Trisynaptic circuit

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 lead 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 (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.

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

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On September 1st, 1953, William Scoville used a hand crank and a cheap drill saw to bore into a young man's skull, cutting away vital pieces of his brain and sucking them out through a metal tube. But this wasn't a scene from a horror film or a gruesome police report. Dr. Scoville was one of the most renowned neurosurgeons of his time, and the young man was Henry Molaison, the famous patient known as "H.M.", whose case provided amazing insights into how our brains work. As a boy, Henry had cracked his skull in an accident and soon began having seizures, blacking out and losing control of bodily functions. After enduring years of frequent episodes, and even dropping out of high school, the desperate young man had turned to Dr. Scoville, a daredevil known for risky surgeries. Partial lobotomies had been used for decades to treat mental patients based on the notion that mental functions were strictly localized to corresponding brain areas. Having successfully used them to reduce seizures in psychotics, Scoville decided to remove H.M.'s hippocampus, a part of the limbic system that was associated with emotion but whose function was unknown. At first glance, the operation had succeeded. H.M.'s seizures virtually disappeared, with no change in personality, and his IQ even improved. But there was one problem: His memory was shot. Besides losing most of his memories from the previous decade, H.M. was unable to form new ones, forgetting what day it was, repeating comments, and even eating multiple meals in a row. When Scoville informed another expert, Wilder Penfield, of the results, he sent a Ph.D student named Brenda Milner to study H.M. at his parents' home, where he now spent his days doing odd chores, and watching classic movies for the first time, over and over. What she discovered through a series of tests and interviews didn't just contribute greatly to the study of memory. It redefined what memory even meant. One of Milner's findings shed light on the obvious fact that although H.M. couldn't form new memories, he still retained information long enough from moment to moment to finish a sentence or find the bathroom. When Milner gave him a random number, he managed to remember it for fifteen minutes by repeating it to himself constantly. But only five minutes later, he forgot the test had even taken place. Neuroscientists had though of memory as monolithic, all of it essentially the same and stored throughout the brain. Milner's results were not only the first clue for the now familiar distinction between short-term and long-term memory, but show that each uses different brain regions. We now know that memory formation involves several steps. After immediate sensory data is temporarily transcribed by neurons in the cortex, it travels to the hippocampus, where special proteins work to strengthen the cortical synaptic connections. If the experience was strong enough, or we recall it periodically in the first few days, the hippocampus then transfers the memory back to the cortex for permanent storage. H.M.'s mind could form the initial impressions, but without a hippocampus to perform this memory consolidation, they eroded, like messages scrawled in sand. But this was not the only memory distinction Milner found. In a now famous experiment, she asked H.M. to trace a third star in the narrow space between the outlines of two concentric ones while he could only see his paper and pencil through a mirror. Like anyone else performing such an awkward task for the first time, he did horribly. But surprisingly, he improved over repeated trials, even though he had no memory of previous attempts. His unconscious motor centers remembered what the conscious mind had forgotten. What Milner had discovered was that the declarative memory of names, dates and facts is different from the procedural memory of riding a bicycle or signing your name. And we now know that procedural memory relies more on the basal ganglia and cerebellum, structures that were intact in H.M.'s brain. This distinction between "knowing that" and "knowing how" has underpinned all memory research since. H.M. died at the age of 82 after a mostly peaceful life in a nursing home. Over the years, he had been examined by more than 100 neuroscientists, making his the most studied mind in history. Upon his death, his brain was preserved and scanned before being cut into over 2000 individual slices and photographed to form a digital map down to the level of individual neurons, all in a live broadcast watched by 400,000 people. Though H.M. spent most of his life forgetting things, he and his contributions to our understanding of memory will be remembered for generations to come.

Structures

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 include layers I through III, are mainly input layers that receive signals from other parts of the EC, but also project to hippocampal structures via the perforant path. Layer II of the entorhinal cortex projects mainly to the dentate gyrus and CA3, while layer III is thought to project mainly to the CA1 of the hippocampus. The deep (inner) layers, layers IV to VI, are the main output layers, and send signals to different parts of the EC and other cortical areas.

