Chemical Control of the Brain

Autonomic Nervous System 

The central nervous system (CNS) consists of the brain and spinal cord. It plays a central role in most functions of the body. The CNS communicates with the rest of the body via the peripheral nervous system (PNS). The PNS has two parts, the somatic PNS and visceral PNS. The somatic PNS innervates skin, joints and muscles under voluntary control. The CNS communicates directly with skeletal muscle through a somatic motor fiber. The visceral PNS, also known as the Autonomic Nervous System (ANS), innervates internal organs, blood, vessels, and glands. The lower motor neurons lie outside the CNS. ANS ultimately deals with involuntary control.

The ANS is divided into two parts, a sympathetic division and parasympathetic division. The two divisions often work against each other. The sympathetic division is known as the “fight or flight” response. An increase in sympathetic activity will likely increase one’s heart rate, breathing rate, sweating, and regulate digestion and immune response. The idea is that the body uses energy toward functions that are necessary to perform in “fight or flight” scenarios. For example, sympathetic activity can be induced by stress, exercise, and exciting stimulus. One of the reasons why I am more prone to getting sick during finals week in school is stress. My immune response is suppressed, making me more vulnerable to illness.

On the other hand, the parasympathetic division deals with processes like digestion, growth, immune response, and energy storage. Therefore, when one isn’t faced by a frightful or highly stimulating environment, the body uses its energy to perform upkeep on the body. The parasympathetic division performs many regulatory functions in the body, such as reducing heart rate and breathing rate. It also stimulates other parts of the body that the sympathetic nervous system suppressed, like digestion. The parasympathetic division can be thought of as an overall rest process, equally necessary to survival as the sympathetic nervous division. 

The sympathetic and parasympathetic divisions both receive input from the CNS. Preganglionic neurons leave the CNS and communicate with post ganglionic neurons in the PNS. Sympathetic ganglions use norepinephrine (NE) as their neurotransmitter, while parasympathetic ganglion use Acytel Choline (ACh). The preganglionic fibers of the sympathetic nervous system are short stemming from the middle third of the spinal cord. On the other hand, the preganglionic fibers of the parasympathetic system are long and come from the brain stem or sacral region of the spinal cord. The harmonic balance between sympathetic and parasympathetic activity is remarkable. It is an efficient and clever way of performing and regulating bodily functions.

 

Hypothalamus

Hypothalamus is a small portion of the brain located below thalamus along the walls of third ventricle. It contains a cluster of small nuclei with multiple crucial functions, including:

  •       maintaining homeostasis
  •       releasing hormones
  •       maintaining light-dark cycle
  •       controlling attention
  •   regulating emotional responses

Hypothalamus is a vital part of the chemical control of the brain and rest of the body. It is highly interconnected with other parts of the CNS, particularly the brainstem and its reticular formation from which it receives most of its inputs. It also has an important function to link the nervous system to the endocrine system via the pituitary gland which in turn is linked to various endocrine glands and organs.

Pituitary gland is divided into two parts: posterior and anterior. Hypothalamus links to posterior pituitary via magnocellular neurosecretory cells which project their axons down the stalk of pituitary and into the posterior lobe. Oxytocin and vasopressin are neurohormones synthesized in the hypothalamus and sent down the axons to the posterior pituitary where they are released into the bloodstream.

Unlike the posterior lobe, which is a part of the brain, anterior lobe is an actual gland. Hypothalamus reaches the axon projections of parvocellular neurosecretory cells down to the capillary bed at the floor of the third ventricle where they release hypophysiotropic hormones to the blood. The blood vessels run down the pituitary stalk and reach the frontal lobe. This network of blood vessels is called hypothalamo-pituitary portal circulation. The secreted hormones cause either a stimulatory or inhibitory response to synthesize and secrete hormones in the anterior pituitary where multiple hormones are secreted to the bloodstream.

Hypothalamus is a great example on how a small region of the brain can be interconnected to multiple other brain regions and from there communicate with the cells of the entire body, acting sort of like a “supergland”.

 

Diffuse modulatory systems

Diffuse modulatory systems can be thought of as collections of core neurons that use a certain neurotransmitter to control a certain aspect of internal commands within the brain. The book used a great analogue for this phenomenon; modulatory systems are similar to volume, treble, and bass controls that change the vibe of a song, but not the song itself. The set of neurons of each system, called the core, has several thousand neurons. Most of the neurons travel from the brain stem of the central core of the brain. The systems are called “diffuse” because information from one axon diffuses to over 100000 postsynaptic neurons. They are able to do this because the neurotransmitters are released into the extracellular fluid, instead of the synaptic cleft, where they can reach more neurons. 

The locus couruleus is a small modulatory system in the pons that releases norepinephrine. The circuitry of the locus couruleus is very vast, one of its 12000 neurons can reach over 250000 synapses. In addition, a neuron in the locus couruleus can have one of its axons in the cerebellar cortex and another in the cerebral cortex. The core neurons play a part in attention, arousal, learning and memory, pain, mood, anxiety, as well as regulating sleep-cycles. Instead of being fully responsible for these aspects, though, the neurons act in strengthening or lessening these different states. Studies have shown that the neurons of the locus coeruleus are activated when something new or exciting is happening in the person’s environment, and are not so active when the person is at rest. 

