Bio Psych Test 3

Learning & memory basics

Learning = a relatively permanent change in behavior (or mental processes) due to experience, measure learning by measuring memory

• Memory = 3-stage process: encoding (taking info in), storage (holding it), retrieval (pulling it back out)

Santiago Ramón y Cajal

“Father of modern neuroscience” and the first to see the neuron

• Hypothesis of Learning: memories might be formed by strengthening the connection between neurons and increasing effectiveness of communication

Donald Hebb’s reverberating circuit

argued that functional modifications of the synapse produced by reverberating circuits serve as the basis for learning in the CNS. Key ingredient = repeated stimulation

• Neurons that fire together, wire together

Atkinson & Shiffrin model

Early model of attention & memory, drawn from a computer analogy. 3 systems: sensory memory (from sensory organs) → STM (brief) → LTM (long periods). Pattern matching/attention sits between sensory memory and STM.

Baddeley’s working memory model

Current models emphasize working memory instead of STM

• 3 components: central executive, phonological loop, visuospatial sketchpad

The 3 parts of working memory

• Central executive = allocates attentional and cognitive resources; controls the other two

• Phonological loop = holds verbal/auditory info through repetition (rehearsal loop)

• Visuospatial sketchpad = holds and manipulates visual/spatial info (picturing things, often while looking elsewhere)

Subtypes of long-term memory

• Procedural = “knowing how” (skills/movement, e.g., riding a bike)

• Declarative = “knowing that,” split into semantic (general knowledge)

• Episodic (personal recollections, e.g., your wedding)

Brain regions for each LTM type

• Semantic: encoded through hippocampus, stored in cortex (primarily temporal lobes)

• Episodic: encoded through hippocampus, stored in cortex (primarily right frontal and temporal cortex)

• Procedural: primarily striatum, plus cerebellum and motor cortex

• hippocampus ENCODES declarative memories; cortex STORES them

Full hippocampal pathway (in order)

Association areas → parahippocampal & perirhinal cortex → entorhinal cortex → (perforant path) dentate gyrus → (mossy fibers) CA3 → (Schaffer collaterals) CA1 → subiculum → back to entorhinal cortex → back to association areas

Association areas & entorhinal cortex

Unimodal & polymodal association areas (frontal, temporal, parietal lobes) send info to the parahippocampal and perirhinal cortex. Both feed the entorhinal cortex = main gateway into the hippocampus

Parahippocampal cortex

Pre-hippocampal area; input from frontal, parietal, and occipital cortices. Contains the parahippocampal place area (PPA), which encodes places been

• Megevand et al.: stimulating the PPA made a patient perceive places

Perirhinal cortex

Pre-hippocampal area responsible for recognition of objects. Sends input to entorhinal cortex (along with parahippocampal cortex)

Perforant path vs mossy fibers vs Schaffer collaterals

• entorhinal cortex → dentate gyrus

• dentate gyrus → CA3

• CA3 axons releasing NT onto CA1 (CA3 → CA1)

Dentate gyrus & subiculum

• receives perforant path input from entorhinal cortex, sends mossy fibers to CA3; where Bliss & Lomo recorded LTP

• receives CA1 output and sends it back to the entorhinal cortex

Bliss & Lomo (1973): who, what, method

paper on long-lasting potentiation of synaptic transmission in the dentate area

• Anesthetized adult male & female rabbits. Surgically exposed the hippocampus. Electrically stimulated the perforant path. Recorded fields of neuronal activity in the dentate gyrus

Bliss & Lomo results / what is LTP?

