4. Neurophysiology

Neurophysiology  

 neurons and glia  

- Neurons – reception, conduction, and transmission  

-Glial cells – housekeeping 

 

 Neurons consist of dendrites (antennae), cell body (factory), axon (wire) and terminal boutons (axon ending) 

Diagram on slide 3 😉 

How do neurons communicate?  

 -Action potential – brief electrical impulse  

-Membrane potential (mp)– difference in electrical charge between the inside and the outside of the cell– about -70 mV  

-Neuron is said to be polarized. 

Minus means it is more negative inside the cell than outside the cell. Polarized means there is a difference in charge across the neuronal membrane 

Why is the resting potential of a neuron negative?  

four kinds of ions responsible for mp +  

 -Na+  ions (sodium ions)  

-K+ ions (potassium ions)  

-Cl- ions (chloride ions) 

-Protein – ions  

Forces that help maintain the resting potential of the neuron  

-Diffusion  

-Electrostatic pressure  (+ attract to -, - repel -, + repel +) 

-Resting membrane potential is produced by a balance between the forces of diffusion and electrostatic pressure 

- Despite these forces, no single class of ions is distributed equally on the two sides of the neuronal membrane - WHY? Sodium potassium pump, selective permeability of the neuronal membrane? 

Forces that help maintain the resting potential of the neuron  

-Sodium-potassium transporter (pump) Na + and K + are exchanged (3 Na+ ions leave the cell and 2 K + ions enter the cell) 

Selective permeability of the neuronal membrane– (ion channels)  

-K+ ions and Cl- ions can pass through membrane at rest  

-Na + ions cannot pass through membrane as readily at rest 

-Protein – ions cannot pass through membrane at all 

WHen you put this together you have large anions that cannot leave the cell. You have potassium, when the neuron is at rest, K+ is attracted to the –interior but it wants to move outward because of diffusion (force holding it in and force pushing it out are about equal). Cl- eletrostatic pressure wants it to leave the cell, diffusion wants it to go inside the cell (evens out because the forces are about equal. Na+ Diffusion wants the sodium to go inside the cell and the elecrostatic pressure wants sodium to go inside the cell. 

Action Potentials  

-What would happen if the neuronal membrane suddenly became permeable to Na+ ions?  

-Forces of diffusion and electrostatic pressure would cause Na+ to rush into the cell.  

-This is the basis of an action potential 

-What triggers this change in permeability?  

-Membrane (axon hillock) must reach a threshold of excitation (about –55mV) to initiate an action potential. [depolarization = less negative]  

-Causes voltage-gated (dependent) ion channels to open – first Na +  

-As a result, first Na + and then K + rushes in and then K rushes out – an action potential 

Exciteable tissue because of the charge difference?? 

Opening and Closing of Voltage-Activated Sodium and Potassium Channels 

Rising phase: Sodium channels open, potassium channels open 

At the peak between rising phase and repolarization: Sodium channels close 

Repolarization 

Between repolarization and hyperpolarization: Potassium channels start to close 

Hyperpolarization 

Conduction of nerve impulse: 

- Action potential regenerated at each patch of the membrane down the axon  

-Local anaesthetics (e.g. novocaine) act by blocking sodium channels. 

Therefore tissue isn't exciteable and no impulses sent to the brain 

The Synapse  

-Synapse, presynaptic cell, postsynaptic cell. 

 -Terminal bouton.  

-Synaptic cleft action potential ->calcium channels open, vesicles of chemicals (neurotransmitters), rupture into cleft.  

-Neurotransmitters, postsynaptic receptors, trigger fast-acting or slow-acting changes. 

The Synapse  

The Synapse  

-Presynaptic effects  

-autoreceptors (metabotropic)  

-heteroreceptors (metabotropic) respond to chemicals released by postsynaptic or other neurons -dispose of neurotransmitter from cleft:  

1) reabsorbing it (transporters)  

2) breakdown by enzymes 

In the Na+/K+ pump Sodium is like your ex (SALTY) you want them out of your life (generally). Potassium is like your new lover you want them inside you (K?)  (banana) 

Salty banana  LOL 

Speed and Duration 

-Fast-acting – ion channels [ionotropic]  

-Depolarization = excitatory postsynaptic potential (EPSP)  

-Hyperpolarization = inhibitory postsynaptic potential (IPSP)  

