Chapter 5: How do neurons communicate and adapt 

• Chemical message 

  • Acetylcholine - Excites skeletal muscles in the SNS, causing them to contract, and may either excite or inhibit various internal organs in the auto system; Aka ACh

  • The ion channel and its associated receptor determine whether the message will be excitatory or inhibitory. 

  • Otto Lowei first to isolate chemical messenger 

  • Epinephrine (EP) was isolated and purified by jokichi taka mine 

    • Aka adrenalin produced by adrenal gland atop kidneys 

  • The results of both experiments showed that ACh from the vagus nerve inhibits heartbreak when EP from the accelerator nerve excites it 

  • Norepinephrine (NE) is the chemical that accelerates heartbeat and is closely related to EP 

  • Lowei revealed the role of these chemical messengers, aka neurotransmitters - can have either excitatory or inhibitory activity 

  • Neurotransmitters are known by their abbreviations 

  • Neurons are named after the type of chemical neurotransmitter they release 

    • Cholinergic neuron = secretes ACh 

    • Adrenigic neuron = secretes EP 

    • Noradrengic neuron - secretes NE 

  • Outside of the CNS, many chemical messengers circulate in the bloodstreams as hormones 

    • Under the control of the hypothalamus, the pituitary gland releases them to excite/inhibit organs and clans in the ENS and ANS 

  • Neurotransmitters = released from neurons to act locally 

  • Hormones = released from neurons or other tissues and travel far 

  • The difference between neurotransmitters and hormones is the distance travelled from the release point to the receptor they interact with 

• Structure of synapses 

  • 1st discovered in 1950s using electron microscopy 

  • Chemical synapses 

    • Synaptice vessels contain neurotransmitter molecules

      • Dendritic postsynaptic neuron (make a diagram with these labelled) 

        • Microtubule 

        • Mitochodrion 

        • Presynaptic membrane 

        • Neuro transmitter 

        • Channel 

        • Dendritic spine 

        • Postsynaptic receptor 

        • Synaptice vesicle 

        • Synaptic cleft 

        • Storage granule 

  • Channel = serves as ion channels located at axon terminal membrane either to signal release of transmitters or pumps to recapture it after release 

  • Synaptic cleft - small space separating the terminal and dendrite central to synapse function as neurotransmitters must bridge gap to carry message 

  • Tripartile synapses - functional integration and physical proximity

    • Pre and post-synaptic membrane and intimate associated with surrounding astrocytes 

    • Surrounding astrocytes contribute to chemical neurotransmitters by supplying building blocks for neurotransmitter synthesis, confirming the movement of neurotransmitters to synapses and cleaning up excess neurotransmitter molecules 

  • Chemical synapses - the intersection where messenger molecules are released from one neuron to interact with another 

  • Anterograde synaptic transmission - 5 step process of transmitting information across a chemical synapses from pre synaptic side to post synaptice neuron 

    • 1. Neurotransmitter is synthesized somewhere inside the neuron 

    • 2. It's packaged and stored within vesicles at the axon terminal 

    • 3. It is transported to the pre-synaptic membrane and released into the synaptic cleft in response to action potential 

    • 4. It binds to and activates receptors on the postsynaptic membrane 

    • 5. It's degraded or removed, so it won't continue to interact with a receptor and word indefinitely 

  • Steps one and two: synthesized, packaged and stored 

    • Small molecule transmitters are synthesized in the axon terminal from the building blocks that are often obtained from food 

    • Mitochondria in axon terminal provide the energy needed both ot synthesize precursor chemicals into the transmitter and to power transporters 

    • Peptide transmitters are synthesized in the cell body according to instructions in neuron’s DNA 

      • Packaged in membranes on the Golgi body and transported on microtubules in axon terminal also be manufactured with in the presynaptic terminal by ribosomes using mRNA transported to terminal 

    • Lipid transmitters - can't be packaged and stored in vesicles which are composed of lipids; they're synthesized on demand when an action potential reaches the axon terminal 

    • Gaseous transmitters are also generated within cells by enzymes but differ from classical signalling molecules in many ways 

      • Production is regulated. They’re able to permeate cell membranes because of this ability; they’re not stored in the cell

    • Ion transmitters not biochemically synthesized made the heart of dying stars. In the body, they can be packaged and stored in vesicles and then released into the synaptic cleft 

  • 3 locations in axon terminals found neurotransmitters 

    • Granules 

    • Microfilaments 

    • Precynaptic membran 

  • Step 3: neurotransmitter release 

    • Synaptic vesicles loaded with neurotransmitter must dock by release sites on presynaptic membrane. 

    • Vesicles are primed to prepare to fuse quickly in response to calcium (Ca2+) influx. 

    • Release is in motion when an action potential reaches the presynaptic membrane and voltage changes on the membrane. 

    • Primed vesicles quickly fuse with presynaptic membrane in response to Ca2+ influx and empty their contents into synaptic cleft by exocytes

  • Step 4: Receptor activation 

    • Specialized protein molecules embedded in post-synaptic membrane after release of neurotransmitter diffuses across synaptic cleft and binds to them 

      • 1. Transmitter-activated receptors 

      • 2. Ionotropic receptors 

      • 3. Metabotropic receptor 

      • 4. auto receptors (self receptors) 

    • Quantum (qunta) is the number of transmitter molecules 

  • Step 5: Neurotransmitter inactivation 

    • Four ways inactivation is accomplished 

      • 1. Diffusion - some neurotransmitter simply diffuses away from the synaptic cleft and is no longer able to connect to receptors 

      • 2. Degradation - enzymes in synaptic cleft break down transmitter

      • 3. Reuptake - specific membrane transporters to the same neurotransmitter may bring it back into presynaptic axon terminal for reuse 

        • Products of degradation by enzymes may be taken back into the terminal to be reused. 

