SUMMARY

  
Signal Reception
Propagation of an action potentiel
Chemical transmission = conversion of electric signal to a chemical signal
What happens when you burn yourself? What tells you that it hurts and makes you remove your hand, for example ?
How is the heart regulated ?
Huntington Disease : Genetic Part 
Huntington Disease : Protein Part 

INTRODUCTION

The functioning of the human body implies a coordinated activity of the cells which composes it. For animals this coordination is assured thanks to two big intercellular systems of communication : the hormonal system and the nervous system.

Neurons, one of the cells that constitute the nervous system, form a complex network of communication both with each other and with target organs such as muscles, glands, the digestive system or sensory organs. It is a two way communication system, in wich commands are sent to the organs (contraction, relaxation, secretion) and information is gathered from them (position, temperature, tension,presence of light, sound, taste substances). For instance, when you burn your hand, you sensory neurons directly pass a message to motor neurons in order to pull away from the hot object  this is called a reflex. We are going to study the principles and the functioning of these mechanisms by which neurons transmit signals.

SIGNAL RECEPTION

Definition

A neuron is an electrically excitable cell that processes and transmits informations through electrical and chemical signals. Neurons connect to each other to form neural networks. Neurons are the core component of the nervous system, which includes the brain, spinal cord, and peripheral ganglia. A number of specialized types of neurons exist : sensory neurons respond to touch, sound, light, and numerous other stimuli affecting cells of the sensory organs that then send signals to the spinal cord and brain.

Structure

A typical neuron

possesses a cell body, often called the soma, dendrites and an axon. Dendrites are thin structures that arise from the cell body, often extending for hundreds of micrometres and branching multiple times, giving rise to a complex "dendritic tree". An axon is a special cellular extension that arises from the cell body and travels for a distance, as far as one meter in humans or even more in other species. The axon terminal contains synapses, specialized structures where neurotransmitter chemicals are released to communicate with target neurons or target tissues. The cell body of a neuron frequently gives rise to multiple dendrites, but never to more than one axon (see figure 1). 

Reception and transmission

Dendrites receive the information (= signals) and send it to the soma and then to the axon. In the majority of cases, the signal arrives at the dentrite in the form of a neurotransmitter. They are transduced (converted into and transmitted) in the form of an electric signal, an action potential, that traverses the neuron until the endings of the axon. This is what we mean with neurons being excitable cells, they can generate action potentials. At the endings of the axon, the signal is converted into the release of a neurotransmitter which, in turn, will pass on the message to the next neurons or to a target tissue.

PROPAGATION OF ACTION POTENTIAL

The action potential is an electric signal. It corresponds to a fast change in the membran potential, as a consequence of a fast depolarization followed by a repolarisation. 

Because of an asymmetric distribution of ions across the plasma membrabe of all cells, put into place by ion pumps, and because of constant "leakage" of ions through membrane transporters, cells develop a membrane potential (see figure 2). Normally we define the membrane potential as a negative value (inside relative to the outside of the membrane). In the majority of cells the resting potential is around -70mV +/-10mV. What this means is that the flow K+ ions to the outside matches the flow of Na+ ions to the inside. The system is in equilibrium.Thos equilibrium can be disturbed by changing the permeability of the transporter proteins, in the case of neurons, by changing the permeability of the ion-channels fot K+, Na+ or Cl-. This is what neurotransmitters do, they modify ion-channel permeability, and by doing so they can generate, or prevent, action potentials. When the membrane potential reduces, say goiong from -70 to -50 mV, it depolarizes, when the potential increases, going from -70 to say -80mV, it hyperpolarizes. 

 

An essential aspect of excitable cells is that they carry membrane-potential sensitive Na+-channels (also known as voltage sensitive Na+-channels). This distinguishes them from non-excitable cells. When the membrane potential depolarizes to arround -40 mV, the volatge -sensituve Na+-channels open for a very brief period, in the order of 1 to100 milliseconds. The Na+ curtent briefly dominates and the potential changes from -40mV to +30mV. The abrupt change is called an action potential. It propagates very rapidly across the membrane of a neuron until it reaches the end of the axon and then dies out because the voltage-sensitive Na+ automatically close. A subsequant dominance of the K+-current brings the system back to a resting level (around -70 mV), a phenomenon referred to as membrane repolarisation. After a short refractory period, again in the order of milliseconds the process can be repeated. Numerous actions potentials in a row are called spikes. An active neuron is defined as one that produces lots of spikes a weak signal.