High-frequency stimulation of the perforant path increased excitability of downstream dentate gyrus neurons. Baseline increases lasted up to ~3 days, so it was named long-term potentiation (LTP)

• before LTP, stimulating neuron A gives a small EPSP in B; after LTP, the same stimulation gives a bigger EPSP in B

Early LTP vs late LTP

• LOCAL (changes at one individual synapse), SHORT-TERM (rapidly decaying), INDEPENDENT of protein synthesis (cell makes nothing new)

• GLOBAL (whole neuron; requires nucleus activity: gene transcription & translation), LONGER-TERM/more durable, REQUIRES protein synthesis

Glutamate & its receptors

amino acid, main excitatory NT. 11 receptor types: 3 ionotropic (AMPA, NMDA, kainate) + 8 metabotropic (I–VIII). AMPA & NMDA are the key receptors for LTP. At rest the NMDA channel is blocked by a Mg++ ion

Early LTP steps

1. Glutamate released

2. Binds postsynaptic NMDA & AMPA receptors

3. Nothing happens at NMDA because Mg++ blocks it

4. AMPA channel opens → Na+ influx → local depolarization (EPSP)

5. The local EPSP kicks Mg++ out of the NMDA channel

6. With Glu bound, NMDA opens → lets in Na+ AND Ca++
7. Ca++ activates CaMKII
8. CaMKII triggers externalization of EXISTING AMPA receptors
9. Ca++ also activates NOS to make NO
10. NO travels back to presynaptic terminal → more Glu release onto expressed AMPA receptors

Early LTP in one sentence

An AMPA-modulated, NMDA-mediated process involving a Ca++-driven cascade that activates (1) CaMKII to externalize AMPA receptors and (2) NOS to drive NO as a retrograde messenger to enhance glutamate release

Late LTP steps

1. CaMKII activates cAMP

2. CREB activation → gene transcription/translation (neuron makes new proteins, enzymes, cell wall, etc.)

3. Production of nerve growth factors (BDNF = brain-derived neurotrophic factor)

4. Growth of new dendritic spines and new axon terminals → new synapses = synaptogenesis

Electrophysiology: stimulation (before/after)

After synapses grew new structure (new spine/connection). Shows that functional modifications of the synapse DO occur: memories form by strengthening connections between cells (supports Cajal & Hebb).

Long-term depression (LTD): what & how noticed

lasting decrease in signaling/strength between neurons, produced by low-frequency stimulation. Noticed in Bliss & Lomo: some neurons were excited while others fatigued. Some neurons are “suppressed” so other neurons can develop LTP

3 reasons LTD occurs

1. Balancing plasticity: keeps circuits flexible and able to encode new experiences

2. Refining information: sharpens contrast between neurons for precise details and motor learning

3. Erasing or updating: clears old/irrelevant memory traces so storage doesn’t overload or saturate

Dudek & Bear vs Carroll et al

• Stimulated Schaffer collaterals at 1–50 Hz. Above 10 Hz = LTP; below 10 Hz = LTD. Both were prevented by AP5 (an NMDA receptor antagonist)

• Showed LTD is a reduction in AMPA receptors. So LTP = more AMPA receptors at the synapse; LTD = fewer AMPA receptors

LTP, LTD & NMDA receptors

Both require activation of NMDA receptors, and both can be prevented with the NMDA antagonist AP5. Two NMDA receptor subtypes: one allows massive, rapid Ca++ influx → LTP; the other allows low-level but continuous Ca++ influx → LTD

Glutamate-glutamine cycle (synapse diagram)

Presynaptic glutaminase converts glutamine (Gln) → glutamate (Glu); vGluT packs Glu into vesicles. Released Glu is taken up by glial cells (EAAT1/2), converted back to Gln by glutamine synthetase, and sent back to the neuron

SEPT

Framework for studying disorders: Symptomology (symptoms), Etiology (causes), Pathology (changes observed), Treatment

4 types of amnesia

• Retrograde = after brain insult, can’t recall PAST memories

• Anterograde = after brain insult, can’t form NEW memories

• Global = both retrograde and anterograde

• Dissociative = interruption of memory from a change in consciousness, perception, or awareness (caused by trauma/stress)

Causes (etiologies) of amnesia

Dementia, neurodegenerative disorders, anoxia (lack of oxygen), alcohol use, trauma or stress (dissociative amnesia), and hippocampal damage

H.M. (Henry Molaison)

severe epileptic seizures had bilateral medial temporal lobectomy → partial hippocampal removal lead to pure anterograde amnesia

