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Neuron connectivity- how are they connected physically

Neuron connectivity- how are they connected physically


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If Neurons are only connected through synapse and there is no physical connection, how are they just suspended in brain layers?


Neurons are suspended, as you say, in an extracellular matrix. Brain tissues are a little bit more specific. Here I quote a few summaries from literature to answer and give your a perspective on your basic question. In bold I highlight important statements which differentiate the brain's ECM from the ECM found elsewhere in the body.

Barros, Franco & Müller, 2011: An astonishing number of extracellular matrix glycoproteins are expressed in dynamic patterns in the developing and adult nervous system. Neural stem cells, neurons, and glia express receptors that mediate interactions with specific extracellular matrix molecules. Functional studies in vitro and genetic studies in mice have provided evidence that the extracellular matrix affects virtually all aspects of nervous system development and function. Here we will summarize recent findings that have shed light on the specific functions of defined extracellular matrix molecules on such diverse processes as neural stem cell differentiation, neuronal migration, the formation of axonal tracts, and the maturation and function of synapses in the peripheral and central nervous system.

Ruoslahti, 1996: The extracellular matrix of the adult brain tissue has a unique composition. The striking feature of this matrix is the prominence of lecticans, proteoglycans that contain a lectin domain and a hyaluronic acid-binding domain. Hyaluronic acid and tenascin family adhesive/anti-adhesive proteins are also abundant. Matrix proteins common in other tissues are nearly absent in adult brain. The brain extracellular matrix appears to have trophic effects on neuronal cells and affect neurite outgrowth. The unique composition of this matrix may be responsible for the resistance of brain tissue toward invasion by tumors of non-neuronal origin.

Dityatev et al. 2010: The extracellular matrix (ECM) of the central nervous system is well recognized as a migration and diffusion barrier that allows for the trapping and presentation of growth factors to their receptors at the cell surface. Recent data highlight the importance of ECM molecules as synaptic and perisynaptic scaffolds that direct the clustering of neurotransmitter receptors in the postsynaptic compartment and that present barriers to reduce the lateral diffusion of membrane proteins away from synapses. The ECM also contributes to the migration and differentiation of stem cells in the neurogenic niche and organizes the polarized localization of ion channels and transporters at contacts between astrocytic processes and blood vessels. Thus, the ECM contributes to functional compartmentalization in the brain.


It's true, neurons in the brain are really sparse within an extracellular matrix. But I would like to say that there exist several type of synapsis.

The first one, to which you referred is the chemical synapse connecting the synaptic button of first neuron with the post-synaptic membrane of the second neuron. Thus in that case, you think there isn't a direct contact of pre and post synaptic membranes but the electrical signal is converted and transmitted as neurotransmitter through the synaptic cleft. To note, both axons and synaptic cleft are "covered" by other cell types, a particular type of glial cells, the Schwann cell that causes the saltatory nature of the electric signal across the axon and, at level of the synapsis, acts in order to reuptake the released neurotrasmitters.

The second type is the electrical synapse. In this one, post and pre-synaptic compartments of neurons are phisicaly connected by gap junction: these are structurally made by two hemi-channels called connexons and makes the cytoplasms to communicate and thus the electrical signals continue to diffuse thanks these connections. In that case the connection between such cells approach within about 3.8 nm of each other creating a mechanical and electrical continuity (Sheriar G.Hormuzdia et al., 2004)

Thus, when you say "neurons are only connected through synapse and there is no physical connection" it's quite simplistic. In reality, also the chemical synapsis are "connected" mechanically by a large number of cell adhesion molecules that acts in order to make and modulate the connection between neurons. For instance these include neurexins and neuroligins or Ig-domain proteins etc (Missler M, et al. Cold Spring Harb Perspect Biol. 2012). Indeed, the pivotal differences between electrical and chemical s. is the ways by which neuronal cells communicate. In the latter, the distance between pre and post synaptic membranes is wider with respect to the electrical one.


Formation of Autapse Connected to Neuron and Its Biological Function

Autapse is a specific synapse connected to the neuron via close loop, and its functional adjusting is described by applying time-delayed feedback on the membrane potential of the neuron. This paper discussed the possible formation mechanism and biological function of autapse connection on neurons. We believe that the formation and growth of autapse connected to neuron can be associated with injury on axon and blocking in signal transmission thus auxiliary loop is developed to form an autapse. When autapse is set up, it can propagate the signals and change the modes of electrical activities under self-adaption. Based on the cable neuron model, the injury on axon is generated by poisoning and blocking in ion channels (of sodium) thus the conductance of ion channels are changed to form injury-associated defects. Furthermore, auxiliary loop with time delay is designed to restore and enhance signal propagation by setting different time delays and feedback gains. The numerical studies confirmed that appropriate time delay and feedback gain in electric or chemical autapse can help signal (or wave generated by external forcing) propagation across the blocked area. As a result, formation of autapse could be dependent on the injury of neuron and further enhances the self-adaption to external stimuli.

1. Introduction

Neuronal models [1–6] are helpful to understand the main dynamical properties in neuronal activities, and most of the simplified versions have been developed from the biological Hodgkin-Huxley neuron [1] model with the effect of ion channels being considered. Despite the continuous dynamical neuron model, Ibarz et al. [7] argued that map-based neuron model could be also effective to describe the main properties of electrical activities. In fact, the astrocyte [8] also plays important role in regulating the electrical activities of neuron as a result, neuron coupled astrocyte models [9–12] have been proposed to study the seizure-like discharges (SDs) or seizure-like firings (SFs) in neurons. Furthermore, the dependence of electrophysiological activities on energy consumption and metabolism is discussed, and Wang et al. [13–15] proposed an energy model to investigate the mode transition associated with energy supply. It is believed that signal transmission between neurons can be realized by chemical and/or electrical synapse coupling, while Volman et al. [16] argued that the role of gap junction connection between neurons could be much complex during the emergence of epileptic seizures. Ion channels [17] are embedded into the membrane of neuron, and their stochastic on and off can generate channel noise thus the electrical activities of neurons can be changed. As a result, ion channels are blocked to detect the transition of electrical activities in neuron and neuronal network [18–23]. There are some physical factors that should be mentioned during the fluctuation of extracellular and intracellular ion concentration, which can generate electromagnetic induction among cells thus the membrane potentials can be adjusted. Therefore, the authors of [24, 25] suggested that magnetic flux can be used to model the electromagnetic induction on neuronal activities and confirmed that multiple modes of electrical activities can be induced by changing one bifurcation parameter. The realistic neuronal system contains a large number of neurons, and it is believed that network could be helpful to investigate the collective behaviors of neurons [26–30].

By now, oscillator-like neuron models have been improved greatly so that more biological factors can be considered. For example, autapse [31, 32], a specific synapse connected to its body via a close loop, and this type of feedback with time delay can change the electrical activities of neurons [33–35]. Indeed, experimental evidence confirmed the occurrence of autapse [36–40]. It is found that neuron can give sensitive response to autapse driving while chemical autapse can change the electrical activities of neuron in slight way [41–45]. For example, neuron can give rapid response in case of electrical autapse connection, and appropriate feedback type (positive or negative feedback in autapse) can change the excitability of neuron. In case of positive feedback in autapse, neuron can be excited while negative feedback in autapse can calm down the electrical activities in neurons. It is the electrical autapse compared to the chemical autapse that can be more effective to change the mode in electrical activities greatly. For a brief review, please find the survey in [45] and some reference therein. In the case of synchronization of network [46, 47], autapse driving can often enhance the synchronization with appropriated feedback gain and time delay being used, where the collective behaviors of network can be modulated like a pacemaker generated by autapse. Furthermore, appropriate distribution and driving of autapse in the network can regulate and block the collective behaviors like a pacemaker or even a defect that can enhance the pattern formation and synchronization in the network [48–50].

As mentioned in [51], autapse is an unusual type of synapse generated by a neuron on itself and autapse connection can play complex biological function by changing the electrical activities in neuron and neuronal networks [26]. That is, emergence of defects due to negative feedback can block the wave propagation, while regularity is enhanced by pacemaker generated by positive feedback in autapse. Unfortunately, it keeps open on how an autapse can be formed. Indeed, monitoring such growth of autapse is technically challenging due to the requirement for precise capture and long-term analysis of single neuron in three dimensions (3D). The authors of [51] presented a simple two-step photolithography method to efficiently capture single cells in microscale gelatin methacrylate hydrogel rings and culture single neurons these results demonstrated that neural axons grew and consequently formed axonal circles, indicating that our method could be an enabling tool to analyze axonal development and autapse formation. In this paper, we argue that the formation of autapse connected to neuron could be associated with injury on axon that signal propagation is blocked thus another auxiliary loop is developed to help signal transmission and self-adjusting on mode selection of electrical activities.

