Neurophysiology: Neural Signals

Warning:

Sheila (UK)

Sheila fell in her English garden, cutting her leg. She was taken to local

ER where the wound was cleaned and stitched. But she had to return to

ER 3 days later when her face began to ache and she had difficulty

opening her mouth.

She looked unwell and complained of diffuse pain. Her condition

worsened; 24 hours later she developed jaw stiffness, and severe back

and limb spasms. She was transferred to ICU.

The Big

Picture

Simple Ion Forces Permit Electrical Signaling

Key: Semipermeable membrane

(a screen door)

Diffusion causes ions to flow from

areas of high to low concentration,

along their concentration gradient

Electrostatic pressure causes ions to

flow towards oppositely charged

areas (electrical gradient)

diffusion

The Resting Potential

Neurons are just batteries – they store charge to use when needed

Resting

Potential

Cell membrane is a lipid bilayer

Ion channels are proteins spanning the

membrane so ions can pass in and out

Gated channels – open/close in

response to

• voltage changes

• chemicals

• mechanical action

The neuronal cell membrane repels water; so

membranes need ion channels

Ions are surrounded by water, thus they can

enter the cell only through a channel

Origin of the resting membrane (equilibrium) potential

Neuronal membranes are not

permeable to big negatively

charged proteins

Neurons are selectively

permeable to K+ – it enters and

leaves the cell freely. No other

ion does this

At rest, K+ ions move into the

negative interior of the cell

because of electrostatic

pressure

As K+ ions build up inside the cell,

they also diffuse out along the

concentration gradient

K+ reaches equilibrium when ion

movement out is balanced by ion

movement in

Resting Membrane Potential

Sodium-potassium pump pumps Na+ out

and K+ in to maintain the resting potential

Membrane is slightly permeable to sodium ions

(Na+) so they slowly leak in

Distribution of Ions Inside and Outside a Neuron

Beware cheap Japanese restaurants

Tetrodotoxin blocks nerve action by binding to / blocking pores of

voltage-gated, sodium channels in neuron membranes

Fugu 河豚

A 32-year-old man ate three bites of fugu,

then noticed tingling in his tongue and

right side of his mouth followed by ‘light

feeling’, anxiety, and ‘thoughts of dying’

He felt weak and then collapsed

How is this stored charge used?

Graded Potentials The Action Potential

Axon hillock

Graded potentials - occur in dendrites

As graded potentials spread across membrane, they diminish

- like ripples in a pond

As we inject negative ions, the cell

becomes more negative inside

Graded potentials can transform to action potentials

If membrane reaches threshold it triggers an

action potential; inside the cell becomes

briefly positive

This sweeps down the axon to its end

All-or-none property of the action potential

Analogy: rifle firing

Neuron fires at full amplitude or not at all

(then how do we detect different stimulus strengths?)

Summary

Axon hillock

Action potential starts here

Input

Output

Graded potentials start here

Before the synapse

Presynaptic action

How is an action potential sent down the axon?

Let’s start at the axon hillock

Ionic basis of action potential – step by step

At the axon hillock:

1) Voltage-gated Na+ channels open

in response to initial depolarization

2) More voltage-gated channels open

and more Na+ ions enter until

membrane potential hits +40 mV

3) Voltage-gated Na+ channels close

1

2

3

Resting potential is restored

4) As inside of cell becomes

more positive, voltage-gated

K+ channels open

5) K+ moves out and the resting

potential is restored

At peak, concentration gradient pushing Na+

ions in equals positive charge driving them out

5

4

Refractory periods

Absolute refractory phase (AR)

no more action potentials can be

produced

Relative refractory phase (RR)

only strong stimulation can produce

an action potential

AR RR

Refractory periods

Na+ channel

At rest During AP Absolute refractory

period

The inactivation gate acts like the deadbolt on your apartment

door; it locks during the absolute refractory period

Action potentials are regenerated along the axon

Action potentials travel in one direction because of the refractory

state of the membrane after a depolarization

Conduction Speed

Myelin vs. Unmyelinated axons

Periodic paralysis

Genetic defect in Na+ channel in muscle

At the Synapse

This is how the electrical signal jumps across a gap

Electrical signal

Electrical signal

Chemical signal

Sequence of Transmission at Chemical Synapses

1. Action potential travels down axon to

the axon terminal

2. Voltage-gated calcium channels open so

Ca2+ enters

3. Synaptic vesicles fuse with membrane

and release transmitter into the cleft

Neurotransmitter Vesicles

Sequence of Transmission at Chemical Synapses

4. Transmitter binds to postsynaptic receptor – causes EPSP or IPSP

Excitatory postsynaptic potential (EPSP) –

small local depolarization, pushing cell closer to

threshold

 EPSPs result from Na+ ions entering the cell,

making inside more positive

Inhibitory postsynaptic potential (IPSP) –

small local hyperpolarization, pushing cell away

from threshold

 IPSPs result from Cl- ions entering cell,

making inside more negative

EPSPs and IPSPs are integrated by the axon hillock

Dendrites vote, and the axon hillock decides

Cell body

Axon hillockaxon hillock

Cell body

Sequence of Transmission at Chemical Synapses

5. Transmitter may bind to presynaptic

autoreceptors, decreasing release

6. After binding, neurotransmitter is

inactivated by: degradation or reuptake

Neurotransmitter reuptake

All good things must end

Reuptake:

Neurotransmitter degradation

Breakdown/inactivation of

transmitter by an enzyme

Example:

Acetylcholinesterase (AChE)

breaks down acetylcholine

(Ach)

AchE inhibition (Raid)

Electrical synapses exist

Ions flow directly through large

channels into adjacent

neurons, with no time delay

Golgi was right after all

Benefits: faster, allows

neurons to synchronize,

saves energy

Review

1. Transmitter release from

presynaptic neuron…

2. Opens ion channels (e.g., Na+)

in postsynaptic membrane,

3. Creating depolarizing current

(EPSP)…

4. Which passively flows down to

axon hillock to …

5. Trigger action potential that is…

6. Conducted down the axon to

presynaptic terminal…

7. And the cycle continues, from

toe to brain (or brain to toe).

Ligands

Ligands fit receptors to activate or block them: lock-and-key

• Endogenous ligands – neurotransmitters and hormones

• Exogenous ligands – drugs and toxins from outside the body

Acetylcholine

Receptor

ligand

Number of receptors in a neuron varies over time

Receptor number changes rapidly – esp. during

development, with drug use, learning

Up-regulation is an increase in

number of receptors

(nicotine receptors when you

start smoking)

‘sensitization’

Down-regulation is a decrease

(benzodiazepines (Valium, etc.)

down-regulate their receptors)

‘tolerance’

Is there a point to all these neuron facts?

Na+ channel stays

open too long

Normal EEG

Electoencephalogram (EEG): recording of brain activity

A functional test

Tonic-clonic seizure

Seizure Disorders

Generalized convulsions

– abnormal activity

throughout the brain

Characteristic movements

are tonic and clonic

contractions

Seizure is followed by

confusion and sleep

whole-body convulsion

Absence seizure

Seizure Disorders

Absence seizure – brain

waves show generalized

rhythmic activity for only a

few seconds, but hundreds of

times a day

No unusual muscle activity,

except for stopping and

staring

Events during seizure are not

remembered

Focal seizure, Impaired Awareness

Focal seizure, Aware

Focal seizures

Do not involve entire brain

Start in one area

May have jerking of one side

_________

Focal Seizure – normal

awareness

Focal Seizure – impaired

awareness

Abnormal EEG

Myoclonic seizure

Seizure Disorders

Myoclonic (‘muscle jerk’) Seizures

rapid, brief contraction of muscles at the same time on

both sides of the body

Categories of seizures - summary

Partial (focal) onset

Focal seizures (aware)

Focal seizures (awareness impaired)

Generalized onset

Motor

• Myoclonic seizures

• Tonic-clonic seizures (grand-mal)

