Week 4: Neurophysiology, Neurotransmitters, and the Nervous System Flashcards
Neurons role
- Excitable
-Receive sensory information from the outside world
-storing and transmitting that information
-controlling the function of muscles and glands
Glia role
-Play a structural support role
-Also are protective and supply neurons with energy
-Active communicators with neurons via chemical transmission
-More than just support cells
Who first discovered that the nervous system communicated via electrical impulses?
-Italian scientist Luigi Galvani
Who first discovered that the nervous system communicated via electrical impulses?
Italian
scientist Luigi Galvani
Gulvani’s experiments on “animal electricity”. What? + What technology did it inspire?
-Frog legs that were dissected from rest of body. If had copper wire attached to nerves in spinal cord + legs –> sent electrical impulse —> muscles in legs contracted without input of the brain
-Further experiment = frog legs on table when there was lighting/ electrical energy in the air the legs would move
-Galvani’s experiments on “animal electricity” paved the way for the technique of electrophysiology, from which the electrical properties of neurons has been uncovered
-It is now known that neurons communicate by means of all-or-nothing electrical signals called action potentials
Important parts of neuron
-Dendrites (input zone —> connected other neuron or receiving direct sensory input)
-Soma (cell body)
-Axon hillock
-Axon (with Schwann cells/ myelin sheath for insulation —> spaces = nodes of Ranvier)
-Terminals
Generation of action potentials
-Resting potential (-70mv)= due to balance of ions in the extra + intra cellular space
-As the distribution of ions changes within the neuron (i.e. as sodium enters and potassium leaves), the electrical charge changes
-If the neuron is depolarized to around -55 mV (the threshold), the delicate balance that maintains the resting potential breaks down
—> action potential
Hyperpolarization versus depolarization
-Hyperpolarization – when the charge becomes even more negative (even harder to get to threshold)
-Depolarization – when the charge becomes less negative
Action potential course
Conduction of action potentials along the cell
-An action potential is generated at the axon hillock and travels down the cell
-Successive portions of the cell are depolarized and generate their own action potential at the Nodes of Ranvier
Is the strength of the action potentials decreased as it travels down the length of the axon?
Action potentials are non-decremental
—-> They reach the axon terminal with the same strength as which they were initiated near the axon hillock
(occurs because new AP at each node of Ranvier)
The all-or-none law
-Action potentials are always the same
-They do not vary in strength with the strength of the depolarizing stimulus
-Information about stimuli is transmitted by changes in the rate of action potential firing
Rate law
-Information about stimuli is transmitted by changes in the rate of action potential firing (as APs are not graded)
-More rapid APs = stronger stimulus
-Slower rate of firing + more uneven distribution = weak stimulus
Stimulation of the dendrites and cell body
-The dendrites and cell body contain many other proteins and enzymes that modulate cell excitability
—-> Allows for modulation by a number of factors
-Unlike the all-or-none action potential (at the axon hillock), disturbance of the resting potential of dendrites and cell bodies has variable effects i.e. EPSP, IPSP
Post-synaptic potentials (PSPs)
Excitation – opens voltage gated Na+ channels so Na+ comes in
-Depolarization
-Excitatory post-synaptic potential (EPSP)
-Brings the cell closer to firing an action potential
Inhibition – opens voltage gated K+ channels so K+ leaves
-Hyperpolarization
-Inhibitory post-synaptic potential (IPSP)
-More difficult to fire action potentials
Summing of excitation and inhibition
-PSPs (many thousands at a time) are integrated by neurons to determine the rate at which action potentials are generated
Two types of integration:
-Temporal summation
-Spatial summation
Temporal summation
-Signals come in a small time window
—> e.g. 2 EPSPs in rapid succession sum to make depolarisation to threshold more likely
Spatial summation
-Signals from two different inputs arrive at time will summate
How do neurons communicate with one another?
-Communication takes place at the synapse between adjacent neurons
-Voltage-gated calcium channels open in response to AP arriving at terminal of the pre-synaptic action potential
-Calcium causes vesicle contents to be released via exocytosis
-Neurotransmitters in vesicles cross the clef and bind to postsynaptic receptors
-Can have number of effects e.g. open channels to allow sodium in = EPSP.
Types of receptors
-Ionotropic = Neurotransmitter binds to receptor causes opening of ion channel and ions can come into =and out of the cell.
-Metabotropic =
Neurotransmitter binds to receptor but no channel. Instead the attached G-protein (sometimes called second messenger) breaks off and results in a signaling cascade.