CHEMICAL TRANSMISSION = CONVERSION OF ELECTRIC SIGNAL TO A CHEMICAL SIGNAL

Neurons are interconnected in complex arrangements, and sometimes use electrical signals (electrical synapse) but mostly chemical signals (chemical synapse employing neurotransmitters) to transmit impulses from one neuron to the next.

Axon terminals are separated from neighboring neurons by a small gap called a synapse.

Different kind of synapses 

- The neuro-neuronal synapse : the synapse is situated between two neurons.

- The neuro-effector synapse : the synapse is situated between a pre-synaptic neuron and an effector cell (gland,musclu,etc).

- The sensory-neuronal synapse : the synapse is situated between a sensory cell and a post-synaptic neuron.

The chemical synapses

These are the type of synapses that we are going to study. The signal received by the axon terminations is electric so we are going to see how this signal is converted into a chemical signal.
  

From electric signal to neurotransmitter release

Firstly, we know that the pre-synaptic nerve-terminal synthesizes chemically messagers called neurotransmitters. These are often the size of an amino acid (examples dopamine, adrenaline, glutamate or acetylcholine) so small molecules. They are stored in vesicles near the membrane of the nerve-ending at the site of a synapse. Now that the neurotransmitters are created, they have to be released to be able to transmit their message. It is the arrival of the action potential which permits the release of the neurotransmitters by the creation of a depolarization at the axonal termination. Each action potential liberates a certain amount of neurotransmitter. The higher the frequency of the action potential, the more neurotransmitter will be released in time.

Indeed, the arriving action potential leads to the opening of the calcium channels. There is much more calcium outside the neuron than inside and the opening of the calcium channels leads to the entry of the calcium in the cell. The elevated binds proteins attached to the membrane of the synapse and causes the fusion of the vesicles membrane with pre-synaptic membrane, a process referred to as exocytosis. The liberated neurotransmitter diffuses across the synaptic cleft (space between two cells) one will then bind to specific proteins (receptors on the post-synpatic cell (see figure 3).

 A: Neuron (Presynaptic) 

 B: Neuron (Postsynaptic)

1. Mitochondria
2. Synaptic vesicle full of neurotransmitter
3. Autoreceptor
4. Synaptic cleft
5. Neurotransmitter receptor
6. Calcium Canal
7. Fused vesicle releasing neurotransmitter
8. Neurotransmitter re-uptake pump 

WHAT HAPPENS WHEN YOU BURN YOURSELF? WHAT TELLS YOU THAT IT HURTS AND MAKES YOU REMOVE YOUR HAND, FOR EXAMPLE?

First, you have to know that in your skin, you have sensory neurons, more specifically nociceptor neurons.

Sensory neurons have receptors that react when temperature increases (like a burn).

Activated  by the heat, cationic channels open themselves and let pass Ca2+ cations.

There is a depolarization of the membrane and an action potential is created.

The action potential propagates along sensory neuron axon until sensory ganglia. These ganglia are located on each side of the spinal cord. That’s where we find the cell bodies of the nociceptor neurons. (fig. 1)

Then, the action potential goes into the posterior gray columns of the spinal cord. It is relayed to another neuron  by the first synapse of pain transmission.

The message is relayed to a projection neuron which goes from the spinal cord to the brain. This transmission is regulated by interneurons which can increase or decrease it. (fig. 1)

Projection neurons can use two different ways of fibers to go up to the brain:

• By the first pathway, they go up straight to the thalamus, second synapse, and then to the cortex. 
• By the second way, axons project to the parabrachial nucleus, where they establish new synapses. This nucleus send projections to the thalamus, but also to the hypothalamus.

The first pathway leads to a sensory discriminative perception of pain. The second pathway regulates the autonomic nervous system, through the hypothalamus, which leads to an unconscious response, beyond one's control. The heartbeat are an example. (fig. 2)

HOW IS THE HEART REGULATED ?

