Editing Cerebellum (section)

===Microanatomy===
Two types of neuron play dominant roles in the cerebellar circuit: [[Purkinje cell]]s and [[Cerebellum granule cell|granule cell]]s. Three types of [[axon]]s also play dominant roles: [[mossy fiber (cerebellum)|mossy fiber]]s and [[climbing fiber]]s (which enter the cerebellum from outside), and [[parallel fiber]]s (which are the axons of granule cells). There are two main pathways through the cerebellar circuit, originating from mossy fibers and climbing fibers, both eventually terminating in the deep cerebellar nuclei.<ref name=SOB/>

Mossy fibers project directly to the deep nuclei, but also give rise to the following pathway: mossy fibers → granule cells → parallel fibers → Purkinje cells → deep nuclei. Climbing fibers project to Purkinje cells and also send collaterals directly to the deep nuclei.<ref name=SOB/> The mossy fiber and climbing fiber inputs each carry fiber-specific information; the cerebellum also receives [[dopamine]]rgic, [[serotonin|serotonergic]], [[norepinephrine|noradrenergic]], and [[acetylcholine|cholinergic]] inputs that presumably perform global modulation.<ref>{{cite journal | vauthors = Schweighofer N, Doya K, Kuroda S | title = Cerebellar aminergic neuromodulation: towards a functional understanding | journal = Brain Research. Brain Research Reviews | volume = 44 | issue = 2–3 | pages = 103–16 | date = March 2004 | pmid = 15003388 | doi = 10.1016/j.brainresrev.2003.10.004 | s2cid = 7352039 }}</ref>

The cerebellar cortex is divided into three layers. At the bottom lies the thick granular layer, densely packed with granule cells, along with [[interneuron]]s, mainly [[Golgi cell]]s but also including [[Lugaro cell]]s and [[unipolar brush cell]]s. In the middle lies the Purkinje layer, a narrow zone that contains the cell bodies of Purkinje cells and [[Radial glial cell|Bergmann glial cell]]s. At the top lies the molecular layer, which contains the flattened [[dendrite|dendritic]] trees of Purkinje cells, along with the huge array of parallel fibers penetrating the Purkinje cell dendritic trees at right angles. This outermost layer of the cerebellar cortex also contains two types of inhibitory interneuron: [[stellate cell]]s and [[basket cell]]s. Both stellate and basket cells form [[gamma-Aminobutyric acid|GABAergic]] synapses onto Purkinje cell dendrites.<ref name=SOB/>
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|caption1=Microcircuitry of the cerebellum<br />{{hidden|Abbreviations and representations|{{bull}}(+): Excitatory connection<br />{{bull}}(-): Inhibitory connection<br />{{bull}}MF: [[Mossy fiber (cerebellum)|Mossy fiber]]<br />{{bull}}DCN: [[Deep cerebellar nuclei]]<br />{{bull}}IO: [[Inferior olivary nucleus|Inferior olive]]<br />{{bull}}CF: [[Climbing fiber]]<br />{{bull}}CFC: Climbing fiber collateral<br />{{bull}}GC: [[granule cell (cerebellum)|Granule cell]]<br />{{bull}}PF: [[Parallel fiber]]<br />{{bull}}PC: [[Purkinje cell]]<br />{{bull}}GgC: [[Golgi cell]]<br />{{bull}}SC: [[Stellate cell]]<br />{{bull}}BC: [[Basket cell]]| headerstyle=background:#ccccff | style=text-align:center; }}
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|caption2=Transverse section of a cerebellar [[folium (brain)|folium]], showing principal cell types and connections
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==== Layers of the cerebellar cortex ====
===== Molecular layer =====
The top, outermost layer of the cerebellar cortex is the molecular layer. This layer contains the flattened [[dendrite|dendritic trees]] of Purkinje cells, and the huge array of parallel fibers, from the granular layer, that penetrate the Purkinje cell dendritic trees at right angles. The molecular layer also contains two types of inhibitory interneuron: [[stellate cell]]s and [[basket cell]]s. Both stellate and basket cells form [[gamma-Aminobutyric acid|GABAergic]] synapses onto Purkinje cell dendrites.<ref name=SOB/>

