PSY 303 FINAL

Entorhinal Cortex

A change in the response of a cell to input: heightened excitability

Caused by repeated high-frequency activity of that input

Super quick inflow of Ca++, but also a quick outflow

Evoked potential that represents the EPSP of a population of neurons

Voltage AND Ligand gated

Glutamate binds and postsynaptic membrane depolarizes (to eject Mg++)

Entry of Ca++ (which activates CaM-KII)

These mice had overexpressed NMDA receptors

They were smarter and learned much faster

produce larger EPSPs

1 - Insertion of AMPA receptors

2 - Increased activity of existing receptors

3 - Increases glutamate release

4 - Synthesis of new proteins

with more AMPA receptors present, the release of glutamate by the terminal buttons causes a larger EPSP and the synapse becomes stronger

calcium dependent enzyme that may have a role in the establishment of LTP

- may help AMPA receptors to move into the postsynaptic membrane

Enzymes can phosphorylate receptors causing them to stay open longer which creates a higher EPSP

occurs through NO which degrades really fast

Retrograde Signaling: NO diffuses across the membrane of the dendritic spine and goes back to the terminal button of the presynaptic cell

Higher glutamate release from the terminal button

membrane depolarization

release of glutamate

activation of NMDA receptors

entry of calcium ions

activation of enzymes (CaM-KII)

and movement of AMPA receptors into the postsynaptic membrane

resulting LTP lasts longer than a few hours

PKM-zeta mRNA is transcribed from DNA in the nucleus and transported to the dendritic spines.

PKM-zeta mRNA directs the production of the PKM-zeta protein, which activates the enzyme NSF

Activated NSF initiates the movement of AMPA receptors into the dendritic spine as new receptors

 

Once LTP is established at a synapse, chemical "tags" are produced.

These "tags" carry a message to the nucleus to produce proteins

Proteins are captured by "tags," which triggers the establishment of L-LTP 

Decrease in the excitability of a neuron to a particular synaptic input (needs low-frequency stimulation)

Caused when synaptic inputs are activated at the same time that the postsynaptic membrane is either weakly depolarized or hyperpolarized

Decrease in the number of AMPA receptors in the postsynaptic membrane of dendritic spines in vesicles

AMPA receptors removed from the spines during LTP

Low-Frequency rate of stimulation

over a long period of time (to one of the two subunits of NMDA) permits entry of a small but prolonged increase of Ca++ (stays in the cell longer)

Removal of AMPA receptors - smaller EPSPs and reduced strength of synapse

Extinction:  If a synapse is inactive

to extinguish synapses (behaviors)

i.e. Pavlov's dog to stop salivating at the sound of the bell

behavioral paradigm in which organisms learn to predict aversive events.

an unconditional stimulus (US), like an electrical shock, is associated with a particular conditional stimulus (CS), like a room or a tone, resulting in the expression a conditional response (CR), like fear, to the originally neutral stimulus or context.

Eventually, the conditional stimulus (CS) alone can elicit the state of fear (CR).

one can remember what made it affraid

*Survival*

strengthened synapses [around (and within) the amygdala]

For an animal to learn the association between a CS and an US, LTP is necessary at that particular synapse.

Info about the CS (tone) reaches the lateral nucleus of the amygdala.  This nucleus also receives info about the US (foot shock) from the somatosensory system.  Since, these two sources of info converge in the lateral nucleus, this is also probably where LTP responsible for learning through classical conditioning takes place.

The lateral nucleus of the amygdala contains neurons whose axons project to the central nucleus.  Terminal buttons from neurons that transmit auditory and somatosensory info to the lateral nucleus form synapses with dendritic spines on these neurons.  When encountering a painful US, somatosensory input activates strong synapses in the lateral nucleus.  As a result, the neurons in the lateral nucleus begin firing, which activates neurons in the central nucleus, evoking an UR.  If a CS is paired with the painful US, the weaker synapses in the lateral nucleus are strengthened.

As learned behaviors become automatic and routine, they are "transferred" to the basal ganglia.