• Procedural memory intact: he improved at Tower of Hanoi without remembering

• hippocampus is needed to form new declarative memories but not procedural ones

Lonni Sue Johnson

“The Muse of Memory,” Time Magazine (Sept 4 issue). In 2008, severe encephalitis completely destroyed her hippocampus → global amnesia. She could still make art afterward (skill preserved), but her work changed to word-puzzle-style drawings

Stress & memory: glucocorticoids

stress hormones produced by the adrenal glands; the primary one is cortisol. Its receptors (GR) are densely packed in the hippocampus. Prolonged/excessive release is neurotoxic (neurons and glial cells can die)

3 neurotoxic effects of glucocorticoids

1. Energy deprivation: block glucose transport into neurons & astrocytes → low energy supply

2. Glutamate accumulation & excitotoxicity: energy-depleted cells fail to clear glutamate → chronic NMDA activation → overactivation & Ca++ flooding → excess Ca++ activates apoptosis enzymes

3. Cell death in the hippocampus inhibits synaptogenesis and neurogenesis

Excitotoxicity & apoptosis

• cell damage/death from overstimulation by glutamate (too much NMDA activation and Ca++ influx)

• programmed cell death

Dementia and causes

From Latin “demens” = “out of one’s mind.” Loss of mental functioning: cognition, memory, executive planning

• Drugs of abuse (alcohol), prescription meds, hormones & vitamins, other psychological disorders

Korsakoff’s syndrome: symptoms

Identified by Sergei Korsakoff while studying alcoholism. Anterograde amnesia, confabulation (retrograde), mood disturbances. Confabulation = making up false memories

Korsakoff’s syndrome: etiology & pathology & treatment

• non-genetic neurodegeneration from thiamine (vitamin B1) deficiency

• global (MRI shows enlarged ventricles = tissue loss) and mammillary bodies (first hemorrhage, later atrophy). Mammillary bodies are heavily used in recalling past memories

• stop alcohol consumption; nutrition & hydration; thiamine supplements

Pharmacology: liver & alcohol

Liver microsomal enzymes (cytochrome P450) metabolize most psychoactive substances, but NOT alcohol. Alcohol is metabolized by alcohol dehydrogenase → acetaldehyde. Acetaldehyde = toxin & known carcinogen; causes vasodilation, mitochondrial dysfunction, reduced cellular survival

Dr. Alois Alzheimer & prevalence

MCI (mild cognitive impairment, minor forgetfulness) → eventual complete memory loss. Gradual loss of other cognitive functions; mood/perceptual disturbances. Progresses over 10–15 years; typically strikes in the 60s

Alzheimer’s & Down syndrome

People with Down syndrome who live long enough develop Alzheimer’s, which was a genetic clue. Down syndrome = extra 21st chromosome (which carries the APP gene). Neurodegenerative disorders often come from misshapen/wrong proteins causing cell death

Alzheimer’s etiology

Genetic = 60% of cases: ~10% heritable but multiple genes involved; ~50% narrowed to chromosome 19 (ApoE4 allele). Non-genetic = 40% of cases are idiopathic (unknown cause)

2 pathological hallmarks of Alzheimer’s

• Amyloid plaques (β-amyloid protein)

• neurofibrillary tangles (hyperphosphorylated tau)

Amyloid plaques

The “sticky” things Alzheimer saw; made of beta-amyloid (Aβ) proteins. Two harms: (1) clog up the synapse and (2) disrupt the phospholipid bilayer (cell membrane)

Neurofibrillary tangles

Tau proteins form filaments that transport nutrients/waste inside neurons. Excess phosphate ions attach (hyperphosphorylation) → tau changes structure/unwinds → tangles → transport destroyed → cell death

APP & secretases

β-amyloid precursor protein (APP) gets “cut” by secretase enzymes, and the cutting order matters. Alpha = the good; Gamma = the bad (sometimes); Beta = the ugly.