The nine raphe nuclei located in the midline of the brain stem contain a core set of serotonin-containing neurons. Each nucleus sends information to different parts of the CNS. Raphe neurons are modulate the same kind of signals as the locus coeruleus neurons, but especially sleep-wake cycles. Both raphe and locus coereleus neurons form the ascending reticular activation system, which works to “wake up” the forebrain. Serotonin also controls mood and emotional behavior. 

Two modulatory systems in the midbrain release dopamine. One is the substantia nigra. The axons project to the striatum and control voluntary motor movements. The substantia nigra therefore works to create motor responses to stimuli in the environment. Degeneration of neurons in this modulatory system leads to motor disorders like Parkinson’s disease. Another dopaminergic modulatory system in the midbrain is in the ventral tegmental area. The axons of this system project to the frontal cortex and limbic system. Studies have shown that this modulation reinforces adaptive behaviors by releasing dopamine. 

Acetylcholine is the neurotransmitter at two major modulatory systems; the basal forebrain complex and the pontomesencephalotegmental complex. Not much is known about the neurons in the basal forebrain complex, but research has shown that they are the earliest cells to die during Alzheimer’s disease. The cells in the pontomesencephalotegmental complex project to the dorsal thalamus where it affects the excitability of sensory relay nuclei. 

Psychoactive drugs create mind altering effects by interfering with synaptic transmissions in the modulatory systems. Lysergic acid diethylamide (LSD) and the active ingredient in the psilocybe mushroom are very similar to serotonin. Therefore, it is an agonist at the serotonin receptors in the raphe nuclei. LSD causes hallucinations and a general “dream-like” state of mind. While the exact nature of LSD’s effect on the raphe nuclei is unknown, research has suggested that the hallucinations are a result of creating connections between nuclei that are not formed naturally during the release of serotonin. CNS stimulants cocaine and amphetamine interfere with connections at the dopaminergic and noradrenergic systems. These stimulants increase alertness and self-confidence as well as a general sense of euphoria. They “copy” the effects of the sympathetic division. In addition to these effects, cocaine and amphetamine cause users to become dependent on their use because of the increased dopamine transmission in mesocorticolimbic dopamine system. 

 

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Neurotransmitters

This week we focused on neurotransmitters. We learned about the general chemistry and function of neurotransmitters and examined specific types of neurotransmitters in detail. In order for a chemical in the brain to be considered a neurotransmitter, it must be synthesized and stored in the presynaptic neuron, as well as released when triggered. In addition, a response to the release of the chemical from the presynaptic cell must occur in the postsynaptic neuron. Research has concluded that most neurotransmitters are amino acids, amines (derived from amino acids), or peptides (also consisting of amino acids). Neurons are classified into categories based on which kind of neurotransmitter they release (Dale’s Law). Many chemicals that fill the requirements of being a neurotransmitter are also present in other parts of the body. 

We explored two different ways of generating electrical and biochemical signals in the postsynaptic neuron; transmitter-gated ion channels and G-protein coupled receptors. Transmitter-gated ion channels are faster at transmitting a signal in the postsynaptic neuron than G-protein coupled receptors. Most of these channels contain four hydrophobic segments that spread throughout the membrane with subunits that contain different receptors for different neurotransmitters. The differences between the structures of the channels are what determine which ions and transmitters flow through them.

Amino acid gated channels are responsible for most of the fast synaptic transmissions. The molecular structure of the channel is an indicator of the pharmacology, kinetics, selectivity, and conductance of channels. AMPA, NMDA, and kainate are all glutamate-gated ion channels. AMPA and NMDA-gated channels are responsible for much of the excitatory synaptic transmission in the CNS. They work together, but unlike AMPA, NMDA-gated channels are permeable to calcium ions and are also voltage-dependent as well as transmitter-gated. GABA-gated and glycine-gated channels are selectively permeable to chloride ions. GABA is responsible for much of the synaptic inhibition in the CNS, while glycine is responsible for most of the rest. 

Transmission at G-protein receptors involves the binding of a neurotransmitter to a receptor protein, subsequent activation of G-proteins, and resulting activation of other effectors. Many G-protein coupled receptors have seven alpha helices that penetrate the membrane with a binding site for G-proteins on the inside of the membrane. G-proteins have three subunits, and in the inactive stage, a GDP molecule is connected to one of the subunits. When a receptor with a neurotransmitter binds to a G-protein, it releases the GDP molecule and gets a GTP from the cytosol. From then the G-protein is free to activate other effector proteins. While G-protein coupled transmission involves more steps and is more complex than fast synaptic transmission, this kind of transmission can cause an elaborate network of biochemical reactions, called a signal cascade. Therefore the signal may be amplified, and cause long-lasting changes in cells. Neurotransmitters can activate many subtypes of receptors; this phenomenon is known as divergence, and it can happen at any point of the signal cascade. Many different transmitters can also come together to trigger the same effector; called convergence. These paths of signals can be thought of as a network of information that is amplified and sent along to different neurons. 

