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  Has 5 layers, neurons concentrated 5mm from surface of brain.

  • Layer one is most dorsal, layer 5 is most ventral.

  • Layer 4 receives input mainly from the thalamus, which collects sensory information.

  • Layers 5 and 6 are the output neurons, send information to other parts of the brain.

Neurons

• Neurons are located:

  • Packed a 5mm from cortical surface.

  • Also in brain regions beneath the cortical surface, such as the caudate putamen or striatum.

• Neurons consist of

  • The cell body, or soma.

  • Dendrites (Latin for tree branches), which receive incoming signals from other neurons.

  • Axon hillock, where the soma connects to the axon.

  • Axon, which initiates and propagates action potentials or nerve impulses toward the axon terminals.

    • Ribosomes can be found here, suggesting protein synthesis can take place in an axon

  • Axon terminals, which releases neurotransmitters when activated.

    • Some neurotransmitters can even release two neurotransmitters, but by convention neurons are referred to by their dominant neurotransmitters, for example glutamatergic.

  

• Presynaptic neuron is the term for the first neuron in the sequence, which releases neurotransmitters to the postsynaptic neuron.

  • Terms are relative.

• Each spine on a neuron is a connection to another neuron.

Action potential generation

• At rest, the inside of neurons are more negatively charged than the outside, ranging from around -80 to -50.

  • This is known as hyperpolarisation.

• This hyperpolarisation is maintained by, using transport proteins:

  • Active ion transport - Axon’s actively transport two ions, K+ and Na+, against their concentrations gradients.

    • This is done using sodium-potassium exchange pumps, which are transmembrane proteins that bring K+ ions in and pump out Na+ ions.

    • They have ATPase activity.

    • For every 3 Na+ ions pumped out, only 2 K+ ions are brought in, contributing to the uneven distribution.

  • Facilitated diffusion - The active transport causes a high K+ concentration inside the axon, and a high NA+ concentration in the tissue fluid outside the axon. This leads to facilitated diffusion occurring.

    • However, the membrane is selectively permeable, and is about 100x more permeable to K+ ions.

    • This is due to the channels that diffuse the ions being able to open and close in response to voltages across the membrane (known as voltage-gated), and during resting potential most of the Na+ channels are closed, while only some K+ channels are.

• Hodgkin and Huxley worked discovered the action potential mechanism using squids.

  • Won Nobel prize in Medicine and Physiology in 1963.

  • Discovered this using ion movements.

• 1 - A stimulus generates energy, and once over the -55 mV threshold value the voltage-gated sodium channels in the axon membrane open.

• 2 - Depolarisation: An increasing amount of Na+ ions enter the axon via chemiosmosis, causing the positivity of the axon to increase. This opens more voltage-gated sodium channels, and therefore even more Na+ ions can enter.

  • Depolarisation is the temporary reversal of potential difference, where the inside is less negative than the outside as an action potential is transferred.

• 3 - The potential difference reaches +40 mV from -70 mV, which is the action potential.

  • The Na+ is aiming to reach it’s equilibrium point, but it never does this.

• 4 - Repolarisation: Once this +40 mV is reached, the voltage-gated sodium channels close and K+ ions diffuse out via their concentration gradient. The positivity inside the membrane decreases.

  • These work based on a ball-and-chain mechanism, and are inactivated/ blocked from functioning once membrane is fully depolarised.

• 5 - Hyperpolarisation - More K+ ions diffuse out than Na+ diffuse in, causing the potential difference to be more negative than resting potential.

  • The sodium-potassium exchange pump pumps K+ ions back in and Na+ ions back out, restoring the resting potential.

  • At the original action potential site, sodium channels are inactivated and unable to reopen until resting potential is re-established.

    • This prevents a new action potential from being triggered, therefore preventing the action potential from moving backwards in the axon, keeping in in one direction.

    • This is the absolute refractory period.

  • For the next 5-10 ms, strong enough impulses can cause an action potential to start.

    • This occurs while sodium-potassium transfer pumps are still restoring resting potential.

    • This is known as the relative refractory period.

• There are also graded potentials which disobey the ‘all or nothing‘ rule by increasing on size based on stimulus.

  • These can be found in the retina.

Signal transmission

• The all or nothing law states that:

  • If stimulus intensity does not reach the threshold value, no action potential is generated.