If you open a chloride channel may go from –70 to –75 which moves the neuron further away from generating an action potential....it is therefore inhibitory 

-Action potential depends on algebraic sum of all the inputs to the cell 

Slow……

Slow – releases a chemical inside the cell (second messenger)(e.g. cAMP) [metabotropic]  

-May open ion channels  

-May alter other aspects of cell functioning  

-G-protein sub-unit breaks off to trigger action  

long term changes  

-kinases - longer acting than second messengers  

Permanent changes  

-Transcription factors (e.g. CREB, c-fos) - alter the expression of DNA and can change the production of ion pumps, ion channels and even synapses.  

Neuromodulate

-neuromodulator – Neurotransmitters can cause quick changes because of these metabotropic receptors, neurotransmiters not only infuence whether or not the next neuron fires can also influence how they respond to another neurotransmitter.  

Neuromodulators- Neurotransmitters that can trigger both fast and slow are called neuromodulators. They cahnge (increase/decrease) the response to OTHER neurotransmitters 

not carrying any specific information, but making neurons that will store that particular information? Not carrying information that is happening at that time just saying hey notice what is going on. 

Neurotransmitter is a first messenger, the creation of a second chemical that can be used to do this is the second messenger? 

We think memories involve metabotropic receptors and their influence on the cell eg. Forming more receptors 

Anatomy of Nervous System 

Peripheral Nervous System (PNS) and Central Nervous System (CNS)  

CNS consists of the brain and spinal cord.  

PNS consists of 2 divisions  

-1. somatic nervous system: movement (out) and sensory (in)  

-2. the autonomic nervous system: keeps the internal machinery of the body working properly. 

- A. sympathetic – increases energy supply (e.g. increase in heart and breathing rate)  

-B. parasympathetic – promotes energy conservation (e.g. increase digestion) 

Diagram 

Sympathetic makes connections of cell in the ganglia 

Parasympathetic has more direct connections 

But don't need to worry about that level of detail? 

Spinal cord  

-long tube of neural tissue surrounded by the vertebral column.  

-grey matter in the middle of the column – cell bodies; axons travelling up and down – white matter. 

Anatomy of the brain.  

Hindbrain   

Medulla Oblongata: 

- medulla – breathing, heart rate, vomiting, salivation, coughing, sneezing  

-the respiratory centre sensitive to many drugs (e.g. barbiturates, opiates, and alcohol). Overdose on these durgs usually results ni death because you stop breathing 

-some drugs activate the vomiting centre (includes chemoreceptor trigger zone in the area postrema) to cause nausea and vomiting (e.g. opiates) 

 

Hindbrain is made up of medulla, pons, and the cerebellum 

Locus Coeruleus  

hind-brain nucleus, diffuse projections, NE, mood and arousal  

Cerebellum:  

-25 responsible for initiation and co-ordination of body movements.  

-Practised motor programs are stored here.  

Sprucing up an event so that you're more likely to remember it, this is the system he was referring to (the locus coeruleus) FLashbulb memories 

Midbrain  

Reticular activating system – diffuse projection, important role in activation of the cortex  

-raphe system – diffuse, serotoninergic, plays an important role in the maintenance of sleep (maybe, maybe not). 

Periaqueductal Gray  

-central core of base of brain 

-relays pain messages to cortex.  

-rich in opiate receptors, one of the sites where opiates (e.g. morphine) produce analgesia (relief from pain). 

Tryptophan you get in your diet, it breaks down into seratonin 

There is a very small percentage of the population that lack an enzyme to break tryptophan down and it can cause it to be dangerous 

Ventral Tegmental Area (VTA) 

 - Dopamine neurons make up mesolimbic system (axons make up part of the medial forebrain bundle projecting to various forebrain limbic system areas including the nucleus accumbens) and the mesocortical system projecting to the cortex.  

Many drigs that are addictive seem to activate this systen. So we will be talking about the dopamine theory of addiction. 

Substantia Nigra 

-Dopamine neurons make up nigrastriatal system (projects to basal ganglia) 

Dammage to this system is responsible for Parkinson's disease (underactivity of this section causes parkinsons), will talk more about this  later 

 Forebrain  

Basal Ganglia  

-striatum – caudate nucleus and putamen (input)  

-input from thalamus and cortex  

-Globus palladus– (output to cortex)  

-“Motor loop”  

-coordination of motor control  

-DA input from substantia nigra (nigrastriatal)  

-DA deficiency - Parkinsons Disease  DA means dopamine? 