Ventral Tegmental Area (VTA) - group of DA-ergic neurons whose terminal buttons go to the

Nucleus Accumbens (NAC) - nucleus of the basal forebrain (neurons in the NAC project to the Basal Ganglia) 

Medial Forebrain Bundle (MFB) - fiber bundle that connects the VTA with the NAC.  Stimulation of this area releases DA in the NAC

Release of DA causes the LTP that is necessary for operant learning

- Detect the presence of a reinforcing stimulus (something good happened)

- Strengthen synapse between neurons that detect the discriminative stimulus (the sight of a lever) and the neurons that produce the instrumental response (lever press)

Most typically found in the hippocampal formation, these neurons are linked to patterns of activity

- very specific

- have spatial receptive fields

- they are activated when an animal is in a particular location in the environment (reflects the location of where an animal "thinks" it is)

Tasks that rely on the hippocampus (i.e. relational learning) cause an increase in neurogenesis

Maturation of dendritic trees of newborn neurons and their integration into neural circuits of the hippocampus were accelerated when animals were trained on a spatial learning task.

NMDA is essential for LTP and LTD

Blocking NMDA receptors to the lateral ventricle impaired learning and prevented normal learning-induced changes in neurogenesis.  This suggests that LTP may play a role in the incorporation of newborn neurons into circuits that store new memories

Increases neurogenesis

- endorphine release

- enhances learning

Decreases neurogenesis

- cortizol release

- negatively effects the hippocampus

Caused by damage to the hippocampus or areas that are directly connected to the hippocampus

Cannot remember OLD memories

- damage to the sensory cortex

Cannot retain any NEW information

- damage to the hippocampus

Info is stored short-term in the hippocampus and then stored long-term in the sensory cortex

More complex memories take longer to process into "stored" memories

Reterograde Amnesia - Could only remember stuff from before his surgery

Hippocampus was removed due to his epilepsy

He was able to learn through practice - even without remembering that he had done the task before

PERMANENT Anterograde Amnesia caused by a defficiency in Thiamine (B1)

Destruction of the mamillary cell bodies

most commonly caused by chronic alcohol abuse: prevents the intestine from being able to absorb B1

Can also be caused by malnutrition

Size

Location

Ischemic

Hemorrhagic

those that plug up a blood vessel and obstruct the flow of blood (backflows) - neurons begin to die from a lack of blood supply (presence of excessive amounts of glutamate)

Severity is determined by the location

Treatment: administer anticoagulant drugs

rupture of a cerebral blood vessel

Blood seeps out of a defected blood vessel and accumulates within the brain, putting pressure on surrounding brain tissue and damaging it as the blood clots

Treatment: administer a clotting agent to stop the "leak"

severity of a seizure is how far the uncontrolled firing spreads from its origin

a seizure that begins at a focus and remains localized

a seizure that involves most of the brain

a partial seizure, starting from a focus and remaining localized, that causes a change in conciousness (unresponsive) - not a loss of conciousness.

a partial seizure, starting at a focus and remaining localized, that produces a loss of conciousness.

a generalized, tonic-clonic seizure involving most of the brain, that results in a convulsion

NOT common!!! Has 2 phases: Tonic and Clonic

First phase of a grand mal seizure, when all of the patient's skeletal muscles contract at the same time

the phase of a grand mal seizure when the patient shows rhythmic jerking movements

A type of seizure disorder often seen in children; periods of inattention which are not remembered

Looks like: simple partial seizure

most common - scarring (injury, stroke, developmental abnormality)

*from injuries - seizures may not occur until several months later*

- Drugs and Infections that cause High Fevers: most common in children (affects about 3% children under 5)

- Drug abuse: Sudden removal of inhibition - leaves the brain in a hyperexcitable condition 

• *Alcohol: Receptors are blocked
• *Barbiturates: GABA systems (inhibitory when firing) no longer hyperactive

Anticonvulsants: prevent future seizures

• - Potentiate inhibitory systems (GABA)
• - CNS inhibitor

Surgery:

• - Removal of target if not responding to anticonvulsants
• - Typically region of temporal lobe

Temporal Lobe

they're inhibitory when they fire

focal starting points

Brain disease:

• - contagious
• - brain has a sponge-like appearance
• - moves like a virus

• - Bovine TSE: mad cow disease
• - Creutzfeldt-Jakob Disease: prion protein disease (kuru) 

Form of TSE

• 1st: Dementia
• 2nd: Speech
• 3rd: Motor

Kuru: form of human prion protein disease that was transmitted through cannibalism

accumulation of misfolded prion protein (PrPSc)

Apoptosis can be triggered externally, by a chemical signal telling the cell that it's no longer needed, or internally, by evidence that biochemical processes in the cell have become disrupted so that the cell is no longer functioning.