  • If initiated, however, it will always be the same size of and always remains this size as no energy is lost in transmission.

    • Increases in stimulus intensity don’t increase action potential, but increase the frequency of action potential generation.

  • This is done to allow neurons to act as a filter for minor stimuli, therefore not overloading the brain with nervous impulses.

• There are types of summation, when action potentials are built up to:

  • Temporal summation - Where multiple action potentials are passed on, building up to reach the threshold value.

  • Spatial summation - Several pre-synaptic neurons contribute to the same post-synaptic neuron, building up to an action potential.

  • These can occur simultaneously.

Limiting factors

• Speed of conduction:

  • Myelination - Insulates the axon, therefore increasing transmission.

    • Myelinated nerve fibres only depolarise at areas of low resistance, which is the nodes of Ranvier, which is where the voltage-gated ion channels occur. This is therefore where Na+ ions enter.

    • This leads the action potential to seemingly jump from node to node, which is known as saltatory conduction.

    • This also prevents ions from leaking out of the membrane, as myelin traps them in.

    • It is rapid due to nodes of Ranvier being 1 mm apart.

    • Multiple sclerosis is a demyelinating disorder.

  • Axon diameter - Bigger axons have less resistance on the inside, allowing for faster ion movement.

• Dendrites are limited by:

  • If a charge is injected, charge is lost easily due to leakiness.

    • The length constant is the distance over which voltage decreases by 63%

  • Time constant - Time for the voltage to increase or decrease by 63%.

Synapses

• There are two types of synapse:

  • Electrical - these neurons directly touch and have what is referred to as openable windows.

    • They are attached by gap junctions, and can share transmission via passing on of sodium ions.

    • These can be found in the retina.

    • Extremely fast, but allow for no modulation or complex transmission.

  • Chemical - the gap is 20 nm, which is too large for the impulse to jump.

    • It is the majority of synapses.

    • Axon branches lie close to dendrites of other neurons without touching, and the impulse is instead transmitted via neurotransmitters.

    • These chemicals diffuse across the synaptic cleft, from the pre-synaptic membrane of one neuron to the post-synaptic neuron of an adjacent neuron, which transmits the impulse.

    • Slower, but allow for modulation and more complex communication.

Chemical synapses

• This has 4 steps:

  • When an action potential reaches the pre-synaptic end bulb, the membrane permeability is altered, which opens voltage-dependent calcium channels.

    • These diffuse into the end of the bulb, down a concentration gradient from the synaptic cleft.

  • This influx of Ca+ causes snare proteins which attach synaptic vesicles in the pre-synaptic bulb to the membrane to activate, bringing vesicles closer until fusion occurs.

    • This releases the neurotransmitter via exocytosis, into the synaptic cleft.

  • This then diffuses across the cleft to bind to a receptor - an intrinsic protein - in the post-synaptic membrane.

  • This causes the receptor protein to change shape, which opens a channel to allow Na+ ions to diffuse in down a concentration gradient, from the synaptic cleft.

    • This depolarises the post-synaptic neuron, and once depolarised above the threshold value an action potential is generated.

• There are two types of receptors:

  • Ligand (neurotransmitter)-gated ion channels/ ionotropic - There are 5 of these on a membrane. They become ion channels that allow, normally sodium, ions to flood in.

    • This depolarises/hyperpolarises the axon.

    • Faster, but less range of actions.

  • G-protein-coupled receptor/ metabotropic: The G protein is activated and can either interact with a separate effector protein to open a separate ion channel or activate secondary messengers.

    • 5% of human genome codes for GPCRs.

    • Incredibly useful as they amplify signals, therefore not much neurotransmitter binding is needed.

      • For example, 1 neurotransmitter can activate secondary and tertiary messengers.

      • Adenine monophosphate (AMP) is an example of a secondary messenger that causes sleepiness, it’s attachment to receptors is blocked by caffeine.

    • Targeted by 45% of industry drugs, such as SSRIs.

    • Slower, but more range of actions.

• There are multiple methods to stop neurotransmitter action:

  • Active reuptake - A molecule in presynaptic neuron takes in any surplus neurotransmitters.

    • Prozac and other SSRIs blocks these reuptake proteins.

  • Enzymatic degradation - The neurotransmitter is broken down in the cleft.

    • Cholinergic synapses breaks down acetylcholine via acetylcholinesterase, and choline and acetate is recycled back into presynaptic cleft to make more acetylcholine.