2. Autapse Formation Mechanism and Model Description

The ability to monitor axonal growth of single neuron and autapse formation in 3D may provide fundamental information relating to many cellular processes, such as axonal development, synaptic plasticity, and neural signal transmission. In this section, the possible physical mechanism for autapse growth will be discussed. According to Figure 1, appropriate external forcing can generate possible response on the neuron and action potential can be triggered to propagate along the axon. However, signal transmission can be terminated or blocked when the axon is injured, for example, poisoning in ion channels or heterogeneity on local area of the axon. As a result, neuron can develop new loop or secondary loop to help signal transmission. For the oscillator-like neuron model developed from the Hindmarsh-Rose neuron [52, 53] and Hodgkin-Huxley neuron model [54, 55], the electrical autapse current and chemical autapse current are, respectively, described as follows:


Functions and Classification

Communication by neurons can be divided into four major steps. First, a neuron receives information from the external environment or from other neurons. For example, one neuron in the human brain may receive input from as many as one hundred thousand other neurons. Second, the neuron integrates, or processes, the information from all of its inputs and determines whether or not to send an output signal. This integration takes place both in time (the duration of the input and the time between inputs) and in space (across the surface of the neuron). Third, the neuron propagates the signal along its length at high speed. The distance may be up to several meters (in a giraffe or whale), with rates up to 100 meters (328 feet) per second. Finally, the neuron converts this electrical signal to a chemical one and transmits it to another neuron or to an effector such as a muscle or gland.

When combined into networks, neurons allow the human body memory, emotion, and abstract thought as well as basic reflexes. The human brain contains an estimated one hundred billion neurons which relay, process, and store information. Neurons that lie entirely within the brain or spinal cord are referred to as interneurons and make up the central nervous system . Other neurons, receptors, and afferent (sensory) neurons are specialized to receive signals from within the body or from the external environment and to transmit that information to the central nervous system. Efferent neurons carry signals from the central nervous system to the effector organs (muscles and glands) of the body. If an efferent neuron is connected to a muscle, it is also called a motor neuron.

The ability of a neuron to carry out its function of integration and propagation depends both upon its structure and its ability to generate electrical and chemical signals. While different neurons have different shapes, all neurons share the same signaling abilities.


Formation of Autapse Connected to Neuron and Its Biological Function.

Neuronal models [1-6] are helpful to understand the main dynamical properties in neuronal activities, and most of the simplified versions have been developed from the biological Hodgkin-Huxley neuron [1] model with the effect of ion channels being considered. Despite the continuous dynamical neuron model, Ibarz et al. [7] argued that map-based neuron model couldbe also effective to describe the main properties of electrical activities. In fact, the astrocyte [8] also plays important role in regulating the electrical activities of neuron as a result, neuron coupled astrocyte models [9-12] have been proposed to study the seizure-like discharges (SDs) or seizure-like firings (SFs) in neurons. Furthermore, the dependence of electrophysiological activities on energy consumption and metabolism is discussed, and Wang et al. [13-15] proposed an energy model to investigate the mode transition associated with energy supply. It is believed that signal transmission between neurons can be realized by chemical and/or electrical synapse coupling, while Volman et al. [16] argued that the role of gap junction connection between neurons could be much complex during the emergence of epileptic seizures. Ion channels [17] are embedded into the membrane of neuron, and their stochastic on and off can generate channel noise thus the electrical activities of neurons can be changed. As a result, ion channels are blocked to detect the transition of electrical activities in neuron and neuronal network [18-23]. There are some physical factors that should be mentioned during the fluctuation of extracellular and intra-cellular ion concentration, which can generate electromagnetic induction among cells thus the membrane potentials can be adjusted. Therefore, the authors of [24,25] suggested that magnetic flux can be used to model the electromagnetic induction on neuronal activities and confirmed that multiple modes of electrical activities can be induced by changing one bifurcation parameter. The realistic neuronal system contains a large number of neurons, and it is believed that network could be helpful to investigate the collective behaviors of neurons [26-30].

By now, oscillator-like neuron models have been improved greatly so that more biological factors can be considered. For example, autapse [31,32], a specific synapse connected to its body via a close loop, and this type of feedback with time delay can change the electrical activities of neurons [33-35]. Indeed, experimental evidence confirmed the occurrence of autapse [36-40]. It is found that neuron can give sensitive response to autapse driving while chemical autapse can change the electrical activities of neuron in slight way [41-45]. For example, neuron can give rapid response in case of electrical autapse connection, and appropriate feedback type (positive or negative feedback in autapse) can change the excitability of neuron. In case of positive feedback in autapse, neuron can be excited while negative feedback in autapse can calm down the electrical activities in neurons. It is the electrical autapse compared to the chemical autapse that can be more effective to change the mode in electrical activities greatly. For a brief review, please find the survey in [45] and some reference therein. In the case of synchronization of network [46, 47], autapse driving can often enhance the synchronization with appropriated feedback gain and time delay being used, where the collective behaviors of network can be modulated like a pacemaker generated by autapse. Furthermore, appropriate distribution and driving of autapse in the network can regulate and block the collective behaviors like a pacemaker or even a defect that can enhance the pattern formation and synchronization in the network [48-50].

As mentioned in [51], autapse is an unusual type of synapse generated by a neuron on itself and autapse connection can play complex biological function by changing the electrical activities in neuron and neuronal networks [26]. That is, emergence of defects due to negative feedback can block the wave propagation, while regularity is enhanced by pacemaker generated by positive feedback in autapse. Unfortunately, it keeps open on how an autapse can be formed. Indeed, monitoring such growth of autapse is technically challenging due to the requirement for precise capture and long-term analysis of single neuron in three dimensions (3D). The authors of [51] presented a simple two-step photolithography method to efficiently capture single cells in microscale gelatin methacrylate hydrogel rings and culture single neurons these results demonstrated that neural axons grew and consequently formed axonal circles, indicating that our method could be an enabling tool to analyze axonal development and autapse formation. In this paper, we argue that the formation of autapse connected to neuron could be associated with injury on axon that signal propagation is blocked thus another auxiliary loop is developed to help signal transmission and self-adjusting on mode selection of electrical activities.

2. Autapse Formation Mechanism and Model Description

The ability to monitor axonal growth of single neuron and autapse formation in 3D may provide fundamental information relating to many cellular processes, such as axonal development, synaptic plasticity, and neural signal transmission. In this section, the possible physical mechanism for autapse growth will be discussed. According to Figure 1, appropriate external forcing can generate possible response on the neuron and action potential can be triggered to propagate along the axon. However, signal transmission can be terminated or blocked when the axon is injured, for example, poisoning in ion channels or heterogeneity on local area of the axon. As a result, neuron can develop new loop or secondary loop to help signal transmission. For the oscillator-like neuron model developed from the Hindmarsh-Rose neuron [52,53] and Hodgkin-Huxley neuron model [54,55], the electrical autapse current and chemical autapse current are, respectively, described as follows:

[mathematical expression not reproducible], (1)

where [g.sub.e] and [g.sub.c] are the gains for electrical and chemical autapse, respectively. x is membrane potential of neuron described in HR neuron model. [tau] is time delay (intrinsic response time delay, and it is different form the propagation time delay due to finite propagation speed of signals between neurons) in electrical autapse and [tau]' is the time delay in chemical autapse. x(t) is the sampled membrane potential of neuron, [V.sub.syn] is reversal potential in synapse and is used to discern excitatory synapse at [V.sub.syn] = 2 and for inhibitory synapse at [V.sub.syn] = -2. The ratio parameter [lambda] and threshold [theta] for synapse are often selected as [lambda] = [theta] and d = -0.25 in previous investigations, respectively. In fact, the anatomical structure of neuron should be considered in case of signal transmission in neuron for example, the signal propagation along axon should be investigated in detail. Our cable-injured neuron model can be illustrated in Figure 1.

