S. D. V. Stephens

notes / Basic Neuroscience and Geometry of Neuroscience / chapter 2: Brain and Behavior

4 Learning and Memory

This lecture has three aims: to understand how the brain is plastic to its environment, to describe how the brain develops, and to explain how learning is formed and maintained.

Experience changes the brain

In a classic enrichment experiment, rats lived from 25 to 105 days of age in an “Environmental Complexity and Training cage”: a large wire cage shared by many rats, fitted with ladders, shelves, a running wheel and other objects to explore. Their brains were then compared with those of rats raised in isolation.

Bar chart of brain weight in isolated and enriched rats: the cortex is about 6% heavier in enriched rats, while the rest of the brain weighs about the same in both groups.

The cortex of the enriched rats weighed about 6% more than that of the isolated rats (about 665 against 630 on the graph’s weight scale), while the rest of the brain weighed about the same in both groups (about 900).

Besides brain weight, the effects of environmental enrichment extended to:

  1. an increase in the number of neurons,
  2. an increase in the amount of neurotransmitters,
  3. an increase in the number of synapses, and
  4. an increase in the amount of myelination.

Hebb and the principles of plasticity

Donald Hebb (1904–1985) summed up the idea in a phrase: “Neurons that fire together wire together.” Experience can enhance or reduce synapses, and in this way alter the brain and its function. Hebb proposed this before anyone had seen a synapse: the first microscopic views of synapses came almost a decade after he put these ideas forward.

Hebb’s principles of experience-based plasticity:

  • 1. Use it or lose it.
  • 2. Use it to improve it. Two things strengthen a synapse:
    • 3. repetition of stimulation;
    • 4. intensity of stimulation.
  • 5. Regional and functional specificity.

Principles 1, 2 and 5 are the three main Hebbian principles; 3 and 4 are the two ways of “using it to improve it.”

Use it or lose it: long-term depression

Only synapses that are being actively used are maintained.

Three panels of a neuron with two input synapses: both inputs active, then the red input falls silent, then the unused red synapse withdraws while the active blue one stays.

The diagram follows one neuron with two input synapses. At first both inputs are active (+ + +). Then the red input stops firing, and finally that unused synapse withdraws from the neuron, while the blue input, still in use, stays.

At the level of a single synapse, “use it or lose it” takes the form of long-term depression.

Definition 4.1 (Long-term depression). Long-term depression (LTD) is a long-lasting weakening of a synapse: afterwards, the same input produces a smaller excitatory postsynaptic potential (EPSP) in the receiving neuron.

Graph of EPSP slope over time: steady near 1.4, then after 10 minutes of 1–10 Hz stimulation it drops to about 0.8 and stays low for two hours, with sample EPSPs smaller after than before.

In the experiment shown, the slope of the EPSP (a measure of the synapse’s strength) held steady at about 1.4 for half an hour. The input was then stimulated at a low frequency (1–10 Hz) for 10 minutes. Afterwards the EPSP slope fell to about 0.8 and stayed down, drifting to about 0.7 two hours later. Sample EPSPs recorded before and after show the same thing: the response after LTD is clearly smaller.

The mechanism:

  • Activation of AMPA and NMDA receptors is required to maintain a synapse. AMPA and NMDA receptors are types of glutamate receptors.
  • A lack of (or only weak) AMPA and NMDA receptor activation reduces the number of these receptors on the cell membrane, which decreases the excitability of the neuron.
  • A lack of activation of these receptors causes structural breakdown of the synapse.

LTD in practice

  • LTD is necessary for synaptic pruning (see below).
  • It underlies cognitive flexibility: un-learning bad habits and fears, and overcoming addiction.
  • Neurodegenerative diseases are characterized by widespread LTD in the brain.
  • Loss of beneficial synapses increases the risk of mental health disorders.

Use it to improve it: long-term potentiation

Synaptic strength can be enhanced by

  1. repeated stimulation, and
  2. particularly strong stimuli (for example, drugs).

Functions are preserved with use.

An input synapse used normally beside the same synapse after repeated or strong stimulation, which ends in a larger, stronger terminal.

In the diagram, an input that is stimulated more (+ + + + + in place of + + +) ends in a larger terminal: the synapse has grown stronger.