In this article, we will study how the brain is linked with the control of the heartbeat. Indeed, we all have already noticed that our heart has not the same rhythm when we are sleeping than when we are doing a physical activity. Nonetheless, this control of the heart rate occurs even if we don’t want to or even if we don’t think about it. Then our will has no link with this control and it is not a reflex either because if the heart rate increases or decreases, it is in fact in response to a physiologic demand from the organism. So we want to understand how the nervous system can act according to the circumstances, and to do so, we will study the autonomic nervous system because it controls this unconscious mechanism.

  

To begin with, we discovered that in embryonic stages, the heart is created from the third to the seventh week. Its rhythm is 90 beats per minutes and at this stage, the nervous cells multiply but they are linked neither each other nor to the heart.

At the end of the third month, all the organs are correctly placed and the nervous system takes the control of the heart.

Moreover, someone who undergo a cardiac transplant and whom heart has been disconnected from the nervous system, has a heart rate of 100 beats per minutes (either during an activity or at rest).

These two examples show that the “ordinary” frequency is about 90 or 100 beats per minutes when the brain does not control the heartbeat.

Nevertheless, the nervous system is essential to the heart because it permits to adapt the cardiac rhythm according to the energetic demand of the organism. Indeed, when we sleep, the frequency goes down until 50 beats per minutes whereas during a physical effort (or because of the stress), it can go up to 180 beats per minutes.

In 1921, Loewi created an experiment based on an isolated heart which showed the role of the brain on the heart rate. In fact, the scientist immersed two frog hearts in two jars filled with a liquid and related each other by a pipe in order to let the liquid of the first jar go into the second jar. Then, Loewi stimulated the vagus nerve of the first heart whom heart rate slowed down. He also observed that the heartbeat of the second heart decreased too (whereas its vagus nerve has not been stimulated). Loewi deduced that the cardiac rhythm is controlled by a chemical substance (which was in the liquid) which is secreted by the vagus nerve. Therefore, this experiment shows that the nervous system controls the cardiac rhythm thanks to chemical secretions.

 In addition, we discovered the two main molecules which control the heart rate: noradrenalin and acetylcholine.

The first one is a neurotransmitter which takes part to the first subsystem of the autonomic nervous system: the sympathetic nervous system. Therefore, the noradrenalin is released when the sympathetic fibers are stimulated and its effect is excitatory: it permits to accelerate the cardiac rhythm. Thus, the sympathetic system takes part in case of physical activity (in this case the organism needs more energy and oxygen so it is essential that the heart rate increases to respond to the need). It intervenes also when we are stressed (in this case, the adrenalin, which is a hormone secreted by the adrenal medulla, plays the same role than the noradrenalin on the cardiac rhythm since it has a sympathomimetic action. However, if it has the same role than the noradrenalin [an inotropic and chronotropic effect], the adrenalin (blog adrenalin) is not a neurotransmitter because it is not secreted in a synapse. Indeed, it is secreted in the blood and it amplifies the noradrenalin effect when it reaches the heart).

The second molecule, the acetylcholine; takes part to the second subsystem of the autonomic nervous system: the parasympathetic nervous system. This system has an effect rather opposed to the previous system since it has an inhibitory effect. The noradrenalin is a neurotransmitter which permits to decrease the cardiac rate and it is secreted when the parasympathetic nerve (or vagus nerve) is stimulated. Hence the parasympathetic system intervenes for example when we are sleeping, or when the body is immersed (indeed, the heartbeat slows down in order to preserve the oxygen to stay longer in the water), or when the arterial pressure is too high (the baroreceptors of the carotid sinus stimulate the parasympathetic center and this release the acetylcholine which decreases the heart rate). 

Despite the fact that we have seen that the heart beats at 90-100 beats per minutes without the intervention of the nervous system, the average frequency is 70-75 beats per minutes. This diminution of 20% is due to the fact that actually, the brain never stops to control the heart. Indeed, the parasympathetic and sympathetic systems send impulses to the sinoatrial node without stopping and since the parasympathetic fibers send more impulses, the heartbeat is globally decelerated (in comparison to what it should be). We call this phenomenon the vagal tone because it is due to the vagus nerve.

All these examples permit us to understand that the cardiac control is governed by the brain which never stops to control the heart (either while we are sleeping or while a physical activity).

Heart rate is regulated by the autonomic nervous system which occurs unconsciously, but this control requires the coordination of several actors. In fact, the first are the receptors (baro-chemoreceptors) which capture the blood pressure variations or the blood composition (When its parameters values are too far from its references values because of the situation or the external environment).