      • 4. Astrocyte uptake - neurotransmitters taken by nearby astrocytes can also store certain transmitters for re-export to the axon terminal 

  • Varieties of synapses 

    • 1. Dendrodendritic 

    • 2. Axodendritic 

    • 3. Axoextracellular 

    • 4. Axosomatic 

    • 5. Axosynaptic 

    • 6. Axoaxmic 

    • 7. Axosecretory 

  • Main chemical synapses 

    • 1. Axomuscular synapse - axon synapses with muscle end plate releasing ACh 

    • 2. Axodendritic synapses 

  • Electrical synapses - main 

    • Where two neurons intracellular fluids or cytoplasm can come into direct contact 

    • Gap junctions are formed when connected proteins in one cell membrane connect and create a hemichannel that connects to a hemichannel in an adjacent cell, passing ions back and forth 

      • Eliminate brief delay in information flaw that occurs in chemical transmitter 

      • Increase signalling diversity between neurons 

  • Excitatory synapses vs. inhibitory synapses 

    • Excitatory

      • Found on shafts and spines of dendrites 

      • Round synaptic vesicles 

      • Material on pre and post-synaptic membranes are denser 

      • Cleft is wifer 

      • Active zone is larger 

    • Inhibitory 

      • Occur more on cell body 

      • Vesicles are flattened 

      • The material is less dense compared 

      • Synaptic cleft narrower 

      • The active zone is smaller 

    • Differences between results in the neuron split into two zones 

      • Excitatory dendritic tree 

      • Inhibitory cell body 

• Varieties of neurotransmitters and receptors 

  • 4 criteria for identifying neurotransmitters 

    • 1. The transmitter must be synthesized in the neuron or otherwise be present in it 

    • 2. When a neuron is excited, the transmitter must be released and produce a response in some target

    • 3. The same response must be obtained when transmitters are experimentally placed on the target 

    • 4. A mechanism must exist for removing transmitters from their site of action after their work is done 

  • Neurotransmitter applies to chemicals that have these functions 

    • Carry a message from the presynaptic membrane of one neuron to another by influencing postsynaptic membrane voltage 

    • Changes the structure of a synapse 

    • Communicate by sending messages in opposite direction reuptake of transmitters on presynaptic side 

  • Classes of neurotransmitters 

    • 1. Small molecule transmitters - synthesized from dietary nutrients and packaged so they're ready to be used in axon terminals 

      • Best known small molecule neurotransmitters 

        • Acetycholine ACh 

        • Amines 

          • Dopamine (DA) 

          • Histamine (H)

          • NE & EP

          • Serotonin (5-HT) 

        • Amino acid 

          • Gamma-aminobutyric acid (GABA)

          • Glutamate (Glu) 

          • Glycine (Gly) 

        • Purines 

          • Adensoine 

          • Adenosine triphosphate (ATP)

    • 2. Peptide transmitters (Neuropeptide) 

      • Synthesized through translation of mRNA instructed by neurons in DNA; multifunctional chains of amino acids that alter neurotransmitters 

      • Opioids = Met-enkephalin, dynorphin, beta-endorphin 

      • Neurohypophyseal = vassopressin, oxytocin 

      • Secretins = secretin, motilin, glucagon, growth hormone release factor 

      • Insulins = insulin, insulin growth factors 

      • Gastrins = gastrin, cholecystokinin 

      • Somatostatins = somatostatin 

      • Tachykins = neurokinin A, Neurokinin B, substance P 

    • 3. Lipid transmitters 

      • Endocannabinoids synthesized at postsynaptic to act on receptors at presynaptic 

        • Anandamine (AEA) and 2-arachidonoylglycerol (2-AG) are both derived from arachidonic acid

    • Gaseous transmitters 

      • Cell synthesizes these transmitters on demand 

      • Three types 

        • Nitric oxide (NO)

        • Carbon Monoxide (CO) 

        • Hydrogen sulfide (H2S) 

    • Ion transmitters 

      • Evidence recently classified zinc (Zn2+) as a transmitter 

  • Acetylcholine synthesis steps 

    • Firstly, Acetylo enzyme acacetylCoA carries acetate to the synthesis site 

    • Secondly, a second enzyme, choline acetyltransferase (ChAT), transfers acetate to choline 

    • Thirdly, forms synthesize ACh and are released into the synaptic cleft 

    • Fourthly diffuses to receptor sites on post membrane AChE breaks down transmitter by separating acetate from choline 

    • Fifthly, broken products can be taken back in the  presynaptic terminal for reuse 

  • Amine synthesis 

    • Tyrosine is the precursor chemical to L-dopa to dopamine to norepinephrine to epinephrine 

    • The rate-limiting factor tyrosine hydroxylase is limited, and so is the rate at which DA. NE. EP can be produced regardless of how much tyrosine is present 

    • Histidine amino acid that serves as prime biological source of transmitter histamine (H) 

      • H converted by enzyme histidine decarbozylase into histamine 

  • Serotonin synthesis 

    • 5-HT = Hydrozytryptamine synthesized from amin acid L-tryplophan 

  • Amino acid synthesis 

    • Glu and GABA = amino acid transmitter 

    • GABA is formed by the simple modification of a Glu molecule 

    • In the forebrain and cerebellum, Glu = excitatory transmitter and GABA = inhibitory transmitter 

    • Glycine (Gly), a common inhibitory transmitter in the brainstem and spinal cord, acts within the renshaw loop 

  • Purines 

    • Are synthesized as nucleotides, aka a kind of molecules that are in DNA & RNA 

    • ATP consists of a molecule of adenine attached to a ribosome sugar molecule and three phosphate groups 

