their inhibitory influence on SNr and VTh to decline. Thus SNr and VTh neurons are disinhibited resulting in net excitement causing them to activate upper motor neurons commanding a movement. Cortical activation of the basal ganglia thus eventually results in excitement (disinhibition) of motor neurons causing movement to take place.
In the indirect pathway of movement, excitation (e.g. cortical input to the basal ganglia) results in net inhibition of upper motor neurons. In this pathway the medium spiny neurons in the striatum project to the external segment of the globus pallidus. These neurons in turn project to the internal segment of the globus pallidus and to the subthalamic nuclei which forms a feedback loop to the internal globus pallidus.
Cortical excitement of medium spiny neurons causes them to inhibit external globus pallidus neurons. These tonically inhibiting neurons thus decrease their inhibitory influence on the internal globus pallidus and the subthalamic nuclei.
Globus pallidus neurons tonically inhibit VTh and SNr neurons. Since the inhibitory influence from the external globus pallidus is now reduced, these neurons show stronger activity thus increasing their inhibition of SNr and VTh neurons.
The projections of the external globus pallidus to the subthalamic nuclei causes these neurons to increase their firing rate, since the globus pallidus neurons are inhibited by medium spiny neurons. The subthalamic nuclei have excitatory projections to the internal globus pallidus thus causing the internal globus pallidus neurons to increase their inhibititory influence on SNr and VTh.
Eventually excitatory inputs from the cortex results in net inhibition of upper motor neurons thus preventing them from initiating a movement.
Ventral striatal MSNs
The direct pathway of the ventral striatum within the basal ganglia mediates reward-based learning and appetitive motivational salience, aka incentive salience, which is assigned to rewarding stimuli.
- Yager LM, Garcia AF, Wunsch AM, Ferguson SM (August 2015). "The ins and outs of the striatum: Role in drug addiction". Neuroscience. 301: 529–541. doi:10.1016/j.neuroscience.2015.06.033. PMC . PMID 26116518.
[The striatum] receives dopaminergic inputs from the ventral tegmental area (VTA) and the substantia nigra (SNr) and glutamatergic inputs from several areas, including the cortex, hippocampus, amygdala, and thalamus (Swanson, 1982; Phillipson and Griffiths, 1985; Finch, 1996; Groenewegen et al., 1999; Britt et al., 2012). These glutamatergic inputs make contact on the heads of dendritic spines of the striatal GABAergic medium spiny projection neurons (MSNs) whereas dopaminergic inputs synapse onto the spine neck, allowing for an important and complex interaction between these two inputs in modulation of MSN activity ... It should also be noted that there is a small population of neurons in the NAc that coexpress both D1 and D2 receptors, though this is largely restricted to the NAc shell (Bertran- Gonzalez et al., 2008). ... Neurons in the NAc core and NAc shell subdivisions also differ functionally. The NAc core is involved in the processing of conditioned stimuli whereas the NAc shell is more important in the processing of unconditioned stimuli; Classically, these two striatal MSN populations are thought to have opposing effects on basal ganglia output. Activation of the dMSNs causes a net excitation of the thalamus resulting in a positive cortical feedback loop; thereby acting as a ‘go’ signal to initiate behavior. Activation of the iMSNs, however, causes a net inhibition of thalamic activity resulting in a negative cortical feedback loop and therefore serves as a ‘brake’ to inhibit behavior ... there is also mounting evidence that iMSNs play a role in motivation and addiction (Lobo and Nestler, 2011; Grueter et al., 2013). For example, optogenetic activation of NAc core and shell iMSNs suppressed the development of a cocaine CPP whereas selective ablation of NAc core and shell iMSNs ... enhanced the development and the persistence of an amphetamine CPP (Durieux et al., 2009; Lobo et al., 2010). These findings suggest that iMSNs can bidirectionally modulate drug reward. ... Together these data suggest that iMSNs normally act to restrain drug-taking behavior and recruitment of these neurons may in fact be protective against the development of compulsive drug use.
- Ferré S, Lluís C, Justinova Z, Quiroz C, Orru M, Navarro G, Canela EI, Franco R, Goldberg SR (June 2010). "Adenosine-cannabinoid receptor interactions. Implications for striatal function". Br. J. Pharmacol. 160 (3): 443–453. doi:10.1111/j.1476-5381.2010.00723.x. PMC . PMID 20590556.