Substantia projects to the basal ganglia which is trying to decide whether to do the movement or not. 

Limbic system 

-interconnected nuclei under the cortex.  

-control of motivations and emotions (many drugs act here).  

Hypothalamus:  Very critical area of real estate 

-tiny, many nuclei (eating, drinking, sexual behaviour, temperature, fluid balance…)  

-fibre pathway (highway through hypothalamus) called medial forebrain bundle (MFB)  

-animals love to stimulate MFB  

-controls pituitary gland (master endocrine gland) 

 

Pituitary gland releases "releasing hormones" that allow other glands to release their hormones 

Hippocampus, Amygdala and septum, Thalamus

Hippocampus– memory including spatial; may be important for place preference  

Amygdala and septum– emotional significance  

-Amygdala -- fear conditioning, site of action for anti anxiety drugs (e.g. benzodiazepines)  

Thalamus– sensory switchboard all senses except for smell go through the thalamus before being directed through a certain part of the cortex 

 

Diagram 

Cerebral Cortex 

-Immediately beneath the skull and surrounding the rest of the brain.  

-Subserves a number of complex functions such as the integration of sensory information and the production of gross and fine movements.  

-Lobes: frontal (decision making + motor), parietal (body senses), occipital (vision), temporal (auditory + complex vision) 

Brain Development 

-1/4 of adult size by birth and almost to full size by age 1 year.  

-Development is complex, involving cell production and differentiation (before birth), migration, and the formation of axonal connections – all under chemical control!.  

-Drugs that cause malformations in the developing fetus are called teratogens. 

Neurotransmitters 

 

 •Monoamines: 

-Catecholamines 

-Norepinephrine (NE) 

-Dopamine (DA) 

-Epinephrine (E) 

-Indoleamines 

-Serotonin (5-hydroxytryptamine, 5-HT) 

-Imidazoleamine 

-Histamine 

 •Acetylcholine (Ach) first NT discovered, works with muscle fibers, large vertebrates were easy to work with...thats why it was the first discovered 

 •Adenosine 

 •Endocannabinoids mimic our own endo____ system. Certain plants also have the right hape that they can mimic that system 

-2-AG, anandamide 

 •Amino acids 

-Gamma-aminobutyric acid (GABA)  predominant inhibitory nt in the brain, commonly produces IPSPS 

-Glycine 

-Glutamate predominant excitatory nt in the brain, produces EPSPs often 

-Aspartate 

 •Gaseous (NO,CO) 

 •Peptides  short chains of amino acids, made by the nucleus 

-Substance P 

-Opioid substances  

-Enkephalines 

-Endorphins 

-Somatostatin 

Acetylcholine:

  •Motor and other neurons are “cholinergic”  

-Basal forebrain complex (cortical activation and memory)  

-Pontomesencephalotegmental complex (REM sleep)  

•Many insecticides and nerve gases block the activity of acetylcholinesterase (AChE– enzyme to breakdown acetylcholine)  

•Nicotinic and muscarinic receptors  

•Curare – paralysis, Botox – muscle relaxation 

 

Diagram 

Biogenic Monoamines 

• Catecholamines (NE,DA) and the indolamine 5-HT  

•CA's produced from tyrosine tyrosine hydroxylase rate limiting  

•5-HT is converted from tryptophan 

• Enzymes breaking down monoamines are called MAO and COMT. 

 

Some ways drugs effect monoamine transmission (agonist = enhance, antagonist =  weaken):  

-Blocks conversion of tyrosine to L-dopa (AMPT - antagonist)   

- Blocks conversion of tryptophan to 5-HT (PCPA - antagonist) blocks reabsorption of neurotransmitter (cocaine and some antidepressants agonists)   By blocking reuptake, it is staying in the cleft and therefore it is an agonist. Prozac works by blocking the reuptake of seratonin 

-Blocks receptors (antagonists -- antipsychotic drugs block dopamine receptors; LSD blocks some types of 5-HT receptors) 

The Tale of Three Dopamines 

- Mesolimbic (VTA to nucleus accumbens) and mesocortical (VTA to cortex) travels along MFB  