      • Vasodilation = dialation of blood vessals 

• Varieties of receptors 

  • Classes of receptors 

    • An ionotropic receptor allows ions to move across the membrane and has 2 parts: a binding site for a neurotransmitter and a pore or a channel

    • Metabotropic receptor has a binding site but no pore for ions to flow 

    • Each receptor is coupled to a G protein that binds to other proteins 

      • 3 sub-units: alpha, beta and gamma 

  • Metabotropic receptor steps 

    • First, the transmitter binds to a receptor in both reactions 

    • Second, a binding of transmitter triggers activation of a G protein in both reactions 

    • Third, an alpha subunit of a G protein binds to a channel using a structural change in the channel that allows ions to pass through it 

    • Fourth, an alpha Subunit binds to an enzyme, which activates a second messenger 

    • Fifth, the second messenger can activate other cell process 

      • Can perform one of several actions 

        • It can bind to a membrane-bound channel, changing the channel's structure and altering ion flow through the membrane 

        • Can initiate a reaction that incorporates intracellular protein molecules into cell membrane resulting in  information of new ion channels 

        • Can bind to sites on cells' DNA to initiate or terminate the production of specific proteins 

    • This receptor also allows for the possibility that a single neurotransmitter binding to a receptor can activate an escalating sequence of events called an amplification cascade 

      • Results in lots of downstream proteins being either deactivated or activated 

• Neurotransmitter systems and behaviour 

  • Neurotransmission in SNS

    • Motor neurons are called cholinergic neurons because ACh is the main neurotransmitter. 

    • Main SNS receptor - Nicotinic Acetylcholine receptor (nAChr) 

      • ACh binds to this receptor, and its pore opens to permit ion flow. This depolarizing muscle fiber 

      • The nicorinic receptor pore is large enough to permit the simultaneous efflux of K+ and influx of Na+ 

  • Dual Activating Systems of ANS

    • Has two levels: parasympathetic and sympathetic 

      • Both are controlled by preganglion cholinergic neurons that project from the CNS 2 levels of the spinal cord.

      • CNS neurons synapses with parasympatheitic post ganglion neurons that contains NE 

    • Fight or flight system 

      • Spinal cord to sympathetic preganglion neuron to automatic ACh ganglion to sympathetic post ganglion neuron to NE Neurons to organs 

    • Rest and digest system 

      • Spinal cord to parasympathetic preganglion neuron to ACh automatic ganglion to parasympathetic post ganglionneuron to ACh neurons to organs 

    • Neurotransmitter activity has excitatory effects in one location and inhibitory effects in another, which mediates parasympathetic and sympathetic divisions, forming a complementary automatic regulating system that maintains the body's internal environment under dynamic circumstances. 

  • ENS Autonomy 

    • It can act without CNS input using main classes of neurotransmitter, but top among small molecule neurotransmitter used by ENS is serotonin and dopamine. 

    • Sensory ENS Neurons detect both the mechanical and chemical conditions in the gastrointestinal system. 

  • Four activating systems in CNS 

    • Cholinergic system - ACh 

      • High AChE flows through the concentrations, indicating the presence of cholinergic terminals.s

        • AChE flows through the cortex and especially dense basal ganglia

        • Many cholinergic synapses are connections from ACh nuclei in the brainstem 

      •  This system participates in typical waking behaviour attention and memory 

        • Can be recorded through EEG

      • Profound loss of cholinergic neurons = alzheimer disease 

        • Strategies to treat focuses on the use of drugs that inhibit the enzyme acetylcholinesterase elevating levels of ACh or raise the number of nicotinic receptors 

    • The dopaminergic system has two systems 

      • 1. Nigrostriatal dopaminergic system 

        • Plays a role in coordinating movement 

        • parkinsonism when most dopamine neurons in the substantia nigra are lost 

      • 2. Mesolimbic dopaminergic system 

        • Neurotransmitter most affected in addiction behaviours that involve a loss of impulse control 

        • Addictive behaviours stimulate this system, enhancing responses to environmental stimul, i thus making those stimulations attractive and rewarding 

        • Excessive activity is proposed to play a role in schizophrenia 

    • Noradenergic system 

      • Plays a part in learning by stimulating neurons to change their structure; also facilitates healthy brain development and contributes to organizing movements 

      • Noradrenergic neuron - uses NE as its transmitter

      • Behaviours and disorders associated with this system involve emotions 

        • Major depression - related to decreased activity of noradrengic neurons 

        • Mania - increased activity of these neurons 

        • Decreased NE activity associated with ADHD 

    • Serotonergic system

      • Maintains waking activity and serotonin plays a role in learning 

      • Two forms of depression exist; one is related to NE, and the other is related to serotonin 

      • Various symptoms of schizophrenia related to an increase in serotonin activity imply multiple forms of it 

      • Decreased serotonergic activity is related to symptoms of OCD 

      • Abnormalities in sriotonergic nuclei and conditions like sleep apnea and SIDS 

  • Neuromodulation 

    • Neuromodulators are neurotransmitters that facilitate each of these activating systems 

    • Chemical messengers are released from a neuron and act on receptors distributed over some regions of the brain 

    • The difference between neurotransmitters and neuromodulators is the distance they travel from their release point

    • They interact with metabotropic (g-protien coupled) receptors to initiate a second messenger signalling a cascade that induces a long-lasting signal 

      • They can alter the firing characteristics and plasticity of GABAergic, glutamatergic and other neurons

• Hormones 

  • Hierarchical control of hormones 

    • First, the hypothalamus produces neurohormones that stimulate the pituitary gland in response to sensory stimulation and cognitive activity 

      • This stimulation of the gland to secrete releasing hormones into circulatory system

    • Second on these instructions, the pituitary gland sends hormones into the bloodstream to target endocrine glands 

    • Third, the endocrine glands release their hormones that stimulate the target organs 

