PSYCH 202 (Ian's content)

Formation of the neural tube

• Neural crest → PNS

• Neural tube → CNS

• Inside of neural tube → ventricles and spinal canal

• Somites → spinal vertebrae

Anencephaly

Failure to close neural tube on anterior side

Spina bifida

Failure to close neural tube on posterior side

Forebrain

Telencephalon - cerebral hemispheres

Diencephalon → thalamus

Midbrain

Mesencephalon

Hindbrain

Metencephalon

Myelencephalon (medulla)

Development of the cerebral cortex (7 weeks)

Neurons forming 1000s per min

Development of the cerebral cortex (14 weeks)

Hemispheres visible

Development of the cerebral cortex (9 months)

Synaptogenesis and myelination still occurring

8 stages of cortical development

1. Neural proliferation

2. Neural migration

3. Neural differentiation

4. Axonal growth

5. Dendritic growth

6. Synaptogenesis

7. Myelination

8. Neuronal death

Neural proliferation

• Begins with neural tube closure

• New cells born in ventricular zone (glial cells)

Neural proliferation

• 1 mother cell produces ~10,000 daughter cells

• All neurons (100 billion in total) are produced pre-natally

• Rate of proliferation extremely high (1,000/min)

Neural migration

• Non-dividing cells migrate from ventricular zone to marginal zone

• Creates a radial, inside-out pattern of development

• Somal translocation

• Glial-mediated migration

• Neurons also migrate tangentially (across layers)

Neural differentiation

• Migrating cells structurally and functionally immature

• Turn into a useful cell once migrated

Axonal growth

• Occurs at a growth cone

• Some axons extend a distance that is 40,000 times the width of the cell body it is attached to

Dendritic growth

• Occurs at a growth cone

• similar to axonal growth

Synaptogenesis

• linking together of billions of neurons

• 1 neuron makes up to 1000 synapses with other neurons

• Overproliferation (max synapses @ 2 years)

• Therefore pruning

Overproliferation

More synapses than we need, needs pruning

Pruning

Severing unnecessary synapses to become more efficient → @ 16 years, only 50% of original synapses remain

Myelination

Glial cells wrap themselves around axons

• Begins before birth in primary motor and sensory areas

• Continues into adolescence/young adulthood in certain brain regions

Neuronal death

• As many as 50% of neurons created in the first 7 months of life die

• Structure of the brain is a product of sculpting AND growth (our experiences throughout development affect brain structure)

Atypical synapse formation

May be the basis of schizophrenia

Atypical synaptic pruning

May be the basis of ASD

Meninges (skin → cortex)

1. Skin

2. Skull

3. Dura mater

4. Arachnoid mater

5. Subarachnoid space (looks like spiderweb, contains CSF)

6. Pia mater

7. Cerebral cortex

Oligodendrocyte

• Myelinates axons

• Gaps in myelination = nodes of ranvier

Resting membrane potential

• -70mV = resting membrane potential

• -60mV = threshold for firing AP

K+

• K+ concentration high outside = low inside

• 90mV of pressure from concentration gradient (outward)

• 70mV of electrostatic pressure (inward)

• K+ tends to leak out of the cell

Cl-

• High concentration outside of cell

• 70mV of pressure from concentration gradient (inward)

• 70mV of electrostatic pressure (outward)

• Cl- tends to be relatively balanced

Na+

• Na+ in high concentration outside of the cell

• 70mV of electrostatic pressure (inward)

• 50mV of pressure from concentration gradient (inward)

• Tends to leak into the cell

Sodium-Potassium transported

• Pumps 3 Na+ out

• Pumps 2 K+ in

• Opposing natural migration of ions

Ion channels

• Influx of Na+ → depolarisation (EPSP)

• Efflux of K+ → hyperpolarisation (IPSP)

• Influx of Cl- → hyperpolarisation (IPSP)

• Influx of Ca2+ → activation of enzyme

EPSP (excitatory post-synaptic potential)

