PSYC 304 - Midterm 2

what happens when a neurotransmitter molecule binds to a poststynaptic receptor?

1. Depolarization of the membrane (excitatory postsynaptic potential) - decrease membrane potential from -70 to -67 mV

2. Hyperpolarize the membrane (inhibitory postsynaptic potential) -increase membrane potential from -70 to -72 mV

excitatory postsynaptic potential

increase likelihood that postsynaptic neuron will fire an action potential (change of voltage on dendrites) when binding to a receptor

what happens when a neurotransmitter molecule binds to a poststynaptic receptor?

1. Depolarization of the membrane (excitatory postsynaptic potential) - decrease membrane potential from -70 to -67 mV

2. Hyperpolarize the membrane (inhibitory postsynaptic potential) -increase membrane potential from -70 to -72 mV

excitatory postsynaptic potential

increase likelihood that postsynaptic neuron will fire an action potential (change of voltage on dendrites) when binding to a receptor

inhibitory postsynaptic potential

decrease likelihood that the postsynaptic neuron will fire an AP

how is the transmission of postsynaptic potentials (PSPs)?

• graded: different sizes

• rapid: travels fast

• decremental: further you get, weaker it becomes

• larger the potential, the more neurotransmitters binding to more receptors

spatial summation

EPSPs arriving at different synapses summed all together

• strongest ones are the ones closes to the axon - need a lot to reach action potential

temporal summation

multiple EPSPS arriving in rapid succession to a neuron - produce a larger EPSP

where do the different potentials generate?

• post-synaptic on dendrites

• action on axons

what needs to happen for action potentials to generate?

• EPSPS reach dotted line of threshold potential (-60 to -55 mV)

• sum of EPSPs and IPSPs that reaches axon initial segment is sufficient enough to depolarize membrane above threshold of excitation (-55 mV)

• only lasts for 1-2 milliseconds

action potential

rapid, brief reversal of polarity at the membrane, from negative to positive

• main method of brain communication

• once you reach the voltage threshold

• all or none

what is the size of an action potential?

Always the same size/shape/ no matter the cells

How do neurons convey magnitude if action potential always looks the same?

through changing frequency/pattern of action potentials

• rate coding: strong signal = more firing

• temporal coding: specific patterns of firing depending on signal

• population coding: strong signal = more neurons used

how does reversing polarity happen?

channels (voltage-gated Na channels) open at voltage threshold. (~55mV)

• when enough EPSPs arrive at the same time, membrane depolarizes enough to reach Na+ channels’ threshold → channels open

voltage-activated ion channels (Na)

1. Depolarization: Na+ coming into cell from gradient force (make cell positive)

2. Cross 0 mv to positive

3. Inactivated state: ball and chain - ball flips up to inside and plugs the channel

4. absolute refractory period: inactivated state to resting potentional = no neurons firing

Which direction does Na+ want to flow in the cell?

wants to go inside the cell → makes cell more positive

what happens in a rapid, huge depolarization?

Na channels open and cell quickly flips from negative to positive - Na+ channels have built-in inactivation gate and shut off automatically after ~1 ms

• Na channels stay inactivated until membrane goes back to resting potential (absolute refractory period)

K+ channels during repolarization

leak channels are always open, but are overwhelmed by forces against Na+ - even more open during AP

• at peak of AP, membrane is positive because cell is very porous for K

which direction does K want to flow during repolarization?

wants to move outside of cell to return it to resting potential

hyperpolarization

slow closing of voltage-gated K+ channels - also contains a refractory period (can have action potential, it just takes more work)

• returns to resting potential

• Na/K pump restores ion balance over time - has no effect on AP

subthreshold stimulation of an axon

excitatory potential is produced, but not sufficient to elicit an AP

suprathreshold stimulation of an axon

excitatory potential is produced that exceeds threshold of excitation and produces an AP that continues undiminished down axon (conduction)

conduction in an unmyelinated axon

Na channels present all along axon - decaying slightly as signal goes, but constantly regenerated by voltage spreading to neighbouring Na channels

• slows the process down slightly

conduction in a myelinated axon

speeds up action potential conduction - insulating substance, lose less energy due to resistance