The model is set up on cable neuron model, auxiliary loop is developed when the axon is injured in local area, and new dendrites can be triggered close to the injured area on the axon and then are connected to other dendrites connected to the soma. As a result, important signal can be transmitted along the auxiliary loop called autapse under positive feedback. The feedback gain and time delay can be selected to recover the original signal propagation. The second biological function of autapse is that electrical modes of neuronal activities can be selected under appropriate negative feedback in autapse. That is to say, negative feedback in autapse can play similar function as inhibitory synapse. For further dynamical investigation and discussion, our proposed neuron model driven by autapse can be expressed as follows:

[mathematical expression not reproducible], (2)

where C and D denote the membrane capacitance and the diffusive coefficient, respectively. V(x) represents membrane potential at position x and [I.sub.aut] is the autapse current. The function f(V(x), p) describes the local kinetics of electrical activities, p = <[G.sup.K.sub.max], [G.sup.Na.sub.max], [G.sub.L]>is the parameters such as conductance for ion channels, and [G.sup.K.sub.max], [G.sup.Na.sub.max], [G.sub.L] is the maximal conductance for potassium channels, sodium channels, and leakage current associated with chloridion channels. For simplicity, local kinetics of the cable neuron model can be described by Hodgkin-Huxley equations as follows:

[mathematical expression not reproducible], (3)

where [V.sub.Na], [V.sub.K], and [V.sub.L] are the reversal potentials for the sodium, potassium, and leakage currents, respectively. It is suggested that the gating dynamics of each ion channel are assumed to be governed by four independent gates, each of which can switch between an open and a closed conformation. The gating variables n, m, and h describe the mean ratios of the open gates of the working channels, and the factors [n.sup.4] and [m.sup.3]h are the mean portions of the open ion channels within the membrane patch. The voltage-dependent opening and closing rates [[alpha].sub.y](V), [[beta].sub.y](V) and y = m,n,h are defined in [56-58]. The abnormal area on the axon could be formed due to channels blocking for example, the potassium or sodium ion channels can be, respectively, blocked or disabled by adding cell toxins such as tetraethylammonium (TEA) and/or tetrodotoxin (TTX) in experiments. As reported in [56], the poisoning of sodium channels causes only a small, practically negligible variation of the resting voltage a reduction in the number of working potassium channels changes dramatically the qualitative behavior of the spiking activity. In fact, neuron and its axon can be regarded as injured when the ion channels of sodium or potassium are blocked thus the conductance of channels is changed in parameter values. As a result, the conductance of ion channels in the abnormal area (heterogeneity) can be defined as follows:

[mathematical expression not reproducible], (4)

where the active ratios [[chi].sub.Na] and [[chi].sub.K] are the fractions of working channels, that is, nonblocked ion channels, to the overall number of potassium ([N.sub.K], [N.sub.Na]) ion channels, respectively.

According to Figure 1, the electrical and chemical autapse current on the feedback loop are defined by

[mathematical expression not reproducible], (5)

where the axon orientation (or direction) is used for x-axis for mathematical description, the variable [x.sub.post] represents the beginning point to follow the injured area where autapse can be developed, and the parameters in (5) are described the same as shown in (1). That is to say, when normal signal propagation is blocked along the axon, auxiliary loop is required to form autapse connection. To ensure effective formation of autapse, some dendrites can be developed from the soma to connect the synapse developed from the area close to injured area, and then autapse can be formed. Therefore, the autapse current can be written as follows:

[mathematical expression not reproducible]. (6)

That is to say, a new autapse can be developed from the soma and the injured area synchronously. As a result, blocked signals can be transmitted along the autapse under positive feedback with appropriate feedback gain and time delay being used. When the autapse is set up, negative feedback in the autapse can be helpful for the selection of modes for electrical activities by applying appropriate feedback gain and time delay. The formation of autapse also develops the self-adaption of neuron thus appropriate response can be selected during the signal propagation in neuron and between neurons.

3. Results, Discussion, and Open Problems

The formation of autapse is independent of the feedback loop, and the time delay in the autapse could accounts for the beginning and end of the autapse formation. When the autapse is formed, electrical autapse makes neuron give sensitive response to external forcing compared to the chemical autapse driving. In fact, this type of intrinsic time delay is finite and both of chemical and electrical autapse can cooperate with the signal processing and transmission for mixed signals such as time-varying stimuli on the neuron. The abnormality and injury on the axon can be described by ion channel blocking for example, the conductance of ion channels is selected with diversity the active channel numbers can be controlled by active agents or blocking agents.

In numerical studies, the active ratios [[chi].sub.Na] and [[chi].sub.K] can be selected with different values to describe the injury degree. Sampled action potentials besides the abnormality or heterogeneity can be recorded, and appropriate time delay and gain in the autapse can ensure the signal propagation and recovery because the blocked signals can be transmitted along the autapse. In the case of network, the autapse formation and driving can regulate the collective behaviors and prevent collapse of network [59,60] by generating a pacemaker-like ordered wave. Extensive investigation asks for biological verification and detailed numerical studies. To present further description and understanding for this problem, numerical studies have been carried out. For simplicity, the conductance for sodium channels in local area is switched from [G.sub.Na] = 120 mS/[cm.sup.2] to [G.sub.Na] = 25.5 mS/[cm.sup.2], the axon is divided into 201 nodes (the results are independent of the node number or length of axon, the length of axon is set as 100 space units and space step is 0.5 for numerical studies), the diffusion coefficient is set for D = 1.06, membrane capacitance is selected by C = 1 [mu]F/[cm.sup.2], and injured area is selected between nodes i = 120 and 130, and the autapse develops from node i = 3,131 (or i = 3,135). Firstly, the effect of electric autapse is investigated under different time delays and the results are plotted in Figure 2.

It is confirmed that appropriate time delay in electric autapse is effective to propagate the blocked signal along the axon, and the information is kept complete by detecting the sampled time series. Extensive numerical results found that electric autapse can find appropriate time delay (e.g., [tau] = 14.5) to overcome the blocking and propagate the blocked signals the sampled time series for membrane of nodes backward and forward the injured area can reach delayed synchronization completely. The effect of gains in electric autapse is also investigated, and the results are plotted in Figure 3.

It is found that the gain in the electric autapse also plays important role in enhancing signal propagating along the axon. The selection in gain can induce positive and negative feedback along the autapse loop, and negative feedback in electric autapse is helpful to propagate the blocked signal due to self-adaption, while positive feedback can generate new exciting source to further block the signal propagation. Surely, appropriate time delay in electric autapse can be effective to propagate signal and overcome the blocked area under positive feedback, and the results are plotted in Figure 4.

The results in Figure 4 confirmed that appropriate time delay can be found to set appropriate electric autapse so that the signal can be passed across the blocked or injured area. That is to say, when autapse is formed, appropriate time delay and gain can be verified for the biological function of electric autapse. Furthermore, it is interesting to check the function of chemical autapse, and the external forcing current is still imposed on the node i = 3. To discern and enhance the blocking effect on ion channels, inhibitory chemical autapse is investigated by setting [V.sub.syn] = -2, and the results are plotted in Figure 5.

It is confirmed that large feedback gain in chemical autapse is helpful to propagate the signal across the injured area when appropriate time delay is applied on the chemical autapse. Furthermore, the feedback gain in chemical autapse is switched to negative value, and the results are plotted in Figure 6.

According to the results in Figures 5 and 6, the developed chemical autapse can be effective to help the blocked signal propagate across the injured area. We also checked the case for excitatory autapse similar results are verified. Therefore, the formation and development of autapse connection enhance the self-adaption of neuron thus signal can be propagated to overcome the blocking in the injured area.

Extensive numerical results confirmed that both of electric and chemical autapse (excitory and/or inhibitory) can confirm the biological function that signal can be propagated across the blocked area by applying appropriate time delay and feedback gain in the autapse. We also checked the case when some ion channels of potassium are blocked, and similar results are approached that appropriate time delay and gain in autapse are effective to reproduce (or restore) the blocked signals as well.

As mentioned above, synapse can be trigged close to the badly injured area and autapse can be formed to select appropriate time delay and gain, so that blocked signal (action potential or continuous wave) can be transmitted completely. The auxiliary loop for autapse can be effective to correct and restore the original signal successfully. In fact, our results just argue the possible formation mechanism and biological function for autapse in theoretical assumption and numerical verification. It is interesting for biological experts to check these results in experiments and detect possible formation of autapse connected to axon of neuron by carefully injuring such as poisoning in some ion channels of neuron.