  • Classes and Functions of Hormones 

    • Peptide hormones - like insulin, growth hormones, and endorphins 

      • Made by cellular DNA the same way as other proteins 

      • Bind to metabotropic receptors on the cell membrane generating a 2nd messenger that affects cell physiology or gene transcription 

    • Amino acid hormones - melatonin and thyroxine are derived from AA

      • Melatonin is primarily released by the pineal gland 

      • Thyroxine produced by the thyroid gland = regulates metabolism 

    • Lipid hormones/ecosanoids are water-hating (hydrophobic) and fat-loving (lipophalic) 

      • Prostaglandins play a role in inhibiting bloodclots, regulating blood flow, and both promoting inflammation and counteracting it 

      • Thromboxaine acts in opposite to the above effects by facilitating blood clots 

    • Steroid hormones - testosterone and cortisol 

      • Synthesized from cholesterol and are lipid (fat) soutable 

      • Diffuse away from their sites of synthesis in glands 

        • Gonads, adrenal cortex and thyroid 

      • Bind to steroid receptors on cell membrane or in cell and frequently act on cellular DNA to influence gene transcription 

  • Functional groups of hormones (steroids & peptide) 

    • Homeostatic hormones - maintain a state of internal metabolic balance and regulate physiological systems 

      • Meineralocorticoids - control both the concentration of water in blood and cells as well as levels of sodium, potassium and calcium in the body 

      • Promote digestive functions 

      • Diabetes mellitus - disorder caused by a failure of pancreatic cells to secrete any or enough insulin 

        • Hyperglycemia - blood sugar levels rise 

        • Hypoglycemia - blood sugar levels fall 

      • Hunger and eating 

        • Leptin secreted by animal fat (adipose) tissue inhibits hunger 

        • Gherlin is secreted by the gastrointestinal tract, regulating growth hormones, energy use and induces hunger

          • Both action receptors on the same neurons of arcuate nucleus of the hypothalamus 

    • Gondal hormones - control reproductive functions 

      • Instructs the body to develop as male (testosterone) or female (estrogen) 

      • Influences sex behaviour and conception 

      • In women, it controls the menstrual cycle (Proestergene and estrogen), labour and delivery, and the release of breastmilk (prolactin & oxytocin = the bonding hormone) 

    • Glucocorticoids - a group of steroid hormones secreted in times of stress are important in protein and carbohydrate metabolism as well as controlling blood sugar levels and cellular absorption 

      • Hormones are activated in psychologically challenging events or emergencies to prepare the body to cope by fighting or fleeing 

  • Anabolic androgenetic steroids 

    • Members of a class of synthetic hormones related to testosterone 

      • Has muscle building (anabolic) and masculizing (androgenic) effects 

    • Anabolic steroids were synthesized originally to build muscle mass and enhance endurance 

    • Health risks associated with anabolic steroid use 

      • Administering results in the body to stop producing its own testosterone, which reduces fertility and spermatogenesis in men 

      • Increased aggression and increased risk of heart attack and stroke 

      • Liver and kidney function compromised and increased risk of tumors 

      • Baldness may be enhanced 

      • Approved treatment for hypogonadalment and muscle loss due to trauma 

      • Women = enlarged clitoris, aches, increased body hair, deep voice 

  • Stress and glucocorticoids 

    • Engineering stress - a process where an agent exerts force 

    • Stressor - stimulus that challenges the body's homeostasis and triggers arousal 

    • Stress response - compromising behavioural and psychological changes both arousal and attempts to reduce stress 

      • Begins when the body is subjected to a stressor, especially when the brain perceives a stressor and responds with arousal directed from the brain by the hypothalamus 

  • Two responses of stress 

    • Fast response 

      • The sympathetic division of ANS is activated to prepare the body and its organs for fight or flight 

      • The parasympathetic division stimulates the medulla on the interior of the adrenal gland to release epinephrine 

      • Adrenaline surge preps the body for sudden bursts of activity

    • Fast acting pathway 

      • First, the hypothalamus sends neural messages through the spinal cord 

      • Second, sympathetic division of ANS is activated to stimulate the medulla of the adrenal gland 

      • Third, the adrenal medulla releases epinephrine into the circulatory system 

      • Fourth, epinephrine activates the body’s cells, endocrine glands and the brain 

    • Slow response 

      • Controlled by the steroid cortisol, a glucocorticoid released from the outer layer of the adrenal gland 

      • Activating the cortisol pathway takes anywhere from a few minutes to a few hours 

      • Cortisol function, including turning off all bodily systems not immediately required to deal with a stressor 

        • Shuts down reproductive function and inhibits the production of growth hormone: it concentrates the body's energy on dealing with stress 

    • Slow acting pathway 

      • First, the hypothalamus releases CRH into the pituitary gland 

      • Second, the pituitary gland releases AClH, which acts on the cortex of the adrenal gland

      • Third, the adrenal cortex releases cortisol into the circulatory system 

      • Fourth, cortisol activates the body's cells, endocrine glands and the brain

  • Ending a stress response 

    • What happens when it's not shut down?

      • The body continues to mobilize energy at the cost of energy storage 

      • Proteins are used up, resulting in muscle wasting and fatigue 

      • Growth hormone is inhibited so body can't grow 

      • The gastrointestinal system remains shut down, reducing the intake and processing of nutrients to replace used resources. 

      • Reproductive functions are inhibited. 

      • The immune system is suppressed, contributing to the possibility of infection or disease. 

    • Sapolski found the hippocampus plays a role in turning off the stress response. 

      • The hippocampus contains a high density of cortisol receptors, and it has axons that project to the hypothalamus. 

      • It is well suited to detecting cortisol in the blood and instructing the hypothalamus to reduce blood cortisol levels. 