Nonmotor

• Absence seizures (petit-mal)
Neurophysiology: Neural Signals Warning: Sheila (UK) Sheila fell in her English garden, cutting her leg. She was taken to local ER where the wound was cleaned and stitched. But she had to return to ER 3 days later when her face began to ache and she had difficulty opening her mouth. She looked unwell and complained of diffuse pain. Her condition worsened; 24 hours later she developed jaw stiffness, and severe back and limb spasms. She was transferred to ICU. The Big Picture Simple Ion Forces Permit Electrical Signaling Key: Semipermeable membrane (a screen door) Diffusion causes ions to flow from areas of high to low concentration, along their concentration gradient Electrostatic pressure causes ions to flow towards oppositely charged areas (electrical gradient) diffusion The Resting Potential Neurons are just batteries – they store charge to use when needed Resting Potential Cell membrane is a lipid bilayer Ion channels are proteins spanning the membrane so ions can pass in and out Gated channels – open/close in response to • voltage changes • chemicals • mechanical action The neuronal cell membrane repels water; so membranes need ion channels Ions are surrounded by water, thus they can enter the cell only through a channel Origin of the resting membrane (equilibrium) potential Neuronal membranes are not permeable to big negatively charged proteins Neurons are selectively permeable to K+ – it enters and leaves the cell freely. No other ion does this At rest, K+ ions move into the negative interior of the cell because of electrostatic pressure As K+ ions build up inside the cell, they also diffuse out along the concentration gradient K+ reaches equilibrium when ion movement out is balanced by ion movement in Resting Membrane Potential Sodium-potassium pump pumps Na+ out and K+ in to maintain the resting potential Membrane is slightly permeable to sodium ions (Na+) so they slowly leak in Distribution of Ions Inside and Outside a Neuron Beware cheap Japanese restaurants Tetrodotoxin blocks nerve action by binding to / blocking pores of voltage-gated, sodium channels in neuron membranes Fugu 河豚 A 32-year-old man ate three bites of fugu, then noticed tingling in his tongue and right side of his mouth followed by ‘light feeling’, anxiety, and ‘thoughts of dying’ He felt weak and then collapsed How is this stored charge used? Graded Potentials The Action Potential Axon hillock Graded potentials - occur in dendrites As graded potentials spread across membrane, they diminish - like ripples in a pond As we inject negative ions, the cell becomes more negative inside Graded potentials can transform to action potentials If membrane reaches threshold it triggers an action potential; inside the cell becomes briefly positive This sweeps down the axon to its end All-or-none property of the action potential Analogy: rifle firing Neuron fires at full amplitude or not at all (then how do we detect different stimulus strengths?) Summary Axon hillock Action potential starts here Input Output Graded potentials start here Before the synapse Presynaptic action How is an action potential sent down the axon? Let’s start at the axon hillock Ionic basis of action potential – step by step At the axon hillock: 1) Voltage-gated Na+ channels open in response to initial depolarization 2) More voltage-gated channels open and more Na+ ions enter until membrane potential hits +40 mV 3) Voltage-gated Na+ channels close 1 2 3 Resting potential is restored 4) As inside of cell becomes more positive, voltage-gated K+ channels open 5) K+ moves out and the resting potential is restored At peak, concentration gradient pushing Na+ ions in equals positive charge driving them out 5 4 Refractory periods Absolute refractory phase (AR) no more action potentials can be produced Relative refractory phase (RR) only strong stimulation can produce an action potential AR RR Refractory periods Na+ channel At rest During AP Absolute refractory period The inactivation gate acts like the deadbolt on your apartment door; it locks during the absolute refractory period Action potentials are regenerated along the axon Action potentials travel in one direction because of the refractory state of the membrane after a depolarization Conduction Speed Myelin vs. Unmyelinated axons Periodic paralysis Genetic defect in Na+ channel in muscle At the Synapse This is how the electrical signal jumps across a gap Electrical signal Electrical signal Chemical signal Sequence of Transmission at Chemical Synapses 1. Action potential travels down axon to the axon terminal 2. Voltage-gated calcium channels open so Ca2+ enters 3. Synaptic vesicles fuse with membrane and release transmitter into the cleft Neurotransmitter Vesicles Sequence of Transmission at Chemical Synapses 4. Transmitter binds to postsynaptic receptor – causes EPSP or IPSP Excitatory postsynaptic potential (EPSP) – small local depolarization, pushing cell closer to threshold  EPSPs result from Na+ ions entering the cell, making inside more positive Inhibitory postsynaptic potential (IPSP) – small local hyperpolarization, pushing cell away from threshold  IPSPs result from Cl- ions entering cell, making inside more negative EPSPs and IPSPs are integrated by the axon hillock Dendrites vote, and the axon hillock decides Cell body Axon hillockaxon hillock Cell body Sequence of Transmission at Chemical Synapses 5. Transmitter may bind to presynaptic autoreceptors, decreasing release 6. After binding, neurotransmitter is inactivated by: degradation or reuptake Neurotransmitter reuptake All good things must end Reuptake: Neurotransmitter degradation Breakdown/inactivation of transmitter by an enzyme Example: Acetylcholinesterase (AChE) breaks down acetylcholine (Ach) AchE inhibition (Raid) Electrical synapses exist Ions flow directly through large channels into adjacent neurons, with no time delay Golgi was right after all Benefits: faster, allows neurons to synchronize, saves energy Review 1. Transmitter release from presynaptic neuron… 2. Opens ion channels (e.g., Na+) in postsynaptic membrane, 3. Creating depolarizing current (EPSP)… 4. Which passively flows down to axon hillock to … 5. Trigger action potential that is… 6. Conducted down the axon to presynaptic terminal… 7. And the cycle continues, from toe to brain (or brain to toe). Ligands Ligands fit receptors to activate or block them: lock-and-key • Endogenous ligands – neurotransmitters and hormones • Exogenous ligands – drugs and toxins from outside the body Acetylcholine Receptor ligand Number of receptors in a neuron varies over time Receptor number changes rapidly – esp. during development, with drug use, learning Up-regulation is an increase in number of receptors (nicotine receptors when you start smoking) ‘sensitization’ Down-regulation is a decrease (benzodiazepines (Valium, etc.) down-regulate their receptors) ‘tolerance’ Is there a point to all these neuron facts? Na+ channel stays open too long Normal EEG Electoencephalogram (EEG): recording of brain activity A functional test Tonic-clonic seizure Seizure Disorders Generalized convulsions – abnormal activity throughout the brain Characteristic movements are tonic and clonic contractions Seizure is followed by confusion and sleep whole-body convulsion Absence seizure Seizure Disorders Absence seizure – brain waves show generalized rhythmic activity for only a few seconds, but hundreds of times a day No unusual muscle activity, except for stopping and staring Events during seizure are not remembered Focal seizure, Impaired Awareness Focal seizure, Aware Focal seizures Do not involve entire brain Start in one area May have jerking of one side _________ Focal Seizure – normal awareness Focal Seizure – impaired awareness Abnormal EEG Myoclonic seizure Seizure Disorders Myoclonic (‘muscle jerk’) Seizures rapid, brief contraction of muscles at the same time on both sides of the body Categories of seizures - summary Partial (focal) onset Focal seizures (aware) Focal seizures (awareness impaired) Generalized onset Motor • Myoclonic seizures • Tonic-clonic seizures (grand-mal) Nonmotor • Absence seizures (petit-mal)
Neurotransmitters and Neuropharmacology In 2019: 70,630 drug overdose deaths In the last 12 months: 106,584 drug overdose deaths; most involved opioid US drug overdose deaths Remember Sheila? She has tetanus Tetanospasmin ( ) binds irreversibly to membrane at synapse, blocking release of glycine from axon terminals, causing generalized rigidity Opisthotonus So, we now focus here: Don A retired accountant developed tremor and slowing of movements and was diagnosed with Parkinson disease. His neurologist prescribed levodopa to restore dopamine levels. A couple of years later, motor symptoms start to fluctuate and dopamine receptor agonist ropinirole was added to treatment. A few months later, he developed a strong interest in gambling, first buying lottery tickets and then visiting a casino almost every day. He concealed his gambling, and lost $100,000. He came for consultation 5 weeks ago, and ropinirole was replaced with a monoamine oxidase inhibitor drug. He now reports his interest in gambling has disappeared. Ionotropic Metabotropic Two Receptor Subtypes Two Types of Synapses Direct Ionotropic receptors open when bound by a transmitter (ligand-gated ion channel) Indirect Metabotropic receptors recognize the transmitter but instead activate G-protein Metabotropic receptors in more detail 75% of all drugs act via this receptor type An agonist initiates normal effects of the receptor An antagonist prevents a receptor from being activated by other ligands Drugs Can Affect Synaptic Transmission at Many Steps (AGO = agonist; ANT = antagonist; NT = neurotransmitter) Amino acids make me gagg Glutamate Most common excitatory neurotransmitter in brain and spinal cord Ionotropic receptors Glutamate – metabotropic receptors Glutamate also acts on mGluRs – slower metabotropic receptors Excitotoxicity – neural injury such as stroke or head trauma causes excess release of glutamate, which kills neurons Tre Summary of glutamate’s actions GABA Most common inhibitory neurotransmitter in brain GABAA - ionotropic, produces fast inhibitory effects GABA agonists, like Valium and barbiturates, are potent tranquilizers Summary of GABA’s actions Glycine Major inhibitory neurotransmitter in spinal cord Symptoms appear within 20 minutes, starting with stiffness of the neck, twitching