The biological function and formation of autapse were discussed. We argued that the formation and development of autapse connection could result from the self-adaption and self-protection of neuron. Abnormal neurodevelopment or injury on the neuron (axon) makes blocking in signal transmission along the axon of neuron and signal communication between neurons. Following the abnormal area or heterogeneity, new synapse can be formed to connect the soma or dendrites connected to the soma, and autapse is generated by setting auxiliary loop via synapse connection. Switch between positive and negative feedback in autapse is self-adaptive for mode selection in electrical activities as a result, signal communication and transmission become available. These discussions could be helpful to understand the formation mechanism for autapse and its biological functions.

The authors declare that they have no competing interests.

This work is partially supported by the National Natural Science Foundation of China under Grant nos. 11365014 and 11672122.

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Chunni Wang, (1) Shengli Guo, (1) Ying Xu, (1) Jun Ma, (1,2) Jun Tang, (3) Faris Alzahrani, (2) and Aatef Hobiny (2)

(1) Department of Physics, Lanzhou University of Technology, Lanzhou 730050, China

(2) NAAM-Research Group, Department of Mathematics, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia

(3) College of science, China University of Mining and Technology, Xuzhou 221116, China

Correspondence should be addressed to Jun Ma [email protected]

Received 9 September 2016 Revised 4 January 2017 Accepted 17 January 2017 Published 28 February 2017

Academic Editor: Mattia Frasca

Caption: Figure 1: Schematic diagram of injured neuron driven by autapse: action potential is propagated along the axon and the local kinetics of electrical activities will be described by Hodgkin-Huxley neuron model. Abnormal area on the axon is generated by blocking channels of sodium or potassium thus the conductance is used as bifurcation parameter. When neuron (axon) is injured, synapse is triggered to form auxiliary loop thus autapse can be formed.


CONNECTOMICS

It is widely believed that in order to understand how the nervous system works, one needs to know where neural processes go and with which cells they connect. Conventionally, this kind of information is obtained by labeling a small number of neurons from one sample and then pooling data from multiple samples in order to infer the organization of the complete circuit.

However, this approach is not useful if there is significant variation from sample to sample. In this work an alternative approach was attempted: obtain the complete wiring diagram (connectome) of a circuit by tracing out all the processes in one sample. Confocal microscopy was used in transgenic mice that express fluorescent protein in motor neurons to generate tens of thousands of images of axons that innervate a small ear muscle. These images were analyzed with semi-automated tracing tools to get the full wiring diagram.

Comparison of each neuron and its counterpart on the opposite side of the animal revealed that each connectome was unique. Furthermore axonal arbors appeared to be much longer than expected from the well known hypothesis that wiring length of axons should be minimized. Thus mammalian muscle function is implemented with a variety of wiring diagrams that differ substantially in anatomical form, even within a common genetic background. This result suggests that in mammals the structure of the nervous system is unfettered from strict genetic determinism.


Neuron connectivity- how are they connected physically - Biology

By the end of this section, you will be able to do the following:

  • Describe the basis of the resting membrane potential
  • Explain the stages of an action potential and how action potentials are propagated
  • Explain the similarities and differences between chemical and electrical synapses
  • Describe long-term potentiation and long-term depression

All functions performed by the nervous system—from a simple motor reflex to more advanced functions like making a memory or a decision—require neurons to communicate with one another. While humans use words and body language to communicate, neurons use electrical and chemical signals. Just like a person in a committee, one neuron usually receives and synthesizes messages from multiple other neurons before “making the decision” to send the message on to other neurons.

Nerve Impulse Transmission within a Neuron

For the nervous system to function, neurons must be able to send and receive signals. These signals are possible because each neuron has a charged cellular membrane (a voltage difference between the inside and the outside), and the charge of this membrane can change in response to neurotransmitter molecules released from other neurons and environmental stimuli. To understand how neurons communicate, one must first understand the basis of the baseline or ‘resting’ membrane charge.

Neuronal Charged Membranes

The lipid bilayer membrane that surrounds a neuron is impermeable to charged molecules or ions. To enter or exit the neuron, ions must pass through special proteins called ion channels that span the membrane. Ion channels have different configurations: open, closed, and inactive, as illustrated in (Figure). Some ion channels need to be activated in order to open and allow ions to pass into or out of the cell. These ion channels are sensitive to the environment and can change their shape accordingly. Ion channels that change their structure in response to voltage changes are called voltage-gated ion channels. Voltage-gated ion channels regulate the relative concentrations of different ions inside and outside the cell. The difference in total charge between the inside and outside of the cell is called the membrane potential.

Figure 1. Voltage-gated ion channels open in response to changes in membrane voltage. After activation, they become inactivated for a brief period and will no longer open in response to a signal.

Link to Learning

This video discusses the basis of the resting membrane potential.

Resting Membrane Potential

A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell, as shown in (Figure). The difference in the number of positively charged potassium ions (K + ) inside and outside the cell dominates the resting membrane potential ((Figure)). When the membrane is at rest, K + ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient. However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps brings two K + ions into the cell while removing three Na + ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid. It should be noted that chloride ions (Cl – ) tend to accumulate outside of the cell because they are repelled by negatively-charged proteins within the cytoplasm.

The resting membrane potential is a result of different concentrations inside and outside the cell.
Ion Concentration Inside and Outside Neurons
Ion Extracellular concentration (mM) Intracellular concentration (mM) Ratio outside/inside
Na + 145 12 12
K+ 4 155 0.026
Cl − 120 4 30
Organic anions (A−) 100

Figure 2. The (a) resting membrane potential is a result of different concentrations of Na+ and K+ ions inside and outside the cell. A nerve impulse causes Na+ to enter the cell, resulting in (b) depolarization. At the peak action potential, K+ channels open and the cell becomes (c) hyperpolarized.

Action Potential

A neuron can receive input from other neurons and, if this input is strong enough, send the signal to downstream neurons. Transmission of a signal between neurons is generally carried by a chemical called a neurotransmitter. Transmission of a signal within a neuron (from dendrite to axon terminal) is carried by a brief reversal of the resting membrane potential called an action potential. When neurotransmitter molecules bind to receptors located on a neuron’s dendrites, ion channels open. At excitatory synapses, this opening allows positive ions to enter the neuron and results in depolarization of the membrane—a decrease in the difference in voltage between the inside and outside of the neuron. A stimulus from a sensory cell or another neuron depolarizes the target neuron to its threshold potential (-55 mV). Na + channels in the axon hillock open, allowing positive ions to enter the cell ((Figure) and (Figure)). Once the sodium channels open, the neuron completely depolarizes to a membrane potential of about +40 mV. Action potentials are considered an “all-or nothing” event, in that, once the threshold potential is reached, the neuron always completely depolarizes. Once depolarization is complete, the cell must now “reset” its membrane voltage back to the resting potential. To accomplish this, the Na + channels close and cannot be opened. This begins the neuron’s refractory period, in which it cannot produce another action potential because its sodium channels will not open. At the same time, voltage-gated K + channels open, allowing K + to leave the cell. As K + ions leave the cell, the membrane potential once again becomes negative. The diffusion of K + out of the cell actually hyperpolarizes the cell, in that the membrane potential becomes more negative than the cell’s normal resting potential. At this point, the sodium channels will return to their resting state, meaning they are ready to open again if the membrane potential again exceeds the threshold potential. Eventually the extra K + ions diffuse out of the cell through the potassium leakage channels, bringing the cell from its hyperpolarized state, back to its resting membrane potential.

Art Connection

Figure 3. The formation of an action potential can be divided into five steps: (1) A stimulus from a sensory cell or another neuron causes the target cell to depolarize toward the threshold potential. (2) If the threshold of excitation is reached, all Na+ channels open and the membrane depolarizes. (3) At the peak action potential, K+ channels open and K+ begins to leave the cell. At the same time, Na+ channels close. (4) The membrane becomes hyperpolarized as K+ ions continue to leave the cell. The hyperpolarized membrane is in a refractory period and cannot fire. (5) The K+ channels close and the Na+/K+ transporter restores the resting potential.

Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K + through voltage-gated K + channels. Which part of the action potential would you expect potassium channels to affect?

Potassium channel blockers slow the repolarization phase, but have no effect on depolarization.