===== Purkinje layer =====
[[File:PCP4 immunohistochemistry in human cerebellum.jpg|thumb|upright=0.8|Purkinje cells in the human cerebellum (in orange, from top to bottom 40X, 100X and 200X magnification) stained according to published methods<ref name="Felizola et al">{{cite journal | vauthors = Felizola SJ, Nakamura Y, Ono Y, Kitamura K, Kikuchi K, Onodera Y, Ise K, Takase K, Sugawara A, Hattangady N, Rainey WE, Satoh F, Sasano H | title = PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues | journal = Journal of Molecular Endocrinology | volume = 52 | issue = 2 | pages = 159–67 | date = April 2014 | pmid = 24403568 | pmc = 4103644 | doi = 10.1530/JME-13-0248 }}</ref>]]
[[Purkinje cell]]s are among the most distinctive neurons in the brain, and one of the earliest types to be recognized—they were first described by the Czech anatomist [[Jan Evangelista Purkyně]] in 1837. They are distinguished by the shape of their dendritic tree: the dendrites branch very profusely, but are severely flattened in a plane perpendicular to the cerebellar folds. Thus, the dendrites of a Purkinje cell form a dense planar net, through which parallel fibers pass at right angles.<ref name=SOB>{{cite book |title=The Synaptic Organization of the Brain | veditors = Shepherd GM |chapter=Ch. 7 ''Cerebellum'' |year=2004 |publisher=Oxford University Press |location=New York |isbn=978-0-19-515955-4 |vauthors=Llinas RR, Walton KD, Lang EJ }}</ref> The dendrites are covered with [[dendritic spine]]s, each of which receives synaptic input from a parallel fiber. Purkinje cells receive more synaptic inputs than any other type of cell in the brain—estimates of the number of spines on a single human Purkinje cell run as high as 200,000.<ref name=SOB/> The large, spherical cell bodies of Purkinje cells are packed into a narrow layer (one cell thick) of the cerebellar cortex, called the ''Purkinje layer''. After emitting collaterals that affect nearby parts of the cortex, their axons travel into the [[deep cerebellar nuclei]], where they make on the order of 1,000 contacts each with several types of nuclear cells, all within a small domain. Purkinje cells use [[GABA]] as their neurotransmitter, and therefore exert inhibitory effects on their targets.<ref name=SOB/>

Purkinje cells form the heart of the cerebellar circuit, and their large size and distinctive activity patterns have made it relatively easy to study their response patterns in behaving animals using [[extracellular field potential|extracellular]] recording techniques. Purkinje cells normally emit [[action potential]]s at a high rate even in the absence of the synaptic input. In awake, behaving animals, mean rates averaging around 40&nbsp;Hz are typical. The spike trains show a mixture of what are called simple and complex spikes. A simple spike is a single action potential followed by a [[Refractory period (physiology)|refractory period]] of about 10&nbsp;ms; a complex spike is a stereotyped sequence of action potentials with very short inter-spike intervals and declining amplitudes.<ref>{{cite journal | vauthors = Eccles JC, Llinás R, Sasaki K | title = The excitatory synaptic action of climbing fibres on the Purkinje cells of the cerebellum | journal = Journal of Physiology | volume = 182 | issue = 2 | pages = 268–96 | date = January 1966 | pmid = 5944665 | pmc = 1357472 | doi = 10.1113/jphysiol.1966.sp007824 }}</ref> Physiological studies have shown that complex spikes (which occur at baseline rates around 1&nbsp;Hz and never at rates much higher than 10&nbsp;Hz) are reliably associated with climbing fiber activation, while simple spikes are produced by a combination of baseline activity and parallel fiber input. Complex spikes are often followed by a pause of several hundred milliseconds during which simple spike activity is suppressed.<ref name=Simpson>{{cite journal |title=On climbing fiber signals and their consequence(s) |vauthors=Simpson JI, Wylie DR, De Zeeuw CI |journal=Behav. Brain Sci. |volume=19 |year=1996 |pages=384–398 |doi=10.1017/S0140525X00081486 |issue=3}}</ref>