• Excitatory and GRADED

• closer to -60mV threshold

• Influx of Na+, depolarisation

IPSP (inhibitory post-synaptic potential)

• Inhibitory and GRADED

• further from -60mV threshold

• Efflux of K+

• Influx of Cl-

Spatial summation

• EPSP + EPSP = greater EPSP

• IPSP + IPSP = greater IPSP

• EPSP + IPSP = cancelled out

Temporal summation

• 2 EPSPs in rapid succession = larger EPSP

• 2 IPSPs in rapid succession = larger IPSP

Chemically gated channels

Neurotransmitter binds → opens Na+ channel → depolarisation (EPSPs) → temporal/spatial summation → crosses -60mV threshold → action potential to neighbouring dendrites

Voltage-gated channels

Sodium channels that fire when the axon hillock reaches -60mV (after receiving AP from another neuron) → creates synapse

Action potential

1. Neuron at rest: inside negatively charged compared to outside (polarised)

2. Neuron stimulated: positive charges flow into neuron (depolarised)

3. After some time: positive charges forced back out of neuron (hyperpolarised)

4. Neuron at rest (polarised)

Action potentials - all or nothing

So much Na+ rushes into the neuron that it goes wayy past the threshold (even into positive mV)

Movement of ions during AP

1. Na+ channels open, Na+ flows into the cell

2. K+ channels open, K+ begins to flow out of the cell

3. Na+ channels close, no more Na+ enters the cell

4. K+ continues to leave cell, causes membrane potential to return to resting level

5. K+ channels close, Na+ channels reset

6. extra K+ diffuses away

Nodes of Ranvier

Myelin insulates the action potential → nodes of ranvier jumpstart them before they move onto the next myelinated sections

Synaptic vesicles

Hold neurotransmitters for storage, release when neuron is stimulated

Synapse

Space between axon and dendrite. Action potential stimulates the release of neurotransmitters into the synapse

Receptor sites

Neurotransmitters bind, causing a change in potential

Ionotropic receptors

Ion-channel-linked receptor

• Binding site of channel recieves neurotransmitter

• Ion channel opens, causes ion flow

• Ligand-gated channels

• Lock and key model

FAST/TRANSIENT LOCAL EFFECTS

Metabotropic receptors

G-protein linked receptor

• Neurotransmitter binds → subunit of g-protein breaks off and stimulates synthesis of a second messenger

• Creates cascade of effects

• Transmitter + receptor → G-protein activated → g-protein stimulates ATP to cAMP → cAMP to PkA → phosphorylates K+ channels

Agonist drug

Amplifies transmitter

• Direct agonist → binds competitively to same receptor site as neurotransmitter, higher affinity

• Indirect agonist → binds non-competitively to different receptor site to neurotransmitter

Antagonist

Blocks transmitter

• Direct antagonist → binds competitively to same receptor site as neurotransmitter, higher affinity

• Inverse agonist → binds non-competitively to different receptor site to neurotransmitter

Two mechanisms of neurotransmitter deactivation

1. Reuptake

2. Deactivating enzymes (acetylcholinesterase)

Aceylcholine (Ach)

Excitatory transmitter

• nAChR (nicotinic receptor = ionotropic), opens Na channels = EPSPs

• mAChR (muscarinic receptor = metabotropic), opens K+ channels = IPSPs

Transmitter essential for entire cortex (axons spread across whole brain)

Cholinergic anagonists

Curare (plant)

• Affects neuromuscular junction

• paralysis

Cholinergic agonists

Nicotine

• CNS agonist

• increases attention/arousal

Acetylcholinesterase inhibitors

• Inhibit the cholinesterase enzyme from breaking down Ach, increasing level and duration of the transmitter

• e.g. Physostigmine → benefits in treating Alzheimer’s

Glutamate (Glu)

Excitatory transmitter

• Na+ influx, EPSPs

• Mostly ionotropic, some metabotropic

Schizophrenia related to glutamate irregularity

PCP

Glutamate antagonist → binds to inside of the glutamate receptor, blocks Na+ and Ca2+

