The chimpanzees were super good at the memory game.

Also: performing a bilateral lesion of the prefrontal cortex in chimpanzees showed caused deficits in working memory and executive functioning skills.... so that's how we know where it is.

Just about everything. Association cortices, thalamus, amygdala, and ventral striatum.

Uses noradrenergic, serotoninergic, cholinergic, and dopaminergic systems.

• Cue Phase (when image is flashed)
• Delay Phase
• Stimulus Phase (when stimulus is shown)

The delay phase is when our brain is most active because we are using our working memory to maintain a representation of the image in our brain.

Schizophrenia and ADHD. 

Dopamine- but too much is bad.

Because they increase DA signalling.

Methylphenidates (Ritalin) and amphetamines (Adderall)

They can enhance WM because NE plays a significant modulatory role in the PFC so more NE can help increase EF and WM.

Ex: clonidine and guanfacine

1. The inability to suppress inappropriate automatic responses.
2. The inability to suppress reponse to irrelevant stimuli.

Memories that involve the recall of facts or events; conscious memory; memory that can be verbalized.

Medial temporal lobe (involved the hippocampus)

Subconscious memory.

1. Procedural (skills and habits): Striatum
2. Priming: neocortex
3. Simple Classical Conditioning Emotional Responses: amygdala
4. Simple Classical Conditioning of Motor Responses: cerebellum
5. Nonassociative Learning: relfex pathways

Increases anxiety in the amygdala.

V1a receptor antagonists may be anxiolytics

• MeCP2: Rett Syndrome
• FMRP
• Neuroligins and neurexins

1. Amygdala
2. Hippocampus
3. Parahippocampal Gyrus
4. Cingulate Gyrus

The hypothalamus, nucleus accumbens of the ventral striatum, orbital and medial prefrontal cortex

1. Prefrontal Cortex: working memory and response selection
2. Hippocampus: contextual memory (have you experienced the stimulus before and what did you do?)
3. Striatum: procedural memory (e.g., reflexes)
4. Hypothalamus: activates sympathetic nervous system
5. Pariaqueductal Gray: analgesia/opioids
6. MA Nuclei: increased arousal, alertness, and vigilance

Anxiety: benzodiazepines, beta blockers

Depression: SSRIs and trycyclics

Flumazenil, an antagonist of the benzo site.

Beta-carboline is an inverse agonist, so causes the opposite effect of benzos.

BDZs are positive allosteric modulators, while barbiturates actually open the site.

Barbiturate site.

• Diazepam: long half-life, used for GAD
• Lorazepam: short half-life, used as hypnotic

• Clonazepam: high potency benzo used for panic disorder
• Buspirone: 5HT1A partial agonist used for GAD

They are both such high potency that they act like barbiturates

Despite being tricyclics, they are highly selective.

Clomipramine is hightly selective for 5HT reuptake while Desipramine is highly selective for NE uptake.

• BENZODIAZEPINES; SSRIs for those who don't respond well to those
• Benzos
• Beta blockers

The HPA (hypothalamic-pituitary-adrenal) pathway.

Too much activation leads to depression.

The CRF1 receptors (with antagonists) to tamp down the negative feedback

1. Reserpines which depleted NE, 5HT, and DA resulted in depression (cued scientists in)
2. MAOIs were used to stop MA depletion
3. SSRIs were used but resulted in relapse because of tryptophan depletion.
4. NRIs were used by also lead to relapse because of a-methylparatyrosine

Genetics. So monozygotic twins are 50% at risk if the other has it.

0.5%-1%

1. DISC1
2. DTNBP1
3. NRG1
4. DAOA
5. COMT
6. RGS4

Candidate genes because none are direct causes

The micro-deletion on chromosone 22, at 22q11.2

It boosts risk 30-fold

• Development
• Environmental chemicals
• Drugs pharmaceuticals
• Aging
• Diet
• DNA methylation/histome modification

This is why dizygotic twins are more likely than siblings to get both get schizo, because of same environment.

They lack it/have major defecits.

The number set test: they lack the projection of what the command is and cannot do the test if there is a delay.

They have decreased gray matter.

Gray matter is the axons and dendrites of neurons, so they have less of them (related to the genetic mutation in 22q11)

They are NMDA receptor antagonists: changes in glutaminergic signalling can lead to schizo like symptoms

They increase glutamate release in PFC

Any D2 receptor antagonists, alpha-1 receptor, 5HT receptor, or histamine receptor.

The D2 receptors are the only effective one.

They are all nonselective (except the D2 obviously)

Extrapyramidal Motor Effects: PD like side effects (rigidity, resting tremor, acute dystonia/sudden and spastic muscle contractions in face and neck, anxiety and restlessness, late onset involuntary choreiform movements).

Tardive Dyskinesia: the choreiform movements are irreversible and will never go away.

L-dopa

Co-administration of antimuscarnics (e.g., benztropine)

• 1st gen: chlorpromazine and haloperidol

1. Clozapine (lowest extrapyramidal effects): the most efficacious, unique MOA, but not the most potent
2. Aripiprazole: a D2 partial agonist
3. Olanzipine: good pharmalogical profile and cholinergic antagonist activity: induces metabolic syndrome however and can precipitate diabeetus
4. Risperidone

• Intrinsic: driven by inner signals
• Extrinsic: driven by death receptors

Cysteine-containing Aspartate-Specific Proteases.

They are the family of proteases that help carry out apoptosis.

Mitochondria are involved in this pathway.

Caspase 9 is the initiator caspase for this.