A specific, recognizable feature of Purkinje neurons is the expression of [[calbindin]].<ref>{{cite journal | vauthors = Whitney ER, Kemper TL, Rosene DL, Bauman ML, Blatt GJ | title = Calbindin-D28k is a more reliable marker of human Purkinje cells than standard Nissl stains: a stereological experiment | journal = Journal of Neuroscience Methods | volume = 168 | issue = 1 | pages = 42–7 | date = February 2008 | pmid = 17961663 | doi = 10.1016/j.jneumeth.2007.09.009 | s2cid = 10505177 }}</ref> Calbindin staining of rat brain after unilateral chronic sciatic nerve injury suggests that Purkinje neurons may be [[Adult neurogenesis|newly generated]] in the adult brain, initiating the organization of new cerebellar lobules.<ref name="ReferenceA">{{cite journal | vauthors = Rusanescu G, Mao J | title = Peripheral nerve injury induces adult brain neurogenesis and remodelling | journal = Journal of Cellular and Molecular Medicine | volume = 21 | issue = 2 | pages = 299–314 | date = February 2017 | pmid = 27665307 | pmc = 5264155 | doi = 10.1111/jcmm.12965 }}</ref>
[[File:3 recon 512x512.jpg|thumb|center|A mouse Purkinje cell injected with fluorescent dye]]
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===== Granular layer =====
[[File:Parallel-fibers.png|right|thumb|Granule cells (GR, bottom), parallel fibers (horizontal lines, top), and Purkinje cells (P, middle) with flattened dendritic trees]]
[[Cerebellar granule cell]]s, in contrast to Purkinje cells, are among the smallest neurons in the brain. They are also the most numerous neurons in the brain: In humans, estimates of their total number average around 50 billion, which means that about 3/4 of the brain's neurons are cerebellar granule cells.<ref name=SOB/> Their cell bodies are packed into a thick layer at the bottom of the cerebellar cortex. A granule cell emits only four to five dendrites, each of which ends in an enlargement called a ''dendritic claw''.<ref name=SOB/> These enlargements are sites of excitatory input from mossy fibers and inhibitory input from [[Golgi cell]]s.<ref name=SOB/>

The thin, [[myelin|unmyelinated]] axons of granule cells rise vertically to the upper (molecular) layer of the cortex, where they split in two, with each branch traveling horizontally to form a '''parallel fiber'''; the splitting of the vertical branch into two horizontal branches gives rise to a distinctive "T" shape. A human parallel fiber runs for an average of 3&nbsp;mm in each direction from the split, for a total length of about 6&nbsp;mm (about 1/10 of the total width of the cortical layer).<ref name=SOB/> As they run along, the parallel fibers pass through the dendritic trees of Purkinje cells, contacting one of every 3–5 that they pass, making a total of 80–100 synaptic connections with Purkinje cell dendritic spines.<ref name=SOB/> Granule cells use [[glutamic acid|glutamate]] as their neurotransmitter, and therefore exert excitatory effects on their targets.<ref name=SOB/>

[[File:Cerebellar glomerulus.tif|thumb|Diagram of the layers of the cerebellar cortex showing a [[Glomerulus (cerebellum)|glomerulus]] in the granular layer.]]
Granule cells receive all of their input from mossy fibers, but outnumber them by 200 to 1 (in humans). Thus, the information in the granule cell population activity state is the same as the information in the mossy fibers, but recoded in a much more expansive way. Because granule cells are so small and so densely packed, it is difficult to record their spike activity in behaving animals, so there is little data to use as a basis for theorizing. The most popular concept of their function was proposed in 1969 by [[David Marr (neuroscientist)|David Marr]], who suggested that they could encode combinations of mossy fiber inputs. The idea is that with each granule cell receiving input from only 4–5 mossy fibers, a granule cell would not respond if only a single one of its inputs were active, but would respond if more than one were active. This combinatorial coding scheme would potentially allow the cerebellum to make much finer distinctions between input patterns than the mossy fibers alone would permit.<ref name=Marr/>

====Mossy fibers====
[[Mossy fiber (cerebellum)|Mossy fiber]]s enter the granular layer from their points of origin, many arising from the [[pontine nuclei]], others from the spinal cord, [[vestibular nuclei]] etc. In the human cerebellum, the total number of mossy fibers has been estimated at 200 million.<ref name=SOB/> These fibers form excitatory synapses with the granule cells and the cells of the deep cerebellar nuclei. Within the granular layer, a mossy fiber generates a series of enlargements called ''rosettes''. The contacts between mossy fibers and granule cell dendrites take place within structures called [[glomerulus (cerebellum)|glomeruli]]. Each glomerulus has a mossy fiber rosette at its center, and up to 20 granule cell dendritic claws contacting it. Terminals from [[Golgi cell]]s infiltrate the structure and make inhibitory synapses onto the granule cell dendrites. The entire assemblage is surrounded by a sheath of glial cells.<ref name=SOB/> Each mossy fiber sends collateral branches to several cerebellar folia, generating a total of 20–30 rosettes; thus a single mossy fiber makes contact with an estimated 400–600 granule cells.<ref name=SOB/>