      • If cortisol levels remain elevated because of consistent stress, cortisol eventually damages the hippocampus, reducing its size.

Lecture 5: How do neurons communicate and adapt 

• A chemical message 

  • An early research question that helped figure out how neurons communicate had to do with studying the control of heart rate in animals. 

    • A faster heart rate is excited or exercising 

    •  Slower heart rate when resting 

  • It was found that chemicals relay excitatory messages (speed up) and inhibitory messages ( slow down) 

• Acetylcholine & the Heart 

  • Otto Loewi (1921): frog heart experiment 

    • Role of the vagus nerve and neurotransmitter ACh in slowing heart rate 

  • Acetylcholine 

    • 1st neurotransmitter discovered in PNS and CNS 

    • Activates skeletal muscles in the SNS 

    • It may excite or inhibit internal organs in the ANS

  • How does a neuron transmit a message? 

    • Through a chemical signal 

  • Loewi also investigated epinephrine and norepinephrine 

• Neurotransmitters 

  • Definition: A chemical released by a neuron onto a target 

    • Has an excitatory or inhibitory effect 

  • Outside the CNS, many of these same chemicals can be found in the bloodstream and act as hormones. 

    • Hormones have distinct targets and act slower than neurotransmitters

• Synapse Structure

  • A chemical synapse: where the axon terminal of one neuron comes near to receptive sites on another neuron (dendritic spine) 

  • This is where neurotransmitters are released from one neuron (from the axon terminal) to excite or inhibit the next neuron. 

  • Most synapses in the mammalian nervous system are chemical 

• Structure of chemical synapses 

  • Presynaptic membrane (axon terminal) - where the action potential terminates to release the neurotransmitter 

  • Postsynaptic membrane (dendritic spine) - the receiving side of the chemical message 

    • Where EPSPs or IPSPs are generated 

  • Synaptic cleft (space between) - small gap where the neurotransmitters diffuse from presynaptic to postsynaptic membrane 

  • Synaptic vesicle (presynaptic) - small spheres made of a phospholipid bilayer (cell membrane) that contain molecules of one or more neurotransmitters 

  • Storage granule (presynaptic) - membranous compartment that holds several vesicles containing neurotransmitter(s) 

  • Postsynaptic receptor (postsynaptic) - a molecule with a neurotransmitter binding site 

  • Transporter - protein molecule that pumps substances across a membrane 

• Neurotransmitter in 5 steps (SSRRR) 

  • Neurotransmitter is synthesized somewhere inside the neuron 

  • It is packaged and stored within vesicles at the axon terminal 

  • It is transported to the presynaptic membrane and released into the synaptic cleft in response to an action potential  

  • It binds to and activates receptors on the postsynaptic membrane 

  • It is then degraded or removed so it will not continue to activate a receptor indefinitely (inactivation)

• Anterograde synaptic transmission

  • Steps 1& 2 neurotransmitters are made in 2 general ways

    • Some (small) kinds can be synthesized (manufactured) in axon terminal 

      • Building blocks come from food (pumped into cell via transporter)

    • Other larger kinds are synthesized in the cell body 

      • Instructions are given in DNA (peptide transmitters) 

      • Transported in microtubules to axon terminal 

  • Step 3 - Neuron transmitter release 

    • At the terminal, the action potential opens voltage-sensitive calcium channels. 

    • Calcium enters the terminal and binds to the protein calmodulin 

    • This complex can bind to vesicles 

      • Causes some to empty their contents into the synapses 

      • Causes others to get ready to empty their contents

  • Step 4 - Receptor site activation 

    • After its release, neurotransmitter diffuses across the synaptic cleft and can captivate receptors on the postsynaptic membrane 

    • Transmitter-activated receptors - protein that has a binding site for a specific neurotransmitter is embedded in the membrane of a cell 

    • On the postsynaptic side, neurotransmitter binding may lead to 

      • Depolarizing - the postsynaptic to EPSP in the postsynaptic neuron

      • Hyperpolarizing - the postsynaptic to IPSP in the postsynaptic neuron 

      • Starting other chemical reactions, these can: 

        • Modulate (alter) excitatory or inhibitory effects

        • Influencing other functions of the postsynaptic neuron 

      • Neurotransmitters can also interact with receptors on the preysnaptic membrane 

        • Autoreceptor - self receptor on the same neuron releases  

    • Step 5 - neurotransmitter inactivation 

      • Diffusion - some neurotransmitter diffuses away from the synaptic cleft 

      • Degradation - enzymes in synaptic cleft break down the neurotransmitter 

      • Reuptake - transmitter is brought back into the presynaptic axon terminal to be reused by products of enzyme degradation also may be brought back in to be reused 

      • Astrocyte uptake - nearby astrocytes take in neurotransmitter, which may be exported to the axon terminal for reuse 

• Varieties of synapses 

  • In the nervous system, synapses vary widely 

  • Each type is specialized in location structure, function and target

  • Through connections to the dendrites, cell body, or axon of a neuron, a transmitter can control the actions of the neuron in various ways 

    • Dendrodendritic - sebdrites send messages to other dendrites 

    • Axodendritic - axon terminal of one neuron synapses on dendritic spine of another 

    • Axoextracellular - terminal with no specific target, secretes transmitter into extracellular fluid 

    • Axosomatic - axon terminal ends on cell body 

    • Axosynaptic - axon terminal ends on another terminal 

    • Axoaxonic - axon terminal ends on another axon 

    • Axosecretory - axon terminal ends on tiny blood vessels and secretes transmitter directly into blood 

• Electrical synapses 

  • Gap junction 

    • Fused presynaptic and postsynaptic membranes 

    • Allows action potential to pass directly from one neuron to the next 

  • Electrical synapses are fast 

  • Chemical synapses are more flexible (amplify or diminish signal) 

