Fun

Big picture questions

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?

https://theelearningcoach.com/learning/10-definitions-learning/

Learning is the process of acquiring new understanding, knowledge, behaviors, skills, values, attitudes, and preferences. https://en.wikipedia.org/wiki/Learning

  • Non-associative
    • \(A(t+1) = f(A(t))\)
    • Habituation (\(\dot f < 0\)), sensitization (\(\dot f > 0\))
  • Associative
    • \(A \rightarrow B\)
    • Classical & operant/instrumental conditioning
    • Sequence, observational, episodic, semantic…learning

What is memory?

  • A: Information encoding, storage, retrieval

Are there different types of memory?

  • 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 Brains
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 Human memory stores all types of information in patterns of synaptic connections and ???
Computers render these sequences differently based on information about the type of data stored Brains retrieve or recall different forms of information based on ???
Digital computers were inspired by mathematical models of neurons Neurons can be simulated by mathematical models implemented in computers
McCulloch-Pitts [artificial neuron](https://en.wikipedia.org/wiki/Artificial_neuron)

McCulloch-Pitts artificial neuron

Biological bases of memory

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

“a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons.[2] The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.” https://en.wikipedia.org/wiki/Long-term_potentiation

LTP discovery (Bliss & Lømo, 1973)

  • Granule cell neurons in hippocampus dentate gyrus (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

Mechanisms of LTP plasticity

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

Pathways to plasticity

  • Glu release activates
    • ionotropic AMPA Glu receptors
    • metabotropic Glu receptors
    • N-methyl-D-aspartate (NMDA) Glu receptors
  • \(Ca^{++}\) entry via NMDA receptor activates protein kinases (CaMKII and PKAII)
  • Early LTP (up to few hours)
    • protein kinases phosphorylate (add \(P\) group to) postsynaptic AMPA receptors
    • Increase current flow through AMPA (Glu) receptors
  • Late LTP
    • depends on protein synthesis to generate new AMPA receptor
    • insertion of new AMPA receptors into postsynaptic membrane
  • Retrograde signal generator influences presynaptic response
LTP

LTP

Eric R. Kandel

Eric R. Kandel

‘Hebbian’ learning via NMDA receptor

  • N-methyl-D-aspartate receptor (NMDA-R)
    • Name derived from agonist molecule that selectively binds to the receptor
  • ‘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

NMDA clinical significance

  • Memantine (Alzheimer’s Disease treatment)
    • NMDA-R antagonist
    • Controls over-activation and \(Ca^{++}\) excitotoxicity?
  • NMDA-R 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
  • Linked to analgesic effects of nitrous oxide (laughing gas; \(NO\))
  • Alcohol (ethanol) inhibits (Ron & Wang, 2011)

Spike-timing-dependent plasticity

How to learn/remember “causal chains?”

  • e.g., lightning THEN thunder
  • unusual food THEN indigestion
[[@caporale2008spike]](http://dx.doi.org/10.1146/annurev.neuro.31.060407.125639)

(Caporale & Dan, 2008)

[[@caporale2008spike]](http://dx.doi.org/10.1146/annurev.neuro.31.060407.125639)

(Caporale & Dan, 2008)

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

Memory systems

Lashley’s search for the ‘engram’

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

(K. S. Lashley & Clark, 1946)

Modern views

  • Cerebral cortex less central to “engram-like” memory than other areas
[[@squire_memory_2004]](http://dx.doi.org/10.1016/j.nlm.2004.06.005)

(Squire, 2004)

Hippocampus

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

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

Santiago Ramon Y Cajal; Source: Wikipedia

Santiago Ramon Y Cajal; Source: Wikipedia

[[@kjelstrup_finite_2008]](http://dx.doi.org/10.1126/science.1157086)

(Kjelstrup et al., 2008)

[[@maguire2000navigation]](http://dx.doi.org/10.1073/pnas.070039597)

(Maguire et al., 2000)

[[@maguire2000navigation]](http://dx.doi.org/10.1073/pnas.070039597)

(Maguire et al., 2000)

[[@maguire2000navigation]](http://dx.doi.org/10.1073/pnas.070039597)

(Maguire et al., 2000)

[[@sherry_hippocampal_1989]](http://dx.doi.org/10.1159/000116516)

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

  • (Gilmore’s view) Humans have repurposed hippocampal system for other cognitive uses, e.g., semantic memory, language

Cerebellum

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
https://www.pbs.org/wgbh/nova/article/corkin-hm-memory/

https://www.pbs.org/wgbh/nova/article/corkin-hm-memory/

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_alzheimers_2009]](http://doi.org/10.1136/bmj.b158)

(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?

