Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of
GABAergic inhibitory cell representing 95% of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s within the human
striatum
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives gluta ...
, a
basal ganglia
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...
structure.
Medium spiny neurons have two primary
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...
s (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 (such as the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
) and promote associated behaviors;
these neurons express
D1-type dopamine receptors,
adenosine A1 receptor
The adenosine A1 receptor is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.
Biochemistry
A1 receptors are implicated in sleep promotion by inhibiting wake-promoting cholinergic ne ...
s,
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 receptor
The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.
Structure
This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane al ...
s (A2A),
heterotetramer
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer c ...
s, and
enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephal ...
.
Both types express
glutamate receptor
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...
s (
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
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hyp ...
(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
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...
s, 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 (SNpr) 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
The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the ...
, which then sends glutamatergic projections to the GPi and SNpr.
Both the GPi and SNpr send inhibitory projections to nuclei within the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
.
Function
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
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all direct ...
).
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
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells ...
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
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
and
neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. NPY has been identified as the most abundant peptide present in the ma ...
.
Dorsal striatal MSNs
Direct pathway
Anatomy
The
direct pathway within the basal ganglia receives excitatory input from the cortex, thalamus, and other brain regions. In the direct pathway, medium spiny neurons project to the
internal division of the globus pallidus (GPi) or the
substantia nigra pars reticula (SNpr or SNr). These nuclei project to the deep layer of the
superior colliculus and control fast
eye movements
Eye movement includes the voluntary or involuntary movement of the eyes. Eye movements are used by a number of organisms (e.g. primates, rodents, flies, birds, fish, cats, crabs, octopus) to fixate, inspect and track visual objects of inter ...
(saccades), and also project to the ventral thalamus, which in turn projects to upper motor neurons in the
primary motor cortex (precentral gyrus).
The SNr and GPi outputs are both tonically active inhibitory nuclei and are thus constantly inhibiting the thalamus (and thus motor cortex). However, transient activity in (inhibitory) direct pathway medium spiny neurons ultimately disinhibits thalamus projections to the motor cortex and enables movement.
Indirect pathway
Anatomy
The
indirect pathway also receives excitatory input from various brain regions. Indirect pathway medium spiny neurons project to the
external segment of the globus pallidus (GPe). Like the GPi, the GPe is a tonically active inhibitory nucleus. The GPe projects to the excitatory
subthalamic nucleus
The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the ...
(STN), which in turn projects to the GPi and SNr.
When the indirect pathway is not activated, activity in the STN is suppressed by the GPe, which translates to decreased SNr/GPi activity downstream and thus increased thalamic and motor cortex neuron activity. When indirect pathway neurons fire, GPe neurons are inhibited, which disinhibits the STN. The STN then excites SNr/GPi neurons, suppressing thalamus/motor cortex activity.
Functional distinctions
Classic models of
striatal
The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
function have posited that activation of the direct pathway leads to movement, whereas activation of the indirect pathway leads to the termination of movement. This model is supported by experiments demonstrating that
optogenetically stimulating direct pathway medium spiny neurons increases locomotion, whereas stimulating indirect pathway medium spiny neurons inhibits locomotion. The balance of direct/indirect activity in movement is supported by evidence from
neurodegenerative disorders, including
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...
(PD), which is characterized by loss of
dopamine neurons projecting to the striatum,
hypoactivity in direct pathway and hyperactivity in indirect pathway neurons, along with motor dysfunction. This results in loss of normal action selection, as loss of dopamine drives activity in the indirect pathway, globally inhibiting all motor paradigms. This may explain impaired action initiation, slowed actions (
bradykinesia), and impaired voluntary motor initiation in Parkinson's patients. On the other hand,
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an uns ...
, which is characterized by preferential degradation of indirect pathway medium spiny neurons, results in unwanted movements (
chorea) that may result from impaired movement inhibition and predominant direct pathway activity. An alternative related hypothesis is that the striatum controls action initiation and selection via a ’center-surround’ architecture, where activation of a subset of direct pathway neurons initiates movements while closely related motor patterns represented by surrounding neurons are inhibited by
lateral inhibition via indirect pathway neurons. This specific hypothesis is supported by recent
calcium-imaging work showing that direct and indirect pathway medium spiny neurons encoding specific actions are located in spatially organized ensembles.
Despite the abundance of evidence for the initiation/termination model, recent evidence using
transgenic mice expressing calcium indicators in either the direct or indirect pathway demonstrated that both pathways are active at action initiation, but neither are active during inactivity, a finding which has been replicated using simultaneous two-channel calcium imaging. This has led to somewhat of a paradigm shift in models of striatal functioning, such that newer models posit that the direct pathway facilitates wanted movements, whereas the indirect pathway simultaneously inhibits unwanted movements. Indeed, more sophisticated techniques and analyses, such as state-dependent optogenetics, have revealed that both pathways are heavily involved in action sequence execution, and that specifically, both striatal pathways are involved in element-level action control. However, direct pathway medium spiny neurons mostly signal sequence initiation/termination and indirect pathway medium spiny neurons may signal switching between subsequences of a given action sequence. Other evidence suggests that the direct and indirect pathway oppositely influence the termination of movement—specifically, the relative timing of their activity determines if an action will be terminated.
Recent experiments have established that the direct and indirect pathways of the dorsal striatum are not solely involved in movement. Initial experiments in an
intracranial self-stimulation paradigm suggested opposing roles in
reinforcement for the two pathways; specifically, stimulation of direct pathway medium spiny neurons was found to be reinforcing, whereas stimulation of indirect pathway medium spiny neurons was aversive. However, a subsequent study (using more physiologically relevant stimulation parameters) found that direct and indirect pathway stimulation was reinforcing, but that pathway-specific stimulation resulted in the development of different action strategies.
Regardless, these studies suggest a critical role for reinforcement in the dorsal striatum, as opposed to the striatum only serving a role in movement control.
Ventral striatal MSNs
Direct pathway
The direct pathway of the ventral striatum within the basal ganglia mediates reward-based learning and appetitive
incentive salience, which is assigned to
rewarding stimuli.
Indirect pathway
The indirect pathway of the ventral striatum within the basal ganglia mediates aversion-based learning and aversive motivational salience, which is assigned to
aversive stimuli.
References
Further reading
* Bear, Mark F; Connors, Barry W.; Paradiso, Michael A.
''Neuroscience, Exploring the Brain'' Lippincott Williams & Wilkins; Third Edition (1 February 2006).
* 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{{refend
External links
NIF Search – Medium Spiny Neuronvia the
Neuroscience Information Framework
Neurons
Addiction
Basal ganglia