Next we will discuss two different kinds of neurons in more detail. 

Cholinergic Neurons

Acetylcholine (ACh) is a neurotransmitter used in various systems of the body. It is commonly known as the neurotransmitter that binds to nicotinic ACh receptors in neuromuscular junctions, in which nicotine is an agonist. Another type of receptor is the muscarinic ACh receptor in the heart, in which muscarine is an agonist. Most neurotransmitters are either amino acids, amines derived from amino acids, or peptides made up of amino acids. These types of neurotransmitters are common because they are considered the basic chemicals of life. On the other hand, ACh is derived from acetyl CoA, which is a product of cellular respiration in the mitochondria, and choline used for fat metabolism. CoA and choline are also abundant in human cells.

Cholinergic neurons have an interesting mechanism for creating ACh in the synapse. The main enzyme required for making ACh is choline acetyltransferase (ChAT). ChAT is transported from the soma to the neuron terminals. It combines choline and acetyl CoA to create ACh. ACh is subsequently packed into vesicles by transporters. The presynaptic terminal’s source of choline comes from the extracellular space. A cotransporter is used that brings in Na+ and choline into the presynaptic terminal. The transport of choline into the presynaptic terminal is considered the rate-limiting step in the formation of ACh.

Another extremely important enzyme for cholinergic neurons is acetylcholinesterase (AChE). AChE performs the reverse reaction of ChAT by breaking ACh into choline and acetylcholine in the synaptic cleft. AChE has one of the fastest catalytic rates of all enzymes. AChE is essential to regulating the excitation of cholinergic neurons, which is a reason why it is the target of attack for many nerve agents. Inhibition of AChE results in ACh overload producing constant nerve stimulation. Consequently, nerves become fatigued which can lead to respiratory paralysis if left untreated. In addition, blood pressure and heart rate drop significantly. 

This August, Russian opposition activist, Alexi Navalny, was poisoned in Russia with a deadly chemical nerve agent inhibiting AChE called Novichok (Simmons, 2020). He was transported to Germany, put on a respiratory ventilator, and survived. Novichok was developed by the Soviet Union. Novichok causes sudden cardiac arrest and respiratory paralysis. One of the drugs used to treat Mr. Navalny was atropine. In class we learned that atropine is an antagonist to muscarinic ACh receptors. Therefore, in the absence of functioning AChE, atropine can act as a regulatory mechanism to reduce the firing of neurons by keeping the ion channels with muscarinic ACh receptors closed. Atropine isn’t a cure but a quick solution to counteract the deadly, sudden effects of Novichok. Atropine is derived from “deadly nightshade,” a plant that in normal circumstances is toxic. However, in Mr. Navalny’s case, deadly nightshade saved his life (Simmons, 2020). 

 

Amino acidergic neurons

There are many amino acids that serve as a neurotransmitter, like glutamate, glycine and gamma-aminobutyric acid (GABA) from which only GABA is uniquely used as a neurotransmitter in the brain and spinal cord. Therefore, we mainly focus on GABA, even though many aspects of its working principles can also be applied to other neurotransmitter amino acids. GABA is a four-carbon non-protein amino acid that is synthesized in large quantities only by GABAergic neurons. 

GABA is synthesized from glutamate through decarboxylation via glutamate decarboxylase enzyme. The release of GABA is a similar mechanism as with other neurotransmitters. When a nerve impulse reaches axon terminal, the vesicles containing GABA degranulates and GABA is released into the synaptic cleft where it reaches the postsynaptic neuron. There are two types of GABA receptors where the molecule can bind to, GABAA  and GABAB. GABAA is a chloride ion channel coupled receptor which causes an increase in the chloride ion influx into the neuron. GABAB is a G-protein coupled receptor that causes an increased opening of potassium channels transmitted by second messengers. They also decrease the activity of adenyl cyclase enzyme and calcium channels. All of the effects mentioned above increase depolarization of the neurons, therefore increasing the threshold potential. Hence, GABA is responsible for decreasing neuronal excitability and participating in multiple inhibitory nervous signals.

Since GABAergic neurons are inhibitory, they have numerous effects in the body such as relieving anxiety and stress in addition to controlling blood pressure and heart rate, just to name a few. Studies have also found that altered GABA signaling is associated with different brain diseases like ADHD, depression, anxiety and epilepsy. For instance, the latter is associated with ionic changes in postsynaptic GABAA receptors which causes decreased expression of these receptors. GABA mimetic drugs can therefore be used to treat epilepsy patients. (The Human Memory, 2020)

GABA, The Human Memory, 2020. Available (accessed on 11.10.20): https://human-memory.net/gaba/

Simmons, Ann. “What Is Novichok, the Nerve Agent Used to Poison Alexei Navalny?” The Wall Street Journal, Dow Jones & Company, 17 Sept. 2020, www.wsj.com/articles/what-is-novichok-the-nerve-agent-used-to-poison-alexei-navalny-11599072960.