muscles, and feeling of suffocation, then violent convulsions in which the body is arched and the head bent backward. After a minute muscles relax, but a touch or noise causes convulsions to recur, or they recur spontaneously, every few min. Strychnine blocks glycine: Catecholamine Synthesis Rate-limiting Cases 3-year-old identical twins from London had severely low muscle tone, mental retardation, and seizures Biochemical analysis of CSF revealed low activity of tyrosine hydroxylase Dopamine infusions temporarily improved their symptoms How did this help? Two Dopamine Pathways in the Brain Motor control Addiction; learning; schizophrenia Norepinephrine Pathways in the Brain Mood, arousal, sexual behavior Serotonin Pathways in the Brain Sleep, sexual behavior, anxiety Gas neurotransmitters Serves as a retrograde transmitter by diffusing back into presynaptic neuron This synchronizes neighboring neurons Nitric oxide (NO), produced in dendrites, diffuses instantly Acetylcholine Two types of ACh receptors: Nicotinic and Muscarinic Ach receptors Nicotinic – most are  Ionotropic  Excitatory  Peripheral Muscles use nicotinic ACh receptors – paralysis with an antagonist such as curare Muscarinic – most are  Metabotropic  Excitatory or inhibitory  CNS Muscarinic ACh receptors blocked by scopolamine alter cognition Cholinergic Pathways in the Brain Basal forebrain Classes of Neurotransmitters Endogenous Opiates Peptides that bind to opioid receptors and relieve pain (analgesics) Addictive Enkephalins Endorphins Endogenous opiates Dynorphins Endorphins are produced by brain during: exercise, excitement, pain, eating spicy food, love, and orgasm Endogenous opiates produce analgesia and a feeling of well-being Neuromodulatorsindirectly affect transmitter release or receptor response Adenosine is normally released with catecholamines; it inhibits catecholamine release via presynaptic autoreceptors Caffeine blocks effect of adenosine Caffeine thus  catecholamine release, causing arousal FYI: Mayo Clinic Proceed Aug. 2013: A study of 40,000 individuals found greater than 50% increased mortality in young men and women who drank more than 4 cups a day But moderate coffee intake LOWERS all-cause mortality BMJ 2017; 359: j5024 During wakefulness adenosine builds up, making us sleepy Drug classes and Addiction Dad joke alert Antipsychotic (neuroleptic) drugs Class of drugs to treat schizophrenia and aggressive behavior Typical neuroleptics are dopamine (D2) antagonists Antidepressants Monoamine oxidase inhibitors (MAOIs) prevent breakdown of monoamines at the synapse Accumulation of monoamines is the major action of antidepressants Antidepressants – Two main modern classes Tricyclics (older) increase norepinephrine and serotonin at synapses by blocking their reuptake into presynaptic axon terminals Selective serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft cause serotonin to accumulate in synapses, with fewer side effects than tricyclics Anxiolytics, or tranquilizers, reduce nervous system activity Benzodiazepine agonists act on GABAA receptors and enhance inhibitory effects of GABA via Clinflux Allopregnanolone is one endogenous benzodiazepine (‘endozepine’) FYI: Diazepam-binding inhibitor is another (released by astrocytes) Anxiolytics GABAA complex Barbiturates are depressing Block sodium channels on neurons to prevent inflow of sodium ions Barbiturates also increase flow of chloride ions across the neuronal membrane Main medical use now is for anesthesia and epilepsy Q5. How does this drug (in gray) work? A. Increase chloride conductance B. Block chloride channels C. Metabotropic conductance D. Increase sodium conductance Alcohol markedly reduces brain metabolism Alcohol has complex effects on behavior In low doses it is a stimulant, turning off cortical inhibition, reducing social constraints and anxiety At higher doses alcohol is a sedative See! I clasp the cup whose power Yields more wisdom in an hour Than whole years of study give, Vainly seeking how to live. Wine dispenses into air Selfish thoughts, and selfish care. Dost thou know why wine I prize? He who drinks, all ill defies: And can awhile throw off the thrall Of self, the God we worship – all! Omar Khayyam: In Praise of Wine, c.1100 Alcohol’s effects are biphasic Initial stimulant phase followed by a depressant phase Alcohol affects several neurotransmitter systems Inhibits glutamate (excitatory transmitter) at low doses Acts at GABAA receptor to increase binding of GABA (inhibitory transmitter) Effect at glutamate and GABA receptors is sedation, anxiety reduction, muscle relaxation, inhibited cognitive and motor skills Pleasurable effects: stimulation of dopamine, opiate, serotonin, cannabinoid Seizures during alcohol withdrawal are due in part to compensatory increase in glutamate receptors over time (C,D) OJ is a 45 yo man who presents to the ED after a seizure during his first day at a local alcohol/drug rehab center. He was ordered by the court to attend this center after his second drunk driving violation in one year. It has been about 60 hours since his last drink Drink shrinks your brain Alcohol damages cerebellum and frontal lobe Neurons, glia can recover! Fetal alcohol syndrome Small head Opiates Binds to opioid receptors in the brainstem, especially locus coeruleus and the periaqueductal gray Opium and Morphine Opium contains morphine, a potent analgesic What is the origin of heroin? Heroin is named for ‘heroic’ Bayer sought a new Aspirin and Codeine replacement Bayer marketed Heroin as a cure for codeine addiction; it worked Quickly discovered that it metabolizes into morphine Oops. 1898 Case 53 y/o man is found down in the driveway of a house. EMS arrives and on exam he is comatose, and his pupils are tiny (2mm) and barely react to light. An IV is inserted and he is given naloxone Within a minute he arouses and opens his eyes Diagnosis? Fentanyl overdose Drug overdose death rates, by age Marijuana – active ligand is THC (tetrahydrocannabinoid) Brain has cannabinoid receptors that bind anandamide and 2-AG (2 arachidonoyl glycerol) (endocannabinoids) Endocannabinoids: retrograde signaling molecules activate cannabinoid receptors on nearby neurons Lipophilic molecules (can’t store in vesicles), thus exist as part of the membrane Synthesized 'on-demand‘ 3000 BC - Indian medical practice used marijuana to treat appetite loss Marijuana  Impairs short-term memory - hard to learn complex tasks  Slows reaction time - impairing driving skills  Alters judgment/decision making  Alters mood - calmness; in high doses, anxiety, paranoia excites inhibits TL;DR ‘Dave’s not here’ www.youtube.com/watch?v= JFjWROpbD98 CB receptors concentrate in brain areas that influence: pleasure, memory, concentration, time perception, appetite, pain, coordination Nicotine Primary psychoactive and addictive drug in tobacco Nicotine activates nicotinic ACh receptors in ventral tegmental area (DA) In the periphery, it activates muscles and causes twitching Centrally, it increases alertness Nicotine the addictive component Smoking risk is mostly due to other compounds in tobacco, not nicotine Smoking is primary cause of preventable death in the world Kills 493,000 people a year in the US; 4,000,000 worldwide (Heroin kills 4000 people/year in US) Withdrawal symptoms are mild (but 7% increase in workplace accidents on Britain’s ‘No Smoking Day’) Good news, sort of U.S. Smoking Rate Falls To Historic Low Only 5% of each attempt to quit are successful; about the same as for heroin Cocaine Leaves from coca shrub alleviate hunger, enhance endurance and sense of well-being. Not particularly addictive Cocaine, a purified extract: • enters the brain more rapidly, thus highly addictive Cocaine Cocaine-amphetamine-regulated transcript (CART) - peptide involved in pleasure sensations from these drugs and in appetite suppression Cocaine blocks monoamine transporters, especially dopamine – enhancing their effects Amphetamine Amphetamine and methamphetamine are synthetic stimulants - block reuptake and increase release of catecholamines Short-term effects - alertness, euphoria, stamina Long-term abuse leads to sleeplessness, weight loss, schizophrenic symptoms Trending Methamphetamine made from P2P P2P crystal meth made by the ton in Mexico started in 2016 It now accounts for > 95% of meth in US https://www.theatlantic.com/magazine/archive/2021/11/the-new-meth/620174/ Stimulants for ADHD Adderall - dextroamphetamine Ritalin - methylphenidate Brain imaging studies show stimulants increases activity in prefrontal cortex, some subcortical regions, and cerebellum - all centers for executive function Cortico-thalamic networks control inhibitory attentional and impulse control systems and process internal and external stimuli. ADHD medications stimulate these inhibitory networks to function better Hyperactive behavior (fidgeting) stimulates those brain networks to work better. When medication stimulates these networks, the behavior becomes unnecessary FYI LSD resembles serotonin LSD effects are unpredictable. They depend on amount taken, user’s personality, mood, expectations, and surroundings Effects: dilated pupils, increased heart rate and blood pressure, sweating, sleeplessness, and tremors The user may feel different emotions at once or swing from one to another. LSD  delusions and visual illusions Sensations cross over: users can hear colors and see sounds Scientific Reports, 2017; 7: 46421 Serotonin agonist on receptors in visual cortex Phencyclidine (PCP) (angel dust) PCP produces depersonalization and detachment from reality Its many side effects include combativeness and catatonia Glutamate NMDA receptor antagonist Ecstasy (MDMA) Amphetamine analog: MDMA blocks the serotonin reuptake transporter (which removes serotonin from the synapse); thus • MDMA prolongs serotonin signal excessive release of serotonin • MDMA causes oxytocin release • Approved for PTSD treatment Its primary effects in brain are on neurons that use serotonin What's trending in 2024? Synthetic opiates Carfentanil - heroin-like high, but it's 10,000 times more potent than morphine Lethal dose of carfentanil is 20 micrograms, about size of one grain of salt Psychodelics There are currently over 80 active Phase II trials with psychedelic medicines, such as psilocybin, MDMA, ketamine, and ibogaine, for depression, PTSD, addiction, and anxiety. Psilocybin reboots the brain’s default functional networks. The network reestablishes