Two classes of MSNs, which are homogeneously distributed in the striatum, can be differentiated by their output connectivity and their expression of dopamine and adenosine receptors and neuropeptides. In the dorsal striatum (mostly represented by the nucleus caudate-putamen), enkephalinergic MSNs connect the striatum with the globus pallidus (lateral globus pallidus) and express the peptide enkephalin and a high density of dopamine D2 and adenosine A2A receptors (they also express adenosine A1 receptors), while dynorphinergic MSNs connect the striatum with the substantia nigra (pars compacta and reticulata) and the entopeduncular nucleus (medial globus pallidus) and express the peptides dynorphin and substance P and dopamine D1 and adenosine A1 but not A2A receptors (Ferréet al., 1997; Gerfen, 2004; Quiroz et al., 2009). These two different phenotypes of MSN are also present in the ventral striatum (mostly represented by the nucleus accumbens and the olfactory tubercle). However, although they are phenotypically equal to their dorsal counterparts, they have some differences in terms of connectivity. First, not only enkephalinergic but also dynorphinergic MSNs project to the ventral counterpart of the lateral globus pallidus, the ventral pallidum, which, in fact, has characteristics of both the lateral and medial globus pallidus in its afferent and efferent connectivity. In addition to the ventral pallidum, the medial globus pallidus and the substantia nigra-VTA, the ventral striatum sends projections to the extended amygdala, the lateral hypothalamus and the pedunculopontine tegmental nucleus. Finally, unlike the dorsal striatum, the substantia nigra pars reticulata is not a main target area for the ventral striatum, which preferentially directs its midbrain output to the substantia nigra pars compacta and the VTA (Heimer et al., 1995; Robertson and Jian, 1995; Ferré, 1997). It is also important to mention that a small percentage of MSNs have a mixed phenotype and express both D1 and D2 receptors (Surmeier et al., 1996). ... A2A receptors are localized predominantly postsynaptically in the dendritic spine of enkephalinergic but not dynorphinergic MSNs, co-localized with D2 receptors ... Presynaptically, CB1 receptors are localized in GABAergic terminals of interneurons or collaterals from MSNs, and also in glutamatergic but not in dopaminergic terminals ... Postsynaptically, CB1 receptors are localized in the somatodendritic area of MSN (Rodriguez et al., 2001; Pickel et al., 2004; 2006; Köfalvi et al., 2005) and both enkephalinergic and dynorphinergic MSNs express CB1 receptors (Martín et al., 2008).
- Nishi A, Kuroiwa M, Shuto T (July 2011). "Mechanisms for the modulation of dopamine d(1) receptor signaling in striatal neurons". Front Neuroanat. 5: 43. doi:10.3389/fnana.2011.00043. PMC . PMID 21811441.
Dopamine plays critical roles in the regulation of psychomotor functions in the brain (Bromberg-Martin et al., 2010; Cools, 2011; Gerfen and Surmeier, 2011). The dopamine receptors are a superfamily of heptahelical G protein-coupled receptors, and are grouped into two categories, D1-like (D1, D5) and D2-like (D2, D3, D4) receptors, based on functional properties to stimulate adenylyl cyclase (AC) via Gs/olf and to inhibit AC via Gi/o, respectively ... It has been demonstrated that D1 receptors form the hetero-oligomer with D2 receptors, and that the D1–D2 receptor hetero-oligomer preferentially couples to Gq/PLC signaling (Rashid et al., 2007a,b). The expression of dopamine D1 and D2 receptors are largely segregated in direct and indirect pathway neurons in the dorsal striatum, respectively (Gerfen et al., 1990; Hersch et al., 1995; Heiman et al., 2008). However, some proportion of medium spiny neurons are known to expresses both D1 and D2 receptors (Hersch et al., 1995). Gene expression analysis using single cell RT-PCR technique estimated that 40% of medium spiny neurons express both D1 and D2 receptor mRNA (Surmeier et al., 1996).
- Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, Lluís C, Casadó V, Volkow ND (June 2015). "Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer". Neuropharmacology. 104: 154–60. doi:10.1016/j.neuropharm.2015.05.028. PMID 26051403.
caffeine-induced increases in D2R availability in the ventral striatum were associated with caffeine-induced increases in alertness (Volkow et al., 2015). ... Fig. 2. Brain maps showing significant differences in D2R/D3R availability (nondisplaceable binding potential or BPND), between placebo and caffeine
- Benarroch, Eduardo E. (2012-07-17). "Effects of acetylcholine in the striatum. Recent insights and therapeutic implications". Neurology. 79 (3): 274–281. doi:10.1212/WNL.0b013e31825fe154. ISSN 1526-632X. PMID 22802594.
