• Learning & memory

• 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

• 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

• A: Information encoding, storage, retrieval
• Dimensions
  • 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 (familiar or novel) vs. recall

• Changes in patterns of neural activity
• Changes in connectivity
  • New synapses
  • Altered synapses (strengthened or weakened)
• Computers have separate memory stores; brains store info everywhere

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).

• N-methyl-D-aspartate receptor (NMDAR)
• '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

• Memantine (Alzheimer's Disease treatment) blocks NMDAR
  • Controls over-activation and \(Ca^{++}\) excitotoxicity?
• Implicated in effects of phencylidine (PCP)
  • Link to glu hypothesis of schizophrenia?

• Ketamine is NMDA receptor antagonist
  • anesthesia, sedation pain relief
  • possible short-term relief for depression
• Analgesic effects of nitrous oxide (laughing gas; NO)
• Ethanol inhibits (Ron and Wang 2011)

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

• 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

• Long-term potentiation (LTP)
  • Synaptic NMDA receptors
• Long-term depression (LTD)
  • Extrasynaptic NMDA receptors
  • Lowered level of synaptic receptor activation

• Granule cell neurons in hippocampus DG
• \(\theta\) band (10–20 Hz) stim for 10–15 sec, or 100 Hz stim for 3–4 sec
• shortened response latency, increased EPSP, increased population response over minutes or hours

• number of synaptic receptors
• quantity of NT released
• effectiveness of postsynaptic response

• \(Ca^{++}\) 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

• Memory of what or how recalled/recognized
  • Facts/events/places/feelings vs. skills
• Memory of when?
  • Immediate vs. distant past
• Memory for how long?
  • Seconds vs. years

• Dense in NMDA receptors
• Central "hub" in network?
  • No, based on anatomical or functional connectivity
  • But yes, when modeling "information flow" (Mišić et al. 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

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

• Acquired loss of memory
• ≠ normal forgetting
• Note: computers don't forget

• 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

• Retrograde ('backwards' in time)
  • Damage to information acquired pre-injury
  • Temporally graded
• Anterograde ('forward' in time)
  • Damage to information acquired/experienced post-injury

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.

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

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

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

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

• 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 and Iliffe 2009)

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

• Acetylcholinesterase (AChE) inhbitors (e.g. Aricept)
• NMDAR partial antagonists (e.g., Memantine)

• 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

• Multiple types of learning & memory
• Learning & memory distributed across the brain
• Hippocampus + PFC critical areas binding together sensory/semantic info stored elsewhere
• Changes in synaptic #, strength, connectivity provide cellular basis