====Climbing fibers====
Purkinje cells also receive input from the [[inferior olivary nucleus]] on the contralateral side of the brainstem via [[climbing fiber]]s. Although the inferior olive lies in the [[medulla oblongata]] and receives input from the spinal cord, brainstem and cerebral cortex, its output goes entirely to the cerebellum. A climbing fiber gives off collaterals to the deep cerebellar nuclei before entering the cerebellar cortex, where it splits into about 10 terminal branches, each of which gives input to a single Purkinje cell.<ref name=SOB/> In striking contrast to the 100,000-plus inputs from parallel fibers, each Purkinje cell receives input from exactly one climbing fiber; but this single fiber "climbs" the dendrites of the Purkinje cell, winding around them and making a total of up to 300 synapses as it goes.<ref name=SOB/> The net input is so strong that a single action potential from a climbing fiber is capable of producing an extended complex spike in the Purkinje cell: a burst of several spikes in a row, with diminishing amplitude, followed by a pause during which activity is suppressed. The climbing fiber synapses cover the cell body and proximal dendrites; this zone is devoid of parallel fiber inputs.<ref name=SOB/>

Climbing fibers fire at low rates, but a single climbing fiber action potential induces a burst of several action potentials in a target Purkinje cell (a complex spike). The contrast between parallel fiber and climbing fiber inputs to Purkinje cells (over 100,000 of one type versus exactly one of the other type) is perhaps the most provocative feature of cerebellar anatomy, and has motivated much of the theorizing. In fact, the function of climbing fibers is the most controversial topic concerning the cerebellum. There are two schools of thought, one following Marr and Albus in holding that climbing fiber input serves primarily as a teaching signal, the other holding that its function is to shape cerebellar output directly. Both views have been defended in great length in numerous publications. In the words of one review, "In trying to synthesize the various hypotheses on the function of the climbing fibers, one has the sense of looking at a drawing by Escher. Each point of view seems to account for a certain collection of findings, but when one attempts to put the different views together, a coherent picture of what the climbing fibers are doing does not appear. For the majority of researchers, the climbing fibers signal errors in motor performance, either in the usual manner of discharge frequency modulation or as a single announcement of an 'unexpected event'. For other investigators, the message lies in the degree of ensemble synchrony and rhythmicity among a population of climbing fibers."<ref name=Simpson/>

====Deep nuclei====
{{Main|Deep cerebellar nuclei}}
[[File:Gray707.png|thumb|right|upright=1.25|Sagittal cross-section of human cerebellum, showing the dentate nucleus, as well as the pons and inferior olivary nucleus]]
The [[deep cerebellar nuclei|deep nuclei]] of the cerebellum are clusters of gray matter lying within the white matter at the core of the cerebellum. They are, with the minor exception of the nearby vestibular nuclei, the sole sources of output from the cerebellum. These [[nucleus (neuroanatomy)|nuclei]] receive collateral projections from mossy fibers and climbing fibers as well as inhibitory input from the Purkinje cells of the cerebellar cortex. The four nuclei ([[Dentate nucleus|dentate]], [[Globose nucleus|globose]], [[Emboliform nucleus|emboliform]], and [[Fastigial nucleus|fastigial]]) each communicate with different parts of the brain and cerebellar cortex. (The globose and the emboliform nuclei are also referred to as combined in the [[interposed nucleus]]). The fastigial and interposed nuclei belong to the spinocerebellum. The dentate nucleus, which in mammals is much larger than the others, is formed as a thin, convoluted layer of gray matter, and communicates exclusively with the lateral parts of the cerebellar cortex. The flocculus of the flocculonodular lobe is the only part of the cerebellar cortex that does not project to the deep nuclei—its output goes to the vestibular nuclei instead.<ref name=SOB/>

The majority of neurons in the deep nuclei have large cell bodies and spherical dendritic trees with a radius of about 400&nbsp;μm, and use [[glutamic acid|glutamate]] as their neurotransmitter. These cells project to a variety of targets outside the cerebellum. Intermixed with them are a lesser number of small cells, which use [[Gamma-Aminobutyric acid|GABA]] as a neurotransmitter and project exclusively to the [[inferior olivary nucleus]], the source of [[climbing fiber]]s. Thus, the nucleo-olivary projection provides an inhibitory [[Feedback#Biology|feedback]] to match the excitatory projection of climbing fibers to the nuclei. There is evidence that each small cluster of nuclear cells projects to the same cluster of olivary cells that send climbing fibers to it; there is strong and matching topography in both directions.<ref name=SOB/>