• only find Na channels at Nodes of Ranvier (gaps between myelin) since AP can move passively by electricity

neurotransmission

end of signal transmission

• terminal boutons with vesicles of neurotransmissions

• AP depolarizes boutons → cause voltage-gated Ca+ channels to open → SNARE complex activates → fuses vesicles with membrane → nts released into synapse

synapse

dendrite membrane has special receptors that fit like lock and key with certain nts

• receptors are often just closed channels that open when they bind with nts

types of potentials

look at image

Berthold, 1849: first experiment on hormones

loss of function experiment - testes removed or reimplanted into abdominal cavity in roosters

• developed normally in both the control and reimplant condition

• restoration of unction with native or donor testes

• make a secretory blood-borne chemical" - brain isn’t only thing involved

hormones

released primarily by glands (sometimes other tissues), primarily into bloodstream (sometimes locally), primarily by animals (sometimes by plants)

exocrine vs. endocrine glands

endocrine glands release hormones

exocrine glands release fluid outside of body

neurocrine function

neural communication - sends electrical signals

endocrine function

releases hormones into blood stream

autocrine function

cells release signals to itself - hormone bind to receptors on the same cell (autoreceptors)

paracrine function

cells release to neigbouring cells (strongest effects on closest cells)

pheromone function

release hormones to other within species to smell

allomone function

one organism releases hormones that other species smell

principles of hormone function

• slow-acting, gradual (effects in hours to weeks)

• changes in intensity/probability

• behaviour and hormone release are reciprocal (cause each other)

• multiplicity of action - differ based on targets and effects

• secretion is pulsatile/rhythmic (occurs at some points in day/month)

• can interact

• need receptors

hypothalamus and hormones

junction between NS and endocrine system

• contains neuroendocrine cells (neurosecretory cells)

• some hormones also nts and some nts can be released by glands and neurons

peptide hormones

mostly outside cell - long strings of amino acids

amine hormones

mostly outside cell - single amino acid

steroid hormone

cross plasma membrane - similar structurally to cholesterol

hormone receptors

GCPRs - typically at the membrane, faster than neurotransmission

• can also be in the cell (intracellular): usually near nucleus, transcription, slower

• steroid hormones are intracellular

radioimmunoassay

measures hormone levels in the blood

autoradiography

measures brain areas affected by hormone

immunohistochemistry

measures horomones by creating antibody for hormone receptor to bind onto

immunocytochemistry

measures hormones by taking a section of tissue to look at receptors

in situ hybridization

measures hormones by taking a complementary strand of RNA and adding a fluorescent tag to see where a hormone receptor is

hormone negative feedback mechanisms

similar to synapse feedback - autocrine feedback, target cell feedback, brain regulation, brain and pituitary regulation, certain hormones for certain things

autocrine feedback

same as autocrine hormone - release hormones that bind on same cell

target cell feedback

target cell's response to a hormone regulates the further release of that hormone by the original cell

brain regulation of hormone

hypothalamus interacts with pituitary glands and generates activity in endocrine cells

pituitary gland

other side of NS/endocrine intersection - has anterior and posterior divisions

posterior pituitary gland

• axons coming thalamus, down infundibulum to capillaried

• releases hormones in capillaries

• no dedicated endocrine cells

• axons relese oxytocin and vasopressin/anti-diuretic hormone (ADH) into blood

oxytocin

stimulates uterine contraceptions; milk letdown reflex

ADH

releases when dehydrated - conserves water through blood vessel constriction

• alcohol inhibits ADH release - why it makes you urinate/more dehydrated

anterior pituitary gland

• neuroendocrine cells terminate at median eminence, release tropic hormones

• hormones carried via hypophyseal portal veins

• tropic hormones cause further hormone releases

adrenal glands

• adrenal cortex (gets hormones) and medulla (gets inputs from CNS)

• cortex releases steroid hormones: glucocorticoids (cortisol), mineralocorticoids (aldosterone), sex steroids (androstenedione) - synthesized on demand via ACTH

• medulla releases amine hormones: epinephrine and norepinephrine

thyroid glands

releases thyroid hormones: thyroxine, triiodothyronine

• amines that act like steroids

• regulate growth and metabolism

• activating effect on NS - needs iodine

pineal glands

releases melatonin

• has photoreceptors (third eye?)