  • Excitatory and inhibitory messages 

    • Excitatory synapse (type 1) 

      • Typically located on dendrites 

      • Have a wide cleft 

      • Round vesicles 

      • Large active zone

    • Inhibitory synapses (type 2) 

      • Typically located on the cell body 

      • Flat vesicles 

      • Narrow cleft 

      • Small active zone 

• Varieties and characteristics of neurotransmitter

  • Some are inhibitory at one location and excitatory at another 

    • It may interact with different receptors in different locations 

  • More than one neurotransmitter may be active at a single synapse

  • No simple one-to-one relationship between a single neurotransmitter and a single behaviour 

• Four criteria for identifying neurotransmitters

  • One, a transmitter must be synthesized or present in neuron 

  • Two, when released, the transmitter must produce a response in a target cell 

  • Three, the same receptor actions must be obtained when the transmitter is experimentally placed on the receptor 

  • Four, there must be a mechanism for removal after the transmitters' work is done 

  • A neurotransmitter may also 

    • Carry a message from one neuron to another by influencing the voltage on the postsynaptic membrane (create EPSP or IPSP) 

    • Enact events that change the structure of a synapse (bigger or smaller) 

    • Communicate by sending messages in opposite direction (dendrite back to axon) 

      • Retrograde (reverse-direction) messages can influence the release or reuptake of the transmitters on the presynaptic side

• 4 classes of neurotransmitters 

  • Small molecule transmitters 

    • Class of quick-acting neurotransmitters 

    • Synthesized from dietary nutrients and packaged ready for use in axon terminals 

    • Acetylcholine synthesis 

      • Choline and Acetate 

      • Via enzyme-choline acetyltransferase (ChAT)

      • Breakdown of acetylcholine 

        • Via acetylcholineesterase (AChE) 

    • Synthesis of thre amines from the same precursor

      • Tyrosine (amino acid) → L-dopa (enzyme 1) → dopamine (enzyme 2)→ norepinephrine (enzyme 3)→ epinephrine

    • Amino acid transmitters 

      • Glutamate - main excitatory transmitter 

      • GABA - main inhibitory transmitter 

        • Formed by a simple modification of glutamate molecule 

  • Peptide transmitter (Neuropeptides)

    • A chain of amino acid that acts as aneurotransmitter (tiny protien) 

    • Synthesized through translation of mRNA from the neurons' DNA 

      • Act slowly and aren't replaced quickly 

    • Most are transported by the microtubules to the amazon terminals 

    • Don’t bind to an ion channel - don’t directly cause EPSP/IPSP 

      • Indirectly influence cell structure and function 

    • Generally act as hormones 

    • Some respond to stress 

    • Oxytocin - bond of mother with her infant 

    • Contribute to learning 

    • Regulate eating and drinking, pleasure and pain 

    • Opioids like morphine and heroin mimic the actions of natural brain peptides (endorphins, enkephalins) 

  • Lipid transmitter 

    • The main example is endocannabinoids (endogenous/natural cannabinoids)

      • Anandamide 

      • 2- AG (2-arachidonoulglycerol) 

        • Both are derived from arachidonic acid and unsaturated fatty acid 

  • Gaseous and Ion Transmitter 

    • Gaseous transmitters

      • Neither stored in synaptic vesicles nor released from them 

      • Synthesized in cell as needed; easily crosses the cell membrane 

      • Example - nitric oxide (NO) and carbon monoxide (CO)  

    • Ion transmitters 

      • Recent evidence has led researchers to classify zinc as a transmitter 

      • Is packaged into vesicles - usually with another transmitter like Glutamate- and released into the synaptic cleft

• Endocannabinoids 

  • Lipohilic (fat-loving) molecules 

    • Not soluble in water or stored in vesicles 

  • Synthesized at post-synaptic membrane 

    • Diffuse across the synaptic cleft (retrograde signalling)

    • Interact with receptors on presynaptic membrane 

    • Can reduce the amount of small molecule transmitters being released 

  • Act on the CB1 receptor in the CNS

    • Found at glutamate (+) and GABA (-) synapses 

    • Cannabinoids act as a neuromodulator - inhibiting the release of glutamate and GABA

    • can decrease both neuronal excitation and inhibition 

• Schematic representing 

  • The stimuli and potential sources of endocannabinoids that are present in the circulation 

  • Potential targets of endocannabinoids, together with the cannabinoid receptor subtype that is involved 

• Two classes of neurotransmitter receptors 

  • Ionotropic Receptor

    • Embedded membrane protein with two parts 

      • One is a binding site for a neurotransmitter 

      • Two, a pore that regulates ion flow leads to EPSP or IPSP

    • When a neurotransmitter attaches to the binding site, the pore opens or closes, changing the flow of ions 

    • Allows movement of ions like sodium, calcium and potassium across the cell membrane 

  • Metabotropic receptor

    • Embedded membrane protein with a binding site for a neurotransmitter but no pore 

    • Indirectly produces changes in nearby ion channels or the cells metabolic activity. 

    • Linked to a G protein that can affect other receptors or act with a second messenger to affect other cellular processes 

      • G protein - When activated by neurotransmitter binding, a protein if it detaches and can bind to and influence other proteins in the cell membrane or cytoplasm 

      • Second messenger - a chemical that carries a message to initiate a biochemical process 

        • Can bind to a channel and alter ion flow through membrane 

        • Activated by a neurotransmitter (first messenger) 

        • Example of action 

          • Alter ion flow in a membrane channel 

          • Formation of new ion channels 

          • Production of new proteins through DNA 

      • First messenger - neurotransmitter acts at neurons membrane to bring a signal 

      • Second messenger - a molecule inside the postsynaptic neuron enables the received message from the first messenger to act at different locations within the postsynaptic neuron. 

