Memory#
How memory came to be understood, from the neuron doctrine to Kandel's work on synapses, genes and long-term potentiation.
About this chapter
A historical account in two parts. The first covers how neurons were found to be separate cells that signal in one direction (Cajal, Sherrington), that the signal is electrical along the axon (Adrian, Hodgkin and Huxley), and that it is chemical across the synapse (Dale, Loewi, Katz).
The second part is about memory itself. Patient H.M. showed that memory is a separate function and that the hippocampus is needed to turn short-term memories into long-term ones. Kandel’s work on Aplysia then found the mechanism: short-term memory changes how much transmitter a synapse releases, while long-term memory needs new proteins (cAMP, PKA, CREB) and grows or removes synapses. The chapter closes with place cells, Alzheimer’s and consciousness. The brain basics chapter covers the same molecules in more detail.
History#
The neuron doctrine has four parts: the neuron is the unit, synapses separate neurons, specific neurons connect to specific others, and signals flow one way.
The Neuron Doctrine – the neuron is the fundamental building block and elementary signaling unit of the brain
Golgi – develops silver staining method which allows Cajal to see entire neuron
Santiago Ramon y Cajal – Spanish anatomist who simplifies neuron forest and looks at individual neurons, develops model with dendrites, cell body, and axon
4 parts: neuron, synapse, connection specificity (specific neurons connect to specific others), dynamic polarization (signals travel in one direction)
Freud looks into Cajal’s theories, but doesn’t incorporate them
1906 – they share Nobel despite Golgi hating Cajal’s theories
1955 – Cajal’s intuitions borne out conclusively
Next generation#
The next steps: Sherrington found that neurons integrate inputs and that some inputs inhibit, Adrian that spikes all have the same size and intensity is coded by their frequency, Hodgkin and Huxley found the voltage-gated Na⁺ and K⁺ channels, and Dale, Loewi and Katz showed that most synapses are chemical and release transmitter in quanta.
Sherrington – builds on Cajal’s work – finds that neurons integrate signals and some signals are inhibitory
Shares Nobel with Adrian in 1932 – Adrian is younger and grateful
Phases of Nerve Signaling
Galvani discovers electrical activity in animals, Helmholtz measures speed of electrical signals in neurons
Adrian measures action potentials and sees that they all have the same size and that intensity correlates with their frequency
Bernstein (student of Helmholtz) finds that ions carry the electrical current – he investigates only the potassium ion
Ionic hypothesis – Hodgkin, Huxley (and Katz) – find sodium, potassium in squid axon using voltage clamp, discover voltage-gated channels, win Nobel in 1963
Interneuronal signaling
1920s – Dale and Loewi find that synaptic transmission is chemical - use acetylcholine in frogs
synaptic potential – has different sizes, slower – only over synapses (can be excitatory or inhibitory, can generate action potential)
long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity
Eccles – believed in spark theory (synaptic transmission was electrical), but after talking to Popper disproves it with Katz and believes in soup theory (synaptic transmission is chemical)
Glutamate – major excitatory neurotransmitter
GABA – main inhibitory transmitter
Katz’s lab later showed there are a few synapses that are electrical
Katz – found that neurotransmitters were released by voltage-gated gates letting in Ca ions
Packets of neurotransmitters called quanta are released in synaptic vesicles
Confirmed in in 1955
Modern generation#
Read the Aplysia bullets as a chain: serotonin from a modulatory interneuron raises cAMP in the sensory neuron, which boosts glutamate release for minutes; repeated pulses send PKA into the nucleus to switch on CREB, and the resulting proteins build new synapses that last.
Four Lobes
Frontal – working memory and lots of stuff
Temporal – auditory processing, language, and memory
Parietal – sensory information
Occipital – vision
Brain maps - Marshall showed that, even though the different sensory systems carry different types of information and end up in different regions of the cerebral cortex, they share a common logic in their organization: all sensory information is organized topographically in the brain in the form of precise maps of the body’s sensory receptors
Broca and Wernicke find that specific brain regions are in charge of specific functions
Broca’s area- expression of language
Werknicke’s area – perception of language
Patient H.M. – research by Brenda Milner
He couldn’t store new memories although he could learn new skills
Memory is a distinct mental function, clearly separate from other perceptual, motor, and cognitive abilities.