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Chemical Senses and the Eye

Chemical Senses

The two most familiar chemical senses to humans are gustation (taste) and olfaction (smell). Based on the textbook reading, olfaction seems to be significantly more complex than gustation. Smell seems to contribute much more to taste than the taste receptor cells on one’s tongue.  When people get sick, they will often get stuffy noses and lose their sense of smell. A loss of smell also results in a significant loss of taste. I have also learned to pinch my nose when I need to consume something that tastes awful to reduce my sense of taste.

Gustation can detect five main types of senses. These include salty, sour, sweet, bitter, and Unami. All other senses of taste come from olfaction. Certain areas of the tongue have papillae which contain taste receptor cells. These receptor cells transduce in response to chemical stimulus. There are three main types of transduction, ions may directly pass through ion channels (salty and sour), chemicals may block ion channels (sour), or chemicals may bind to G-protein-coupled receptors in the membrane and activate second messengers to open ion channels (bitter, sweet, and unami).

Eating something salty results in sodium diffusing into a receptor cell, depolarizing the membrane, activating voltage-gated sodium and calcium channels, which consequently release vesicle filled with serotonin to the gustatory afferent neuron. Eating something sour will result in H+ ions blocking K+ channels depolarizing the membrane, which opens voltage-gated sodium and calcium channels signaling vesicles filled with serotonin to undergo exocytosis. Sweet, bitter, and unami type chemicals undergo a G-protein-coupled receptor transduction pathway. The ability to taste bitter was vital to human survival because many poisons contain bitter taste. However, senses of taste can adapt as many people enjoy coffee, which is bitter. All of these tastes are processed in the brain. The primary gustatory axons connect to the brain stem, which leads to the thalamus (ventral posterior nucleus), and ends up in the gustatory cortex.

Olfaction begins at the olfactory epithelium. The olfactory epithelium contains three types of cells, receptor cells, supporting cells which produce mucus, and basal cells which are the source of new receptor cells. An interesting fact we learned this week is that olfactory receptor cells have a four to eight-week life cycle. The mucus layer allows chemicals to dissolve and attach to cilia. This results in transduction of the receptor cells. The signal converges at the olfactory bulb and can lead two to two different pathways to the brain. The path to the orbitofrontal cortex is longer and belongs to conscious thought. The olfactory bulb can also pass its signal straight to the olfactory cortex. The olfactory bulb is very complex and intricately maps receptor cell types in its glomeruli. Smells are encoded both spatially and temporally. There is a lot of research currently on population coding and olfactory maps.

The eye

The eye is a specialized organ that has the ability to detect, localize, and analyze light. 

The cornea is the layer of the eye through which light first travels into the eye. Then, the light enters the pupil, the black part in the middle of the eye. The colored iris is in charge of controlling how much light can enter the eye by enlarging or dilating the pupil. This phenomenon  is similar to how a camera lens works. Behind the pupil is the lens. The lens also changes shape in  order to focus the light onto the retina. The lens thickens when focusing on things that are close and spreads flatter when focusing on this further away. The retina is the last layer of the eye onto which the image is formed. Photoreceptors are cells that are specialized to sense light and they are tightly packed in the retina. There are two types of photoreceptors: cones and rods. Cones sense details and colors and they are dense in an area of the retina called the fovea. Rods have the ability to control night vision as well as peripheral vision. There are more rods than cones and they are mostly located in the peripheral area. Therefore, the two types of photoreceptors differ in the kind of images they sense. The photoreceptors are each connected to a nerve fiber. The nerve fibers bundle together to form the optic nerve. 

  

Figure 1: Structure of the human eye

The way that light energy is transformed into an image on the retina is through membrane potential changes and a subsequent chemical signal. Electromagnetic radiation is absorbed by photopigment called rhodopsin in outer segments of the photoreceptor. This triggers G-proteins, which the cause effector enzymes to set forth a chain of events that causes ion channels to close and membrane potential thus changes. Membrane potential in the dark is more positive than in other neurons and contrary to most action potentials, membrane potential hyperpolarizes in response to light triggers. Special channels let in sodium ions in a flow called the dark current. These sodium channels are stimulated to close by cyclic guanosine monophosphate (cGMP), an enzyme that is reduced by light. When the sodium channels close, membrane hyperpolarizes. An interesting thing noted in  the reading is that the transduction of signals in photoreceptors is similar to that of olfactory cells. The neurotransmitter involved in the chemical signal is glutamate. 

The only source of output from the retina is from the action potentials from ganglion cells. Each photoreceptor is linked with two retinal neurons, bipolar cells and horizontal cells. Bipolar connect photoreceptors directly to ganglion cells and horizontal cells send information “horizontally” and also affect other bipolar cells and photoreceptors. Information from about 97 million photoreceptors is condensed and sent through the pathways to ganglion cells as action potentials. The mapping of images into optic nerve fibers is not event; instead in some areas, such as the fovea, less photoreceptors send information to each ganglion cell. This means that the images are crisper in the fovea.

