Memory capacity of the human brain?

• 1e12 neurons
• 1e3 synapses/neuron
• 1e15 synapses or 1.25e14 bytes
• 1e9 gigabyte, 1e12 terabyte, 1e15 petabyte

http://www.scientificamerican.com/article.cfm?id=what-is-the-memory-capacity

What is learning?

• Q: Acquisition of new or change in existing knowledge, skills, …
• Non-associative
  • \(A(t+1) = f(A(t))\)
  • Habituation (\(\dot f < 0\)), sensitization (\(\dot f > 0\))
• Associative
  • A -> B
  • Classical & operant/instrumental conditioning
  • Sequence, observational, episodic, semantic

What is memory?

• A: Information encoding, storage, retrieval

Are there different types?

• Facts/events/places/feelings vs. skills
• Short vs. long-term
  • Working memory ~ short-term maintenance for guiding action
• Explicit (declarative: semantic vs. episodic) vs. implicit (procedural)
• Retrospective (from the past) vs. prospective (to be remembered)
• Recognition (judgment of familiarity or novelty) vs. recall

How do computers and brains compare?

• Computers have separate memory and processing stores

• Brains store info everywhere, but there are specialized regions

• Computer memory has specific addresses

• Brains store in distributed networks

• Computer memory is (usually) non-volatile

• Memories in brains naturally fade

• Computer memory stores all types of information–images, sounds, text, data–as binary sequences, e.g., 01101110

• Computers render these sequences differently based on information about the type of data stored

• Digital computers were inspired by mathematical models of neurons

McCulloch-Pitts artificial neuron

Donald Hebb’s Insight

“When an axon of cell A is near enough to excite cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficacy, as on of the cells firing B, is increased.”

(Hebb, 1949, p. 62)

“Neurons that fire together wire together.”

(Lowell & Singer, 1992, p. 211)

Long-term potentiation (LTP) as model of Hebbian learning

Pathways to plasticity

• \(Ca^{++}\) entry activates protein kinases (CaMKII and PKAII)
• Early LTP
  • protein kinases phosphorylate (add \(P\) group to) postsynaptic AMPA receptors
  • Increased current flow through AMPA (glu) receptors
• Late LTP
  • insertion of new receptors into membrane
• Retrograde signal generator influences presynaptic response

‘Hebbian’ learning via NMDA receptor

• N-methyl-D-aspartate receptor (NMDA-R)
• ‘Coincidence’ detector
  • Sending cell has released NT
  • Receiving cell is/has been recently active
• Chemically-gated AND
  • Ligand- (glutamate/aspartate + glycine) gated
  • Sending cell active
• Voltage-gated
  • \(Zn^{++}\) or \(Mg^{++}\) ion ‘plug’ removed under depolarization
  • \(Na^+\) & \(Ca^{++}\) influx; \(K^+\) outflux
  • Receiving cell responds

• NMDA receptor function may vary by location on neuron
  • Long-term potentiation (LTP)
    • Synaptic NMDA receptors
  • Long-term depression (LTD)
    • Extrasynaptic NMDA receptors
    • Lowered level of synaptic receptor activation

Spike-timing-dependent plasticity

How to learn/remember “causal chains”?

• e.g., lightning THEN thunder
• unusual food THEN indigestion

(Caporale & Dan, 2008)

(Caporale & Dan, 2008)

• A before B: strengthen A->B
• A after B: weaken A->B
• Neural Plasticity
  • Lasting changes in neural firing, connectivity
• NMDA receptor molecular mechanism for implementing LTP and spike-timing-dependent plasticity

Lashley’s search for the ‘engram’

• Is memory ‘localized’ like sensory and motor functions? (Lashley, 1944)

““the area subdivisions are in large part anatomically meaningless and misleading as to the presumptive functional divisions of the cortex””

(Lashley & Clark, 1946)

Modern views

• Cerebral cortex less central to “engram-like” memory than other areas

(Squire, 2004)