-Over activity of mesocortical contributes to schizophrenia (treat with dopamine antagonists) 

2 predominant dopamine systems, mesolimnic and mesocortical, the third system is the  

- Third dopamine system projects from substantia nigra to the basal ganglia (nigrastriatal system) 

-Damage produces Parkinson’s disease (treat with dopamine agonists like L DOPA)  

-Overactive nigrastriatal system may be responsible for Tourette Syndrome 

Additional info on dopamine

Give L-dopa and now the 20% cells that are left are now creating more dopamine, they can now move and feed themselves because the motor loop is being completed. Dopamine cant be just given because it cnnot cross the BBB, but L-dopa can 

Tourette's syndrome –make spontaneous movements that they are unable to inhibit the signals, give a dopamine antagonist to treat?? 

 

If you give dopamine agonists to a parkinsons patient, what side effects might occur? 

Wouldn't just boost dopamine in the nigra striatal.  It would also effect mesolimbic and mesocortical (can cause psychotic symptoms) 

This also can happen when you give drugs to schizophrenia patients they can develop parkinsons like movement troubles 

Norepinephrine and serotonin

Norepinephrine  

-locus coeruleus  

-arousal and attention  

Serotonin  

-raphe nuclei  

-mood, dreaming, aggression 

GABA and Glutamate

GABA:  

-universal inhibitory neurotransmitter.  

- GABAA receptors opens chloride channel  

-5 subunits, diverse because 15 subunits to choose from  

-antianxiety drugs such as benzodiazepines enhance GABA receptors Glutamate  

- major excitatory (receptors: kainate, AMPA, NMDA)  

-NMDA receptor has many binding sites other than glutamate  

-MG2+ blocks unless membrane significantly depolarized, letting Ca+ through triggering long-term changes (e.g. memory mechanism)  

-PCP, ketamine act here 

Other small molecule neurotransmitters 

-adenosine, 4 metabotropic receptors, wakefulness  

-endocannabinoids (2-AG, anandamide)  

-CB1 receptors are abundant, metabotropic, and involved in retrograde transmission  

-CB2 receptors in the periphery  

-nitric oxide, soluble gas 

It is a retrograde messenger, works in the opposite direction as most other neurotransmitter. It can mock whatever neurotransmitter typically acts on that receptor?It can be excitatory or inhibitory 

 

NO works by diffusing through the cell membrane (no receptors for it) But it can influence a cell once it goes through the membrane. (this is laughing gas!!) 

Peptides:  

-short chain of amino acids  

-enkephalins (about 5 aa’s) and endorphins (16-30 aa’s) are two classes  

-opiates (morphine and heroin) activate their receptors  

-several types of metabotropic receptors  

-analgesic and euphoric 

 

Brain Imaging  

1. Electrical Recordings  

-EEG  

-Recording of electrical activity in the brain, which appears as waves of various widths and heights      Measuring the net result of 1000s of cells, its the average of the electric currents of this area. It is meaningful because certain wave patterns are associated with different states of consciousness. Fast little waves when you are using your brain, large slow waves is when you're not conscious (large because all firing at once then not firing at all, synchronous) , with the small waves they are all firing when they need to (no need for synchrony) 

-ERP  

-EEG waves associated with a particular event or task averaged over a large number of trials  

-Advantage  

-Very good temporal resolution 

EEG wave forms and ERP 

Delta waves in deep sleep or certain kinds of coma 

. Structural Imaging Techniques 

 -Allow for the observation of large abnormalities of the brain, such as damage resulting from strokes and tumors  

-Examples  

- CT: computerized axial tomography  

-X-rays to make 3D image  

-MRI: magnetic resonance imaging  

-A strong magnetic field is passed through the brain and a rotating scanner detects various patterns of electromagnetic changes 

3 Functional Imaging  

- Relies on changes that take place within the brain as a result of increased consumption of glucose or oxygen in active areas of the brain 

-Examples  

-PET: positron emission tomography  

-increased glucose consumption in active brain areas  

-fMRI: functional magnetic resonance imaging  

-Increased oxygen consumption in active brain areas 

2 deoxyglucose, 2DG,  it gets circulated by glucose but it gets stuck in the process of metabolism and it accumulates in cells, but it will accumulate in the cells that are the most active.