    • Receptor Subtypes

      • A neurontransmiiter may 

        • Bind to an ionotropic receptor and have an excitatory or inhibitory effect on the target cell. 

        • Bind to a metabotropic receptor and have an inhibitory or excitatory effect on the target cell. 

        • Example Acetylcholine 

          • Activates ionotropic receptors on muscles for excitation 

          • Activates metabotropic receptors on hear to inhibit

• Neurotransmitter systems and behaviour 

  • Somatic and automatic nervous system 

    • Neurotransmission in the SNS 

      • Cholinergic neuron (motor neuron) 

        • Uses ACh as its main neurotransmitter 

        • Excites skeletal muscles to cause contractions 

      • Nicotine ACh receptor (nAChr) 

        • ACh or nicotine binds to this receptor, which leads to its pore opening to allow ion flow and depolarizes its muscle fibre. 

        • The nicotinic receptor pore allows simultaneous efflux of potassium and influx of sodium. 

        • Nicotine (tobacco) activates the nAChr the same way as ACh 

        • Nicotinic receptors all over the brain 

    • The ANS 

      • Cholinergic neurons from the CNS control both ANS divisions

        • Sympathetic (fight or flight) 

        • Parasympathetic (rest and digest)

          • Norepinephrine is also involved in the fight or flight response 

  • Each neurotransmitter may interact with a number of receptor subtypes specific to that neurotransmitter 

  • Each subtype has slightly different properties and activities 

    • Located in different parts of the brain or body 

    • Presence or absence of binding sites for other molecules 

    • How long a channel remains open or closed 

    • Ability to interact with intracellular signaling molecules 

  • A single neuron may use one transmitter at one synapse and a different transmitter at another synapse 

  • Different transmitters may coexist in the same terminal or synapses

  • Don’t associate a simple cause and effect relationship between a neurotransmitter and a behaviour

• Four activating systems in the CNS

  • Activating systems 

    • Neural pathways that coordinate brain activity through a single neurotransmitter

    • The cell bodies of neurons that produce the neurotransmitters are located in nuclei in the brainstem 

      • Their axons distribute the neurotransmitter to large areas of the brain 

  • Cholinergic system (frontal cortex, corpus callosum, basal forebrain nuclei, mid-brain nuclei)

    • Active in maintaining attention and waking EEG pattern 

    • Thought to play a role in memory by maintaining neuron excitability 

    • Death of cholinergic neurons and decreases in ACh in the neocortex are thought to be related to alzheimer disease 

  • Dopaminergic system (nigrostratal pathways, substantia nigra, caudate nucleus)

    • cerebellum, ventral tegmentum, nucleus accumbens in basal ganglia = mesolimbic pathways 

      • Dopamine release causes repetition of behaviours 

      • Thought to be the neurotransmitter system most affected by addictive drugs and behavioural addictions 

      • Increases in dopamine activity may be related to schizophrenia

      • Decreases in dopamine activity may be related to deficits of attention 

    • Nigrostriatal pathways 

      • Active in maintaining normal motor behavior 

      • Loss of dopamine is related to muscle refisity and dyskinesia in parkinson division.

  • Noradrenergic system (norepinephrine) 

    • Active in maintaining emotional tone 

    • Decreases in NE activity are thought to be related to depression 

    • Increases in NE are thought to be related to mania 

    • Decreased activity is associated with ADHD (locus coeruleus)

  • Serotonergic system (Raphe Nuclei)

    • Active in maintaining waking eeg pattern 

    • Changes in serotonin activity are related to OCD, tics and schizophrenia 

    • Decreases in serotonin activity are related to depression 

    • Abnormalities in brainstem 5-HT neurons are linked to disorders like sleep apnea and SIDS 

• Hormonal hierarchy 

  • Hypothalamus - produces neurohormones to stimulate the pituitary gland 

  • Pituitary gland - secretes releasing hormones to influence target endocrine glands (adrenal and thyroid glands) 

  • Target endocrine glands - release appropriate hormones into the blood to act on target organs and tissues 

• Classes and functions of hormones 

  • Steroid hormone 

    • Fat-soluble, synthesized from cholesterol

  • Peptide hormone

    • Synthesized by cellular DNA affects the target cells physiological systems 

    • Ex. insulin, growth hormone 

  • Homeostatic hormones 

    • Maintain internal metabolic balance and regulation of physiological systems. 

  • Gondal (sex) hormones 

    • Control of reproductive functions and sexual development and behaviour 

  • Glucocorticoids 

    • Secreted in times of stress 

    • Important protein and carbohydrate metabolism (cortisol) 

• Stress response

  • Activating a stress response

    • Fast acting pathway 

    • Slow acting pathway 

      • Both mobilize the body's resources to confront a stressor and repair stress damage (cortisol) 

  • Ending a stress response  

    • Normal stress responses are brief 

    • Stress responses are turned on and off in the brain 

    • Sapolsky (2005) 

      • The hippocampus can detect cortisol in the blood and instruct the hypothalamus to reduce blood cortisol levels. 