itself when the acute effects of the drug wore off, but small differences from pre-psilocybin scans persist for months Drugs, addiction, and reward Addiction is a chronic, usually relapsing brain disorder that causes compulsive drug use, despite harmful consequences to the addict and to those they are near Although the initial decision to take drugs is voluntary, brain changes that occur over time challenge a person’s self-control and ability to resist intense impulses urging them to take drugs NIDA InfoFacts: Understanding Drug Abuse and Addiction Addiction Tolerance – decreased sensitivity to a drug as a result of taking it Sensitization - increased sensitivity to a drug as a result taking it Physical Dependence – caused by withdrawal symptoms (not the reason people continue to take most drugs) Psychological Dependence – Compulsive and repetitive use, craving Addiction Addiction is:  preoccupation with obtaining a drug  compulsive use of the drug despite adverse consequences  a high chance of relapse after quitting Withdrawal is  a negative reaction when drug use is stopped The basis for addiction is reward Reward is the positive effect any agent has on the user Mesolimbocortical dopamine system is the major reward system Abused drugs increase dopamine in VTA This dopamine system underlies addictive effects of:  Drugs  Food  Sex  Gambling  Warm fuzzies  Reddit upvotes  TicTok likes, etc. A Neural Pathway in Addiction Patient B-19, a 24-year-old man who suffered from depression and obsession-compulsion, was wheeled into the operating room, where electrodes were implanted at 9 sites deep in his brain, and 3 months were allowed to pass. The electrode implanted near the MFB produced pleasure. When B-19 was given free access to the stimulator, he quickly began mashing the button ‘like an 8-year-old playing Donkey Kong. ‘ "During these sessions, B-19 stimulated himself to a point that, behaviorally and introspectively, he was experiencing an almost overwhelming euphoria and elation and had to Median forebrain bundle be disconnected despite his vigorous protests." Why does drug rehab usually fail? Craving In addicts: delta FosB builds up in neurons with each drug exposure, remains activated for years after last drug exposure delta FosB remodels the nucleus accumbens, which perpetuates craving, and high relapse in treated addicts Nucleus accumbens Addiction: Pharmacologic treatment strategies 1) Agonistic treatments mimic the drug’s effects, but are milder • Buprenorphine for opiate addiction • Nicotine patch  Chantix stimulates nicotine receptors more weakly than nicotine does (it’s a partial agonist) Controversy: Is it wrong to give an addict another addictive drug as treatment? ‘I count him braver who overcomes his desires than he who overcomes his enemies’ - Aristotle These replace the drug, which helps with motivation Addiction: Pharmacologic treatment strategies 2) Antagonistic treatments block drug effects • Opiate addiction - naltrexone; Alcohol addiction - baclofen interferes with the dopamine pathway to block craving • Antagonistic treatments don’t replace the drug, so compliance depends on addict’s motivation to quit 3) Aversive treatments cause violent reaction if drug is used • Antabuse for alcohol addiction
Brain Development Esme Brain Weight as a Function of Age Human brain development 3 parts: forebrain, midbrain, hindbrain Forebrain becomes largest part of our brain • Two cerebral hemispheres • Cortex (outer cerebral hemisphere) is wrinkled, which increases surface area A ridge is a gyrus A groove is a sulcus Six stages of CNS development Neurogenesis Migration Differentiation Synaptogenesis Neuronal cell death Synaptic refinement Human brain, 14 weeks Human brain, 18 weeks Our CNS begins as a plate with 3 layers… Ectoderm Mesoderm Endoderm …then rolls up into a tube Ectoderm becomes skin and the neural plate becomes central nervous system Neurulation via Claymation Neurulation in a Zebrafish Case A junior high school student had a seizure at school, and was brought to CMC neurology clinic for evaluation Tuberous sclerosis 1 Neurogenesis Mitosis produces neurons and glial cells in the area next to the central canal microcephaly Failure of mitosis produces microcephaly 2 Cell migration Double-band cortex 3 Differentiation Medulloblastoma in a 7-month-old girl 4 Synaptogenesis Autism 5 Neuronal cell death Fragile X syndrome Apoptosis 6 Synapse Refinement Apoptosis Birth 3 mo 2 yrs the devil is in the details So let’s go through the stages again, with some of those details Think how things might go wrong, because they do Easy enough - but Human brain, 14 weeks Six stages of CNS development Neurogenesis Migration Differentiation Synaptogenesis Neuronal cell death Synaptic refinement 1 Neurogenesis Precursor (stem) cells divide to form ventricular zone Ends by about birth A handful of stem cells survive! Cells will leave ventricular zone to become either neurons or glial cells Zika virus patient with microcephaly Six stages of CNS development Neurogenesis Migration Differentiation Synaptogenesis Neuronal cell death Synaptic refinement Human brain, 14 weeks Human brain, 18 weeks 2 Migration A B C D A. You and your twin sister leave for college! B. Your twin gets cold feet and goes back home C and D. You enjoy college. Your sister becomes a cloner 2 Migration Radial precursor cells Radial cell axon Traveling cell 2 Migration Disorders of migration cause brain malformations Pachygyria Normal Six stages of CNS development Neurogenesis Migration Differentiation Synaptogenesis Neuronal cell death Synaptic refinement Human brain, 14 weeks Human brain, 18 weeks Whew! I made it to my correct spot Now what? I sent my axon out to connect to my neuron neighbor How will I know Mr/Ms Right when I find him/her? Axons are guided by chemicals released by targets Chemoattractants are chemicals that attract certain growth cones Chemorepellants repel growth cones Chemoattractants/ chemorepellants Filopodia and Lamellipodia are outgrowths of growth cones. Both adhere to the local environment and pull the cone in a particular direction Growth cones are sensory-motile organelles at tip of growing axons and dendrites Chemoattractants/repellants act at close or long range Chemoaffinity: Each cell has a genetic chemical identity that guides its development Long-range chemoattraction 3 Differentiation Cells in notochord release protein Sonic hedgehog that directs cells in spinal cord to become motoneurons (gold) Induction is the influence of a set of cells on the fate of nearby cells: Notochord induces developing neurons to become motoneurons notochord motor sensory motor sensory Six stages of CNS development Neurogenesis Migration Differentiation Synaptogenesis Neuronal cell death Synaptic refinement Human brain, 14 weeks Human brain, 18 weeks 4 Synaptogenesis Spines proliferate after birth, and connections are affected by experience Neuron cell body increases in size to support the dendritic tree HPC neuron, 24h old HPC neuron, 3 weeks DNA- blue; microtubules- green; actin- red Six stages of CNS development Neurogenesis Migration Differentiation Synaptogenesis Neuronal cell death Synaptic refinement Human brain, 14 weeks Human brain, 18 weeks 5 Neuronal cell death Diablo binds to inhibitors of apoptosis proteins (IAPs), which normally inhibit caspases Without IAP inhibition, caspases dismantle cell Caspases cut up proteins and DNA Apoptosis starts with Ca++ influx mitochondria to release Diablo Survival of the Fittest Neurons compete for 1) chemicals target cells make (neurotrophic factors) 2) synaptic connections Without enough of both, they die Some mental retardation is due to this 6 Synaptic pruning in normal humans Apoptosis at the dendrite spine level Synaptic pruning failure: Fragile X syndrome Neuron, 2010; 66 (2): 191 Normal Fragile X syndrome Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are produced by targets and taken up by incoming neurons, keeping them alive or helping them regrow after injury Neurotrophic Factors NGF synapse selection Action of Neurotrophic Factors neuron selection Sensitive period of development When experience makes permanent alterations Early (not late) visual deprivation can lead to blindness Amblyopia – early impairment of vision in one eye causes vision loss in that eye Even misalignment of the eyes causes amblyopia Image is blurred because the eyes are slightly misaligned amblyopia Ambylopia Infants with cataracts removed after 6 months have poor facial recognition later In development of visual cortex, axons from each eye compete for synaptic targets Autism Autism – a rising diagnosis Autism – Clinical Features 1 Communication/language Range from no verbal communication to complex skills Two common impairments: Delayed language Echolalia 2 Lack of social interaction Impaired nonverbal behavior Failure to share enjoyment with others Look away; poor eye contact 4 Odd movements Abnormal posture and movements Repeated gestures/mannerisms Autism Features 3 Repetitive behaviors, obsessions and perseveration Self-injurious behavior 5 Predictability Change in routine is stressful May insist on invariant furniture arrangement, food, TV shows Autism occurs in children from gifted to retarded Most have mental retardation – 75% have IQ below 70 Savant syndrome is very rare 6 Intellectual function Autism Features General theory of autism Genes Trends in Cognitive Sciences, September 2011 Tito Neuron, 2014 Autistic brains are hyperconnected locally Dendritic spines on neurons An autistic brain (left) Normal neuron (right) Normal Autistic Are we still talking about vaccines and autism? People who know, aren’t Dozens of studies conclusively show no relation Why does the myth persist? Maybe because: • Autism becomes evident about the time vaccinations are given (but a closer look shows autistic symptoms even before) • Success in controlling measles, mumps, diphtheria, polio has made parents complacent • Celebrity influence: Jenny McCarthy, a former Playboy bunny, advocated on Oprah against vaccines. 24% of parents in U. Michigan survey said they trust celebrities like her for vaccine information Esme has Rett syndrome X-linked progressive autism spectrum disorder with intellectual disability that affects girls in early childhood Seemingly normal development for ~12 months followed by loss of: • purposeful hand use • spoken language and development of: • gait abnormalities • hand stereotypes