• Euphoria

• Psychotic behaviour

Dopamine

Metabotropic → can be either excitatory or inhibitory

• D1 → mediate excitatory neurotransmission

• D2 → mediate inhibitory neurotransmission

Dopaminergic antagonists

• Antipsychotics → control psychosis (also 5HT antagonist, aids social behaviour)

• Risperdal, Zyprexa

Dopaminergic agonists

• Amphetamines

• Cocaine

• meth

• Affect 5HT and other neurotransmitters

Serotonin (5HT)

• Metabotropic OR ionotropic

• Excitatory OR inhibitory

• Ascend into rest of brain

Serotonergic agonists

• SSRIs → Prozac (Fluoxetine), Zoloft

• Block serotonin reuptake = relief of depresssion

Serotonergic antagonists

• Antipsychotics

• Risperdal, zyprexa

GABA (gamma-aminobutyric acid)

Inhibitory transmitter

• opens Cl channels

• IPSPs

GABA(A) → ionotropic

GABA(B) → metabotropic

GABA(A) agonists

• Benzodiazepines (Xanax, valium, librium)

• Reduction of anxiety

• Alcohol, barbiturates

• Baclophen = GABA(B) agonist → slower acting than benzos

GABA(A) antagonists

Bicuculline

• Narcolepsy treatment

• Risk of epileptic seizures → overexcitement with wrong dose (RISKY!!!!)

GABA(A) receptor

• many binding sites

• Many GABA agonists can bind at once

• Therefore dangerous to take many

• Benzos + alcohols = fatal (stacking effects)

RO15-4513

Alcohol antagonist

• no effect of alcohol → proposed treatment for alcoholics

• BUT alcoholics may drink more to counteract the drug so FAIL :(

Ventral tegmental area

• Contains DA neurons

• Beginning of DA reward circuit (VTA → Nacc)

• Stimulated by recreational drugs that involve dopamine and serotonin

Depressants

• Alcohol

• Benzodiazepines

• Barbiturates

• GABA(A) agonists

Nucleus accumbens (Nacc)

• At the bottom of basal ganglia

• under caudate nucleus

• When dopamine is released into Nacc, creates reward feeling → drugs boost artificially

Rat lever dopamine experiment

• Electrode stimulating VTA → Nacc pathway

• Press lever = electrical current

• Become addicted to dopamine reward

• Prefer lever over food and drink

• Drug-seeking behaviour

Stimulants

• Caffeine → 90% of Americans consume caffeine daily

• Nicotine → Most frequently used addictive drug

• Ephedrine → Diet pill, decongestant, bronchodilator

Cocaine

• Most powerful stimulant of natural origin

• Found in plant, documented by Incas

• 5-10% of EM visits are due to cardiac complications related to cocaine abuse

Cocaine Mechanism

Blocks DA reuptake

• Stays in Nacc

Amphetamines

• Dextroamphetamine → synthesized in 1939, abuse first noted in 1940s

• Methamphetamine

• Methylphenidate (Ritalin) → concentrated in frontal lobe

• MDMA/molly

Amphetamine indications

ADHD

• Methamphetamine

• Methylphenidate (Ritalin)

• Pemoline (rare liver failure)

Short-term weight loss

• Methamphetamine

Narcolepsy

• Methylphenidate (Ritalin)

Amphetamine mechanism

• Blocks MAO

• Releases more DA

• Sometimes blocks reuptake

Physiological effects

Dopaminergic cells all over the brain

Low dose:

• Hyperactivity, tachycardia, hypertension, constipation, euphoria, anxiety, irritability

High doses:

• seizure, psychosis, stroke, coma, heart attack, death

Hallucinogens

• Lysergic acid diethylamide (LSD) → synthetic derivative of monoethylamide in morning glory seeds

• Mescaline + Psilocybin (Magic mushrooms)