The central visual system

Previously we saw the many ways how eyes are quite similar to cameras in their functioning. However, after the visual information leaves the retina and enters neural pathways there are much more complex structures that are capable of doing so much more compared to a simple camera. Central visual system is responsible for, for instance, combining the visual fields of both eyes, extracting information about differences in brightness and color in addition to detecting motion.

Each eye sees a part of the visual space that defines its visual field. The central portion of both hemifields are viewed by both retinas, creating a binocular visual field. The axons of ganglion cells exit the eyes via retinofugal projection which is a neural pathway consisting of the optic nerve, the optic chiasm where axons from nasal retinas cross and the two optic tracts. Because the optic nerves cross, the left visual hemifield is viewed by the right hemisphere and the right hemifield is viewed by the left hemisphere.

The optic tracts project to four subcortical regions of the brain: (1) the lateral geniculate nucleus (LGN) that gives rise to axons that project to primary visual cortex via optic radiation, (2) the superior colliculus, that controls the orienting eye and head movements, (3) the hypothalamus that regulates the circadian rhythms, and (4) the pretectum, that controls the pupillary light reflect.

 

Figure 2. The structures of retinofugal projection and the processing of visual fields.

 

LGN is the main target of retinal ganglion cells. It receives input from both eyes and relays the information to the primary visual cortex. The retinal M-type and P-type ganglion cells respectively project to two ventral magnocellular layers and four dorsal parvocellular layers of the LGN. Each of the six LGN layers receives inputs from either the ipsilateral or contralateral eye i.e. the axons from the left eye project to layers 1, 4 and 6 of the right LGN and the axons from the right eye project to the layers 2, 3 and 5. There are also six koniocellular layers K1-K6 that lie ventral to each “main” layer of the LGN. This is where all nonM—nonP-type ganglion cells project.

Magnocellular and Parvocellular layers each contain specific visual functions. Magnocellular layers are involved in detecting fast moving stimuli whereas parvocellular layers are  responsible for processing of color and fine detail.  Therefore, selective lesions in these areas cause lesions in only some visual functions without impairing the entire vision.

The primary visual cortex (V1) has an organization where neighboring cells in the retina feed information to neighboring places in the target structure i.e. the 2D structure of the retina is mapped onto the 2D surface of subsequent structures in V1. This phenomenon is called retinotopy. However, this mapping is often distorted because the visual space is not uniformly sampled in retina (high density of ganglion cells in fovea) and discrete point of light activates many cells in retina due to overlapping receptive fields. As was seen in LGN, V1 also has a layered structure which divides the labor in the cortex and keeps the inputs from two eyes separate.

In order for the brain to make sense of the visual world and to combine all the visual input, there are three pathways within V1 that work in parallel: (1) magnocellular pathway, (2) parvo-interblob pathway, and (3) the blob pathway. These pathways are briefly modeled in Figure 3.

Figure 3. A hypothetical model of parallel pathways in the primary visual cortex.

Via these pathways, the brain forms the images we know, with color, shape and motion. However, these pathways are just hypothetical and further research shows that the signals from each pathway mix and and the receptive field properties overlap making the understanding of visual information processing even more difficult.

The striate cortex is only one area of the cortex that processes visual information. Beyond V1 are located another two dozen distinct extrastriate areas of the cortex whose full functions are still under debate. However, there appears to be at least a dorsal stream and a ventral stream which are responsible for observing movement and recognizing objects, respectively. When inspecting the central visual system as a whole, we can clearly see a pattern throughout: there is a division of labor principle, i.e. a group of cells or cortical areas may contribute to perception, some dealing more with color or shape, others more with motion. However, the detailed principle on how this information is perceived as coherent images, is still quite unknown.

 

Figure 1. Available (accessed on 4.10.2020):

https://www.thoughtco.com/how-the-human-eye-works-4155646 

Figure 2. Available (accessed on 2.10.20): http://brain.phgy.queensu.ca/pare/assets/Central%20Pathways%20handout.pdf

Figure 3. Bear, M., Connors, B., PAradiso, M. Neuroscience: Exploring the brain, Fourth edition. 2015, pp. 355.

 

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Synapses and integration

Electrical synapses

Electrical synapses are mechanically and electrically conductive links between two neurons or a neuron and another cell. They occur at gap junctions, the gap being about 3.5 nm wide spanned by proteins called connexins. Six connexins form a connexon unit and two connexon units form a gap junction channel that spans through the presynaptic and postsynaptic membrane.

Since the information is conducted via electric current in gap junctions, the transmission is extremely fast especially in channels that are large in diameter. The speed allows synchronicity of action potentials which seems to be vital for fine timing of motor control.