Neurons:

• unipolar

  • single extension

  • receptive and output

  • left to right and vice versa

  • travels through axon

    • it's like a cable

  • fast— like the quickest logical pathway

  • speed

  • unprocessed info so if you step on a nail you won't know what kind of knife or nail it is but the pain will go to your brain much faster

• bipolar —- I don't understand the difference between unipolar and bipolar

  • one axon

  • one dendrite

  • usually sensory

• multipolar

  • most common type

  • many inputs

  • only one road out of it

  • much slower

  • 10 thousand entrances for one cell!!

Selective input, unipolar will pass most things along while multipolar will pick and choose

The brain consists of two kinds of cells:

• Neurons

• Glia

  • four kinds

    • astrocytes

      • most numerous glial cells in the brain

      • fill in spaces between neurons for support

      • brings some food like a mother to the neuron from blood vessels that don't directly touch the neurons

      • takes care of the neuron

        • when drunk for example there is an excess of chemicals such as potassium causing the neuron to fire and making a hangover these cells come in like a mom and absorb those like with a mom

      • provide the blood-brain barrier

      • regulate the composition of the extracellular space

      • one-to-one ratio of these cells to neurons and problems such as tumors can occur when the ratio is off like when they choose to replicate

        • holds the brain still for example when you run the brain jiggles and shuts down but this one holds it in place and holds you down

        • it's like a filter of what can and cannot go from the blood to the neurons in the brain

    • oligodendrocytes

      • wraps axons with myelin sheaths inside the brain and spinal cord

      • each one wraps several axons

      • !!!!!!!!!! THERE IS a gap in the myelin sheath called the nodes of Ranvier

      • disease of this one can cause MS

        • autoimmune disease the body attacks the myelin and injures the axon

    • ependymal cells

      • line ventricles, secrete and absorb spinal fluid

    • microglia

      • move around and clean up trash aka dead neurons and glia

      • they scan around for abnormalities such as cancer and they try to kill it

  • without them, the neurons can't survive

  • sometimes when they do their job to kill viruses they also kill the innocent bystander the brain

neurons by function:

• sensory neurons

  • respond to the environment such as light odor touch

• motor neurons

  • contract muscles or glands

• interneurons

  • receive input from and send input to other neurons

    • integration

We have a brain because we decide to move for no other reason

to move or to not to move

The type of neuron we focus on is the Pyramidal cell

Dendritic spines have neural plasticity — their ability to change their shape and make a different kind of neuron

built to be able to change so we can learn

rapidly changes based on experience

immune system is also able to change

synapses—where neurons hook up

• chemical and electrical information

• synaptic cleft

  • the gap

• presynaptic is the energy

• PUT THE DIAGRAM IN

Central nervous system

• brain and spinal cord

• precise control they are both on at the same time

• it's too hard to turn something on from 0 so they are on at the same time

• Sympathetic activation

  • prepares the body for action

  • when you're stressed your whole body turns on even if it's wasteful

• Parasympathetic activation

  • no emergency turns everything off one by one

  • rests and digests

Terms

Medial - MIDDLE

Ipsilateral - SAME SIDE

anterior - HEAD END

proximal - NEAR CENTER

dorsal - TOWARDS BACK

lateral - TOWARD THE SIDE

contralateral - OPPOSITE SIDE

posterior - TAIL END

distal - TOWARD PERIPHERY

ventral - TOWARD THE BELLY

Coronal - Separates brain from front to back— resembles a butterfly

Sagittal (midsagittal) - slices the brain not the midline so you can see what is in each half