• Alpha cuts first, then gamma → harmless fragments (p3, C83), no problem

• Beta cuts first, then gamma → Aβ proteins → plaques

Aβ in healthy vs Alzheimer’s brains

Healthy (non-Alz) 50–60 year olds test Aβ positive too

Healthy: Aβ = 5–10% of proteins. Alzheimer’s: Aβ = 40–50% of proteins

Presenilins

It’s genes (PSEN1 & PSEN2) code for presenilin proteins, which are part of the secretase enzymes. Alterations to these genes may cause secretase dysfunction

Gene table: APP & ApoE4

• chromosome 21; onset 45–65; 2–3% of FAD; <1% of all cases

• chromosome 19; onset 60+; % FAD “depends”; 40–50% of all cases

Gene table: Presenilin 1 & 2

• chromosome 14; onset 30–60 (early onset); 70–80% of FAD; 5–10% of all cases

• chromosome 1; onset 40–70 (normal onset); 20% of FAD; 2–3% of all cases

Gene table: quick comparisons

FAD = familial (inherited) Alzheimer’s disease. Most FAD cases = Presenilin 1. Most cases overall = ApoE4. Earliest onset = Presenilin 1 (30–60)

ApoE (apolipoprotein E) alleles

• ApoE4 = increased risk (25%)

• ApoE3 = per lecture, seems to confer resilience

• ApoE2 = third variant (E2 is protective one)

Alzheimer’s brain damage

Global cell death: ~3% of brain mass lost per year. Most damaged: hippocampus, entorhinal cortex, neocortex (association areas), locus coeruleus, raphe nuclei. First structure lost: nucleus basalis of Meynert

Nucleus basalis of Meynert

Releases acetylcholine (ACh) and projects to the neocortex. It’s the first structure lost in Alzheimer’s, so ACh drops → early symptoms (getting lost, etc.). Diagram also shows the pedunculopontine nucleus (PPN), another ACh source, projecting to the thalamus

Treatment: AChEIs

AChE breaks down ACh in the synapse. Acetylcholine esterase inhibitors block → increase ACh

• Drugs: donepezil, rivastigmine, galantamine, help for about 2–3 years

Treatment: BACE inhibitors & intellectual stimulation

they target β-secretase → decrease Aβ; minimal to moderate symptom improvement; in prodromal (early-stage) Alzheimer’s, symptoms WORSENED

• Billings et al. (2007): mice given intellectual stimulation had delayed onset; similar in humans

Treatment: immunization against Aβ

Idea: a vaccine creating immunity to Aβ. Schneck et al. (1999) & Bard et al. (2000) = pre-clinical (animal) studies. Monsenego & Weiner (2003) = clinical trials

Treatment: monoclonal antibodies

Anti-amyloid drugs that bind to amyloid plaques and help remove them: aducanumab, lecanemab, donanemab. Results: reduced plaques but minimal improvement in cognition; depends on disease progression. Donanemab: IV once a month for 18 months; binds plaques so microglia (brain immune cells) clear them

Dominy et al. (2019): background & key terms

“Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors”

• Why: Aβ production resembles an immune response, and studies linked chronic periodontitis (CP, gum disease) and P. gingivalis infection to Aβ, dementia, and Alzheimer’s. P. gingivalis = gum disease bacterium that secretes gingipains (proteases): RgpB and Kgp

Dominy et al. (2019): human tissue findings

• Samples from middle temporal gyrus; AD patients vs. age- and sex-matched controls

• AD brains: 96% positive for RgpB, 91% for Kgp; controls: 39% and 52%

• Strong correlation between tau levels and gingipain load

• Not seen in Parkinson’s, Huntington’s, or ALS samples

• AD patients’ CSF had P. gingivalis DNA; controls’ did not

Dominy et al. (2019): lab & mouse experiments

• In vitro (in a dish): more gingipains → more tau cleavage (positive dose-response)

• In vivo (living mice): saline or gingipain inhibitors injected, then gingipains into the hippocampus 90 min later; tissue collected 7 days later. Saline group had significant neurodegeneration; inhibitor group had none.

• Oral P. gingivalis infection → brain infection and increased Aβ

• More Aβ → more bacterial death, so Aβ may be an antibacterial/immune response

• Takeaway: gingipain inhibitors could be a possible treatment