Short-term memory and long-term memory can be stored separately. Loss of medial temporal lobe structures, particularly loss of the hippocampus, destroys the ability to convert new short-term memory to new long-term memory.
There is explicit and implicit memory (implicit is a collection of processes)
Milner showed that at least one type of memory can be traced to specific places in the brain
Early Eric Kandel
Gets lucky start recording in hippocampus
Decides to start recording in Aplysia – large and has only 20,000 neurons separated into nine ganglia (human brain ~ 100 billion)
Hypothesizes that persistent changes in the strength of synaptic connections results in memory storage
just as neurons and their synaptic connections are exact and invariant, so, too, the function of those connections is invariant.
First, we found that the changes in synaptic strength that underlie the learning of a behavior may be great enough to reconfigure a neural network and its information-processing ability
a given set of synaptic connections between two neurons can be modified in opposite ways— strengthened or weakened—by different forms of learning.
Third, the duration of short-term memory storage depends on the length of time a synapse is weakened or strengthened.
Fourth, we were beginning to understand that the strength of a given chemical synapse can be modified in two ways, depending on which of two neural circuits is activated by learning—a mediating circuit or a modulatory circuit
Learning may be a matter of combining various elementary forms of synaptic plasticity into new and more complex forms, much as we use an alphabet to form words.
forgetting had at least two phases: a rapid initial decline that was sharpest in the first hour after learning and then a much more gradual decline that continued for about a month.
Homosynaptic - the depression occurred in the same neural pathway that was stimulated
Strengthening synapses = greater responses
Short-term to Long-term
Memory consolidation – short-term is subject to disruption
Head injuries or seizures can lead to retrograde amnesia – you forget what was in you short-term memory
Electric shocks were able to get rid of short-term memory
A short-term memory lasting minutes is converted—by a process of consolidation that requires the synthesis of new protein—into stable, long-term memory lasting days, weeks, or even longer
Long-term memory results in growing or shedding synapses
As the memory fades, the number of synapses goes almost back to normal, with the difference accounting for relearning a task easier
Recall
Based on cues, in the case of Aplysia gill-withdrawal, external stimulus
Short-term
Short-term memory changes are presynaptic - during short-term habituation lasting minutes, the sensory neuron releases less neurotransmitter, and during short-term sensitization it releases more neurotransmitter
Relies on interneurons:
Mediating circuits – produce behavior directly, sensory neurons that innervate the siphon, the interneurons, and the motor neurons that control the gill-withdrawal reflex
Modulatory circuits - not directly involved in producing a behavior but instead fine-tunes the behavior in response to learning by modulating—heterosynaptically—the strength of synaptic connections between the sensory and motor neurons
For example, in gill-withdrawal sensitization, interneurons release serotonin into the presynaptic terminals of the sensory neurons
This generates a long, slow synaptic potential in the motor neurons
Ionotropic receptors – neurotransmitter-gated, open ion channels
Metabotropic receptors – gated, activate enzymes; these enzymes can make cyclic AMP, act much longer
Serotonin binds to metabotropic receptors in the presynaptic terminal of sensory neurons increasing the amount of cAMP and in turn the amount of glutamate
This was verified in studies of Drosophila
Sensory regions map to specific places in brain, keeping proximity
Pavlov
Habituation – animal repeatedly presented with neutral sensory stimulus learns to ignore it
Sensitization – animal learns strong stimulus is dangerous and enhances its defensive reflexes
Classical Conditioning – pair neutral stimulus with potentially dangerous stimulus, animal learns to respond to neutral stimulus
Long-term memory
Proteins must be made - DNA makes RNA, and RNA makes protein
The serotonin itself was able to make new synapses grow via synthesis of proteins in the nucleus
Genes
There are effector genes which mediate cellular functions and regulatory genes which switch them on and off
Genes have regions called promoters and repressors and regulatory proteins must bind to these in order to express them
With repeated pulses of serotonin, kinase A move into the nucleus – turn on regulatory protein called CREB which turns on some genes
Also requires turning off other genes
MAP kinase also moves into nucleus and depresses CREB-2
Together, activating CREB and deactivating CREB-2 transfers short-term memories to long-term
Synaptic marking – the proteins produced in the nucleus know which synapses to go to because of their short-term changes
Proteins must be synthesized locally at the synapses
Dormant mRNA is sent to all the synapses
There is a protein called CPEB that is activated by serotonin and is required by the synapses to maintain protein synthesis
Resembles a prion – special protein with dominant and recessive conformation, dominant can be harmful
Dominant is self-perpetuating – turns recessive into dominant
Explicit memory - depends on the elaborate neural circuitry of the hippocampus and the medial temporal lobe, and it has many more possible storage sites.
