Mossy fiber (hippocampus)

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Diagram of a Timm-stained cross-section of the mouse hippocampus. The hippocampal subregion CA3-CA4 is indicated in black, stippled, and hatched areas. Black areas: suprapyramidal (SP), intra- and infrapyramidal (IIP) and hilar (CA4) mossy fiber terminal fields originating from the dentate gyrus. Stippled area: strata oriens (OR) and radiatum (RD). Hatched area: stratum lacunosum-moleculare (LM). CA1, subregion of the hippocampus without mossy fibers; FI, fimbria hippocampi; FD, fascia dentata; OL and ML, outer and middle molecular layers of the fascia dentata; SG, supragranular layer; GC, granular cells. Diagram of a Timm-stained cross-section of the hippocampus.JPEG
Diagram of a Timm-stained cross-section of the mouse hippocampus. The hippocampal subregion CA3–CA4 is indicated in black, stippled, and hatched areas. Black areas: suprapyramidal (SP), intra- and infrapyramidal (IIP) and hilar (CA4) mossy fiber terminal fields originating from the dentate gyrus. Stippled area: strata oriens (OR) and radiatum (RD). Hatched area: stratum lacunosum-moleculare (LM). CA1, subregion of the hippocampus without mossy fibers; FI, fimbria hippocampi; FD, fascia dentata; OL and ML, outer and middle molecular layers of the fascia dentata; SG, supragranular layer; GC, granular cells.

In the hippocampus, the mossy fiber pathway consists of unmyelinated axons projecting from granule cells in the dentate gyrus that terminate on modulatory hilar mossy cells [2] [3] and in Cornu Ammonis area 3 (CA3), [4] a region involved in encoding short-term memory. [5] [6] These axons were first described as mossy fibers by Santiago Ramón y Cajal as they displayed varicosities along their lengths that gave them a mossy appearance. [7]

Contents

The axons that make up the pathway emerge from the basal portions of the granule cells and pass through the hilus (or polymorphic cell layer) of the dentate gyrus before entering the stratum lucidum of CA3. Granule cell synapses tend to be glutamatergic (i.e. excitatory), though immunohistological data has indicated that some synapses contain neuropeptidergic elements including opiate peptides such as dynorphin and enkephalin. There is also evidence for co-localization of both GABAergic (i.e. inhibitory) and glutamatergic neurotransmitters within mossy fiber terminals. [8] [9] GABAergic and glutamatergic co-localization in mossy fiber boutons has been observed primarily in the developing hippocampus, [10] but in adulthood, evidence suggests that mossy fiber synapses may alternate which neurotransmitter is released through activity-dependent regulation. [11]

Anatomy

Mossy fibers in the hippocampus project from the dentate gyrus to CA3. The pathway consists of varicose granule cell axons that terminate on the dendrites of hilar mossy cells and pyramidal cells in CA3. [4] They form three morphologically different synaptic terminals, which include large mossy terminals, filopodial extensions within the mossy terminals, and small en passant boutons. Each of these synapse types is functionally distinct. [12]

Synaptic terminals

Mossy fibers form multiple synapses with the elaborate dendritic spines of CA3 pyramidal cells in the stratum lucidum of the hippocampus. These complex spines are known as thorny excrescences. [4] [13] Thorny excrescences also cover the proximal dendrites of mossy cells in the hilus. Hilar thorny excrescences are more dense and complex than those in CA3. It has been shown that the axons of granule cells from the dentate gyrus synapse with hilar mossy cells and GABAergic interneurons including basket cells before reaching pyramidal cells in the CA3 region, [4] providing input from the entorhinal cortex through the perforant pathway. Hilar mossy cell activation is thought to be necessary for the proper function of these inhibitory basket cells on CA3 pyramidal cells, although evidence has shown that sodium channel receptors can regulate basket cell function as well. [7]

The three synaptic terminals types – mossy terminals, filopodial extensions, and en passant synaptic varicosities – differ in synaptic output. Large mossy terminals synapse with 11–15 different CA3 pyramidal cells and 7–12 mossy cells. [12] En passant boutons with 25–35 synaptic connections and filopodial extensions with 12–17 make up a significant portion of total granule cell synaptic terminals and are mainly responsible for the excitation of GABAergic interneurons. The type of synaptic terminal expressed therefore dictates the downstream targeting of granule cells. [4] [12] The high convergence onto pyramidal cells and divergent projections onto interneurons suggests a primarily modulatory role for the mossy fiber pathway in the hippocampus. [12] [2]

The synapses of the mossy fibers contain zinc, which can be stained with a Timm staining. [14]

Projections

The dentate gyrus receives excitatory projections from neurons in layer II of the entorhinal cortex as well as input from surrounding neuroglia. [15] The unmyelinated granule cell axons of the mossy fiber pathway express both GABA receptors and glutamate receptors along their membranes that allow them to be modulated by both excitatory and inhibitory input from nearby glial cells. [16] [17] Axons from the entorhinal cortex synapse primarily on the dendritic spines of outer layer dentate granule cells. [18] The entorhinal cortex passes sensory information from neocortical structures to the hippocampal formation. [17] The pathway allows sensory information to reach the hippocampus for encoding.