Accumulation of PrPSc (misfolded, abnormal prion proteins) may be providing such a signal. 

simple proteins found primarily in the membrane of neurons

- may have a role in synapse function and in preservation on myelin sheath

- resistant to protein-destroying (proteolytic) enzymes: done by breaking the peptide bonds that hold a protein's amino acids together

- also resistant to levels of heat that would denature normal proteins

The functions of a protein are determined largely by its  shape

If the structure is misfolded, there will be problems with function or there will be an entirely new function.

Once misfolded PrPSc is introduced into a cell, it causes normal PrPc to become misfolded too; the process of this transformation ultimately kills them.

Because they are misfolded, "Pac-Man" enzymes cannot get to the synapse to break them apart

Primary symptoms: poverty of movement

• - muscular rigidity
• - slowness of movements
• - a resting tremor
• - postoral instability

Caused by:

- Loss of DA tone: degeneration (slow decline) of the nigrostriatal system

- We know that it's DA loss; but what causes the neurons to die is unknown . . . abnormal accumulation of alpha synuclein? 

the DA-secreting neurons of the substantia nigra that send axons to the basal ganglia

degenteration of this system: Parkinson's

a "pac-man" protein normally found in the presynaptic membrane (terminals), where it may be involved in synaptic transmission in DAergic neurons.

acts as a molecular chaperone, assisting in the folding and refolding of synaptic chaperone proteins called SNAREs

abnormal accumulations are said to be the cause of neural degeneration in Parkinson's

*suggested that the presence of alpha-synulein, an increase in Ca++ inside the cell, and elevated DA in the cell combine to kill these neurons*

found in surviving DA neurons

abnormal circular structures found within the cytoplasm -dense protein core contains alpha-synuclein

Hereditary

* mutation of the Parkin Gene - causes a loss of function making it a recessive disorder: NOT causal; but may be linked with DA synthesis

• - If one parent has it: chances are increased by 1%
• - If both parents have it: 13%

Drug Abuse

* One dose of MPTP induced Parkinson's (MPPP similar to Opiodis)

Deprenyl: An antidipressant that blocks the effects of MPTP - slows the progression of Parkinson's

L-DOPA: DA precursor - increased level of L-DOPA in the brain causes a patient's remaining DAergic neurons to produce/secrete more DA and (for a time) alleviates the symptoms of the disease

• Surgery: Stem cell (fetal tissue) transplants
• - stimulation

Inherited basal ganglia disease - degeneration of caudate nucleus and putamen (Slow decline in loss of GABA neurons = loss of inhibition)

Genetic Cause: a mutation of a gene on Chromosome 4 - a repeated sequence (33) of bases (CAG) coding for the amino acid glutamine, which causes huntingtin (Htt) to contain an elongated stretch of glutamine.  Htt becomes misfolded and forms aggregations that accumulate in the cell nucleus.

Glutamine repeat: 33 = Htt

The cause of death of neurons is apoptosis.

- Starts with choreatic movements

Dyskinesias: uncontrollable movements

- Then, loss of intellectual abilities

- Next, emotional disturbances (irritability/ apathetic)

- Finally, (after 10-15yrs) death

50/50

Mom: YES

Dad: NO

NO treatment ...  just assorted efforts - NO cure

Research Targets

- Function of Htt

- Effects of mutation

- Apoptosis

Unknown Origin: may be some genetic component (APP mutation - early onset for hereditary AD)

- Plaques: linked to cause; but size/ amount is not predictive of severity of disease

- Cholinergic Hypothesis: The first (and most) neurons that are lost are cholinergic neurons of the basal forebrain

- Excitotoxicity: neurons fire so much they kill themselves of

- Tau Hypothesis: Hyperphosphorylated Tau proteins leading to death of neurons

Mutation of Presenilin: protein by a faulty gene and causes the APP to be converted into AB42

The presense of excessive amounts of AB in the cytoplasm of cells appears to be the cause of neural degeneration ... Not the formation of extracellular plaques.