When a Purkinje cell axon enters one of the deep nuclei, it branches to make contact with both large and small nuclear cells, but the total number of cells contacted is only about 35 (in cats). Conversely, a single deep nuclear cell receives input from approximately 860 Purkinje cells (again in cats).<ref name=SOB/>

====Compartments====
[[File:microzone.svg|thumb|right|upright=1.25|Schematic illustration of the structure of zones and microzones in the cerebellar cortex]]
From the viewpoint of gross anatomy, the cerebellar cortex appears to be a homogeneous sheet of tissue, and, from the viewpoint of microanatomy, all parts of this sheet appear to have the same internal structure. There are, however, a number of respects in which the structure of the cerebellum is compartmentalized. There are large compartments that are generally known as ''zones''; these can be divided into smaller compartments known as ''microzones''.<ref name=AppsGarwicz/>

The first indications of compartmental structure came from studies of the receptive fields of cells in various parts of the cerebellar cortex.<ref name=AppsGarwicz/> Each body part maps to specific points in the cerebellum, but there are numerous repetitions of the basic map, forming an arrangement that has been called "fractured somatotopy".<ref>{{cite journal | vauthors = Manni E, Petrosini L | title = A century of cerebellar somatotopy: a debated representation | journal = Nature Reviews. Neuroscience | volume = 5 | issue = 3 | pages = 241–9 | date = March 2004 | pmid = 14976523 | doi = 10.1038/nrn1347 | s2cid = 30232749 }}</ref> A clearer indication of compartmentalization is obtained by [[immunostain]]ing the cerebellum for certain types of protein. The best-known of these markers are called "zebrins", because staining for them gives rise to a complex pattern reminiscent of the stripes on a zebra. The stripes generated by zebrins and other compartmentalization markers are oriented perpendicular to the cerebellar folds—that is, they are narrow in the mediolateral direction, but much more extended in the longitudinal direction. Different markers generate different sets of stripes, the widths and lengths vary as a function of location, but they all have the same general shape.<ref name=AppsGarwicz/>

Oscarsson in the late 1970s proposed that these cortical zones can be partitioned into smaller units called microzones.<ref>{{cite journal | vauthors = Oscarsson O |title=Functional units of the cerebellum-sagittal zones and microzones |journal=Trends Neurosci. |year=1979 |volume=2 |pages=143–145 | doi = 10.1016/0166-2236(79)90057-2 |s2cid=53272245 }}</ref> A microzone is defined as a group of Purkinje cells all having the same somatotopic receptive field. Microzones were found to contain on the order of 1000 Purkinje cells each, arranged in a long, narrow strip, oriented perpendicular to the cortical folds.<ref name=AppsGarwicz/> Thus, as the adjoining diagram illustrates, Purkinje cell dendrites are flattened in the same direction as the microzones extend, while [[parallel fiber]]s cross them at right angles.<ref name=SOB/>

It is not only receptive fields that define the microzone structure: The [[climbing fiber]] input from the [[inferior olivary nucleus]] is equally important. The branches of a climbing fiber (usually numbering about 10) usually activate Purkinje cells belonging to the same microzone. Moreover, olivary neurons that send climbing fibers to the same microzone tend to be coupled by [[gap junction]]s, which synchronize their activity, causing Purkinje cells within a microzone to show correlated complex spike activity on a millisecond time scale.<ref name=AppsGarwicz/> Also, the Purkinje cells belonging to a microzone all send their axons to the same small cluster of output cells within the [[deep cerebellar nuclei]].<ref name=AppsGarwicz/> Finally, the axons of [[basket cell]]s are much longer in the longitudinal direction than in the mediolateral direction, causing them to be confined largely to a single microzone.<ref name=AppsGarwicz/> The consequence of all this structure is that cellular interactions within a microzone are much stronger than interactions between different microzones.<ref name=AppsGarwicz/>

In 2005, Richard Apps and Martin Garwicz summarized evidence that microzones themselves form part of a larger entity they call a multizonal microcomplex. Such a microcomplex includes several spatially separated cortical microzones, all of which project to the same group of deep cerebellar neurons, plus a group of coupled olivary neurons that project to all of the included microzones as well as to the deep nuclear area.<ref name=AppsGarwicz>{{cite journal | vauthors = Apps R, Garwicz M | title = Anatomical and physiological foundations of cerebellar information processing | journal = Nature Reviews. Neuroscience | volume = 6 | issue = 4 | pages = 297–311 | date = April 2005 | pmid = 15803161 | doi = 10.1038/nrn1646 | s2cid = 10769826 }}</ref>