Signaling cascade
-Can happen as a result of g-protein coupled metabotropic receptors
= Chain reaction that causes biochemical changes in the cell
-More long lasting/ permanent changes (e.g. changes in gene expression) than what it typically seen as a result of ionotropic receptors
Presynaptic effects of neurotransmitters
Autoreceptors =
-Contain a binding site for neurotransmitters
-Regulate the amount of neurotransmitter released from the presynaptic neuron (can act as a brake)
i.e. if enough neurotransmitter is being released that it is ‘spilling out’ and reaction the auto receptors at ‘the sides’ of the presynapse then this is too much.
Heteroreceptors =
-Like autoreceptors, but respond to chemicals released by the post-synaptic cell
-Regulate the amount of neurotransmitter released from the presynaptic neuron
—–> in other words, a number of ways that release from the presynaptic cell is regulated
Terminating the signal
-Reuptake = taking the neurotransmitter back into the presynaptic neuron for repacking and retransmission. Most common method (as don’t want to waste what has already been made). Accomplished by special proteins called transporters.
-Deactivation = synapse may contain an enzyme which breaks down the neurotransmitter. Parts may be taken back into the presynaptic cell for remanufacturing
Two divisions of the nervous system
Central nervous system – CNS
The brain and spinal cord
Cell bodies called nuclei (grey matter), axons called tracts (white matter)
Peripheral nervous system – PNS
Everything outside the brain and spinal cord
Cell bodies called ganglia, axons called nerves
Somatic nervous system
-Made up of all the sensory nerves from the conscious senses
-Allows us to interact with our environment
-Sensory system as well as motor nerves
-Uses acetylcholine as its primary neurotransmitter
Autonomic nervous system
-Sensory systems we are not usually aware of – blood pressure, functioning of organs, levels of hormones
-Parasympathetic (rest + digest) and sympathetic systems (fight or flight)
Parasympathetic
-In charge most of the time
-Rest and digest system
Keeps the internal functioning of the body running smoothly
Sympathetic
-Connected to the same organs as parasympathetic division
-In times of danger, takes over to help body prepare for sudden expenditures of energy – Fight or flight response —> overactive in those with anxiety
Difference in neurotransmitter use (sympathetic versus parasympathetic)
-Parasympathetic uses acetylcholine
-Sympathetic uses adrenaline
Spinal cord
-Part of the CNS
-Serves as a relay station between sensory and motor neurons and the brain
-Transmits sensory signals (coming via the dorsal horn) to the brain
-Transmits motor signals from the brain to the muscles (exits the spinal cord through the ventral horn)
-interneuron in the spinal cord between sensory and motor inputs
The brain
-Part of the CNS
-Estimated to contain 100 billion neurons
-Each neuron synapses onto 1,000 other neurons
-Each neuron receives an average of 10,000 synapses
Where do drugs act?
Drugs act on neurons and synapses in the brain
Hindbrain
-Medulla oblongata
-Respiratory center
-pons
-Locus coeruleus
-Cerebellum
Medulla oblongata
Involved in proper functioning of the autonomic nervous system
Respiratory centre
-In same area as medulla oblongata (roughly)
-Depressed by several types of drugs (barbiturates, opioids, alcohol)
-Death by overdose and brain damage are caused by depression of this centre
Pons
-Relays motor information from the cortex to the cerebellum
-Drugs can effect motor coordination via this
Locus coeruleus
-Contains majority of norepinephrine neurons in brain
-Projects to higher cortical areas through the medial forebrain bundle
-Associated with depression
Cerebellum
-“Little brain”
-Functions primarily as a component of the motor system
-Damage to the cerebellum impacts coordination, memory, and fine muscle movements
-Also plays a role in certain cognitive tasks and possibly some diseases
-Alcohol impacts this structure (causes coordination problems when drunk)
Midbrain
-Reticular formation
-Periaqueductal gray (PAG)
-Substantia nigra
-Ventral tegmental area (VTA)
Reticular formation
-Descending reticular formation =
Projects axons down through spinal cord
Involved in autonomic responses (breathing and heart rate, swallowing, coughing)
-Ascending reticular formation=
Controls level of arousal, selective attention, and wakefulness
-Raphe nuclei =
Important source of serotonin in the brain (implicated in anxiety and depression)
Periaqueductal gray (PAG)
-Pain sensation and defensive behaviour
-Stimulation of PAG produces an immediate reduction in pain (opioid receptors) –> Analgesia acting on this system to achieve pain killing effects.
-Receives input from the amygdala: “Punishment” system, Animals will work to avoid stimulation of this area.
Substantia nigra
-Sends dopamine projections to the basal ganglia (involved in motor behaviour)
-Deterioration of this pathway associated with Parkinson’s disease – > a lot of work currently been done surrounding this.