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.

Fornix

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]

Thalamus

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]

Amygdala

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.

References

^ Andersen, P. (1975). Organization of hippocampal neurons and their interconnections. In R.L. Isaacson & K.H. Pribram (Eds.) The Hippocampus Vol. I(pp. 155-175), New York, Plenum Press.
^ Adamec, R. E. (1991). "Partial kindling of the ventral hippocampus: Identification of changes in limbic physiology which accompany changes in feline aggression and defense". Physiology & Behavior. 49 (3): 443–453. doi:10.1016/0031-9384(91)90263-n. PMID 1648239. S2CID 1135890.
^ Amaral DG, Witter, MP. 1995. Hippocampal formation. In: Paxinos G, editor. The rat nervous system, 2nd ed. San Diego: Academic Press.
^ Florian, C.; Roullet, P. (2004). "Hippocampal CA3-region is crucial for acquisition and memory consolidation in Morris water maze task in mice". Behavioural Brain Research. 154 (2): 365–374. doi:10.1016/j.bbr.2004.03.003. PMID 15313024. S2CID 40897061.
^ Vann, Seralynne D. (2010). "Re-evaluating the role of the mammillary bodies in memory". Neuropsychologia. 48 (8): 2316–2327. doi:10.1016/j.neuropsychologia.2009.10.019. PMID 19879886. S2CID 2424758.
^ Aggleton, John P.; O'Mara, Shane M.; Vann, Seralynne D.; Wright, Nick F.; Tsanov, Marian; Erichsen, Jonathan T. (2010). "Hippocampal-anterior thalamic pathways for memory: Uncovering a network of direct and indirect actions". European Journal of Neuroscience. 31 (12): 2292–307. doi:10.1111/j.1460-9568.2010.07251.x. PMC 2936113. PMID 20550571.
^ Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Chapter 26, The Association Cortices. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11109/
^ Pang, D. S.; Robledo, C. J.; Carr, D. R.; Gent, T. C.; Vyssotski, A. L.; Caley, A.; Franks, N. P. (2009). "An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action" (PDF). Proceedings of the National Academy of Sciences. 106 (41): 17546–17551. Bibcode:2009PNAS..10617546P. doi:10.1073/pnas.0907228106. PMC 2751655. PMID 19805135.
^ Komisaruk, B. R. (1970). "Synchrony between limbic system theta activity and rhythmical behavior in rats". Journal of Comparative and Physiological Psychology. 70 (3): 482–492. doi:10.1037/h0028709. PMID 5418472.
^ Buzsáki, G (2002). "Theta oscillations in the hippocampus". Neuron. 33 (3): 325–340. doi:10.1016/s0896-6273(02)00586-x. PMID 11832222.
^ What is in the composition of air n.d. Retrieved October 27, 2014 from http://chemistry.about.com/od/chemistryfaqs/f/aircomposition.htm.
^ WebMD. (2012, October 5). Sleep apnea. Retrieved October 4, 2014 from http://www.webmd.com/sleep-disorders/guide/understanding-obstructive-sleep-apnea-syndrome.
^ Pang, D. S.; Robledo, C. J.; Carr, D. R.; Gent, T. C.; Vyssotski, A. L.; Caley, A.; Franks, N. P. (2009). "An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action" (PDF). Proceedings of the National Academy of Sciences. 106 (41): 17546–17551. Bibcode:2009PNAS..10617546P. doi:10.1073/pnas.0907228106. PMC 2751655. PMID 19805135.
^ Vertes, R. P.; Albo, Z.; Di Prisco, G. V. (2001). "Theta-rhythmically firing neurons in the anterior thalamus: Implications for mnemonic functions of Papez's circuit. [Letter]". Neuroscience. 104 (3): 619–625. doi:10.1016/s0306-4522(01)00131-2. PMID 11440795. S2CID 9563384.

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