Electrical synapses, more specifically those formed by connexin 36 (Cx36), are also involved in creating emotional memories. Bissiere et al. blocked either neuronal gap junctions or Cx36 within the dorsal hippocampus on rats testing this hypothesis. The experiment caused significant impairment of context-dependent fear learning, memory, and extinction. (Bissiere et al., 2011) This finding provides understanding of the functional roles of electrical synapses in mechanisms of fear learning and memory in the adult mammalian brain, but it may also point toward new therapeutic treatment of trauma and anxiety disorders.

 

Chemical synapses

Most synaptic transmission in the human nervous system is chemical. In chemical synapses, there is a presynaptic and a postsynaptic membrane, separated by a synaptic cleft. The cleft is filled with matrix that “glues” the membranes together. On the presynaptic side of the synapse are vesicles, inside which are the neurotransmitters.The neurotransmitter is the chemical that acts as the means of communication between the presynaptic and postsynaptic neurons. They belong to three categories: amino acids, amines, and peptides. Different neurons release different neurotransmitters and they are synthesized in different ways. On the presynaptic side, protein mass resembling pyramids poke into the cytoplasm of the membrane form the area where neurotransmitters are released, also known as the active zone. The protein mass on the postsynaptic side, called the postsynaptic density, is the area in which the neurotransmitter receptors are. The receptors’ job is to convert the chemical signal from the neurotransmitter into a signal that can be interpreted by other neurons (change in membrane potential or chemical change). 

Chemical synaptic transmission contains many steps. The neurotransmitter is synthesized either by proteins already in the neuron or synthesized by specific enzymes. After synthesizing, transporter proteins pack the neurotransmitter into vesicles. The neurotransmitter release is activated by an action potential in the axon terminal. As a consequence, voltage-gated calcium channels in the active zone open up. The increase in calcium concentration causes the neurotransmitter release. The vesicle releases the neurotransmitter into the postsynaptic cleft through exocytosis. This process can be quite fast, sometimes 0.2 msec from the calcium release. After release, the membrane of the vesicle reforms through endocytosis and is recycled to be used again.

In the synaptic cleft neurotransmitters in the synaptic cleft find specific receptor proteins and bind to them. The receptor protein conformation changes and the protein as a result works differently. Neurotransmitter receptors include transmitter gated ion channels and G protein coupled receptors. Transmitter gated ion channels have 4-5 subunits that form a pore, through which ions can pass through when the binding of a neurotransmitter causes the pore to open. If the channel is permeable to Na+, the postsynaptic membrane will depolarize, causing an excitatory postsynaptic potential (EPSP). If it is permeable to Cl-, the membrane will hyperpolarize, causing an inhibitory postsynaptic potential (IPSP). For G protein coupled receptors, neurotransmitters bind to proteins within the postsynaptic membrane, which then cause the activation of G-proteins, which then activate effector proteins. The effects of a neurotransmitter binding to G protein coupled receptors are slower, more long-lasting, and more diverse than voltage gated ion channels. 

 

Synaptic integration

Synaptic integration is the brain’s form of neuronal computation. A neuron can convert thousands of inputs into an action potential output. This process begins with excitatory postsynaptic potentials (EPSP). Transmitter-gated channels open in the post synaptic membrane bringing an inward depolarizing current, causing the EPSP. The amount of inward current is proportional to the amount of neurotransmitter released from the presynaptic terminal.

Quantal analysis is a method that compares the amplitudes of EPSPs to estimate how many vesicles of neurotransmitters were released by the presynaptic terminal. The quantum is a measure that reflects the number of neurotransmitters in a single vesicle and the number of postsynaptic receptors. EPSPs are integer multiple responses to miniature postsynaptic potentials because of the idea that neurotransmitters are released in packets, or vesicles.

EPSPs are subsequently summed in two ways, spatially and temporally. The EPSPs evoked by different dendrites are summed at the axon hillock. If the potential difference at the axon hillock exceeds a threshold voltage, then an action potential is propagated along the axon. Spatial summation is the summation of multiple EPSPs evoked at different synapses of a dendrite. Temporal summation is the summation of multiple EPSPs evoked in rapid succession at a single synapse (from a single neuron). 

EPSPs evoked closer to the axon hillock hold more weight than those that are farther from the axon hillock. This is because the membrane depolarization decays over distance due to inward ionic current “leaking” out of the neuron through ion channels (rm) and loss of potential due to the internal resistance of the neuron (ri). This voltage decay is characterized by a length constant, which is a function of ri and rm. Also, EPSPs that are generated in rapid succession at a synapse hold a lot of weight. Therefore, the location and electrical activity of synapses are very important to the weight the input neuron has on the output neuron’s decision to fire or not.

Similarly, the location and amount of activity of inhibitory synapses holds a lot of weight on the axon hillock potential. Inhibitory synapses usually contain ion channels that allow an influx of anions like chlorine. These kinds of synapses hyperpolarize the membrane potential. They hold a lot more weight the closer they are to the axon hillock. They are analogous to electrical shunts.

Something new we learned in this reading was that the dendrites can have electrically excitable membranes. In other words, they are not always passive. This allows smaller EPSPs to propagate longer distances without dramatic decay. Synaptic integration explains a lot about how certain neurons can hold more weight than others in action potential evocation. It is a critical part to brain wiring and signal propagation.