The other end of the spectrum…

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

[[@Luck2013-uo]](http://doi.org/10.1016/j.tics.2013.06.006)

(Luck & Vogel, 2013)

Summary

References

Bliss, T. V. P., & Lømo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol., 232(2), 331–356. Retrieved from http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.1973.sp010273/full
Burns, A., & Iliffe, S. (2009). Alzheimer’s disease. BMJ, 338, b158. https://doi.org/10.1136/bmj.b158
Caporale, N., & Dan, Y. (2008). Spike timing-dependent plasticity: A hebbian learning rule. Annu. Rev. Neurosci., 31, 25–46. https://doi.org/10.1146/annurev.neuro.31.060407.125639
D’Esposito, M., & Postle, B. R. (2015). The cognitive neuroscience of working memory. Annu. Rev. Psychol., 66, 115–142. https://doi.org/10.1146/annurev-psych-010814-015031
Jirenhed, D.-A., Rasmussen, A., Johansson, F., & Hesslow, G. (2017). Learned response sequences in cerebellar purkinje cells. Proceedings of the National Academy of Sciences of the United States of America, 114(23), 6127–6132. https://doi.org/10.1073/pnas.1621132114
Kitamura, T., Ogawa, S. K., Roy, D. S., Okuyama, T., Morrissey, M. D., Smith, L. M., … Tonegawa, S. (2017). Engrams and circuits crucial for systems consolidation of a memory. Science, 356(6333), 73–78. https://doi.org/10.1126/science.aam6808
Kjelstrup, K. B., Solstad, T., Brun, V. H., Hafting, T., Leutgeb, S., Witter, M. P., … Moser, M.-B. (2008). Finite Scale of Spatial Representation in the Hippocampus. Science, 321(5885), 140–143. https://doi.org/10.1126/science.1157086
Lashley, Karl S. (1944). Studies of cerebral function in learning. XIII. Apparent absence of transcortical association in maze learning. Journal of Comparative Neurology. Retrieved from https://onlinelibrary.wiley.com/doi/abs/10.1002/cne.900800207
Lashley, K. S., & Clark, G. (1946). The cytoarchitecture of the cerebral cortex of ateles; a critical examination of architectonic studies. The Journal of Comparative Neurology, 85(2), 223–305. https://doi.org/10.1002/cne.900850207
Luck, S. J., & Vogel, E. K. (2013). Visual working memory capacity: From psychophysics and neurobiology to individual differences. Trends Cogn. Sci., 17(8), 391–400. https://doi.org/10.1016/j.tics.2013.06.006
Maguire, E. A., Gadian, D. G., Johnsrude, I. S., Good, C. D., Ashburner, J., Frackowiak, R. S., & Frith, C. D. (2000). Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Sciences, 97(8), 4398–4403. https://doi.org/10.1073/pnas.070039597
Mišić, B., Goñi, J., Betzel, R. F., Sporns, O., & McIntosh, A. R. (2014). A network convergence zone in the hippocampus. PLoS Comput. Biol., 10(12), e1003982. https://doi.org/10.1371/journal.pcbi.1003982
Ron, D., & Wang, J. (2011). The NMDA receptor and alcohol addiction. In A. M. Van Dongen (Ed.), Biology of the NMDA receptor. Boca Raton (FL): CRC Press/Taylor & Francis. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21204417
Sherry, D. F., Vaccarino, A. L., Buckenham, K., & Herz, R. S. (1989). The Hippocampal Complex of Food-Storing Birds. Brain, Behavior and Evolution, 34(5), 308–317. https://doi.org/10.1159/000116516
Squire, L. R. (2004). Memory systems of the brain: A brief history and current perspective. Neurobiology of Learning and Memory, 82(3), 171–177. https://doi.org/10.1016/j.nlm.2004.06.005