• from sympathetic NS - as melatonin goes up, gonad hormones go down

• not a target of anterior pituitary

gonads

two compartments - one for sex hormone production, one for gamete production

• GnRH and org GNIH (peptide nts)

testes

sertoli cells - sperm

leydig cells - androgens (testosterone)

ovaries

ova - mature gametes

steroid hormones (progestins)

do hormone influence behaviour?

yes, but more notable limitations in humans than in animals

• our cortex often supersedes many older controls for behaviour

does behaviour influence hormones?

• psychosocial dwarfism: stress can cause reduced release of growth hormones

• more exogenous oxytocin in rats makes them touch each other more → less cause social amnesia (don’t remember each other)

• prarie vole types: prarie voles are monogamous (and have high density oxy), meadow voles are not (have low density oxy)

is oxytocin the love molecule?

Not directly - blocking oxytocin increases sociability, but also increases in-group bias and propensity for revenge

do pheromones meidate behaviour?

not in humans

• animals = yes (vomeronasal organ [VNO])

• we do not really have a VNO

• human pheromone effects (sweat studies) often do not replicate

do stress hormones mediate behaviour?

yes - part of stress response is central (in brain)

• dual pathway, HPA axis, sympathetic NS causes immediate changes in behaviour

• hippocampus maintains stress (suffers under chronic stress)

• Schacter and Singer, 1962: placebo stress vitamin caused less stress response

metabotropic receptors (G-protein-coupled receptors [GPCR])

signalling proteins - don’t allow ions to cross membrane directly

• also utilized the ionotropic receptors

• no holes/channels/pores

• metabolism-like effect

• releases G-proteins when nts bind to receptor

• indirectly cause IPSPs and influence rates of transcription/translation

ionotropic receptors (ligand-gated ion channels)

ligand binds to them and then they open

• Excitatory (EPSPs - lets Na or K into cell) and inhibitory (IPSPs - lets chloride into cell)

• common for glutamate

where are nt receptors most commonly located?

postsynaptic side

presynaptic receptors

• autoreceptors

• heteroreceptors

• both influence how many nts are released

autoreceptors

regulates synthesis and release of own nts

• negative feedback system - don’t want neurons to lose too many nts

• inhibit the axon when they identify too many nts being released (not the same as reuptake)

heteroreceptors

receptors that regulate release of different nts - ex. dopamine binds to norepinephrine

• don’t cause nts to be released but influence how much are released

• the “volume” of the “music”

importance of neurotransmitter clean-up?

without it, nt signals would never ed

• types: diffusion, enzymatic degradation, re-uptake

diffusion

nts floating away from synapse - not common unless we want the nts to bind to neighbouring synapses

enzymatic degradation

specialized enzymes that break down nts into metabolites (can’t activate receptors)

• red to green in image

• MAO, COMT

• not the preferred way - energetically wasteful

re-uptake

repackage nts back into vesicles (into axon and then into vesicle) - most common clean up method

• pre-synaptic = PMAT, DAT (dopamine) - back into axon; VMAT = to vesicles

• astrocytes = PMAT, DAT, NET (can make clean-up faster

drug types

• agonists

• antagonists

• also transporter blockers, reuptake inhibitors, enzyme inhibitors

amino acids

• glutamate

• GABA

monoamines

• catecholamines: dopamine, epinephrine, norepinephrine

• indolamines: serotonin

acetylcholine

is its own neurotransmitter system

small-molecule neurotransmitters

• amino acids

• monoamines

• acetylcholine

• unconventional neurotransmitters

large molecule neurotransmitters

neuropeptides → opioid peptides

glutamate

• primary excitatory nt

• used throughout brain

• ionotropic and metabotropic receptors

• some glutamate-targeted drugs inhibit nt receptors because they affect negative feedback mechanisms