- Gardoni F, Bellone C (2015). "Modulation of the glutamatergic transmission by Dopamine: a focus on Parkinson, Huntington and Addiction diseases". Front Cell Neurosci. 9: 25. doi:10.3389/fncel.2015.00025. PMC . PMID 25784855.
In particular in the striatum the release of DA rapidly influences synaptic transmission modulating both AMPA and NMDA receptors.
- Reinius B; et al. (March 27, 2015). "Conditional targeting of medium spiny neurons in the striatal matrix". Front. Behav. Neurosci. 9. doi:10.3389/fnbeh.2015.00071.
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- Tepper, JM; Wilson, CJ; Koós, T (Aug 2008). "Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons". Brain Res Rev. 58 (2): 272–81. doi:10.1016/j.brainresrev.2007.10.008. PMC . PMID 18054796.
- Ibáñez-Sandoval, O; Tecuapetla, F; Unal, B; Shah, F; Koós, T; Tepper, JM (May 2010). "Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum". J Neurosci. 30 (20): 6999–7016. doi:10.1523/JNEUROSCI.5996-09.2010. PMC . PMID 20484642.
- Tepper, JM; Tecuapetla, F; Koós, T; Ibáñez-Sandoval, O (Dec 2010). "Heterogeneity and diversity of striatal GABAergic interneurons". Front Neuroanat. 4: 150. doi:10.3389/fnana.2010.00150. PMC . PMID 21228905.
- English, DF; Ibanez-Sandoval, O; Stark, E; Tecuapetla, F; Buzsáki, G; Deisseroth, K; Tepper, JM; Koos, T (Dec 2011). "GABAergic circuits mediate the reinforcement-related signals of striatal cholinergic interneurons". Nat Neurosci. 15 (1): 123–30. doi:10.1038/nn.2984. PMC . PMID 22158514.
- Ibáñez-Sandoval, O; Tecuapetla, F; Unal, B; Shah, F; Koós, T; Tepper, JM (Nov 2011). "A novel functionally distinct subtype of striatal neuropeptide Y interneuron". J Neurosci. 31 (46): 16757–69. doi:10.1523/JNEUROSCI.2628-11.2011. PMC . PMID 22090502.
- Baliki MN, Mansour A, Baria AT, Huang L, Berger SE, Fields HL, Apkarian AV (October 2013). "Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain". J. Neurosci. 33 (41): 16383–16393. doi:10.1523/JNEUROSCI.1731-13.2013. PMC . PMID 24107968.
Recent evidence indicates that inactivation of D2 receptors, in the indirect striatopallidal pathway in rodents, is necessary for both acquisition and expression of aversive behavior, and direct pathway D1 receptor activation controls reward-based learning (Hikida et al., 2010; Hikida et al., 2013). It seems we can conclude that direct and indirect pathways of the NAc, via D1 and D2 receptors, subserve distinct anticipation and valuation roles in the shell and core of NAc, which is consistent with observations regarding spatial segregation and diversity of responses of midbrain dopaminergic neurons for rewarding and aversive conditions, some encoding motivational value, others motivational salience, each connected with distinct brain networks and having distinct roles in motivational control (Bromberg-Martin et al., 2010; Cohen et al., 2012; Lammel et al., 2013). ... Thus, the previous results, coupled with the current observations, imply that the NAc pshell response reflects a prediction/anticipation or salience signal, and the NAc pcore response is a valuation response (reward predictive signal) that signals the negative reinforcement value of cessation of pain (i.e., anticipated analgesia).
- General references
- Bear, Mark F; Connors, Barry W.; Paradiso, Michael A., Neuroscience, Exploring the Brain, Lippincott Williams & Wilkins; Third Edition (February 1, 2006). ISBN 0-7817-6003-8
- Kandel, E. (2006). Principles of neuroscience. (5th Ed.) Wadsworth
- Purves, D., Augustine, G.J. & Fitzpatrick, D. (2004). Neuroscience. (3rd Ed.). SInauer Associates
- Cell Centered Database - Medium spiny neuron