Figure 4. The action potential is conducted down the axon as the axon membrane depolarizes, then repolarizes.

Link to Learning

This video presents an overview of action potential.

Myelin and the Propagation of the Action Potential

For an action potential to communicate information to another neuron, it must travel along the axon and reach the axon terminals where it can initiate neurotransmitter release. The speed of conduction of an action potential along an axon is influenced by both the diameter of the axon and the axon’s resistance to current leak. Myelin acts as an insulator that prevents current from leaving the axon this increases the speed of action potential conduction. In demyelinating diseases like multiple sclerosis, action potential conduction slows because current leaks from previously insulated axon areas. The nodes of Ranvier, illustrated in (Figure) are gaps in the myelin sheath along the axon. These unmyelinated spaces are about one micrometer long and contain voltage-gated Na + and K + channels. Flow of ions through these channels, particularly the Na + channels, regenerates the action potential over and over again along the axon. This ‘jumping’ of the action potential from one node to the next is called saltatory conduction. If nodes of Ranvier were not present along an axon, the action potential would propagate very slowly since Na + and K + channels would have to continuously regenerate action potentials at every point along the axon instead of at specific points. Nodes of Ranvier also save energy for the neuron since the channels only need to be present at the nodes and not along the entire axon.

Figure 5. Nodes of Ranvier are gaps in myelin coverage along axons. Nodes contain voltage-gated K+ and Na+ channels. Action potentials travel down the axon by jumping from one node to the next.

Synaptic Transmission

The synapse or “gap” is the place where information is transmitted from one neuron to another. Synapses usually form between axon terminals and dendritic spines, but this is not universally true. There are also axon-to-axon, dendrite-to-dendrite, and axon-to-cell body synapses. The neuron transmitting the signal is called the presynaptic neuron, and the neuron receiving the signal is called the postsynaptic neuron. Note that these designations are relative to a particular synapse—most neurons are both presynaptic and postsynaptic. There are two types of synapses: chemical and electrical.

Chemical Synapse

When an action potential reaches the axon terminal it depolarizes the membrane and opens voltage-gated Na + channels. Na + ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated Ca 2+ channels to open. Calcium ions entering the cell initiate a signaling cascade that causes small membrane-bound vesicles, called synaptic vesicles, containing neurotransmitter molecules to fuse with the presynaptic membrane. Synaptic vesicles are shown in (Figure), which is an image from a scanning electron microscope.

Figure 6. This pseudocolored image taken with a scanning electron microscope shows an axon terminal that was broken open to reveal synaptic vesicles (blue and orange) inside the neuron. (credit: modification of work by Tina Carvalho, NIH-NIGMS scale-bar data from Matt Russell)

Fusion of a vesicle with the presynaptic membrane causes neurotransmitter to be released into the synaptic cleft, the extracellular space between the presynaptic and postsynaptic membranes, as illustrated in (Figure). The neurotransmitter diffuses across the synaptic cleft and binds to receptor proteins on the postsynaptic membrane.

Figure 7. Communication at chemical synapses requires release of neurotransmitters. When the presynaptic membrane is depolarized, voltage-gated Ca2+ channels open and allow Ca2+ to enter the cell. The calcium entry causes synaptic vesicles to fuse with the membrane and release neurotransmitter molecules into the synaptic cleft. The neurotransmitter diffuses across the synaptic cleft and binds to ligand-gated ion channels in the postsynaptic membrane, resulting in a localized depolarization or hyperpolarization of the postsynaptic neuron.

The binding of a specific neurotransmitter causes particular ion channels, in this case ligand-gated channels, on the postsynaptic membrane to open. Neurotransmitters can either have excitatory or inhibitory effects on the postsynaptic membrane, as detailed in (Figure). For example, when acetylcholine is released at the synapse between a nerve and muscle (called the neuromuscular junction) by a presynaptic neuron, it causes postsynaptic Na + channels to open. Na + enters the postsynaptic cell and causes the postsynaptic membrane to depolarize. This depolarization is called an excitatory postsynaptic potential (EPSP) and makes the postsynaptic neuron more likely to fire an action potential. Release of neurotransmitter at inhibitory synapses causes inhibitory postsynaptic potentials (IPSPs), a hyperpolarization of the presynaptic membrane. For example, when the neurotransmitter GABA (gamma-aminobutyric acid) is released from a presynaptic neuron, it binds to and opens Cl – channels. Cl – ions enter the cell and hyperpolarizes the membrane, making the neuron less likely to fire an action potential.

Once neurotransmission has occurred, the neurotransmitter must be removed from the synaptic cleft so the postsynaptic membrane can “reset” and be ready to receive another signal. This can be accomplished in three ways: the neurotransmitter can diffuse away from the synaptic cleft, it can be degraded by enzymes in the synaptic cleft, or it can be recycled (sometimes called reuptake) by the presynaptic neuron. Several drugs act at this step of neurotransmission. For example, some drugs that are given to Alzheimer’s patients work by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine. This inhibition of the enzyme essentially increases neurotransmission at synapses that release acetylcholine. Once released, the acetylcholine stays in the cleft and can continually bind and unbind to postsynaptic receptors.

Neurotransmitter Function and Location
Neurotransmitter Example Location
Acetylcholine CNS and/or PNS
Biogenic amine Dopamine, serotonin, norepinephrine CNS and/or PNS
Amino acid Glycine, glutamate, aspartate, gamma aminobutyric acid CNS
Neuropeptide Substance P, endorphins CNS and/or PNS

Electrical Synapse

While electrical synapses are fewer in number than chemical synapses, they are found in all nervous systems and play important and unique roles. The mode of neurotransmission in electrical synapses is quite different from that in chemical synapses. In an electrical synapse, the presynaptic and postsynaptic membranes are very close together and are actually physically connected by channel proteins forming gap junctions. Gap junctions allow current to pass directly from one cell to the next. In addition to the ions that carry this current, other molecules, such as ATP, can diffuse through the large gap junction pores.

There are key differences between chemical and electrical synapses. Because chemical synapses depend on the release of neurotransmitter molecules from synaptic vesicles to pass on their signal, there is an approximately one millisecond delay between when the axon potential reaches the presynaptic terminal and when the neurotransmitter leads to opening of postsynaptic ion channels. Additionally, this signaling is unidirectional. Signaling in electrical synapses, in contrast, is virtually instantaneous (which is important for synapses involved in key reflexes), and some electrical synapses are bidirectional. Electrical synapses are also more reliable as they are less likely to be blocked, and they are important for synchronizing the electrical activity of a group of neurons. For example, electrical synapses in the thalamus are thought to regulate slow-wave sleep, and disruption of these synapses can cause seizures.

Signal Summation

Sometimes a single EPSP is strong enough to induce an action potential in the postsynaptic neuron, but often multiple presynaptic inputs must create EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential. This process is called summation and occurs at the axon hillock, as illustrated in (Figure). Additionally, one neuron often has inputs from many presynaptic neurons—some excitatory and some inhibitory—so IPSPs can cancel out EPSPs and vice versa. It is the net change in postsynaptic membrane voltage that determines whether the postsynaptic cell has reached its threshold of excitation needed to fire an action potential. Together, synaptic summation and the threshold for excitation act as a filter so that random “noise” in the system is not transmitted as important information.

Figure 8. A single neuron can receive both excitatory and inhibitory inputs from multiple neurons, resulting in local membrane depolarization (EPSP input) and hyperpolarization (IPSP input). All these inputs are added together at the axon hillock. If the EPSPs are strong enough to overcome the IPSPs and reach the threshold of excitation, the neuron will fire.

Everyday Connection

Brain-computer interface
Amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s Disease) is a neurological disease characterized by the degeneration of the motor neurons that control voluntary movements. The disease begins with muscle weakening and lack of coordination and eventually destroys the neurons that control speech, breathing, and swallowing in the end, the disease can lead to paralysis. At that point, patients require assistance from machines to be able to breathe and to communicate. Several special technologies have been developed to allow “locked-in” patients to communicate with the rest of the world. One technology, for example, allows patients to type out sentences by twitching their cheek. These sentences can then be read aloud by a computer.