 

Bissiere S, Zelikowsky M, Ponnusamy R, Jacobs N, Blair H, Fanselow M. Electrical Synapses Control Hippocampal Contributions to Fear Learning and Memory. Science. Vol 331, Iss. 6013, 2011, pp. 87-91. Available (accessed on 26.9.2020): DOI: 10.1126/science.1193785

 

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Neurons and their properties

 

  • Neurons/glia 

A neuron is a cell with two characteristic properties: electrical excitability and conductivity. Neurons have many functions that divided them into three main types: (1) primary sensory neurons, (2) motor neurons and (3) interneurons. Sensory neurons sense changes in the environment and communicate these changes to other neurons in the central nervous system (CNS). According to this information, the body knows how to response to the stimuli. Motor neurons, on the other hand, receive input from the CNS on how to control the body, including body functions such as muscle movement and gland function. Interneurons are neurons that connect with other neurons. They are the central nodes of neural circuit, enabling communication between sensory or motor neurons with the CNS. They play vital roles for instance in reflexes, neuronal oscillations and neurogenesis.

Neurons are in many ways like “normal” cells. They have nuclei that contains all the genetic information, mitochondria that powers the cell in addition to smooth/rough ER and Golgi apparatus all of which are involved in protein synthesis and/or post-translational processing of the proteins. What differentiates neurons from other cells is their characteristic thread-like shape provided by the cytoskeleton in addition to the neurites connected to the soma i.e. the cell body. Neurites include axons and dendrites. Axons are long projections of the neuron that conduct electrical impulses known as action potentials away from the soma. The axon’s end site is called axon terminal in which the axon comes in contact with other cells and passes information to them via synapse. Dendrites, on the other hand, receive information via synapses from other neural cells and propagate it to the soma. Neurons have usually numerous dendritic branches that form a collective structure called dendritic tree. 

Glial cells, consisting of microglia, astrocytes, and oligodendrocyte lineage cells as their major components are non-neuronal cells in the CNS and PNS that are not electrically excitable. They have four main functions: (1) to surround and support neurons, (2) to supply nutrients and oxygen to neurons, (3) to insulate neurons and (4) to destroy pathogens and remove dead neurons. Most abundant glial cells are astrocytes which fill most of the space between neurons. They regulate the chemical content in the extracellular space and envelop synaptic junctions prohibiting the leaking of neurotransmitters beyond synaptic cleft. Myelinating glia provide layers of membrane to insulate axons which increases the propagation speed of action potentials, thus enabling the fast flow of information in the body. There are two types of myelinating glia: oligodendroglial in the CNS providing myelin to several axons and Schwann cells in the PNS providing myelin to only a single axon. Microglial cells are phagocytes that remove debris left by dead or regenerated cells.

Glia were originally considered as purely non-functional glue for neurons but by ablating single glial cell populations, researchers have confirmed their importance as well as further discovered the functions of glial cells. The literature shows that astrocyte ablations cause negative effects on overall neuronal survival in the cerebellum and in the spinal cord. Astrocyte ablation in cervical spinal cord in mice showed axonal degeneration in addition to paralysis of all limbs caused by the failure to buffer reactive oxygen and nitrogen species. (Schreiner et al., 2015) This indicates that one of the important functions of the astrocytes truly is the regulation of chemical content in the extracellular space by for instance buffering these substances that are damaging to the nervous system. By ablating a microglial cell population on mice, Parkhurst et al. found a loss of motor-dependent synapse formation and a decreased performance in learning tasks (Parkhurst et al., 2013). Additionally, a loss of about 80% of hippocampal microglia resulted in alteration in social behaviour in mice (Torres et al., 2016). These results indicate that the phagocytic properties of microglia are essential in maintaining brain homeostasis. The function of oligodendrocytes is clear as they are the myelin-producing cells that insulate axons allowing fast propagation of action potentials. However, the function of non-myelinating oligodendrocytes present in sparsely myelinated brain regions like the gray matter in the cerebral cortex is a bit more unclear. Studies however show that non-myelinating oligodendrocytes for instance carry transcripts for all major myelin proteins (Paez et al., 2009) and may thus be able to remyelinate denuded axons after injury (Gregersen et al., 2001).

 

  • Neuronal membrane at rest

 

The membrane potential is analogous to a capacitor that is waiting to discharge. The cell membrane has  a resting electrical potential of approximately -70mV. This potential difference arises due to the differences of ion concentrations inside and outside of the cell. The main ions that dictate this potential are sodium and potassium, but also include other ions like chloride and calcium. When the cell membrane is at rest, potassium ions move from inside to outside the cell due to diffusion through leaky potassium ion channels. The leaky potassium ion channel does not allow sodium into the cell because the residues of the channel are selective of ion size with a solvent shell. Only a few potassium ions are required to move to the other side of the membrane to create a potential difference. The net flux of potassium across the membrane stops when the electromotive force pushing potassium into the cell equals the diffusive force pushing potassium out of the cell. The potassium ions that leak to the outside hang around the membrane, leaving negative charge behind on the inside of the cell membrane. 