Ventral tegmental area (VTA)
-Sends dopamine projections to cortical areas
-Involved in the reward circuit for natural rewards and drugs
Forebrain
-Basal ganglia
-Limbic system (including hippocampus + amygdala)
-Thalamus
-Hypothalamus
-Cortex
Basal ganglia
-Involved in voluntary movement, action selection, motor behaviour and habits, eye movement
-Participates in activity “loops” with the thalamus and cortex (process of fine tuning the information the cortex is receiving so that the best action can be decided on).
-A subdivision, the nucleus accumbens, is part of the reward pathway
—> Critically implicated in drug effects and addiction
Limbic system
-Large network of interconnected nuclei
-Hippocampus: Learning and memory. Involved in conditioned place preference (pair administration of drug with certain location so you associate the effects of the drug with the place)
-Amygdala: Processing of emotions –> Fear, aggression, and anxiety
Thalamus
-Relays sensory information to cortex
-Interacts with the reticular formation to regulate arousal
Hypothalamus
-Primary recipient of limbic input
-Maintains homeostasis: Controls metabolism, sexual motivation, hormonal balance, circadian rhythms, instinctual behaviour, and emotions
Cortex
-Most complex and advanced part of the brain
-Integrates information from other brain areas and “decides” on appropriate behaviour
-Controls behaviour by sending outputs to motor neurons
-Responsible for higher-order cognitive processes
—> PFC – heavily impacted by alcohol . Impacts judgement, impulsivity. Particularly impactful when cortex is not fully developed i.e. in teen/ young adults.
Nervous system development
-Involves an extremely complex cascade of events
—-> easy for things to go wrong
-The developing brain is extremely susceptible to drug effects! and can result in developmental dysfunction.
Many drugs result in developmental dysfunction example…
-Teratogens (“monster makers”) =
—> Deformed babies - thalidomide (prescribed to pregnant women when it’s effect wasn’t understood).
—> Brain malformation and severe mental retardation – fetal alcohol syndrome
= Long term effects of many drugs on neonatal development are unknown
Neurotransmitter criteria
In recent years, over 50 substances have been identified that meet the criteria to be considered neurotransmitters
To be considered a neurotransmitter a substance has to:
1) Be synthesized within the neuron by coexisting enzymes
2) Be released in response to cell depolarization
3) Bind to receptors to alter the functioning of the post-synaptic cell
4) Be removed or deactivated from within the synaptic cleft
Steps in neurotransmitter action…
-Neurotransmitters are synthesized from precursors via the action of enzymes.
-Packaged away in vesicles to keep them separate from the internal workings of cells and allow for transportation to the cell membrane
-Neurotransmitters that leak from the vesicles are destroyed by enzymes
-Action potentials and subsequent Calcium being let into cell signals for the vesicles to fuse with presynaptic membrane and cause release of neurotransmitter into the clef
-Release of neurotransmitter bind with autoreceptors on presynaptic neuron to stop further release
-Released neurotransmitter binds to receptors in post synaptic membrane to have effect
-Released neurotransmitter molecules are deactivated by either reuptake or enzymatic degradation.
-Note: can be excitatory or inhibitory depending on the receptor they bind to
Drugs and neurotransmission
-Drugs can impact the process of neurotransmission at any one of these steps
-Agonistic effects =
Drug effects that facilitate the action of a specific neurotransmitter
-Antagonistic effects =
Drug effects that impede the action of a specific neurotransmitter
note: various ways to do both of these things!
Acetylcholine
-First neurotransmitter to be discovered
-Synthesized by combining acetate and choline/choline acetyltransferase
-Degraded by acetylcholinesterase
-Major cholinergic neurons are in the basal forebrain
-Originally thought to be involved in arousal (not on dynamic scale more invovled with circadian rhythms) , but now known to play a crucial role in cognition
-Many cholinergic cognitive enhancers have been produced
-In the peripheral nervous system, involved in autonomic nervous system
Many chemical weapons impact this system – Nerve agents. Prevent the degradation of ACh at neuromuscular junctions —> lead to death
Acetylcholine two receptor types
-Nicotinic – ion channels
-Muscarinic – g-protein coupled
Monoamines
-Another class of neurotransmitter
-Synthesized from one amino acid
-Broken down by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
-Catecholamines – all synthesized from the precursor tyrosine. Depending on what stage of process can get either =
Dopamine
Norepinephrine
Epinephrine
-Serotonin (5-HT) - synthesized from the precursor tryptophan
Dopamine (DA)
-Synthesis steps:
Tyrosine is converted into dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase
DOPA is converted to DA by DOPA decarboxylase
-Involved in numerous psychological processes (e.g., learning, memory)
-The mesolimbic tract is implicated in drug abuse and addiction, and diseases such as schizophrenia
Norepinephrine (NE)
-Synthesized from DA by dopamine-beta-hydroxylase