      • Too much cortisol will damage neurons in the hippocampus 

      • There is a vicious cycle involving prolonged stress, cortisol level and hippocampus functioning 

Chapter 5 Key Terms 

• Acetylcholine (ACh) - first neurotransmitter discovered in PNS and CNS; activated skeletal muscles in SNS; either excites or inhibits internal organs in ANS 

• Activating system - neural pathways that coordinate brain activity through a single neurotransmitter; its cell bodies lie in a brainstem nucleus; axons are distributed through a wide CNS region 

• Alzheimer's disease - degenerative brain disorder related to aging; first appears as a progressive memory loss and later develops Into General dementia

• Amino acid hormone -  a chemical messenger derived from amino acid, most commonly tyrosine

• Anabolic steroids = A class of synthetic hormones related to testosterone, which have both anabolic and androgenic effects, AKA anabolic-androgenic steroid 

• Intro grade synaptic transmission - process that occurs when neurotransmitter is released from a presynaptic neuron

•  Auto receptor-self receptor in a neuronal  membrane which responds to the same transmitter release by a neuron; part of negative feedback loop allowing the neuron to adjust its output

• Carbon monoxide  bracket capital c o closing bracket a gaseous neurotransmitter semicolon activates cellular metabolism

•  Chemical synopsis - Junction at which messenger molecules are released when stimulated by action potential

• cholinergic neuron - any neuron that uses ACH as its main transmitter

• dopamine (DA) - amine transmitter involved in coordinating movement, attention, learning and reinforcing behaviors

•  endocannabinoid - molecules made by the body that have a scene similar structures to cannabinoids

•  Exocytosis - active processes where chemical substances carried in vesicles to the outer membrane fuse with it and release their contents 

• G-protein - guanylnucleotide - Binding protein coupled to a metabotropic receptor semicolon when activated binds to other proteins

•  Gamma-aminobutyric acid (GABA) - amino acid neurotransmitter typically opens chloride channels and inhibits neurons

• Gap Junction - area of contact between adjacent cells where Connexin proteins in each cell form connecting hemichannels when open; the hemichannels allow ions to pass between two cells, AKA electrical synapsis

• Glucocorticoid - one group of steroid hormones like cortisol secreted in times of stress; important in protein and carbohydrate metabolism

• Glutamate (Glu)- amino acid neurotransmitter; typically opens the sodium and calcium channels and therefore excites neurons

•  Gondal (sex) hormone - one of a group of hormones like testosterone that control reproductive functions and strongly influence sexual appearance as male or female

• Histamine (H) - neurotransmitter that controls arousal and waking; important in immune response but can cause the constriction of smooth muscles; when activated in allergic reactions, it constricts the airway and contributes to asthma

• Homeostatic hormone - one group of hormones that maintain the internal metabolic balance and regulate the physiological systems and organisms

•  hydrogen sulfide (H2S) - gaseous neurotransmitter; slow cellular metabolism

•  Ionic receptor - embedded membrane proteins that act as a binding site for a neurotransmitter and a pore that regulates ion flow to directly and rapidly change membrane voltage

•  Lipid hormone - AKA eicosanoid; a chemical messenger derived from lipids like arachidonic acid, which acts on membrane receptors

•  Mania - a disordered mental state of extreme excitement

•  Major depression - a mood disorder characterized by prolonged feelings of worthlessness and guilt, disruption of normal eating habits, sleep disturbances, a general slowing of behavior and frequent thoughts of suicide

•  Metabolic receptor - embedded membrane protein within binding site for neurotransmitter linked to G protein; can affect other receptors or act with second messengers to affect other cellular processes including opening a poor

•  Neuromodulator - a neurotransmitter that alters the firing and synaptic characteristics of other neurons, typically over an extended period

•  Neuropeptide - short multifunctional Amino acid fewer than 100 Amino acids; acts as a neurotransmitter and can act as a hormone

• Nitric oxide (NO)- gaseous neurotransmitter; for example, to dilate blood vessels, digestion and activates cellular metabolism

•  Noradrenic neuron - from adrenaline; a neuron containing neuropinephrine 

•  Norepinephrine (NE) - neurotransmitter that accelerates heart rate and mammals; found in the brain and sympathetic division of the ANS

•  Obsessive compulsive disorder (OCD)- behaviour characterized by uncontrollable repetitive thoughts (obsessions) and compulsive repeated actions

•  Parkinson disease - motor system disorder co-related with dopamine loss in the substancia nigra; characterized by tremors, muscular rigidity and reduction in voluntary movement

•  Peptide hormone - chemical messenger translated from cellular PNA, a short string of amino acid

•  postsynaptic membrane - a membrane on the transmitter or input side of a synopsis

•  presynaptic membrane axon terminal membrane on the transmitter or output side of a synopsis

•  quantum plural quanta - the number of neurotransmitter molecules equivalent to the content of a single synaptic vesicle that produces a just observable change in the depolarization of the postsynaptic terminal

•  rate limiting factor - any chemical inlimited supply that restricts the pace at which another chemical can be synthesized

•  Reuptake - inactivation of a neurotransmitter when membrane transporter proteins bring the transmitter back into Presynaptic axon terminal for sure

• schizophrenia - a behavioral disorder characterized by delusions,, hallucinations disorganized speech, blunted emotion, agitation or immobility, and a host of associated symptoms

•  Second messenger - a chemical that initiates a biochemical process when activated by a neurotransmitter (the first messenger)

•  Serotonin (5 - HT) - amine neurotransmitter; helps to regulate mood and aggression appetite and perception of pain and respiration

•  small molecule transmitter - quick acting neurotransmitter synthesized in the axon terminal from products derived from diet

•  Steroid hormone - fat-soluble chemical messenger synthesized from cholesterol

•  storage granule - membranous compartment that holds several vesicles containing a neurotransmitter

•  subunit - protein molecule that assembles with another protein molecule

•  synaptic cleft- Gap separating the neuronal presynaptic membrane from the postsynaptic membrane

•  synaptic vesicle - membranous compartment that includes a fixed number (Quantum) of neurotransmitter molecules

• transmitter activated receptor - protein that has a binding site for a specific neurotransmitter and is embedded in the membrane of a cell 

• Transporter - a protein molecule that pumps substance across a membrane

• tripartite synopsis-a synopsis between a presynaptic neuron a postsynaptic neuron and an astrocyte

• zinc - and ion transmitter that is packaged and stored in vesicles and when released interacts with several receptors