Then, the information which is received by the receptor is transmitted to the nervous system thanks to the sensory nerve fibers (which are the Hering nerves and Cyon-Ludwig nerves for the sinus and the cardiovascular fibers for the right auricle).

This information is transmitted to the parasympathetic nervous system or to the sympathetic nervous system. It depends on the situation. The parasympathetic nervous system is located in the medulla oblongata. It’s the “inhibitory” system. The second is located in the spinal cord. It’s the “excitory” system.

Between these two nervous centers, there are inhibitory neurons which weaken one of the two systems when the other is stimulated.

Then, the nervous center analyzes the received information and sends a response to the target tissues by the intermediate of the motor nerve fibers (which are in the vagus nerve and the cardiac nerve. The first are connected to the sinus node and the second to the ventricle).

The blood pressure stimulation involves the sympathetic nervous system with the aortic and carotid baro-receptor, the bulbar center, effectors organs (here the heart) and vessels. When the heart needs to be stimulated, the sympathetic nervous system releases noradrenalin which will fix to the myocardial ß1 receptors. This fixing activates the adenylyl cyclase which causes an increase of AMPc and this leads to the activation of the kinase protein. This kinase protein will increase the Ca²⁺ cell permeability and the Ca²⁺ will enter plentifully in the “sarcoplasma”. Then, the Ca²⁺ will bind with the troponin, and this protein complex changes its physical structure to allow the bond between the myosin heads and actin. This bond activates the mechanism of the contractility. That’s why the systolic ejection volume increases (heart rate and strength of ventricular contraction are increasing so the heart pumps more blood).

 The contractility is determinated by the cardiac capacity to supply a given pressure.

That’s why if the strength and heart rate increase, the heart will manage a higher pressure and pump a greater blood volume.

The intervention of the parasympathetic system isn’t the same that the sympathetic system because the parasympathetic and the sympathetic innervations are different. Indeed, the parasympathetic is linked to the auricles and the nodal tissue whereas the sympathetic is linked to the auricles, the nodal tissue and the ventricles. 
 

To conclude, this explains why when you burn yourself, your heart rate increases in few milliseconds.

HUNTINGTON DISEASE

Introduction

Huntington's disease is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. Symptoms commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy to old age. In the early stages, there are changes in personality, cognition, and physical skills. The physical symptoms are usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe enough to be recognized on their own at the earlier stages.

            We will focus on the genetics aspects of the Huntington’s disease, and then, on its cellular mechanism.

Genetics Aspects

            Our organism has two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (Htt), on the chromosome 4p13.3. A part of this gene is a repeated section called a trinucleotide repeat. If the number of repetition is too high in a healthy gene, a dynamic mutation may result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces another form of the protein, called mutant Huntingtin protein (mHtt).

HTT contains a sequence of three DNA bases : Cytosine-Adenine-Guanine (CAG), repeated multiple times (CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the codon for the amino acid glutamine, so a serie of them results in the production of a chain of glutamine, known as a polyglutamine tract (PolyQ tract), and the repeated part of the gene, the PolyQ region.

In a normal situation, the codon CAG is repeated 26 times tops. A sequence of 27 or more glutamines results another form of protein which has different characteristics. This is the mutant Huntingtin protein. From 27 to 35 repetitions, it’s an intermediate form of the disease, appearing after 80 years old, people are not affected. From 36 to 39 repetitions, it’s a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that the symptoms are never noticed. With more than 39 repeats, Huntington disease has full penetrance and can occur under the age of 20. We talk about juvenile Huntington disease. (See the array below)

                                                     Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats

The disease mutation is genetically dominant.  It is not inherited according to sex, but the length of the repeated section of the gene can be influenced by the sex of the affected parent. In fact, if the affected parent is a male, the section will be longer for the offspring, than if it’s a female. That’s why we talk about autosomal dominant inheritance. It means that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. The probability of each offspring inheriting an affected gene is 50%. In rare situations, where both parents have an expanded Huntington’s disease gene, the risk increases by 75%. When either parent has two expanded copies, the risk is 100% (all children will be affected).

The Huntingtin protein interacts with over 100 other proteins, and appears to have multiple biological functions. The behavior of the mutated protein is toxic to certain cell types, particularly in the brain. We will explain you the cellular mechanism