Horizontal - separates the brain from top to bottom

Afferent- carries impulses into a region of interest (sensory) GOING IN

Efferent - carries impulses away from a region of interest (motor) GOING OUT

Parts of the brain

White matter - it just axons bunched together white because myelin sheaths cover the axon

Grey matter - composed of clusters of neuron cell bodies that have a dark grey appearance

The very center of the brain is the thalamus

• what does the thalamus do

around the thalamus is the basal ganglia

• motor control

Around that is the limbic systemic

• how you feel and how you react based on those emotions

• emotional memory regulation

Cerebellum

• motor coordination and learning

• BELL balance

• little brain

Midbrain

• reticular formation

  • sleep and arousal

  • body temperature

Meningies

• brain wrappings

• dura mater

  • hard case to protect the brain

• Subdural space

  • Below the dura its empty space

  • has blood vessels

  • Bleeding in subdural space can cause death

• arachnoid membrane

  • immune function

• subarachnoid space

• pia mater

Brain pulsates normally

high brain pressure stops the pulsing

Subdural hematoma

• Bleeding in the subdural

• squishes the brain

• the more it shifts the smaller the chance of survival is

Basal

Cerebral ventricles

• they make cerebrospinal fluid (CSF)

• Surrounds and cushions the brain

• THE ependymal cells make spinal fluid — TEST QUESTION

• CSF is produced inside the brain circulates and exists in the brain following the arrows

Integration zone

the different zones of the neuron

Santiago Ramon credited between neuron doctrine

difference between Golgi and him

grey matter is cell bodies

What kind of cells in the brain

parasympathetic

SEGMENTS WHERE AXON MEMBRANE EXPOSED

materials moving from soma to terminals along microtubules by anterograde transport use what protein

• kinesin

At the axon Hillock

1. voltage-gated Na^+ channels open in response to initial depolarization

   1. -60 to -40 huge influx of Na at -40 where the gates open

2. more voltage-gated channels open and more Na ions enter until membrane potential hits +40 mV

3. voltage-gated Na channels close

4. as the inside of the cell becomes more positive voltage-gated K channels open

5. K moves out and the sting potential is restored

At peak concentration gradient pushing Na ions in equal positive charge drives them out

Refractory periods

• absolute refractory phase (AR)

  • no more action potential can be produced

  • it's like a gun you can't squeeze the trigger more than once to multiple fires

• relative refractory phase (RR)

  • only strong stimulation can produce an action potential

  refractory periods

  Na+ channel

  the inactivation gate acts like the deadbolt on your apartment door; to lock during the absolute refractory period

  axon potentials are regenerated along the axon

  • there is a do or do not

  • like a gun

  • they fire or they don't fire

  Action potentials travel in one direction because of the refractory state of the membrane after depolarization

  Conduction speed

  • myelin vs unmyelinated axons

  • conduction of action potential moves from each Na gate

• fast conduction speeds and conduction speeds they

1. continuous conduction along an unmyelinated axon

2. the myelin makes it jump from the nodes of Ranvier

3. the myelin makes it much faster and saves energy

periodic paralysis

an activation gate does not work properly

genetic defect in Na channel in muscle

causes muscles to be cramped

at the synapses

electrical signal —> chemical signal —> electrical signal

the sequence of transmission at chemical synapses

1. action potential travels down axon to the axon terminal

2. voltage-gated calcium channels open so Ca enters

   1. all of this is just to open the calcium channels

   2. calcium is too powerful it needs to be regulated like a 10k dollar bill

3. synaptic vesicles fuse with the membrane and release the transmitter into the cleft

4. transmitter binds to postsynaptic receptor —- causes EPSP OR IPSP

   • Inhibitory postsynaptic potential

     • small local hyperpolarization, pushing cell away from threshold

       • IPSPs result from Chlorine (Cl) ions entering cell, making inside more negative

         • excitatory postsynaptic potential EPSP

           • small local depolarization, pushing cell closer to threshold

             • EPSPs result from Na ions entering the cell, making inside more positive

     EPSP and IPSPs are integrated by the axon hillock

     • dendrites vote, the axon hillock decides

5. transmitter may bind to presynaptic autoreceptors, decreasing release

6. after binding, neurotransmitter is inactivated by: degradation or reuptake.

neurotransmitter reuptake

all good things must end

reuptake:

Neurotransmitter degradation

breakdown inactivation of transmitter by an enzyme

Example:

Acetylcholinesterase (AChE) breaks down acetylcholine (Ach)

AcHE inhibition (Raid)

Electrical synapses exist

• ions flow directly through large channels into adjacent neurons, with no time delay

• Benefits: faster, allows neurons to synchronize, saves energy

Golgi was right after all

why doesn't the brain connect all the things

each area has a different purpose and needs privacy like you can't connect all rooms in a hotel

the reason your heart has this is because it pumps at exactly the same time — synchronization is good

Ligands

• ligands fit receptors to activate or block them: lock and key

  • endogenous ligands — neurotransmitters and hormones

  • exogenous ligands — drugs and toxins from outside the body

Acetylcholine receptor

number of receptors in a neuron varies over time

• receptor number changes rapidly -esp. during development, with drug use, learning

  • up-regulation is an increase in number of receptors

    • nicotine receptors when you start smoking

    • sensitizaion

    • nicotine is more effective at the start

  • down-regulation is a decrease

    • benzodiazepines (valium, etc) down-regulate their receptors

    • tolerance

    • desensitization

is there a point to all these neuron facts?

• Na Channel stays open too long

• epilepsy

tonic clinic seizure

• stiff as aboard for 20 seconds

• jerking

generalized convulsions

• abnormal activity throughout the brain

• characteristic movements are the tonic and clinic contractions

• seizure is followed by confusion and sleep

Absence seizure —childhood

• petit mal seizure

• Brain waves show generalized rhythmic activity for only a few seconds activity but hundreds of times a day

• no unusual muscle activity, except for stopping and staring

• events during seizures are not remembered

Focal seizure, impaired awareness

• focal because it's in one part of the brain

Focal seizure, aware

• do not involve the entire brain

• stay in one area

• may have jerking on one side

Myoclonic seizure

• rhythmic shrugging

• Brain patterns are rhythmic

• muscle jerk seizures

• rapid brief contraction of muscles at the same time on both sides of the body

Sheila has tetanus

• tetanospasmin binds irreversibly to the membrane at the synapse blocking the release of glycine from axon terminals, causing generalized rigidity

• opisthotonus

so now we focus on the synapse

• two receptor subtypes

  • ionotropic

    • direct

    • key in the lock

  • metabotropic

    • indirect

    • link between where you put the key

    • 75% of all drugs are this receptor type

an agonist initiates the normal effects of the receptor

• constant

• your key opens the door in the same way your mom's key opens the door

antagonist

• prevents a receptor from being activated by other ligands

• competitive is

  • who gets there first

  • it will go in the lock but it just won't turn

• noncompetitive

  • park next door to the parking spot

drugs can affect synaptic transmission at many steps

AGO= antagonist

ANT = antagonist

NT = neurotransmitter

Amino acids

• four

  • Glutamate

    • the most important neurotransmitter in the brain

    • first hit movie

    • glutamate also acts on mGluRs— slower metabotropic receptors

    • excitotoxicity— neural injury such as stroke or head trauma causes excess release of glutamate which kills neurons

    • calcium activates cell suicide

    • more likely to fire

  • Aspartate

  • Glycine

    • major inhibitory neurotransmitter in the spinal cord

    • symptoms appear within 20 minutes, starting with the stiffness of the neck, twitching muscles, and feeling of suffocation, then violent convulsions in which the body is arched and the head bent backward