The mossy fiber pathway itself projects to CA3. Repetitive stimulation of its neurons leads to progressive use-dependent synaptic depression. These short-term changes in plasticity have been shown to be mediated by sodium channels that receive input from neuroglia. [16] The entorhinal cortex also projects directly to CA3, suggesting that the mossy fiber pathway may be functionally similar to the perforant pathway although microcircuits within the dentate gyrus give the mossy fiber pathway a more modulatory role. [19] Projections to the dentate hilus are excitatory by nature and oppose the inhibitory effects of interneurons on hilar mossy cells. The result is an excitatory feedforward loop on mossy cells as a result of activation by the entorhinal cortex. [2] [15]

Role in learning and memory

In the mouse, a single mossy fiber projection may make as many as 37 contacts with a single pyramidal cell, but innervates only about a dozen different pyramidal cells. In contrast, a single CA3 pyramidal cell receives input from about 50 different granule cells. It has been shown in rodents that the size of the mossy fiber projections can show large interindividual variations, which are to a large part heritable. [20] In addition, these variations show strong correlations with different types of behavior, mainly, but not exclusively, spatial learning. [21]

See also

Related Research Articles

<span class="mw-page-title-main">Hippocampus</span> Vertebrate brain region involved in memory consolidation

The hippocampus is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. The hippocampus is located in the allocortex, with neural projections into the neocortex, in humans as well as other primates. The hippocampus, as the medial pallium, is a structure found in all vertebrates. In humans, it contains two main interlocking parts: the hippocampus proper, and the dentate gyrus.

<span class="mw-page-title-main">Dentate gyrus</span> Region of the hippocampus in the brain

The dentate gyrus (DG) is part of the hippocampal formation in the temporal lobe of the brain, which also includes the hippocampus and the subiculum. The dentate gyrus is part of the hippocampal trisynaptic circuit and is thought to contribute to the formation of new episodic memories, the spontaneous exploration of novel environments and other functions.

<span class="mw-page-title-main">Neural pathway</span> Connection formed between neurons that allows neurotransmission

In neuroanatomy, a neural pathway is the connection formed by axons that project from neurons to make synapses onto neurons in another location, to enable neurotransmission. Neurons are connected by a single axon, or by a bundle of axons known as a nerve tract, or fasciculus. Shorter neural pathways are found within grey matter in the brain, whereas longer projections, made up of myelinated axons, constitute white matter.

<span class="mw-page-title-main">Pyramidal cell</span> Projection neurons in the cerebral cortex and hippocampus

Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal cells are the primary excitation units of the mammalian prefrontal cortex and the corticospinal tract. One of the main structural features of the pyramidal neuron is the conic shaped soma, or cell body, after which the neuron is named. Other key structural features of the pyramidal cell are a single axon, a large apical dendrite, multiple basal dendrites, and the presence of dendritic spines.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

<span class="mw-page-title-main">Basket cell</span>

Basket cells are inhibitory GABAergic interneurons of the brain, found throughout different regions of the cortex and cerebellum.

Schaffer collaterals are axon collaterals given off by CA3 pyramidal cells in the hippocampus. These collaterals project to area CA1 of the hippocampus and are an integral part of memory formation and the emotional network of the Papez circuit, and of the hippocampal trisynaptic loop. It is one of the most studied synapses in the world and named after the Hungarian anatomist-neurologist Károly Schaffer.

An apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus, the entorhinal cortex, the olfactory cortex, and other areas. Dendrite arbors formed by apical dendrites are the means by which synaptic inputs into a cell are integrated. The apical dendrites in these regions contribute significantly to memory, learning, and sensory associations by modulating the excitatory and inhibitory signals received by the pyramidal cells.

<span class="mw-page-title-main">Golgi cell</span>

In neuroscience, Golgi cells are the most abundant inhibitory interneurons found within the granular layer of the cerebellum. Golgi cells can be found in the granular layer at various layers. The Golgi cell is essential for controlling the activity of the granular layer. They were first identified as inhibitory in 1964. It was also the first example of an inhibitory feedback network in which the inhibitory interneuron was identified anatomically. Golgi cells produce a wide lateral inhibition that reaches beyond the afferent synaptic field and inhibit granule cells via feedforward and feedback inhibitory loops. These cells synapse onto the dendrite of granule cells and unipolar brush cells. They receive excitatory input from mossy fibres, also synapsing on granule cells, and parallel fibers, which are long granule cell axons. Thereby this circuitry allows for feed-forward and feed-back inhibition of granule cells.

<span class="mw-page-title-main">Perforant path</span>

In the brain, the perforant path or perforant pathway provides a connectional route from the entorhinal cortex to all fields of the hippocampal formation, including the dentate gyrus, all CA fields, and the subiculum.

The stratum lucidum of the hippocampus is a layer of the hippocampus between the stratum pyramidale and the stratum radiatum. It is the tract of the mossy fiber projections, both inhibitory and excitatory from the granule cells of the dentate gyrus. One mossy fiber may make up to 37 connections to a single pyramidal cell, and innervate around 12 pyramidal cells on top of that. Any given pyramidal cell in the stratum lucidum may get input from as many as 50 granule cells.

