Trisynaptic circuit

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The trisynaptic circuit, or trisynaptic loop is a relay of synaptic transmission in the hippocampus. The circuit was initially described by the neuroanatomist Santiago Ramon y Cajal, [1] in the early twentieth century, using the Golgi staining method. After the discovery of the trisynaptic circuit, a series of research has been conducted to determine the mechanisms driving this circuit. Today, research is focused on how this loop interacts with other parts of the brain, and how it influences human physiology and behaviour. For example, it has been shown that disruptions within the trisynaptic circuit leads to behavioural changes in rodent and feline models. [2]


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 and the dentate gyrus. 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.

EC → DG via the perforant path (synapse 1), DG → CA3 via mossy fibres (synapse 2), CA3 → CA1 via schaffer collaterals (synapse 3) [3]


Entorhinal cortex

The entorhinal cortex (EC) is a structure in the brain located in the medial temporal lobe. The EC is composed of six distinct layers. The superficial (outer) layers, which includes layers I through III, are mainly input layers that receive signals from other parts of the EC. The deep (inner) layers, layers IV to VI, are output layers, and send signals to different parts of the EC and the brain. Layers II and III project to the CA3 area of the hippocampal formation (via the perforant path) and to the granule cells of the dentate gyrus, respectively.

Dentate gyrus

The dentate gyrus (DG) is the innermost section of the hippocampal formation. The dentate gyrus consists of three layers: molecular, granular, and polymorphic. Granule neurons, which are the most prominent type of DG cells, are mainly found in the granular layer. These granule cells are the major source of input of the hippocampal formation, receiving most of their information from layer II of the entorhinal cortex, via the perforant pathway. Information from the DG is directed to the pyramidal cells of CA3 through mossy fibres. Neurons within the DG are famous for being one of two nervous system areas capable of neurogenesis, the growth or development of nervous tissue.

Cornu ammonis 3

The CA3 is a portion of the hippocampal formation adjacent to the dentate gyrus. Input is received from the granule cells of the dentate gyrus through the mossy fibres. The CA3 is rich in pyramidal neurons (like those found throughout the neocortex), which project mainly to the CA1 pyramidal neurons via the Schaffer collateral pathway. The CA3 pyramidal neurons have been analogized as the "pacemaker" of the trisynaptic loop in the generation of hippocampal theta rhythm. One study [4] has found that the CA3 plays an essential role in the consolidation of memories when examining CA3 regions using the Morris water maze.

Cornu ammonis 1

The CA1 is the region within the hippocampus between the subiculum, the innermost area of the hippocampal formation, and region CA2. The CA1 is separated from the dentate gyrus by the hippocampal sulcus. Cells within the CA1 are mostly pyramidal cells, similar to those in CA3. The CA1 completes the circuit by feeding back to the deep layers, mainly layer V, of the entorhinal cortex.

Brain areas associated with the trisynaptic circuit

There are many brain structures that transmit information to, and from the trisynaptic circuit. The activity of these different structures can be directly or indirectly modulated by the activity of the trisynaptic loop.


The fornix is a C-shaped bundle of axons that begins in the hippocampal formation of both hemispheres, referred to as the fimbria, and extend through the crus of fornix, also known as the posterior pillars. The fimbria section of the fornix is directly connected to the alveus, which is a portion of the hippocampal formation that arises from the subiculum and the hippocampus (specifically the CA1). Both crura of the fornix form intimate connections with the underside of the corpus callosum and support the hippocampal commissure, a large bundle of axon that connects the left and right hippocampal formations. The fornix plays a key role in hippocampal outputs, specifically in connecting CA3 to a variety of subcortical structures, and connecting CA1 and the subiculum to a variety of parahippocampal regions, via the fimbria. The fornix is also essential for hippocampal information input and neuromodulatory input, specifically from the medial septum, diencephalic brain structures, and the brain stem.

Cingulate gyrus

The cingulate gyrus plays a key role in the limbic system's emotion formation and processing. The cingulate cortex is separated into an anterior and a posterior region, which corresponds to areas 24, 32, 33 (anterior) and 23 (posterior) of the Brodmann areas. The anterior region receives information mainly from the mamillary bodies while the posterior cingulate receives information from the subiculum via the Papez circuit.