A relatively new line of research for helping paralyzed patients, including those with ALS, to communicate and retain a degree of self-sufficiency is called brain-computer interface (BCI) technology and is illustrated in (Figure). This technology sounds like something out of science fiction: it allows paralyzed patients to control a computer using only their thoughts. There are several forms of BCI. Some forms use EEG recordings from electrodes taped onto the skull. These recordings contain information from large populations of neurons that can be decoded by a computer. Other forms of BCI require the implantation of an array of electrodes smaller than a postage stamp in the arm and hand area of the motor cortex. This form of BCI, while more invasive, is very powerful as each electrode can record actual action potentials from one or more neurons. These signals are then sent to a computer, which has been trained to decode the signal and feed it to a tool—such as a cursor on a computer screen. This means that a patient with ALS can use e-mail, read the Internet, and communicate with others by thinking of moving his or her hand or arm (even though the paralyzed patient cannot make that bodily movement). Recent advances have allowed a paralyzed locked-in patient who suffered a stroke 15 years ago to control a robotic arm and even to feed herself coffee using BCI technology.

Despite the amazing advancements in BCI technology, it also has limitations. The technology can require many hours of training and long periods of intense concentration for the patient it can also require brain surgery to implant the devices.

Figure 9. With brain-computer interface technology, neural signals from a paralyzed patient are collected, decoded, and then fed to a tool, such as a computer, a wheelchair, or a robotic arm.

Link to Learning

Watch this video in which a paralyzed woman uses a brain-controlled robotic arm to bring a drink to her mouth, among other images of brain-computer interface technology in action.

Synaptic Plasticity

Synapses are not static structures. They can be weakened or strengthened. They can be broken, and new synapses can be made. Synaptic plasticity allows for these changes, which are all needed for a functioning nervous system. In fact, synaptic plasticity is the basis of learning and memory. Two processes in particular, long-term potentiation (LTP) and long-term depression (LTD) are important forms of synaptic plasticity that occur in synapses in the hippocampus, a brain region that is involved in storing memories.

Long-term Potentiation (LTP)

Long-term potentiation (LTP) is a persistent strengthening of a synaptic connection. LTP is based on the Hebbian principle: cells that fire together wire together. There are various mechanisms, none fully understood, behind the synaptic strengthening seen with LTP. One known mechanism involves a type of postsynaptic glutamate receptor, called NMDA (N-Methyl-D-aspartate) receptors, shown in (Figure). These receptors are normally blocked by magnesium ions however, when the postsynaptic neuron is depolarized by multiple presynaptic inputs in quick succession (either from one neuron or multiple neurons), the magnesium ions are forced out allowing Ca ions to pass into the postsynaptic cell. Next, Ca 2+ ions entering the cell initiate a signaling cascade that causes a different type of glutamate receptor, called AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, to be inserted into the postsynaptic membrane, since activated AMPA receptors allow positive ions to enter the cell. So, the next time glutamate is released from the presynaptic membrane, it will have a larger excitatory effect (EPSP) on the postsynaptic cell because the binding of glutamate to these AMPA receptors will allow more positive ions into the cell. The insertion of additional AMPA receptors strengthens the synapse and means that the postsynaptic neuron is more likely to fire in response to presynaptic neurotransmitter release. Some drugs of abuse co-opt the LTP pathway, and this synaptic strengthening can lead to addiction.

Long-term Depression (LTD)

Long-term depression (LTD) is essentially the reverse of LTP: it is a long-term weakening of a synaptic connection. One mechanism known to cause LTD also involves AMPA receptors. In this situation, calcium that enters through NMDA receptors initiates a different signaling cascade, which results in the removal of AMPA receptors from the postsynaptic membrane, as illustrated in (Figure). The decrease in AMPA receptors in the membrane makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron. While it may seem counterintuitive, LTD may be just as important for learning and memory as LTP. The weakening and pruning of unused synapses allows for unimportant connections to be lost and makes the synapses that have undergone LTP that much stronger by comparison.

Figure 10. Calcium entry through postsynaptic NMDA receptors can initiate two different forms of synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD). LTP arises when a single synapse is repeatedly stimulated. This stimulation causes a calcium- and CaMKII-dependent cellular cascade, which results in the insertion of more AMPA receptors into the postsynaptic membrane. The next time glutamate is released from the presynaptic cell, it will bind to both NMDA and the newly inserted AMPA receptors, thus depolarizing the membrane more efficiently. LTD occurs when few glutamate molecules bind to NMDA receptors at a synapse (due to a low firing rate of the presynaptic neuron). The calcium that does flow through NMDA receptors initiates a different calcineurin and protein phosphatase 1-dependent cascade, which results in the endocytosis of AMPA receptors. This makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron.

Section Summary

Neurons have charged membranes because there are different concentrations of ions inside and outside of the cell. Voltage-gated ion channels control the movement of ions into and out of a neuron. When a neuronal membrane is depolarized to at least the threshold of excitation, an action potential is fired. The action potential is then propagated along a myelinated axon to the axon terminals. In a chemical synapse, the action potential causes release of neurotransmitter molecules into the synaptic cleft. Through binding to postsynaptic receptors, the neurotransmitter can cause excitatory or inhibitory postsynaptic potentials by depolarizing or hyperpolarizing, respectively, the postsynaptic membrane. In electrical synapses, the action potential is directly communicated to the postsynaptic cell through gap junctions—large channel proteins that connect the pre-and postsynaptic membranes. Synapses are not static structures and can be strengthened and weakened. Two mechanisms of synaptic plasticity are long-term potentiation and long-term depression.

Art Connections

(Figure) Potassium channel blockers, such as amiodarone and procainamide, which are used to treat abnormal electrical activity in the heart, called cardiac dysrhythmia, impede the movement of K+ through voltage-gated K+ channels. Which part of the action potential would you expect potassium channels to affect?

(Figure) Potassium channel blockers slow the repolarization phase, but have no effect on depolarization.

Review Questions

For a neuron to fire an action potential, its membrane must reach ________.

  1. hyperpolarization
  2. the threshold of excitation
  3. the refractory period
  4. inhibitory postsynaptic potential

After an action potential, the opening of additional voltage-gated ________ channels and the inactivation of sodium channels, cause the membrane to return to its resting membrane potential.

What is the term for protein channels that connect two neurons at an electrical synapse?

  1. synaptic vesicles
  2. voltage-gated ion channels
  3. gap junction protein
  4. sodium-potassium exchange pumps

Which of the following molecules is not involved in the maintenance of the resting membrane potential?

Free Response

How does myelin aid propagation of an action potential along an axon? How do the nodes of Ranvier help this process?

Myelin prevents the leak of current from the axon. Nodes of Ranvier allow the action potential to be regenerated at specific points along the axon. They also save energy for the cell since voltage-gated ion channels and sodium-potassium transporters are not needed along myelinated portions of the axon.

What are the main steps in chemical neurotransmission?

An action potential travels along an axon until it depolarizes the membrane at an axon terminal. Depolarization of the membrane causes voltage-gated Ca 2+ channels to open and Ca 2+ to enter the cell. The intracellular calcium influx causes synaptic vesicles containing neurotransmitter to fuse with the presynaptic membrane. The neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane. Depending on the specific neurotransmitter and postsynaptic receptor, this action can cause positive (excitatory postsynaptic potential) or negative (inhibitory postsynaptic potential) ions to enter the cell.

Describe how long-term potentiation can lead to a nicotine addiction.

Long-term potentiation describes the process whereby exposure to a stimulus increases the likelihood that a neuron will depolarize in response to that stimulus in the future. Nicotine exposure causes long-term potentiation of neurons in the amygdala, and activates reward centers of the brain. As nicotine exposure continues, long-term potentiation reinforces the activation of the reward pathways in response to nicotine consumption.


Refining optogenetic methods to map synaptic connections in the brain

Optogenetics is a technique that combines genetics and optics to control neuronal activity, which is based on the discovery of light-sensitive membrane channels within pond algae that control movement in response to light. When genes that produce one such light-sensitive membrane channel, called channelrhodopsin (ChR), are inserted into neurons and subsequently exposed to light, they regulate the flow of ions across cell membranes, increasing the neuron's activity. This allows scientists to discretely control neuronal activity by using pulses of light to activate specific populations of neurons.