Types of neurotransmitters

• Glutamatergic neurons package and transmit glutamate.

  • Glutamate binds to metabotropic receptors.

  • NMDA receptors are widely studied, as they have many special features:

    • They are ligand-gated.

    • They have multiple binding sites for other ions and neurotransmitters than glutamate.

    • At rest, they are blocked by magnesium and ions.

    • They generate EPSPs.

    • They are involved in synaptic plasticity.

• GABA is similar to glutamate as it relies on glial cells to absorb the excess, and this is used to make glutamate.

  • Glutamate is also a precursor for GABA creation.

  • GABA-A has 5 subunits, and GABA binding causes Cl- to move into the neuron.

  • This hyperpolarises the neuron, causing the threshold value to be harder to reach.

    • Uses an ionotropic receptor.

• Dopamine can modulate GABA and glutamate activity.

  

  Dopamine is reabsorbed to lower presence.

  • Degeneration of dopamine neurons in substrata nigra occurs in Parkinson’s.

  • Parkinson's vs normal brain.

• Dopamine is involved in reward learning (Schultz):

  • Reward causes high motivational response, and high amounts of dopamine are released.

  • Once learned, the conditioned stimulus generates dopamine.

  • This is used for predicting rewards.

  • If reward doesn’t come, dopamine activity is reduced.

    • This is what causes prediction errors, which stops dopamine from activating when this stimulus is presented again.

• Dopamine is involved working memory, such as phone numbers.

  • It has been found to be important in short term spatial memory as well as the maintenance and manipulation of information in working memory.

Excitation: inhibition

• Across cerebral cortex, there is a balance between inhibition and excitation.

  • Blue is excitation, red is inhibition.

  • A constant ratio.

• Reduction of GABAergic neurons causes overexcitation, and in post mortem examinations this has been found in SCZ patients.

  • This has also been found in those with ASD.

• When born, GABA is excitatory and remains this way for first 2 weeks of life.

  • This shift is known as the polarity shift.

  • Caused by delayed expression of a transporter protein.

    • Chloride is high inside neurons at birth, and leaves the neuron when GABA attaches, which causes EPSPs.

    • Babies therefore have overactive brains, making seizures more common and less serious.

  • Prenatal infections can prolong this shift, causing issues.

Types of neurons

• Three types of neurons based on locations of synapses:

  • Axosomatic - Occurs if the axon synapses directly with the soma of the postsynaptic neuron.

  • Axodendritic - Occurs when the axon synapses with a dendrite. Most common.

    • Can either inhibit by decreasing postsynaptic membrane potential, or excite by increasing postsynaptic membrane potential.

    • This is known respectively as inhibitory post-synaptic potential (IPSP), or excitatory post-synaptic potential (EPSP).

  • Axoaxonic - Occurs when the axon synapses another axon, often inhibitory.

    • Suppress neurotransmitter release and therefore neurotransmission.

    • This is known as inhibitory postsynaptic potential, or IPSP.

Neuron growth

• It is still not known whether neurotransmitters can be replaced.

  • If this occurs, it must be via stem cells as neurons cannot replicate.

• Some areas of the brain have been found to generate new neurons, such as the hippocampus.

• Neurons are actually pruned in teenage years, and this pruning can be faulted leading to an imbalance in excitation and inhibition.

  • This has been linked to conditions such as ASD and SCZ.

Visual system

• Information conveyed through optic nerve, makes an obligatory synapse in the thalamus, in a region known as the lateral geniculate nucleus.

  • Map is created in the primary visual cortex.

• Special neurons in the primary visual cortex:

  • Simple neurons responds with action potentials when it stimulus moving in one direction.

    • Known as orientation columns, in cerebral cortex that are tuned to direction or orientation of stimuli.

  • Complex neurons are activated when stimuli move in multiple directions.

• Noradrenaline is released from the locus coeruleus when we need to pay attention.

• Schultz discovered that dopamine is released to the frontal lobe and in the basal ganglia when we receive a reward for the first time.

  • With classical conditioning, the conditioned stimulus also releases dopamine, believing there will be a reward.

• Hebb discovered that neurons that fire together have strengthened connections, known as a Hebbian process.

  • One theory is plasticity related proteins (PRP), which are released between neurons to strengthen connections.

  • This is the cause of brain plasticity.