Hippocampus

https://upload.wikimedia.org/wikipedia/commons/5/5b/Hippocampus_and_seahorse_cropped.JPG

• Dense in NMDA receptors
• Central “hub” in network?
  • No, based on anatomical or functional connectivity
  • But yes, when modeling “information flow” (Mišić, Goñi, Betzel, Sporns, & McIntosh, 2014)
• Formation, storage, consolidation of long-term episodic or declarative memories
• Stores info for later transfer to cortex
  • “Engrams” form in hipp & PFC simultaneously, fade in PFC over time (Kitamura et al., 2017)
• Spatial navigation
  • Place cells
  • Grid cells
  • Head-direction cells

(Kjelstrup et al., 2008)

(Maguire et al., 2000)

(Maguire et al., 2000)

(Maguire et al., 2000)

(Sherry, Vaccarino, Buckenham, & Herz, 1989)

Cerebellum

• response timing, sequences, especially in classical conditioning paradigms (Jirenhed, Rasmussen, Johansson, & Hesslow, 2017)

Disorders of memory

Amnesia

• Acquired loss of memory
• ≠ normal forgetting
• Retrograde (‘backwards’ in time)
  • Damage to information acquired pre-injury
  • Temporally graded
• Anterograde (‘forward’ in time)
  • Damage to information acquired/experienced post-injury

Patient HM (Henry G. Molaison)

• Intractable/untreatable epilepsy
• Bilateral resection of medial temporal lobe (1953)
• Epilepsy now treatable
• But, memory impaired
• Lived until 2008

http://www.pbs.org/wgbh/nova/body/corkin-hm-memory.html

HM’s amnesia

• Retrograde amnesia
  • Can’t remember 10 yrs before operation
  • Distant past better than more recent
• Severe, global anterograde amnesia
  • Impaired learning of new facts, events, people
• But, skills (mirror learning) intact

“Every day is alone in itself, whatever enjoyment I’ve had, and whatever sorrow I’ve had…Right now, I’m wondering, have I done or said anything amiss? You see at this moment, everything looks clear to me, but what happened just before? That’s what worries me. It’s like waking from a dream. I just don’t remember.”

Other causes of amnesia

• Disease
  • Alzheimer’s, herpes virus
• Korsakoff’s syndrome
  • Result of severe alcoholism
  • Impairs medial thalamus & mammillary bodies

Patient NA

• Fencing accident
• Damage to medial thalamus
• Anterograde + graded retrograde amnesia
• Are thalamus & medial temporal region connected?

Spared skills in amnesia

• Skill-learning
• Mirror-reading, writing
• Short-term memory
• “Cognitive” skills
• Priming

What does amnesia tell us?

• Long-term memory for facts, events, people
• ≠ Short-term memory
• ≠ Long-term memory for “skills”
• Separate memory systems in the brain?

Alzheimer’s Disease (AD)

• Chronic, neurodegenerative disease affecting ~5 M Americans
• Cognitive dysfunction (memory loss, language difficulties, planning, coordination)
• Psychiatric symptoms and behavioral disturbances
• Difficulties with daily living
• (Burns & Iliffe, 2009)

Progression

(Burns & Iliffe, 2009)

• Post-mortem exams show \(\beta\) amyloid plaques and neurofibrillary tangles

Treatments

• Acetylcholinesterase (AChE) inhbitors (e.g. Aricept)
• NMDA-R partial antagonists (e.g., Memantine)
• Drugs that address amyloid \(\beta\) don’t work especially well
• AD the result of disordered immune response?

What about working memory? (D’Esposito & Postle, 2015)

• LTM representations of target items + attention -> elevated activation
  • Semantic items
  • Sensorimotor items
• Capacity for attended items (in Focus of Attention or FoA) limited ~ 4
• Neural basis
  • sustained activation in PFC
  • subthreshold activation in areas where items are stored

Individual differences in visual WM

(Luck & Vogel, 2013)