Optogenetics is leveraged for mapping connections in the brain by stimulating individual neurons with light and recording the responses of nearby neurons with an electrode. In this manner, scientists ask whether stimulation of a putative presynaptic neuron causes a response in the putative postsynaptic neuron being monitored by the electrode. When ChRs are inserted into neurons using genetic techniques, however, their expression occurs throughout the entire surface of the neuron, from dendrites, the parts of the neuron that receive information, to the axon, the part of the neuron that sends information. The fact that ChR expression is not restricted to one particular domain of the neuron limits the information researchers can collect and interpret about synaptic connectivity, since it can be difficult to determine whether ChR stimulation was generated in a protein located in that neuron's cell body, or in the axon terminal or in the dendrites of other cells that happen to be passing through the light-stimulated area.

In their August publication in eLIFE, MPFI researchers, Christopher A. Baker, Ph.D. and McLean Bolton, Ph.D., described how they optimize optogenetic methods for mapping neural circuits in the brain. Their improved method uses optical techniques to confine light stimulation to a defined disc-like shape deep within living tissue, combined with a genetic approach for spatial restriction of ChR expression to the cell body and proximal dendrites of neurons. The spatially restricted ChR expression allows unmasking of synaptic connections from neurons whose cell bodies lie close to the dendrites of the postsynaptic cell that would have been occluded by direct activation of ChR on its dendrites. Moreover, it ensures that when light stimulation is applied to a particular cell, any recorded responses can reliably be assigned to the activity of that cell and not to the stimulation of axons or dendrites of other cells that happen to be passing within the disc of light stimulation. This method is a reliable way to rapidly evaluate synaptic connectivity with single neuron resolution and also offers enhanced specificity for other experiments involving optogenetic manipulations.

Future directions

According to Dr. Bolton, their goal is to construct precise maps revealing the functional connectivity of synapses, without the loss of information that limits the current optogenetics method. Evaluating neural circuits through optical stimulation promises to reveal much about how the nervous system functions, how it is modified by experience, and how it is disturbed in animal models of neurologic or psychiatric disease. "This optimized method is straightforward and easy to implement with standard two-photon microscopy, opening up many possibilities in research not only at MPFI but also for the entire field of neuroscience," said Dr. Bolton.


Building a brain, cell by cell: Researchers make a mini neuron network (of two)

Tokyo - The human brain is an exquisitely complex, organic CPU, made of trillions of connections between many billions of neurons. Understanding such a complicated organ is a massive scientific undertaking, and researchers often use simplified models to uncover small pieces of the neurological puzzle.

In a report published in Micromachines, researchers at The University of Tokyo Institute of Industrial Science describe their new method to create one such model, using microscopic plates to connect neurons together one cell at a time.

Research into the brain typically involves the use of in vitro cultures, which are collections of neurons grown together in a dish. A culture represents, in effect, a highly pared-down version of a brain, and one that can be chemically or electrically manipulated. While cultures are indispensable to neurological research, they suffer from considerable limitations.

"In vitro culture models are essential tools because they approximate relatively simple neuron networks and are experimentally controllable," study first author Shotaro Yoshida explains. "These models have been instrumental to the field for decades. The problem is that they're very difficult to control, since the neurons tend to make random connections with each other. If we can find methods to synthesize neuron networks in a more controlled fashion, it would likely spur major advances in our understanding of the brain."

The researchers took advantage of recent insights into how neurons behave namely, that geometric shapes can help guide neurons, telling them where and how to grow. In this case, the team used a synthetic neuron-adhesive material to make a microscopic plate. The plate is circular with two protruding rectangles, somewhat resembling a bead on a tight string. They found that this shape guides neurons to grow in a very defined way: when placed onto the microplate, a neuron's cell body settles onto the circle, while the axon and dendrites - the branches that let neurons communicate with each other - grow lengthwise along the rectangles.

"What was especially important in this system was to have control over how the neurons connected," Yoshida adds. "We designed the microplates to be movable, so that by pushing them around, we could physically move two neurons right next to each other. Once we placed them together, we could then test whether the neurons were able to transmit a signal."

Neurons communicate with one another through synapses, specialized structures that let chemical messengers travel from one neuron to the next. Using a technique to visualize the parts of a synapse, the research team found that the microplate-riding neurons were indeed able to form these communication hubs. What was more, the hubs were functional: when one neuron lit up with electrically charged ions, its partner lit up at precisely the same time.

While the team aims to further refine the system (only a small fraction of neurons could be successfully connected through working synapses), the results of the study suggest an important step forward in using microplates for research.

"This is, to the best of our knowledge, the first time a mobile microplate has been used to morphologically influence neurons and form functional connections," lead investigator Shoji Takeuchi concludes. "We believe the technique will eventually allow us to design simple neuron network models with single-cell resolution. It's an exciting prospect, as it opens many new avenues of research that aren't possible with our current suite of experimental tools."

The article, "Assembly and Connection of Micropatterned Single Neurons for Neuronal Network Formation," was published in Micromachines at DOI: 10.3390/mi9050235.

About Institute of Industrial Science (IIS), the University of Tokyo

Institute of Industrial Science (IIS), the University of Tokyo is one of the largest university-attached research institutes in Japan.

More than 120 research laboratories, each headed by a faculty member, comprise IIS, with more than 1,000 members including approximately 300 staff and 700 students actively engaged in education and research. Our activities cover almost all the areas of engineering disciplines. Since its foundation in 1949, IIS has worked to bridge the huge gaps that exist between academic disciplines and real-world applications.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Difference Between Nerve and Neuron

Nerve vs. Neuron

Although nerve and neuron may sound similar to most people, they are, in fact, two different components of the body. However, they are closely related, as nerves are actually projections of neurons.

There are three main types of nerves: Afferent nerves, efferent nerves and mixed nerves. Afferent nerves transmit signals from sensory neurons to the central nervous system efferent nerves transmit signals from the central nervous system to the muscles and glands, and mixed nerves are responsible for receiving sensory information, and for sending information to the muscles. Nerves are also classified as spinal nerves and cranial nerves. The spinal nerves connect the spinal column to the spinal cord, and transmit signals to most of the body, while cranial nerves are found in the brainstem, and they are responsible for the signals to the brain.

The nerve is composed of different types of axons, and it is through these axons that the electrochemical nerve impulses (mentioned above) are transmitted. Nerves are found in the peripheral nervous system. Each nerve is covered by three layers, starting with the inner endoneurium, which covers the nerve fibres the middle layer called the perineurium, and the outer layer over the perineurium, called the epineurium. There are even blood vessels found within a nerve.

On the other hand, neurons are found in the brain, spinal cord and peripheral nerves. Neurons are also named as neurone, or as nerve cells. There are two types of neurons ‘“ the sensory neurons and the motor neurons. Sensory neurons send signals to the brain and the spinal cord, while the motor neurons receive signals from the brain and spinal cord. Therefore, information is transmitted through neurons by electrochemical signaling.

Neurons consist of various parts including the soma, nucleus, extensions called the dendrite tree, and the many axons. The soma is the central part of the neuron, and the nucleus is found within the soma. Dendrites form extensions from the neuron, and axons are the extensions from the soma. Axons are fine structures, and they vary in number from hundreds to thousands. The axon terminals have synapses, and the axon hillock is where the axon emerges from the soma.

Various diseases can occur when there is damage sustained to the nerves or the neurons. Nerve damage may lead to diseases such as carpal tunnel syndrome, immunological diseases like Guillain-Barre syndrome, and neuritis, which is when the nerves become infected. Diabetes could also cause nerve damage, and neuropathy refers to the damage of the blood vessels covering the nerves. Symptoms of the above-mentioned diseases include paralysis, pain, numbness and weakness of the nerves. In some cases, there is even referred pain in a different part of the body due to the damage of certain nerves.

Alzheimer’s disease, Charcott Marie Tooth disease, Myasthenia Gravis and Parkinson’s disease are all caused by damage to the neurons. Symptoms of these diseases include short-term memory loss, loss of sensory perception, agnosia, apraxia, aphasia, akinesia, tremors, muscle rigidity, bradykinesia, and many others.

1.A neuron is an individual cell, whereas, a group of neurons form a nerve.
2.There are two types of neurons ‘“ sensory and motor neurons while there are three types of nerves ‘“ afferent, efferent and mixed nerves.
3.Nerves are found in the peripheral nervous system, while neurons are found in the brain, spinal cord and the peripheral nerves.
4.A neuron can also be called a neurone or a nerve cell.
5.Neurons conduct nerve impulses, while nerves transmit information to various parts of the body.