-Plays a role in attention, sleep, wakefulness, feeding behaviours, and emotion
Serotonin (5-HT)
-Synthesis steps:
Tryptophan is converted to 5-hydroxytryptophan by tryptophan hydroxylase
5-hydroxytryptophan converted to 5-HT by aromatic amino acid decarboxylase
-Drugs used to treat depression target the reuptake of 5-HT (over simplified etiology for depression is that there is not enough serotonin in the brain –> serotonin reuptake allows for more serotonin at the synapses)
Amino acid transmitters : glutamate
-Glutamate – major excitatory neurotransmitter in the brain
-Synthesized from glutamine by glutaminase
-Widespread projections throughout the brain
-Binds to a number of metabotropic and ionotropic receptors
-Action at NMDA receptors thought to be critical for learning and memory (e.g. LTP)
Amino acid transmitters: Gamma-aminobutyric acid (GABA)
–major inhibitory neurotransmitter in the brain
-Synthesized from glutamate by glutamic acid decarboxylase (GAD)
Also requires vitamin B6
-Broken down by GABA aminotransferase
-Widespread projections throughout the brain
Adenosine
-Associated with wakefulness, alertness
-Action of coffee and tea modulated by blocking adenosine receptors
Endocannabinoids
-Retrograde messengers
-Released from post-synaptic neuron
-Modulate release of other neurotransmitters
-Involved in euphoric and addictive effects of opioid drugs
Peptides
- More than 100 have been identified that act as neurotransmitters, neuromodulators, and neurohormones
-5 general categories
5 general categories of peptides
-Brain-gut peptides e.g. signals to eat or that you are full.
-Pituitary peptides e.g. emotion, arousal, sexual behaviour is modulated
-Hypothalamic peptides
-Opioid peptides
-Miscellaneous peptides
Brain imaging techniques (list)
-Positron emission tomography (PET)
-Single photon emission computed tomography (SPECT)
-Magnetic resonance imaging (MRI)
-Functional magnetic resonance imaging (fMRI)
Collectively allows us to learn about structure and function of a person’s brain
Positron emission tomography (PET) : advantages
-Advantages
Allow researchers to directly measure the brain distribution of various drugs
-Local concentrations of receptor sites can be determined by giving tiny doses of radiotracers that contain pharmacologically inactive amounts of drug
-Can be used to assess competition for binding sites
-Can be used to isolate areas of the brain that are active during a mental activity, such as drug craving
-When used with laboratory animals, can help in preclinical assessment of newly developed drugs
Positron emission tomography (PET) : disadvantages
-Low degree of resolution compared to other methods
Difficult to distinguish between small structures in the brain
-Expensive $$$$$$$$$$ due to the technology required to make a tracer
-Because radioisotopes decay quickly, they must be made on site
—> Need a cyclotron – more $$$
Single photon emission computed tomography
-Similar to PET
Advantages =
-Uses radioisotopes that have much longer half-lives.
-Can measure more long-lasting brain functions.
-Cheaper.
Problems =
-Technically challenging
More prone to error
-Even poorer resolution than PET
MRI
-Protons (contained within water) have magnetic field and interact with the signal from the MRI machine
-Some of the molecules have less energy and get the energy from the signals the MRI machine is sending out in order to spin in the same direction
-From this can figure out where the low energy ones are to produce a structural image of the brain
-Can get really clean/sharp brain images from this technique
-MRI doesn’t show you what is going on chemically in the brain (not like PET which gives you activity )
MRI gives anatomy i.e. shows structural abnormalities
fMRI: how does it work?
-What areas of the brain are active when performing a certain task?
-The active area needs oxygen to function which is transported by blood
-The nearby blood vessels increases the amount of blood heading to that area
-Blood had magnetic properties, when change in oxygen level the magnetic field of the blood alters.
-When there is a lot of red blood cells carrying oxygen the signal detected by the scanner is higher
-In FMRI lots of images of the brain are taken quickly and is processed by a computer to show activity during a task
–> shown as a coloured blob i.e. this area is working hard and using lots of oxygen
fMRI: advantages
-Very high resolution
-Safe-do not require injection of radioisotopes
fMRI: disadvantages
-Expensive $$$$$$$$
-People feel highly anxious inside the magnet (not just a matter of being uncomfortable —> can influence the interpretability of the scan)
-People have to hold perfectly still otherwise mess up the image
-No metal can be present – including in the body
Cannot accommodate some patients
-Changes in BOLD signal can result from daydreaming, boredom, or thinking about something outside of the experiment (Brain activity happens no matter what you are doing so need to design experiment well and control for other processes that could be going on).
-Lag times between signal and task events make it difficult to correlate events with brain signal
-Results are highly subject to distortion by data analytic techniques (researchers make arbitrary threshold decisions to distinguish which parts of the brain are important so can easily misrepresent results).