  • GABA

    • most common inhibitory neurotransmitter in the brain

    • make cells less likely to fire

    • GABA is ionotropic —

      • produces fast inhibitory effects

    • GABA-gated Cl- channel

    • GABA agonists, like valium and barbiturates, are potent tranquilizers

    • GABA drug seizure control — stop the firing

Monoamines

• dopamine

  • main neurotransmitter for movement

  • two dopamine pathways in the brain

    • addiction; learning; schizophrenia

      • mesolimbocortical pathway

    • motor control

      • mesostriatal pathway

  • orgasm quick

• norepinephrine pathways

  • mood, arousal, sexual

  • when you feel good in the day

• serotonin

  • sleep, sexual behavior, anxiety

  • raphe nuclei

    • mesencephalic serotonergic cells project to the thalamus, hypothalamus, basal ganglia, and cortex

soluble gases

Gas neurotransmitters

• nitric oxide produced in dendrites diffuses instantly

• serves as a retrograde transmitter by diffusing back into presynaptic neuron

• talk to your neighbor for the answer to the question

• synchronizes local areas of neighboring neurons

Acetylcholine

• nicotinic receptor

  • most are ionotropic

  • excitatory

  • peripheral

  • muscles use nicotinic ACh receptors — paralysis with an antagonist such as curare

• muscarinic

  • most are metabotropic

  • excitatory or inhibitory

  • CNS

  • muscarinic ACh receptors blocked by scopolamine alter cognition

• Cholinergic pathways in the brain

  • basal forebrain

Endogenous Opiates

• pesticides that bind to opioid receptors and relieve pain (analgesics) additive

• Endogenous opiates

  • enkephalins

  • endorphins

  • dynorphins

• endorphins are produced by the brain during: exercise excitement, pain, eating spicy food, love, orgasm

• endogenous opiates produce analgesia and a feeling of well-being

COFFEE TEST QUESTION

Neuromodulators indirectly affect transmitter release or receptor response

• adenosine is normally released with catecholamines; it inhibits catecholamine release via presynaptic autoreceptors

• caffeine blocks the effect of adenosine

• caffeine thus—catecholamine release causing arousal

• during wakefulness, adenosine builds up making us sleepy

Antipsychotic (neuroleptic) drugs

• class of drugs to treat schizophrenia and aggressive behavior

• typical neuroleptics are dopamine antagonists

antidepressants

• monoamine oxidase inhibitors prevent the breakdown of monoamines at the synapse

• accumulation of monoamines is the major action of antidepressants

• Two main modern classes

  • tricyclics (older) increase norepinephrine and serotonin at synapses by blocking their reuptake into presynaptic axon terminals

anxiolytics — ex: treat anxiety

• reduce nervous system activity

• benzodiazepine agonist act on GABAa Receptors enhance inhibitory effects on GABA via Cl- influx

• allopregnanolone is one endogenous benzodiazepine

• FYI diazepam binding inhibitor is another released by astrocytes

Barbiturates are depressing

• they block sodium channels on neurons to prevent the inflow of sodium ions

• they increase the flow of chloride ions across the neuronal membrane

• very addictive not on the market t

• main medical use now is for anesthesia and epilepsy

Alcohol

complex effects on behavior

• in low doses, it is a stimulant that turns off cortical inhibition

• at higher doses, alcohol is a sedative

• alcohol markedly reduces brain metabolism

the effects are biphasic

• more than one neurotransmitter

• lower doses activate one neurotransmitter

• higher doses will affect another

• the first drink will be dopamine

• then GABA — the most common inhibitory neurotransmitter

• NMDA

• How it goes

  • relaxation

  • disinhibition

  • impaired motor function

  • stupor

  • coma

  • death

• affects several neurotransmitter systems

• inhibits glutamate (Excitatory transmitter) at low doses

• the brain defends itself

• chronic activation of inhibits

• makes more glutamate receptors

• seizures during alcohol withdrawal are due in part to a compensatory increase in glutamate receptors over time

  • inappropriate over-excitation due to the increase in glutamate

  • to fix this get a drug that does the same thing as alcohol over time

  • GABA Agonist

• drinking shrinks your brain

  • if you stop drinking your brain can make a partial recovery

  • it damages your cerebellum and frontal lobe

    • neurons and glia can recover

• fetal alcohol syndrome brain is small brain and small head

  • neurons didn't develop probably

  • highway connection left and right is the corpus callosum

    • some children with FAS don't have the corpus callosum and can't do certain things that require much effort

Opiates

• opiates can depress breathing by changing neurochemical activity in the brain stem where automatic body functions are controlled

• opiates can change the limbic system which controls emotions to increase feelings of pleasure

• opiates can block pain messages transmitted through the spinal cord from the body

• opium and morphine

  • opium contains morphine a potent analgesic

    • binds to opioid receptors in the brainstem, especially locus coeruleus and the periaqueductal gray

Marijuana — active ligand is the UHC

• the brain has cannabinoid receptors that bind anandamide and 2-AG )

• the side effects of cannabis are munchies you get hungry

  • so maybe to cure obesity you need a marijuana antagonist so they won't get hungry and lose weight

    • made people's mood go down

• endocannabinoid: retrograde signaling molecules activate cannabinoid receptors on nearby neurons

• lipophilic molecules (Can’t be stored in vesicles) thus exist as a part of the membranes

• synthesized on demand

• Excites the medulla and hypothalamus; inhibits basal ganglia, cerebellum, cerebral cortex, hippocampus, and spinal cord

nicotine

• the primary psychoactive and addictive drug in tobacco

  • in the periphery, it activates muscles and causes twitches

  • centrally it increases alertness

  • nic activates nicotinic ACh receptors in the ventral tegmental area DA

  • DOPAMINE !!!!! DA, ADDICTION, TEST QUESTION

Cocaine

• leaves from coca shrub alleviate hunger, and enhance endurance and sense of well-being. Not particularly addictive

• cocaine, a purified extract:

  • enters the brain more rapidly, thus highly addictive

• cocaine blocks monoamine transporters especially dopamine enhancing their effects

• cocaine amphetamine-regulated transcript (CART)- peptide involved in pleasure sensations from these drugs and appetite suppression

amphetamine — Adderall??

• amphetamine and methamphetamine are synthetic stimulates — that block reuptake and increase the release of catecholamines

• short-term effects — alertness, euphoria, stamina

• Long-term abuse leads to sleeplessness weight loss and schizophrenic symptoms (is there a way to cure schizophrenia from the opposite of this drug??)

ADHD stimulants

• Adderall dextroamphetamine

• Ritalin — methylphenidate

• Adderall is not addictive

• stimulant works to stimulate the inhibitory part of the brain

LSD resembles serotonin

• LSD effects are unpredictable. They depend on the amount taken, the user’s personality, mood, expectations, and surroundings

• effects:

  • dilated pupils, increased heart rate and blood pressure, sweating, sleeplessness, and tremors

• the user may feel different emotions at once or swing from one to another

• LSD—> delusions and visual illusions

• sensations cross ver: users can hear colors and see sounds

• Micro-dosing is very popular

PCP — phencyclidine

• glutamate NMDA receptor antagonist

• PCP produces depersonalization and detachment from reality its many side effects include combativeness and catatonia

Ecstasy (MDMA)

• amphetamine analog:

  • its primary effects are on neurons that use serotonin

  • MDMA blocks the serotonin reuptake transporter w

Tolerance is a decreased sensitivity to a drug while sensitization is the opposite

physical dependence is caused by withdrawal symptoms (NOT the reason people continue to take most drugs

psychological dependence== compulsive and repetitive

addiction is

• preoccupation with obtaining a drug

• compulsive use of the drug despite adverse consequences

• a high chance of relapse after quitting

The dopmine system

• abused drugs increase dopamine in VTA

• this dopamine system underlies addictive effects:

  • drugs

  • food

  • sex

  • gambling

  • warm fuzzies

  • Reddit upvotes

  • tictok likes

  dopamine signals path

  Frontal lobe

  ^

  |

  nucleus accumbens

  ^

  |

  amygdala

  ^

  |

  ventral tegmental area!!!!!

  electrode entered the nucleus accumbens

  Why does drug rehab usually fail

  • we must rewire the brain back again

  • its easy to wire into addiction but very difficult to wire out

  In addicts:

  delta FosB builds up in neurons with each drug exposure, and remains activated for years after the last drug exposure