Muscle Lab

Muscles are multicellular contractile units. They are divided into three types:

As you read about each type of muscle, think about the similarities and differences betweenthem in terms of structure and function.

Skeletal Muscle

Skeletal muscle is mainly responsible for the movement of the skeleton, but is also found in organs such as the globe of the eye and the tongue. It is a voluntary muscle, and therefore under conscious control. Skeletal muscle is specialized for rapid and forceful contraction of short duration.

Each muscle cell is defined by a cell membrane (sarcolemma) and contains many nuclei along its length. The nuclei are displaced peripherally within a cross section of the cytoplasm (sarcoplasm) while a large number of longitudinal myofibrils, groups of arranged contractile proteins, occupy most of the center space. The myofibril contains several important histological landmarks:

  • The myofibril is composed of alternating bands. The I-bands (isotropic in polarized light) appear light in color and the A-bands (anisotropic in polarized light) appear dark in color. The alternating pattern of these bands results in the striated appearance of skeletal muscle.
  • The Z-lines (Zwischenschieben) bisect the I-bands.
  • A light band called the H-band (Heller) sits within each A-band.
  • The M-line (Mittelschiebe) bisects each A-band (and, in doing so, bisects each H-band).

Each myofibril can be understood as a series of contractile units called sarcomeres that contains two types of filaments: thick filaments, composed of myosin, and thin filaments, composed of actin. The individual filaments do not change in length during muscle contraction rather the thin filaments slide over the thick filaments to shorten the sarcomere. The nature of these filaments can be understood in the context of the histological landmarks of the myofibril.

  • The thick filaments are a bipolar array of polymerized myosin motors. The motors on one side of the filament are oriented in the same direction whereas the motors on the other side of the filament are oriented in the opposite direction. The center of the filament lacks motors it contains only the coiled-coil region of the myosins. A set of proteins crosslinks each myosin filament to its neighbors at the center of the filament. These proteins make up the M-line.
  • The thin filaments are attached to a disc-like zone that appears histologically as the Z-line. The Z-lines contain proteins that bind and stabilize the plus ends of actin filaments. Z-lines also define the borders of each sarcomere.
  • The I- and H-bands are areas where thick and thin filaments do not overlap (this is why these bands appear paler under the microscope). The I-band exclusively contains thin filaments whereas the H-band contains exclusively thick filaments.

Skeletal muscles are divided into two muscle fiber types:

  • Slow-twitch (type I) muscle fibers contract more slowly and rely on aerobic metabolism. They contain large amounts of mitochondria and myoglobin, an oxygen-storage molecule. The reddish color of myoglobin is why these fibers may be referred to as red fibers. These muscles can maintain continuous contraction and are useful in activities such as the maintenance of posture.
  • Fast-twitch (type II) muscle fibers contract more rapidly due to the presence of a faster myosin. Type II fibers can be subdivided into those that have large amounts of mitochondria and myoglobin and those that have few mitochondria and little myoglobin. The former primarily utilize aerobic respiration to generate energy, whereas the latter rely on glycolysis. The lack of myoglobin results in a paler color than the slow-twitch muscles, and fast-twitch fibers may therefore be referred to as white fibers. These muscles are important for intense but sporadic contractions for example, those that take place in the biceps.

Most muscles contain a mixture of these extreme fiber types. In humans, the fiber types cannot be distinguished based on gross examination, but require specific stains or treatments to differentiate the fibers.

Neuromuscular Junction and Activation of Skeletal Muscle Cells

Skeletal muscle cells are innervated by motor neurons. A motor unit is defined as the neuron and the fibers it supplies. Some motor neurons innervate one or a few muscle cells whereas other motor neurons can innervate hundreds of muscle cells. Muscles that require fine control have motor neurons that innervate fewer muscle cells muscles that participate in less controlled movements may have many fibers innervated by each neuron. Motor axons terminate in a neuromuscular junction on the surface of skeletal muscle fibers. The neuromuscular junction is composed of a pre-synaptic nerve terminal and a post-synaptic muscle fiber. Upon depolarization, the pre-synaptic vesicles containing the neurotransmitter acetylcholine fuse with the membrane, releasing acetylcholine into the cleft. Acetylcholine binds to receptors on the post-synaptic membrane and causes depolarization of the muscle fiber, which leads to its contraction. Typically, one action potential in the neuron releases enough neurotransmitter to cause one contraction in the muscle fiber.

In muscle cells, the sarcolemma or plasma membrane extends transversely into the sarcoplasm to surround each myofibril, establishing the T-tubule system. These T-tubules allow for the synchronous contraction of all sarcomeres in the myofibril. The T-tubules are found at the junction of the A- and I- bands and their lumina are continuous with the extracellular space. At such junctions, the T-tubules are in close contact with the sarcoplasmic reticulum, which forms a network surrounding each myofibril. The part of the sarcoplasmic reticulum associated with the T-tubules is termed the terminal cisternae because of its flattened cisternal arrangement. When an excitation signal arrives at the neuromuscular junction, the depolarization of the sarcolemma quickly travels through the T-tubule system and comes in contact with the sarcoplasmic reticulum, causing the release of calcium and resulting in muscle contraction.

Smooth Muscle

Smooth muscle forms the contractile portion of the wall of the digestive tract from the middle portion of the esophagus to the internal sphincter of the anus. It is found in the walls of the ducts in the glands associated with the alimentary tract, in the walls of the respiratory passages from the trachea to the alveolar ducts, and in the urinary and genital ducts. The walls of the arteries, veins, and large lymph vessels contain smooth muscle as well.

Smooth muscle is specialized for slow and sustained contractions of low force. Instead of having motor units, all cells within a whole smooth muscle mass contract together. Smooth muscle has inherent contractility, and the autonomic nervous system, hormones and local metabolites can influence its contraction. Since it is not under conscious control, smooth muscle is involuntary muscle.

Smooth muscle fibers are elongated spindle-shaped cells with a single nucleus. In general, they are much shorter than skeletal muscle cells. The nucleus is located centrally and the sarcoplasm is filled with fibrils. The thick (myosin) and thin (actin) filaments are scattered throughout the sarcoplasm and are attached to adhesion densities on the cell membrane and focal densities within the cytoplasm. Since the contractile proteins of these cells are not arranged into myofibrils like those of skeletal and cardiac muscle, they appear smooth rather than striated.

Smooth muscle fibers are bound together in irregular branching fasciculi that vary in arrangement from organ to organ. These fasciculi are the functional contractile units. There is also a network of supporting collagenous tissues between the fibers and the fasciculi.

Cardiac Muscle

Cardiac muscle shares important characteristics with both skeletal and smooth muscle. Functionally, cardiac muscle produces strong contractions like skeletal muscle. However, it has inherent mechanisms to initiate continuous contraction like smooth muscle. The rate and force of contraction is not subject to voluntary control, but is influenced by the autonomic nervous system and hormones.

Histologically, cardiac muscle appears striated like the skeletal muscle due to arrangement of contractile proteins. It also has several unique structural characteristics:

  • The fibers of cardiac muscle are not arranged in a simple parallel fashion. Instead, they branch at the ends to form connections with multiple adjacent cells, resulting in a complex, three-dimensional network.
  • Cardiac muscle fibers are long cylindrical cells with one or two nuclei. The nuclei are centrally situated like that of smooth muscle.
  • Cardiac muscle sarcoplasm has a great amount of mitochondria to meet the energy demands.

Collagenous tissues are found surrounding individual cardiac muscle fibers. There is abundance vascularization within this supporting tissue, which is required to meet the high metabolic demands of cardiac muscle.

The cardiac muscle fibers are joined end to end by specialized junctional regions called the intercalated discs. The intercalated discs provide anchorage for myofibrils and allow rapid spread of contractile stimuli between cells. Such rapid spread of contraction allows the cardiac muscles to act as a functional syncytium. The intercalated discs contain three types of membrane-to-membrane contact:

  • fascia adherens, which are connected to actin filaments to transmit contraction
  • desmosomes, which connect to intermediate filaments of the cytoskeleton
  • gap junctions, which are sites of low electrical resistance that allow the spread of excitation

In addition to the contractile cells, there is a specialized system made up of modified muscle cells whose function is to generate the stimulus for heartbeat and conduct the impulse to various parts of the myocardium. This system consists of sinoatrial node, atrioventricular node, bundle of His, and Purkinje fibers.


Watch the video: How Neurons Communicate (July 2022).


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