Explore the intricate mechanisms of memory formation and recall in this comprehensive document. From molecular processes to systematic functions, uncover the role of neurotransmitters, receptors, and synaptic plasticity. Understand how the hippocampus contextualizes experiences and encodes memories...
Memory
The most general definition of “memory” is nothing but a system persistently changing
its way of responding to a situation (learning). Thus, we can identify a number of molecular
mechanisms that – through neuronal and synaptic plasticity – are able to change the way a neural circuit
responds to stimuli and experiences.
But memory as we embrace it nowadays is not only the capability of a system to give a different response
to the same input (based on something that was memorized): we talk about a slightly higher sense that
refers to the idea that some association is made either between two external events or between an
external event and an internal situation or between two internal situations etc. The core element is that
it is always a problem of association.
Learning means to be able to establish connections. This is the reason why some mechanisms of
learning are particularly important: we have both non- associative mechanisms and associative ones.
The typical non-associative one is described by Kandel with the experiment of an aplysia.
• If you slightly stimulate, by touching, one of the tentacles, then the aplysia is going to retract it.
• After having it done many times, the aplysia is not going to move it anymore as it “learned” that
nothing harmful came after.
It is “associative” in a negative way (i.e. non-associative): as the stimulus is not associated with anything,
it loses every capability of evoking a reaction. Therefore, the same stimulus loses the capability of
producing a reaction.
On the other hand, what happens when you actually
couple a stimulus with a nociceptive effect is that it
becomes an associative-learning:
• If you stimulate pain on the tentacles (you pin
them) of the aplysia, it is going to retract the
tentacle.
• The more you do it, the more it learns that it needs
to avoid contact.
The non-associative learning aspect may be interesting
and certainly there are some aspects in our brain that use
it, but the associative aspects of memory are obviously
much more relevant.
Molecular plasticity
A number of mechanisms produce long-term changes in synaptic efficiency that can account for
persistent changes in the way a neuronal network elaborates information (plasticity).
The most relevant ones are the glutamate-dependent, AMPA+NMDA receptors activation, cerebellar
plasticity (long-term depression), dopamine (and presumably serotonin) dependent plasticity in the basal nuclei, and
spike-time-dependent plasticity (STDP).
The NMDA receptor is the most clear and typical example of nonlinear responsiveness, and the
best mechanism to change the behaviour of a network in response to its own activation.
When glutamate binds to the NMDA receptor the pore in the receptor-channel opens. However, the
pore will typically remain plugged by a magnesium ion, which has entered the extracellular vestibule
of the pore by chance and is strongly attracted toward the negative inside by its 2 positive charges; since
it cannot permeate the channel, it blocks it.
Only if the cell is at least partially depolarized will magnesium leave and the channel will let ions through.
The channel is permeable to calcium, so if the neuron is depolarized (has been activated by some other
stimulus) it will let some Ca2+ in; when this happens, a relatively prolonged depolarizing current
will be observed (the NMDA receptor has high affinity and the bond with glutamate tends to persist). As
a result of pre-existing depolarization + NMDA-mediated current, some calcium may also enter through
voltage-dependent channels.
All this implies that activating a glutamatergic synapse produces a transient depolarization (through
AMPA receptors) that is integrated with all other inputs to elaborate information; the response will
rapidly switch off, but activating the same synapse several times in rapid sequence, or activating two
209 Body At Work II
, Enrico Tiepolo
nearby synapses at short intervals, will open the NMDA receptor channel while the postsynaptic
membrane is being locally depolarized by glutamate (just released at the same or at a nearby synapse),
and Ca2+ level in the postsynaptic cell will rise.
Again, an activation of NMDA receptor will produce different effects depending on whether the postsynaptic neuron is
depolarized or not: this is the reason why glutamatergic systems are so important and it is linked to the associative aspects of
our brain.
Since calcium levels may change depending on the depolarization status, many elements will influence
its concentration:
• Voltage dependent calcium channels
• Superimposed activation of AMPA (which will cause further depolarization)
• Superimposed activation of NMDA receptors which, depending on the state of depolarization,
may or may not add more calcium
Therefore, you may realize that this series of events that can either:
• Change in calcium concentration
• Significantly change in calcium concentration
The cell must react to different Ca2+ concentrations in opposite ways. Calcium will bind to calmodulin
but different levels of increase in cytosolic [Ca2+] will activate it to different extents, triggering different
Ca-calmodulin (CaM) dependent processes.
In neurons:
- low levels of CaM activation activate calcineurin, which is a phosphatase and will shift the balance
towards dephosphorylation of substrates, (weak system as it only enhances the activity of
protein-phosphatase-1).
- higher levels can activate CaMK, a family of powerful kinases which will definitely shift the balance
toward phosphorylation.
This way, differential activations of one or more synapses on a neuron may produce an electrical signal
to be elaborated and nothing more, or alternatively, in addition to it, they may produce
dephosphorylation (or vice versa phosphorylation) of protein substrates, thereby depressing or activating
biochemical paths in the postsynaptic neuron.
Memory and learning processes, based on NMDA activation, are nonlinear and associative.
- They are nonlinear in that a hundred stimuli delivered to the presynaptic neuron may well produce
a total current which is 100 times the one produced by a single stimulus, but if they are delivered at
an appropriate frequency they may produce additional (nonlinear) effects, such as (1)
phosphorylation of critical substrates and possibly long-term potentiation of synaptic efficiency (if
the frequency is high and Ca2+ levels increase significantly), or vice versa (2) dephosphorylation and
possibly long-term depression of synaptic efficiency (if impulses are administered at low rate and
produce mild increases in [Ca2+]).
- It is associative in that for many neurons the activation of a single input at any frequency may not
be able to induce a plastic change, whereas the activation of two or more synapses in the appropriate
210 Body At Work II
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