Intracellular oligomers of AB causes:

• - excitotoxicity
• - synaptic dysfunction
• - supress LTP formation

Alzheimer's: Progressive

• - retrograde amnesia
• - inability to learn new things
• - moments of clarity

Dementia: Sparatic

• - memory loss
• - changes in behavior

Progressive retrograde amnesia: memory loss (most recent memories 1st)

• Impairments performing basic (often familiar) tasks
• - language problems: loss of simple words 

Disorientation

Difficulties in abstraction

• Changes in mood/ Rapid mood swings - violence
• - (40% have Alzheimer's present with psychosis)

Change in initiative - passivity

Eventually, Death

an extracellular deposit containing a dense core of AB protein surrounded by degenerating axons and dendrites and activated microglia and reactive astrocytes

Beta Amyloid plaque: protein contains 40 or 42 amino acids

- AB40 can be dealt with (sliced, cut, excised) via proteins

- AB42 cannot be removed due to the shape and sequence changes

Amyloid Precursor Protein (APP) is responsible for synthesizing AB proteins

• 3 secretases cut different parts of APP
• - alpha secretase
• - beta secretase
• - gama secretase

AB fragment is formed when APP is cut by beta and gama secretase

High concentrations of BA42 (found in AD patients)have a tendency to fold themselves improperly and form aggregations that have a toxic effect on the cell

Microtubule: cytoskeleton and protein transport mechanism

Tau Protein: microtubule protein "glue"

Neurofibrillary Tangles (NFT): dying neurons containing intracellular hyperphosphorylated tau-protein fillaments

- Tau protein becomes hyperphosphorylated which leads to NFTs

- NFTs lead to disintegration of microtubule network and death of neuron: tau is no longer acting as "glue," cell can't maintain structure, and proteins can't get where they need to go.

- When tau proteins are hyperphosphorylated, they stay that way.

- Loss of Cholinergic neurons: The first (and most) neurons that are lost are cholinergic neurons of the basal forebrain

Acetylcholinesterase Inhibitor:

- because Achergic neurons are among the first to be damaged in AD and because these neurons play a role in cortical activation and memory, drugs that inhibit the Ach "pac-man" and thus enhance its activity have been found to improve cognitive activity.  Ach will have a longer effect and remain in the cell longer.

NMDA receptor blocker: prevents exitotoxic destruction of Achergic neurons caused by the entry of excessive amounts of Ca++

• - prevents excitotoxicity
• - reduces the entry amount of Ca++

Arresting AB deposits (vaccine) - major complications

Destroying AB deposits

Cleavage of AB: problem seems to be the order of cleavage not the cleavage site

Production of AB

Related signaling mechanisms

Average age of onset:  between 16-25

• - Men: 16-20
• - Women: 20-30

First Episode: Psychotic break with reality (thoughts and feelings no longer work together normally)

Outcome: Massively Variable

• - Earlier diagnosis and treatment = a better outcome
• - Patient Stability: more stable = better long-term prognosis
• - Medication Success selection

Identifying characteristics of a disorder before the first episode

- At what point do you begin treatment?

10

Affects 1-3% of the poplulation

Ranks Top 10 causes of disability in Developed countries

• Roughly 60% of scizophrenics live in poverty
• - Loss of function is massive

Present in the patient, but not in the normal population

- Delusions: beliefs of prosecution, grandeur, control

- Hallucinations: false perceptions (95% have auditory hallucinations)

- Disorganized thinking and behavior: linear/ logical flow of ideas

Absent in the patient, but normal in the general population - seem to be a result of hypofrontality: decreased activity of the PFC

- Affective (emotional) Flattening/ Blunting: No emotional response

- Sensory-Motor Gating deficits: "reaction control"

- Ambivalence: Don't care

- Avolition: No motivation

- Loose association difficulties in Cognition and Language: things don't "tie together"

- Memory impairments: spatial, encoding/ retrieval of information

Genetic: <50% incidences in 1st degree relatives

- Not heritable (i.e. Identical twins: 1 w/ and 1 w/o)

Environmental Factors implicated: seasonality effect (late winter/ early spring)

Anatomical and Physiological changes: ventricles, grey matter, etc ...