The trisynaptic circuit or trisynaptic loop is a relay of synaptic transmission in the hippocampus. The trisynaptic circuit is a neural circuit in the hippocampus, which is made up of three major cell groups: granule cells in the dentate gyrus, pyramidal neurons in CA3, and pyramidal neurons in CA1. The hippocampal relay involves 3 main regions within the hippocampus which are classified according to their cell type and projection fibers. The first projection of the hippocampus occurs between the entorhinal cortex (EC) and the dentate gyrus (DG). The entorhinal cortex transmits its signals from the parahippocampal gyrus to the dentate gyrus via granule cell fibers known collectively as the perforant path. The dentate gyrus then synapses on pyramidal cells in CA3 via mossy cell fibers. CA3 then fires to CA1 via Schaffer collaterals which synapse in the subiculum and are carried out through the fornix. Collectively the dentate gyrus, CA1 and CA3 of the hippocampus compose the trisynaptic loop.

<span class="mw-page-title-main">Hippocampus anatomy</span> Component of brain anatomy

Hippocampus anatomy describes the physical aspects and properties of the hippocampus, a neural structure in the medial temporal lobe of the brain. It has a distinctive, curved shape that has been likened to the sea-horse monster of Greek mythology and the ram's horns of Amun in Egyptian mythology. This general layout holds across the full range of mammalian species, from hedgehog to human, although the details vary. For example, in the rat, the two hippocampi look similar to a pair of bananas, joined at the stems. In primate brains, including humans, the portion of the hippocampus near the base of the temporal lobe is much broader than the part at the top. Due to the three-dimensional curvature of this structure, two-dimensional sections such as shown are commonly seen. Neuroimaging pictures can show a number of different shapes, depending on the angle and location of the cut.

<span class="mw-page-title-main">Fascia dentata</span>

The fascia dentata is the earliest stage of the hippocampal circuit. Its primary input is the perforant path from the superficial layers of entorhinal cortex. Its principal neurons are tiny granule cells which give rise to unmyelinated axons called the mossy fibers which project to the hilus and CA3. The fascia dentata of the rat contains approximately 1,000,000 granule cells. It receives feedback connections from mossy cells in the hilus at distant levels in the septal and temporal directions. The fascia dentata and the hilus together make up the dentate gyrus. As with all regions of the hippocampus, the dentate gyrus also receives GABAergic and cholinergic input from the medial septum and the diagonal band of Broca.

<span class="mw-page-title-main">Granule cell</span> Type of neuron with a very small cell body

The name granule cell has been used for a number of different types of neurons whose only common feature is that they all have very small cell bodies. Granule cells are found within the granular layer of the cerebellum, the dentate gyrus of the hippocampus, the superficial layer of the dorsal cochlear nucleus, the olfactory bulb, and the cerebral cortex.

Sharp waves and ripples (SWRs) are oscillatory patterns produced by extremely synchronised activity of neurons in the mammalian hippocampus and neighbouring regions which occur spontaneously in idle waking states or during NREM sleep. They can be observed with a variety of imaging methods, such as EEG. They are composed of large amplitude sharp waves in local field potential and produced by tens of thousands of neurons firing together within 30–100 ms window. They are some of the most synchronous oscillations patterns in the brain, making them susceptible to pathological patterns such as epilepsy.They have been extensively characterised and described by György Buzsáki and have been shown to be involved in memory consolidation in NREM sleep and the replay of memories acquired during wakefulness.

<span class="mw-page-title-main">Hippocampus proper</span> Part of the brain of mammals

The hippocampus proper refers to the actual structure of the hippocampus which is made up of four regions or subfields. The subfields CA1, CA2, CA3, and CA4 use the initials of cornu Ammonis, an earlier name of the hippocampus.

Early long-term potentiation (E-LTP) is the first phase of long-term potentiation (LTP), a well-studied form of synaptic plasticity, and consists of an increase in synaptic strength. LTP could be produced by repetitive stimulation of the presynaptic terminals, and it is believed to play a role in memory function in the hippocampus, amygdala and other cortical brain structures in mammals.

The supramammillary nucleus (SuM), or supramammillary area, is a thin layer of cells in the brain that lies above the mammillary bodies. It can be considered part of the hypothalamus and diencephalon. The nucleus can be divided into medial and lateral sections. The medial SuM, or SuMM, is made of smaller cells which release dopamine and give input to the lateral septal nucleus. The lateral SuM, or SuML, is made of larger cells that project to the hippocampus.

An axo-axonic synapse is a type of synapse, formed by one neuron projecting its axon terminals onto another neuron's axon.

References

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  3. ↑ Henze DA, Buzsáki G (2007). "Hilar mossy cells: functional identification and activity in vivo". The Dentate Gyrus: A Comprehensive Guide to Structure, Function, and Clinical Implications. Progress in Brain Research. Vol. 163. pp. 199–216. doi:10.1016/s0079-6123(07)63012-x. ISBN   9780444530158. PMID   17765720.
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