Mammillary bodies

The mammillary bodies are two clusters of cell bodies found at the ends of the posterior fibres of the fornix within the diencephalon. The mammillary bodies relay information from the hippocampal formation (via the fornix) to the thalamus (via the mammillothalamic tract). The mammillary bodies are integral parts of the limbic system and have been shown to be important in recollective memory. [5]


The thalamus is a bundle of nuclei located between the cerebral cortex and the midbrain. Many of the thalamic nuclei receive inputs from the hippocampal formation. The mammillothalamic tract relays information received from the mamillary bodies (via the fornix) and transmits it to the anterior nuclei of the thalamus. Research has shown that the thalamus plays a key role with respect to spatial and episodic memories. [6]

Association cortex

The association cortex includes most of the cerebral surface of the brain and is responsible for processing that goes between the arrival of input in the primary sensory cortex and the generation of behaviour. Receives and integrates information from various parts of the brain and influences many cortical and subcortical targets. Inputs to the association cortices include the primary and secondary sensory and motor cortices, the thalamus, and the brain stem. The association cortex projects to places including the hippocampus, basal ganglia, and cerebellum, and other association cortices. Examination of patients with damages to one or more of these regions, as well as noninvasive brain imaging, it has been found that the association cortex is especially important for attending to complex stimuli in the external and internal environments. The temporal association cortex identifies the nature of stimuli, while the frontal association cortex plans behavioural responses to the stimuli. [7]


The amygdala is an almond-shaped group of nuclei found deep and medially within the temporal lobes of the brain. Known to be the area of the brain responsible for emotional reaction, but plays an important role in processing of memory and decision making as well. It is part of the limbic system. The amygdala projects to various structures in the brain including the hypothalamus, the thalamic reticular nucleus, and more.

Medial septum

The medial septum plays a role in the generation of theta waves in the brain. In an experiment, [8] it has been proposed that the generation of theta oscillations involves an ascending pathway leading from the brainstem to hypothalamus to medial septum to hippocampus. The same experiment demonstrated that injection of lidocaine, a local anesthetic, inhibits theta oscillations from the medial septum projecting to the hippocampus.

Relationship with other physiological systems

Role in rhythm generation

It has been proposed that the trisynaptic circuit is responsible for the generation of hippocampal theta waves. These waves are responsible for the synchronization of different brain regions, especially the limbic system. [9] In rats, theta waves range between 3–8 Hz and their amplitudes range from 50 to 100 μV. Theta waves are especially prominent during ongoing behaviors and during rapid eye movement (REM) sleep. [10]

Respiratory system

Studies have shown that the respiratory system interacts with the brain in generating theta oscillations in the hippocampus. There are numerous studies on the different effects of oxygen concentration on hippocampal theta oscillations, leading to implications of anesthetic use during surgeries, and influence on sleep patterns. Some of these oxygen environments include hyperoxic conditions, which is a condition where there is excess oxygen (greater than 21%). There are adverse effects involved with rat placement in hyperoxia condition. Hypercapnia is a condition where there is high oxygen concentrations with a mixture of carbon dioxide (95% and 5%, respectively). In normoxic conditions, which is basically the air we breath (with oxygen concentrations at 21%). The air we breath is composed of the following five gases: [11] nitrogen (78%), oxygen (21%), water vapor (5%), argon (1%), and carbon dioxide (0.03%). Finally, in hypoxic conditions, which is a condition of low oxygen concentration (less than 21% oxygen concentrations).

There are physiological and psychological disorders related to prolonged exposure to hypoxic conditions. For example, sleep apnea [12] is a condition where there is partial, or complete, blockage of breathing during sleep. In addition, the respiratory system linked to central nervous system via base of brain. Thus, prolonged exposure to low oxygen concentration has detrimental effects on the brain.

Sensorimotor system

Experimental research has shown that there are two prominent types of theta oscillation which are each associated with different related to a motor response. [13] Type I theta waves correspond with exploratory behaviours including walking, running, and rearing. Type II theta waves are associated with immobility during the initiation or the intention of initiation of a motor response.

Limbic system

Theta oscillations generated by the trisynaptic loop have been shown to be synchronized with brain activity in the anterior ventral thalamus. Hippocampal theta has also been linked to the activation of the anterior medial and the anterior dorsal areas of the thalamus. [14] The synchronization between these limbic structures and the trisynaptic loop is essential for proper emotional processing.