Long-term potentiation - synaptic strengthening mechanism in the hippocampus
long-term potentiation describes a family of slightly different mechanisms, each of which increases the strength of the synapse in response to different rates and patterns of stimulation
glutamate acts on two different types of ionotropic receptors in the hippocampus, the AMPA receptor and the NMDA receptor. The AMPA receptor mediates normal synaptic transmission and responds to an individual action potential in the presynaptic neuron. The NMDA receptor, on the other hand, responds only to extraordinarily rapid trains of stimuli and is required for long-term potentiation flow of calcium ions into the postsynaptic cell acts as a second messenger (much as cyclic AMP does), triggering long-term potentiation - allows calcium ions to flow through its channel if and only if it detects the coincidence of two neural events, one presynaptic and the other postsynaptic: The presynaptic neuron must be active and release glutamate, and the AMPA receptor in the postsynaptic cell must bind glutamate and depolarize the cell.
explicit memory in the mammalian brain, unlike implicit memory in Aplysia or Drosophila, requires several gene regulators in addition to CREB
Cognitive science - Kantian notion that the brain is born with a priori knowledge, “knowledge that is … independent of experience.”
Visual system
Different layers respond to different things - each cell in the primary visual cortex responds only to a specific orientation of such light-dark contours
The brain does not simply take the raw data that it receives through the senses and reproduce it faithfully. Instead, each sensory system first analyzes and deconstructs, then restructures the raw, incoming information according to its own built-in connections and rules
What and where are different neural pathways
there is no single cortical area to which all other cortical areas report exclusively, either in the visual or in any other system. In sum, the cortex must be using a different strategy for generating the integrated visual image.
Spatial Map
the hippocampus of rats contains a representation—a map—of external space and that the units of that map are the pyramidal cells of the hippocampus, referred to as “place cells.”
The brain sometimes codes with coordinates centered on the receiver and sometimes relative to the outside world
Attention acts as a filter, selecting some objects for further processing
A modulating circuit involving dopamine in the hippocampus forms spatial maps
The dopamine comes from the cerebral cortex (a higher level part of the brain)
Eric Kandel tried to translate his research into a cure for age-related memory loss
Alzheimer’s: This degeneration of tissue is caused in large part by the accumulation of an abnormal material known as ß-amyloid in the form of insoluble plaques in the spaces between brain cells.
We found that drugs which activate these dopamine receptors, and thereby increase cyclic AMP, overcome the deficit in the late phase of long-term potentiation. They also reverse the hippocampus-dependent memory deficit.
Various disorders are being solved slowly through research
Consciousness
consciousness in people, is an awareness of self, an awareness of being aware.
The brain does reconstruct our perception of an object, but the object perceived—the color blue or middle on the pia no—appears to correspond to the physical properties of the wavelength of the reflected light or the frequency of the emitted sound
Claustrum is connected to a bunch of different brain parts – could regulate attention
viewing frightening stimuli activates two different brain systems, one that involves conscious, presumably top-down attention and one that involves unconscious, bottom-up attention, or vigilance
readiness potential can measure what a person is going to do before they know they want to do it
Key ideas
The neuron doctrine: neurons are separate cells, connected at synapses to specific partners, with signals flowing one way.
Signals are electrical along the axon (spikes of fixed size, with intensity coded by their rate) and chemical across most synapses (transmitter released in quanta).
Patient H.M. showed that memory is a separate function and that the hippocampus is needed to turn short-term memories into long-term ones.
Short-term memory changes how much transmitter existing synapses release; long-term memory needs new proteins (PKA, CREB) and grows or removes synapses.
Hippocampal LTP needs the NMDA receptor, which passes Ca²⁺ only when presynaptic release and postsynaptic depolarization coincide.