The amount of ions needed to create the potential difference is really small. It should also be noted that the extracellular fluid and intracellular fluid are net neutral, so only the membrane locally contains this electrical potential. If the difference in ion concentrations between inside and outside of the cell create an electrochemical gradient that charges the membrane capacitor, how is this gradient created in the first place? Creating an electrochemical gradient seems to go against entropy and must require energy. The sodium potassium pump is the key to creating the ion concentration gradients with a little help from its friend ATP.

         The sodium potassium pump pushes a high concentration of potassium inside the cell and sodium outside the cell. The majority of a neurons’ ATP goes to maintaining the ion concentrations. 

We have also looked into circuit models of the neuron membrane. The neuron membrane can be modeled by a battery (representing the potential difference set by the sodium potassium pump and leaky potassium channels) in parallel with capacitors and resistors. The capacitors represent the membrane holding charge. The resistors have conductance values representing ion channels in the membrane. A high conductance means that ions easily flow through that channel, like the leaky potassium channels. A low conductance means that ions struggle to move across the membrane. However, some of these resistors have varying resistances. For example, the voltage gated sodium channel increases in conductance during an action potential, which is the next topic of this super awesome blog.

 

  • Action potential

 

As mentioned before, neurons are electrically excitable. They send messages to one another through a chain of  electrical signals until they reach the cerebral cortex area of the brain, which is the part of the brain that interprets sensations. An action potential is a signal that propagates from the axon of one neuron to the dendrites of another. 

A graded potential is created in a sensory receptor, specifically a mechanoreceptor. A graded potential is a change in the membrane potential.  The mechanical stimulant is converted to an electrical one, which is then interpreted by the receptor. As a result, gated ion channels in the nerve endings open, which causes ions to flow in , changing the potential inside the cell membrane. Membranes have a resting potential of about -70V. An action potential acts in an “all or nothing” way, meaning it has to get to a certain threshold in order to continue. When the potential of a cell is under the threshold, the voltage-gated channels are shut, but when it gets to threshold, the channels to open and positive sodium ions flow in from the extracellular fluid. This causes the cell membrane to depolarize. The ions move according to their electrical gradient. After the neuron membrane has completely depolarized, the cell reverses this action by opening voltage-induced potassium channels. Potassium ions flow out of the cell. After a short time, the resting membrane is recovered. At the same time, the action potential travels along the axon until it causes a neurotransmitter to be released. A neurotransmitter is a chemical signal that is released at the axon terminal to the synapse of another neuron. They are transported in synaptic vesicles to the synapses (connections) located at the ends of the dendrites of the other neuron. The neurotransmitter released to the dendrites of the interneuron triggers a change in potential in the next neuron. After this potential travels through the axon due to the movement of ions, another neurotransmitter is released at the synapse of another interneuron. The same chain is repeated until some kind of effect happens, such as a muscle contracting or feeling pain. 

References

Bear, Mark F., et al. Neuroscience: Exploring the Brain. 4th ed., Jones & Bartlett Learning, 2016. 

Gregersen R, Christensen T, Lehrmann E, Diemer NH, Finsen B. Focal cerebral ischemia induces increased myelin basic protein and growth-associated protein-43 gene transcription in peri-infarct areas in the rat brain. Experimental Brain Research. Vol. 138, 2001, pp. 384-392. Available (accessed on 18.9.2020): doi:10.1007/s002210100715

Paez P, Fulton D, Spreuer V, Handley V, Campagnoni C, Macklin W, et al. Golli myelin basic proteins regulate oligodendroglial progenitor cell migration through voltage-gated Ca2+ influx. The Journal of Neuroscience. Vol. 29, 2009, pp. 6663–6676. Available (accessed on 18.9.2020):  https://doi.org/10.1523/JNEUROSCI

Parkhurst N, Yang G, Ninan I, Savas N, Yates R, Lafaille J, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. Vol. 155, 2013, pp. 1596–1609. doi: https://doi.org/10.1016/j.cell.2013.11.030

Schreiner B, Romanelli E, Liberski P, Ingold-Heppner B, Sobottka-Brillout B, Hartwig T, et al. Astrocyte depletion impairs redox homeostasis and triggers neuronal loss in the adult CNS. Cell Reports. Vol. 12, 2015, pp. 1377–1384. Available (accessed on 18.9.2020): https://doi.org/10.1002/glia.23055

Torres L, Danver J, Ji K, Miyauchi J, Chen D, Anderson M, et al. Dynamic microglial modulation of spatial learning and social behavior. Brain, Behaviour, and Immunity. Vol. 55, 2016, pp. 6–16. Available (accessed on 18.9.2020): https://doi.org/10.1016/j.bbi.2015.09.001

Tortora, Gerard J. Principles of Anatomy and Physiology. John Wiley & Sons Australia, Ltd, 2019.

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