• often not a great target for drugs because its all over the brain

• typically antagonist drugs

glutamate receptors

• ionotropic: AMPAS, NMDAR, Kainate receptor

• metabotropic: mGluR 1-8

glutamate drugs

antagonists

• barbiturates

• nitrous oxide

• ketamine

• ethanol

agonists? - can cause seizures when excitation is really high since it excites other nts

GABA (gamma-aminobutyric acid)

primary inhibitor nt, used throughout brain

• GABA-A = ionotropic, GABA-B = metabotropic receptors

• also not a great target for drugs because it is everywhere

• agonist and antagonist drugs

GABA drugs

agonists

• benzodiazepines: therapeutic and recreational, reduces anxiety (Xanax, Ativan)

• ethanol: decreases excitation and increases inhibition (also glutamate agonist)

• chloroform

• ether

antagonists looks similar to glutamate agonist, vice versa

where is dopamine in the brain?

originates from 2 nuclei in tegmentum

• substantia nigra pars compacta

• ventral tegmental area

• projects to some, but not all brain areas; also made in hypothalamus

• tyrosine = dietary precursor → converted to DA by enzymes (first converted to DOPA)

DA receptors

D1R-D54/D1-5

• all metabotropic

• some positive modulatory, some negative

what does DA do?

it is NOT the pleasure/reward molecule

does dopamine facilitate motivation for brain stimulation? (Olds and Milner, 1954)

electrodes accidentally hit the ventral tegmental area going to nucleus accumbens → dopamine axons project from VTA to NAcc

• caused rats to self-stimulate dopamine release by pressing a button constantly until exhaustion

• dopamine must be part of pleasure circuit (valid but incorrect conclusion)

• Actually, humans who did this study reported that the sensation was unpleasant but felt compelled to do it

addiction and dopamine

all addictive drugs directly or indirectly increase dopamine transmission

• amphertamine and cocaine directly do

• heroin, nicotine, oxycodone, ethanol, cannabinoids indirectly do

Nicotine only has mildly euphoric effects for heavy smokers - why is it addicting?

stimulates the VTA to NAcc pathway causing a feeling of obligation towards smoking once you start

dopamine and parkinson’s disease

caused by a loss of neurons in substantia nigra pars compacta (SNc) → dopamine producing region in tegmentum

• causes difficulty initiating voluntary, spontaneous behaviour (feel frozen), trembling of extremeties, shuffling gait, stooped posture

how to treat parkinson’s?

gold standard: administering L-DOPA

• dopamine can’t cross blood-brain barrier but L-DOPA can (subsequently convert L-DOPA to dopamine)

• improvement of motor skills

• don’t see great increase in pleasure levels

• high levels of L-DOPA can cause impulsivity, gambling, high sexuality

• other drugs: D1 agonist

dopamine and schizophrenia

• people with it have too much dopamine - not more likely to experience pleasure (have loss of touch with reality)

• individuals with schizophrenia do not have higher baseline pleasure levels

agonist drug

bind to receptors and activates them

antagonists

drugs that block or reverse receptors by binding to them

treatment of schizophrenia

all initial medications are DA D2R antagonists (gradually build up)

• more effective drugs are as agonists = more effecting at treating schizophrenia

• all illicit drugs can increase risk of schizophrenia/schizophrenic symptoms due to increase in DA

psychostimulants and dopamine

cocaine, crack cocaine, methamphetamines, cathinones

• act on different monoamine systems - esp. DA, NE, 5-HT

• crack has highest increase in dopamine - hard to quit

• cause a wide range of effects (including euphoria)

• high doses can cause temporary psychosis

• not easily distinguishable from positive symptoms of schizophrenia

separating pleasure from motivation (Salamone, 1990s)

t-maze task with rats - can choose two options: low effort, low reward vs. high effort, high reward

1. training by blocking one of 2 arms

2. free choice baseline trial: more likely to choose high effort

3. choice + DA antagonist trial

4. choice + DA antagonist + no barrier trial

give them dopamine antagonists = decrease motivation, but no pleasure or preferences (switch preference to low effort)

• when barrier is removed, they switch back to original preference (still with DA antagonist