Suggests that the positive symptoms of schizophrenia are caused by hyperactivity of DAergic synapses in the mesolimbic system, which targets the NAC and amygdala. 

- Initially based on effects of DA antagonists [chlorpormazine (anxiety) - 1st antipsychotic]: eliminated/ diminished positive symptoms.

- Basis for psychopharmacological treatment of schizophrenia

Nigrostriatal DAergic pathway

- Mesolimbic pathway (between VTA and NAC): Positive symptoms - Excess DA

- Mesocortical (part of the prefrontal cortex): Negative symptoms - Decreased DA

*DA is not soley responsible*

- Schizophrenia as a network disorder

Basis: post-mortem findings of changes in glutamate- related markers

- Loss/ Hypofunction of NMDA due to glutamate, leads to a deficit/ surplus of DA

*Glutamate feeds DA and DA feeds glutamate*

"Have all the parts, but the parts aren't functioning correctly"

Used as a last resort!

- DA antagonist

* Based on ability to deal with Positive symptoms*

Efficacy and binding affinity: High

Side effects (ShortTerm): parkinsonion

- Long Term: tardive dyskinesia

All but 1 are antagonists

Efficacy and Binding affinity: Benign (safer) - not just DA - Less likely to produce Parkinsonian side effects and does not cause tardive dyskinesia

- Reduces positive and negative symptoms; and also help some patients who are not helped by traditional antipsychotics

- Partial Agonist:  FDA approved

Challenges: Patient refuses medication - thinks Dr is trying to poison them

Stability and Changing treatments

Comorbid Tendencies: Substance abuse: Incidence of smoking - nicotine

Non-Pharmacological treatments

At lease one manic period (few days) coupled with depressive symptoms

At least one hypo-manic period with depressive symptoms

Manic: 1-4 days

Depression: several months

Rapid Cycling: >/= 4 episodes a year

The more time spent in a depressed state, the greater amount of issues in:

• - cognitive
• - executive
• - sleep
• - learning/ memory

people in the euthymic state still show signs of cognitive impairment after long periods of depression

*manic episodes become more frequent the more they occur*

Unknown

• - arousal systems
• - neuroendocrine
• - genetics?
• - Season of Birth (summer)

Very difficult

- Mood stablizers (2nd messenger, Blocks Na+ channels, Fascilitates GABA): Anti-Epiletic like - CNS depressant

*Creates a greater distance to "travel" for a manic episode*

- Atypical antipsychotics: primary adjunct; but not ideal to use as an antidepressant

No manic state

Must persist: 6+ months in the absence of an external event 

• - Depressed mood
• - Anhedonia
• - appetite and sleep changes
• - psychomotor agitation: restlessness
• - Loss of energy
• - Helplessness

depressed state with more than 3 symptoms of unipolar depression present at the same time

depression with improvement in mood, increased sleep and appetite

"low grade" sustained depression, lasting for more than 2 years

mood disorder characterized by depression, lethargy, sleep disturbances, and a craving for carbohydrates during the winter season when days are short ... usually accompanied by weight gain

Sleep deprivation experienced by new mothers, increases the risk of post-partum depression

Hormonal surges (estrogen/progesteren): sleep helps to amp up estrogen

- 2x higher in women than men

- Residual symptoms:

- Genetic linkage: 70% likely in monozygotic twins (even if not raised together) - same as general population with 1st degree relatives

- multiple points in multiple regions: same gene sequence

Monoamine Hypothesis: Depression is caused by insufficient activity of MAergic neurons

- suggested by the fact that depression can be treated with MAO inhibitors and the drugs that inhibit the reuptake of MA

* MA antagonists can produce the symptoms of depression and MA agonists can reduce them*

Basis of pharmacological treatment: symptoms are not relieved by potent DA agonists; so focus is on 5-HT and NE (norepinephrine)

*Post-Mortem findings: an enlargemt of ventricles (loss of MA neurons)

5-HT Transporter: Fed-Ex truck for 5-HT

• - Alteration in Transporter efficacy or amount
• - unproven

Based on type.