See also: EC-hippocampus system

Related Research Articles

Entorhinal cortex Area of the temporal lobe of the brain

The entorhinal cortex (EC) is an area of the brain's allocortex, located in the medial temporal lobe, whose functions include being a widespread network hub for memory, navigation, and the perception of time. The EC is the main interface between the hippocampus and neocortex. The EC-hippocampus system plays an important role in declarative (autobiographical/episodic/semantic) memories and in particular spatial memories including memory formation, memory consolidation, and memory optimization in sleep. The EC is also responsible for the pre-processing (familiarity) of the input signals in the reflex nictitating membrane response of classical trace conditioning; the association of impulses from the eye and the ear occurs in the entorhinal cortex.

Hippocampus 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 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.

Dentate gyrus 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.

Cingulate cortex Part of the brain within the cerebral cortex

The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cingulate sulcus. The cingulate cortex is usually considered part of the limbic lobe.

Neural pathway

A neural pathway is the connection formed by axons that project from neurons to make synapses onto neurons in another location, to enable a signal to be sent from one region of the nervous system to another. 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.

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.

Papez circuit Neural circuit

The Papez circuit, or medial limbic circuit, is a neural circuit for the control of emotional expression. In 1937, James Papez proposed that the circuit connecting the hypothalamus to the limbic lobe was the basis for emotional experiences. Paul D. MacLean reconceptualized Papez's proposal and coined the term limbic system. MacLean redefined the circuit as the "visceral brain" which consisted of the limbic lobe and its major connections in the forebrain – hypothalamus, amygdala, and septum. Over time, the concept of a forebrain circuit for the control of emotional expression has been modified to include the prefrontal cortex.

Subiculum Most inferior part of the hippocampal formation

The subiculum is the most inferior component of the hippocampal formation. It lies between the entorhinal cortex and the CA1 subfield of the hippocampus proper.

Theta waves generate the theta rhythm, a neural oscillation in the brain that underlies various aspects of cognition and behavior, including learning, memory, and spatial navigation in many animals. It can be recorded using various electrophysiological methods, such as electroencephalogram (EEG), recorded either from inside the brain or from electrodes attached to the scalp.

Hippocampal formation

The hippocampal formation is a compound structure in the medial temporal lobe of the brain. There is no consensus concerning which brain regions are encompassed by the term, with some authors defining it as the dentate gyrus, the hippocampus proper and the subiculum; and others including also the presubiculum, parasubiculum, and entorhinal cortex. The hippocampal formation is thought to play a role in memory, spatial navigation and control of attention. The neural layout and pathways within the hippocampal formation are very similar in all mammals.

Septal area

The septal area, consisting of the lateral septum and medial septum, is an area in the lower, posterior part of the medial surface of the frontal lobe, and refers to the nearby septum pellucidum.

Perforant path

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.

Mossy fiber (hippocampus)

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 and in Cornu Ammonis area 3 (CA3), a region involved in encoding short-term memory. 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. The axons that make up the pathway emerge from the basal portions of the granule cells and pass through the hilus of the dentate gyrus before entering the stratum lucidum of CA3. Granule cell synapses tend to be glutamatergic, 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 and glutamatergic neurotransmitters within mossy fiber terminals. GABAergic and glutamatergic co-localization in mossy fiber boutons has been observed primarily in the developing hippocampus, but in adulthood, evidence suggests that mossy fiber synapses may alternate which neurotransmitter is released through activity-dependent regulation.

Hippocampus 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.

Fascia dentata

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.

Granule cell Type of neuron with a very small cell body

The name granule cell has been used for a number of different types of neuron 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 in the mammalian brain hippocampus seen on an EEG during immobility and sleep. There are three major network oscillation patterns in the hippocampus: theta waves, SWRs and gamma waves. Gamma oscillations are found in all major brain structures, whereas theta and sharp waves are specific to the hippocampus and its neighbouring areas. SWRs are composed of large amplitude sharp waves in local field potential and associated fast field oscillations known as ripples. SWRs are shown to be involved in memory consolidation and the replay of wakefulness-acquired memory. These network oscillations are the most synchronous patterns in the brain, making them susceptible to pathological patterns such as epilepsy.

Hippocampus proper Part of the brain of mammals

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

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.


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