This pathway is the one essential for normal CNS development. 

Pro-survival proteins regulate the intrinsic pathway, making it harder to kill cells. Bcl-2.

Pro-death proteins help trigger and carry out cell death. Bax, Bim, Hrk.

• Apoptosis requires ATP, which necrosis is induced by ATP depletion.
• Apoptosis requires new protein synthesis
• Necrosis involves leakage of cellular contents into extracellular space.
• Necrosis induces an inflammatory response while apoptosis is the "silent death."

• Calpin: breaks down lots of proteins
• Lipases: break down membrane lipids
• NO synthase
• Free radical production
• Endonucleases

They get ubiquinated. This means that ubiquin chains are added to the protein, which help it to get degraded by the proteasome.

They lead to misfolded protein build-up in the cell, which can cause the misfolded protein response.

• AD: amyloid plagues between the neurons and nurofibrillary tangles of Tau proteins within the cell
• PD: lewy bodies within the cell made up of a-synuclein
• HD: mutant Htt gene, which causes so many extra CAG segments that it becomes too long and builds up within the cell
• C-JD: Prion proteins that holes in surrounding neurons
• FTD: TDP-43

• B-secretase: cleaves the extracellular section of the protein to help create Abeta.
• γ-secretase: Cleaves at the Abeta 40 or Abeta 42 site. Abeta 42 tends to be much more toxic than Abeta 40.
• α-secretase: cleaves right in the middle to prevent formation of Abeta

What do the following mutations result in?

• Flernish mutation
• Swedish Mutation
• Presanillin Mutations

• Flernish: decreases the use of α-secretases, making the formation of Abeta more likely
• Swedish: increases the use of B-secretase, creating more Abeta proteins
• Presanillin: this favors β used over γ, making the formation of Abeta 42 much more likely.

They modify the propensity or susceptibility to develop a disease.

ApoE4

4/4 is the worst, 3/4 is the second worst.

The most common is 3/3.

2/3 represents the least likely.

2/4 is just about the same as 3/3.

• β-secreatse inhibitors are used to decrease Abeta, but are hard to get past the BBB.
• R-flurbiprofen: γ-secretase inhibitors promote Abeta 40 over Abeta 42, which helps in the short term but ends up making it worse in the long run

It is a ubiquitin E3 ligase which targets proteins for degradation by adding U-chains to them.

In PD, PARK2 is inactive, so misfolded proteins build up in the cell. PARK2 specifically targets SNCA a lot, making Lewy bodies much more likely.

Striatum --> thalamus --> cortex

This is stupid

The DA neurons from the SN inhibit the inhibitory neurons, which inhibit the other inhibitory neurons, which inhibit the glutaminergic neurons, which activate the inhibitory neurons, which lead to the glutaminergic neurons into the cortex. Long story short, by the DA neurons inhibiting the inhibiting neurons, it stops the inhibition of movement (allows initiation of movement).

The huntingtin gene. There is a CAG repeat on it, resulting in a PolyQ or polyglutamine repeat: there are too many glutamines on the c-terminus. The more glutamine, the worse the disease.

These repeats cause the huntingtin to misfold and aggregrate.

It's genetic. Having one copy of the gene mutation can give you it.

There are no cures and not even any therapies.

Amyotrophic lateral sclerosis.

It attacks neurons in the brain and spinal cord causing muscle weakness and atrophy.

Eventually leads to death due to respiratory failure.

There are motor neurons in the cortex, brain stem, and lower motor neurons that innervate skeletal muscle.

 Limb onset is when lower motor neurons begin to die and it moves up. Ballbar onset is when higher motor neurons being to die and move down.

Familial: 5-10% of all cases; inherited or genetic

Sporadic: no apparent genetic component, it can affect anyone, anywhere, and has no known cause; 90-95% of fall cases.

Mutations in the SOD1 protein.

In mice, this causes them to develop hind limb paralysis.

Basically there are six thousand million different things that can cause ALS and we have no clue which one of them does it.

• Excitotoxicity
• ER Stress
• Proteasome inhibition
• Mitochondrial Dysfunction
• Toxic extracellular mutated SOD1
• O2 production
• Altered axonal transport
• Synaptic vesical defects
• Loss of tight junction proteins

Riluzole. It is anti-glutamatergic.

It is minimally effective, it prolongs life span by about 3 months only.

They inactivate sodium channels.

They cannot bind until the channel has already been activated. Once the channel goes into the inactive state again, these drugs help keep it in that state longer.

It actually blocks sodium channels.

It also increases the amount of free GABA

They are GABAa enhancers.

They are no longer used due to too many side effects

• Occlusive: a blockage of flow to the brain
• Embolic Infarctions: clots from the heart go to the brain and block flow
• Vasospasm: a weakened artery spasms and falls in on itself, stopping blood flow ("mini strokes")
• Hemmoragic: bursting and bleeding into the brain

An enzyme that is created from plasminogen.

It cleaves fibrin to help dissolve clots.

tPA promotes plasmin.

"Super Duty Blood Thinner"

A vitamin K antagonist (many clots use vitamin K). It's very strong, so usually not given until the patient has already had one stroke.

What is nimodpine, tirilazad, and trofermin?

What's similar about them?

• Nimodipine: blocks voltage-gated Ca2+ channels
• Tirilazad: helps to protect lipids
• Trofermin: a fibrablast growth factor that can help repair neurons, connections, and growth.

None of them work.

CGRP antagonists.

CGRP is the principal vasodilatory sustance released from trigeminal ganglia in reponse to cortical spreading depression.