Looking for common trait markers across categories

MAO-I: inhibits MAO (MA pac-man)

Tricyclic Antidepressants: MA (5-HT and NE) Reuptake inhibitors - Increased MA levels, can lead to heart failure

SSRI: Specific Serotonin Reuptake Inhibitor - elevates 5-HT

SNRI: Serotonin and NE Reuptake Inhibitor

SNDRI: Serotonin, NE, and DA Reuptake Inhibitor

ECT: Electroconvulsive Therapy: Frequency of treatment sessions depends on the individual's NS

Endogenous opiates (normally in the brain) are responsible for analgesia: helps us withstand pain to be able to survive (Localized)

Exogenous opiates (Systemic) = Reinforcement mechanism that hits every system

Neural Basis

- Periaqueductal Gray Matter: analgesia 

- Preoptic Area: Hypothermia

- Mesencephalic Reticular Formation (pons: midbrain section): Sedation 

- VTA and NAC: Reinforcement *favorite thing area*

*Reinforcement by releasing DA in the NAC and VTA, activates neurons in the mesolimbic system*

Tolerance and Withdrawl

Antagonist-Percipitated withdrawl research (administering an addictive drug and then blocking its effects with an antagonist): found that the most sensitive spot is the locus coeruleus, followed by the Periaqueductal Gray Matter (PAG neurons)

Increased firing occurs (after long-term administration of drug) once administration stops

If this area is lessioned - there are no withdrawl symptoms

- Dopamine agonists with different sites of action

- Both use mesolimbic DA systems to reinforce behavior.  If this area is inhibited (blocking DA receptors), the addictive behavior lessens: sometimes given antipsychotics

- People who use these drugs have psychotic-like symptoms - i.e. drug induced schizophrenia (positive symptoms - hyperlocomotion)

• - Lasting effects: reduction of DA receptors in caudate nucleus and putamen (could lead to Drug induced Parkinson's); 
•  
• Cocaine

- binds with and deactivates the DA transporter proteins,

- blocking reuptake of DA  

- (Sympathetic NS) Induced ACTH release - CTF (cortocotropic releasing factor)

*ACTH stimulates the production of glucocorticoid, which breaks down protein and turns it into glucose, increases blood flow, turns fat into available energy, and stimulates behavioral responsiveness

Amphetamines

- Stronger than cocaine because they inhibit reuptake and stimulate release of DA

- The reuptake "loading dock" is one-way (into the cell).  With (meth)amphetamines, the flow is reversed.  The trucks keep "delivering," but the DA keeps flowing out - amount of DA is doubled. 

- stimulation of glutamate release

- Methamphetamine is a more potent version of amphetamine (long term effects: Damage to 5-HTergic axons and trigger apoptosis of cells in cerebral cortex, striatum, and hippocampus)

See what is not there or see an exageration of what is there

Lysergic Acid Diethylamide (LSD)

- binding to 5-HT receptors (5-HT2A - agonist in particular - assebling perception): metabotropic: 1 LSD opens multiple channels

- Some affinity (how readily the drug binds) for DA receptors

*Drug-drug interactions: easily overdose*

Phencyclidine (PCP)

- NMDA receptor antagonist

- initially used as an anesthetic (High Dose)

Methylenedioximethamphetamine (MDMA - Ecstacy)

- Somatosensory System: stimulant and dissociative

- Interaction with SERT (re-uptake of 5-HT): chaperone protein from "dock" to reserve

- Causes the cell to reverse re-uptake and dump 5-HT into the synapse

- Induces NE and DA release: senses are hightened and feel great

- serves as an indirect agonist for GABA (fascilitated) and an indirect antagonist for NMDA (shut down) receptors

- Produces positive and negative reinforcement, feeling of euphria and relief of anxiety

*Nalaxone: opiate receptor blocker stops reinforcement*

- Activates DAergic neurons in the mesolimbic system and NAC

- Dangers to fetus (FAS): may trigger apoptosis and cause neurological damage

Tetrahydrocannabinol (THC) stimulates CB1 receptors in hippocampus: memory problems

Site of action: CB1 receptors (cannabinoid)

*blocking CB1 receptors stop reinforcing effects*

- Also releases DA in NAC

- Interferes with (stimulates) CA1 cells in hippocampus

*excessive activation of CA1 cells interferes with normal functioning*