  Delta FosB remodels the nucleus

  cell makes structural change

  adds dendritic spines

  so the repeated exposure to the agent like cocaine

  the neuron changes

  it's been two years since our last dose why do I need more fent??? the brain is like yeah bro I been rewired for addiction

  once an alcoholic always an alcoholic

  the brain is still susceptible to the drug

  cannot predict who will have high and low addiction potential you don't know who will get addicted

  Treatments for addiction:

  1. agonistic treatments mimic the drug effects but are milder

     1. buprenorphine for opiate addiction

     2. nicotine patch

        1. Chantix simulates nicotine receptors more weakly than nicotine does (partial agonist)

     3. These replace the drug which helps with motivation

     4. it's a very popular method because it's easy

  2. Antagonistic treatments block drug effects

     1. why spend money on the drug to get high if you won’t get high

     2. if motivation is high enough then it can work

BIOLOGICAL PHYSICAL DEVELOPMENT

starts flat— neuro plate

put the flat plate into a skull so you crumple it and now it smushed

3 parts : forebrain, midbrain, hindbrain

• two hemispheres

• cortex is outer covering

  • the brown stuff

  • cell bodies

    • white stuff is the axons of the cell bodies

• gyrus is brain tissue

• when the midbrain is formed its big enough it doesn't change size same with hind brain

• the forebrain grows like crazy

Six stages of CNS development

• neurogenesis

• migration

• differentiation

• synaptogenesis

• neuronal cell death

• synaptic refinement

CNS begins as a plate with 3 layers …then rolls up into a tube

ectoderm—outside

• ectoderm becomes skin and the neural plate becomes the central nervous system—TEST QUESTION

• NEUROCONTANIOUS BRAIN SKIN DISEASE

• Gets thicker

• folds neural folds

• makes the neural groove

• competition between the brain and skin

  • how do they decide who gets to be brain and skin

  • they fight it out and the winner gets to be brain

mesoderm—middle

endoderm—

look closely at the skin you see the strange acne—he had a seizure

skin malformation

brain malformation caused the seizure

tuberous sclerosis

• overgrowth of white cells

• grey matter kind of disappears

• way too many astrocytes

1- neurogenesis

• so you need bricks for a house you need 100000 but only 1000, so you make a very small house

• microcephaly—they don't have enough neurons

• failure of mitosis

  • 4 months to make as many bricks as possible, exponential growth of bricks with mitosis

• mitosis produces neurons and glial cells in the area next to the central canal

2- cell migration

• the right number of bricks

• 10k wont fit in one truck

• but 5k on two trucks

• one truck breaks down and runs over a steel pole but the other arrives

• the other truck is left behind— dropped off bricks in the wrong spot

• 5k in Waco 5k in Richardson

• cell bodies go to the cortex

• some cells only made it halfway to the cortex not fully to the outside

  • double cortex

  • dyslexia and epilepsy

    • epilepsy is any part of the cortex

3- differentiation

• 10kbricks made and delivered to the right place

• some make up the house, the driveway

• two types of neurons and glial cells

• how do they decide who gets to be neurons and glial cells

• they fight it out the stronger cells get to become neurons

4—synaptogenesis

• change the spacial orientation

• making new synapses

• what could go wrong with this?

  • autism

    • too many connections

    • how to fix?

    • kill the cell with connections?

  • schizo

    • too little connections

• the cells try to connect with everyone they come in contact with

• some connections could be great some could be terrible

• there is no way to tell up front and you take a risk and connect everybody

• the synapse connections you're pretty much done with year one and def done by year 4

5— neuronal cell death

• If you don't like someone you want them to die

• what do you do?

• bully them on social media and convince them to kill themself

• genes or cell death genes have turned on making the cells kill themselves

• program death genes— apoptosis

• most common mental retardation is fragile X syndrome

  • failure of the death to occur

6—synapse refinement

• the rest of your life spent altering the synapses small tweaks

six stages of CNS development

1— neurogenesis

• precursor stem cells divide to form the ventricular zone

• ends by about birth a handful of stem cells survive

• cells will leave the ventricular zone to become either neurons or glial cells

2— migration

• you and your sister grow together now it is time to leave, your sister gets cold feet and doesn't wanna leave but you do

• your sister is left at home and now make as many babies as possible

• you enjoy college and your sister becomes a cloner

• the first cell is made to stretch and hold that position

• what could go wrong?

• go to the wrong spot

• disorders of migration cause brain malformations

3—differentiation

• new at college time to pick a major

• send out axon to connect to my neuron neighbor

• the best strategy is to meet every single person and weeding out the folks who give you bad info

• cells are making connections—a synapse

• Axons are guided by chemicals released by the target

• you are a party animal, and you have two dorms Chester and Smartppl, Smart ppl smell like cookies and Chester smells like weed. You as a party animal are attracted to the weed smell

• chemoattractant are chemicals that attract certain growth cones

• chemorepellants repel growth cones

• growth cones are sensory motile organelles at the top of growing axons and dendrites

• Filppodia and lamellipodia are outgrowths of growth cones both adhere to the local environment and pull the cone in a particular directions

  • Chemoattractants/repellants act at close or long-range

• the notochord job is to secrete chemicals

• Elon Musk standing at the door with 10k bills and he wants you to be an engineer, ill give you 1mil if you become an engineering major

• poor students come in from the other side of the building and don't even get to choose

• physical proximity, and time as well

• sonic the hedgehog

4—synaptogenesis

• cells get bigger and bigger going into adulthood, and continue to get bigger because they make more and more connections, and rather the connections they make get bigger

5—neuronal cell death

• they kill themselves

• how do you decide what friends can be killed

• help you you keep them and if they hurt you they kill you

• diablo itself won't kill anyone but it'll just whisper in the ear and it binds to inhibitors of apoptosis proteins (IAPs) which normally inhibit caspases

• without IAP inhibition caspases dismantle the cell

• caspases cut up proteins and DNA

• apoptosis starts with Ca++ influx —→ mitochondria to release diablo

• Trey’s brain has a weak BCL2 which keeps the devil in

• Survival of the fittest

  • neurons compete for

    • chemicals target cells make (neurotrophic factors)

    • synaptic connections

  • without enough of both, they die

  • some mental retardation is due to this

• someone applies for a job with connections and they get the job, the person with no connections will not get the job

6—Synaptic pruning in normal humans

• apoptosis at the dendrite spine level

• your brain is not trying to remember everything it'll be disastrous if it was

• synaptic pruning failure can result in Fragile X syndrome

• absence of FMRP high levels of MAP1B mRNA translation

Neurotrophic factors

• nerve growth factor and brain-derived neurotrophic factors are produced by targets and taken up by incoming neurons to keep them alive or help them regrow after injury

does cell death occur only for unipolar neurons?

Sensitive period of development

when experience makes permanent alterations

early(not late) visual deprivation can lead to blindness

amblyopia—early impairment of vision in one eye causes vision loss in that eye

even misalignment of the eyes causes amblyopia

the cells are sending different images so they say if one of the vision cells has to be wrong they kill off those :bad: cells

Eyelid problem, it always closed over the right lid,

in the development of the visual cortex axons from each eye compete for synaptic targets

the right eye is very weak and doesn't make the same connections as the left eye and eventually dies off, in competition, the left eye wins

infants with cataracts removed after 6 months have poor facial recognition

communication/language

autism, speech is like meaningless random sound

range from no verbal communication to complex skills

two common impairments

delayed language echolalia — repeat the last thing you said

2 lack of social interaction

• impaired nonverbal behavior

• failure to share the enjoyment with others looking away poor eye contact

3 repetitive behaviors, obsessions, and perseverations

self-injurious behavior

4

odd movements, abnormal posture, and movements repeated gestures and mannerisms

5 predictability

• change in routine is stressful

• may insist on invariant furniture arrangement, food, TV shows

6 intellectual functions

• autism occurs in children from gifted to retarded

• most have mental retardation — 75% have an IQ below 70

• savant syndrome is very rare

autistic brains are hyperconnected local