Hallucinogenic effects

• Amphetamine-like

• Hyper-arousal of CNS

• Pupil dilation, hyperthermia, hypertension

• Visual and auditory hallucinations

• mood swings

• enhanced sensory inputs

Hallucinogenic mechanism

CNS serotonin (and dopamine) agonism

• PCP interacts with dopamine and 5HT

Psychedelic treatment

Hallucinogens increase

• neurite growth

• spine density

• synaptogenesis

• neuroplasticity

Cannabinoids (THC) - Effects

Psychological:

• Euphoria

• uncontrollable laughter

• increased appetite

• relaxation

• decreased memory

• difficulty concentrating

Physiological:

• Tachycardia

• Red eyes

• Tolerance

• bronchitis, cancer

• Amotivational syndrome

THC mechanism

Agonist at CB1 and CB2 receptors (spread through CNS)

• Anandamide → endogenous ligand

• Interact with DA and 5HT

Therapeutic uses

• Cancer (nausea and vomiting relief)

• AIDS: appetite stimulant for wasting syndrome

• Chronic pain

Opiates

• Morphine, codine, heroin

• Found in opium poppy

Opioid mechanism

• bind to opiate receptors (GABAergic neurones for presynaptic inhibition of dopamine release)

• Opiates block GABA release which causes disinhibition of dopamine release (inhibition of inhibition)

Opioid effects

Alleviate pain BUT produce euphoric feeling

• Sleepiness, concentration difficulties, blurriness, poor night vision, slight anxiety

• Nausea, vomiting, constipation, poor appetite

Methamphetamine users vs control

Significant reduction in grey matter towards medial area of the brain

Addiction

• Drug reinforcement (VTA, Nacc)

• Craving (Cingulate gyrus, prefrontal cortex, orbitofrontal cortex)

• Binge (VTA, Nacc, frontal cortex)

• Withdrawal (Anterior cingulate, prefrontal cortex)

Anterior cingulate cortex

• Related to abstinence of opiates

• Increased activation in withdrawal centre even after years of abstinence

Electroencephalography (EEG)

• Raw signal averaged out via ERP

• Clinically useful as distinct brain states show characteristic EEG signal

• Useful in determining focus of epileptic seizure

• Poor temporal resolution

• Excellent temporal resolution

Event-related potentials

Averaging out many trials of EEG to create a summation of brain activity relative to a time period

• cancels out noise

Spectral analysis

• Delta < 4 Hz

• Theta = 4-7 Hz

• Alpha = 8-14 Hz

• Beta = 15-30 Hz

• Gamma = 30-60 Hz

Magnetoencephalography (MEG)

• Measures magnetic fields associated with large populations of synchronously active neurons

• Similar to EEG but measures magnetic rather than electrical activity (less affected by blurring from the skull)

• Can measure synchrony or event-related changes in signal like EEG

• Good for connectivity maps and localization

What does MEG image?

• EEG measures surface of gyri

• MEG measures inside of gyri

Optically pumped magnetometers (OPMs)

• Alkaline vapor, put a beam through it

• Beam makes vapour molecules align

• Magnetic field applied, makes molecules misalign

• Probe beam measures extent of misalignment

Transcranial Magnetic Stimulation (TMS)

• Electrical currents produce magentic fields

• Electrical wires direct magnetic field into brain

• block or stimulate activity

• Coil placed over target region

• Virtual lesions created

Motor-Evoked potentials

stimulate motor cortex, record input

Magnetic Resonance Imaging (MRI)

• subject placed in standing magnetic field

• Radio frequency pulses applied to manipulate H+

• RF pulse off → energy released

• More energy released from some structures vs. others → oxygenated vs. deoxygenated blood

fMRI

• Takes advantage of the fact that neural activity is followed by blood flow in a highly predictable manner

• Altered blood flow alters the RF signal from active brain regions

• Oxygenated = peak in graph, slowly goes downhill as deoxygenated again

• Excellent spatial resolution (3-6mm), relatively poor temporal resolution (on the order of seconds)

BOLD response

Which parts of the brain are active in an fMRI