Definition 4.2 (Long-term potentiation). Long-term potentiation (LTP) is a long-lasting strengthening of a synapse after high glutamate activity at it: afterwards, the same input produces a larger response in the receiving neuron.

Current in a postsynaptic cell of a normal mouse: a small downward response to the first stimulus and a response several times larger to a same-size stimulus one hour later.

The first graph comes from normal mice. It records the current flowing in a postsynaptic cell after a stimulus to its input (responses are plotted as downward deflections). The response to the first stimulus is a small dip that is over within about 20 ms. One hour later, a stimulus of the same size produces a response several times larger, which takes about 45 ms to return to baseline. Since the stimulus was the same size, the change lies in the synapse.

Graph of EPSP slope over time: steady near 1.0, then after 1 second of 100 Hz stimulation it jumps to about 1.75 and stays near 1.6 for two hours, with sample EPSPs larger after than before.

The second experiment mirrors the LTD one. The EPSP slope held steady at about 1.0; the input was then stimulated at a high frequency (100 Hz) for 1 second. Afterwards the EPSP slope jumped to about 1.75 and was still raised, at about 1.6, two hours later. The sample EPSP after LTP is much larger than the one before.

The mechanism:

  • After high glutamate activity at a synapse, the synapse strengthens.
  • Elevated input to a neuron from its synapses increases the number of AMPA and NMDA receptors on the cell membrane. As a result,
    • less stimulation is needed to trigger action potentials, and
    • the synapse becomes stronger through increased synaptic density.
A normal synapse beside a potentiated one; the potentiated synapse releases more neurotransmitter, has more receptors on the dendritic spine, and has a larger spine with more sodium and calcium entry.

The diagram compares a normal synapse with a potentiated one. In the normal synapse, the presynaptic terminal holds vesicles of neurotransmitter; transmitter released into the synaptic cleft (about 20 nm wide) binds receptors on a dendritic spine and lets Na and Ca into the spine. Going from normal to potentiated raises synaptic strength, and three things have changed: (1) more neurotransmitter is released into the cleft, (2) there are more receptors on the spine, and (3) the spine is larger, with a wider neck, and more Na and Ca flow in.

LTP in practice

  • Strengthening of synapses can last from minutes to several months.
  • LTP forms the foundation of learning, memory, cognition, sensory processing, drug addiction, and most mental health disorders.
  • Alzheimer’s disease and dementia are linked to impaired LTP.

Regional and functional specificity

Synaptic changes happen only in the brain regions specific for that function.

An oxytocin neuron and a dopamine neuron each receive an active input; after cocaine only the input to the dopamine neuron is strengthened.

The diagram shows two neurons, each receiving an active input (+ + +): an oxytocin (OT) neuron and a dopamine (DA) neuron. After cocaine, only the synapse onto the dopamine neuron is strengthened (+ + + + +, larger terminal); the synapse onto the oxytocin neuron is unchanged.

Brain development and pruning

How the brain develops

The slide traces the human brain through development. At 3 weeks the brain is a curved tube with three swellings, the forebrain, midbrain and hindbrain, running on into the spinal cord. By 7 weeks the forebrain has begun to bulge and cranial nerves leave the hindbrain. By 11 weeks the forebrain is much larger than the other parts. Its surface stays smooth until about 6 months, then folds rapidly; at birth the folded forebrain covers most of the brain, the midbrain is hidden beneath it, and the cerebellum and medulla sit at the back and base. A second series of drawings (3, 4, 5, 7 and 11 weeks; 4, 6 and 8 months; newborn) shows the same growth and folding.

Pruning

Maturation of the brain involves a reduction in neurons and synapses!

Definition 4.3 (Pruning). Pruning is the reduction in the number of neurons and synapses during development. It is a normal part of brain maturation.

Approximately 50% (!) of the neurons and synapses that we have as newborns are eliminated by the time we become adults. The slide illustrates the word with a photo of pruning shears cutting back a plant, next to a fluorescent image of a single neuron and its branches.

Changes in neuron number with age

Line graph of neurons in visual cortex against age: about 9 million at birth, a peak of about 14.5 million at 2 weeks, then a decline to about 9 million at 11 years.

Beginning prenatally and continuing until shortly after birth, the number of neurons keeps increasing. Then the number of neurons begins to decrease into adolescence. In the slide’s graph of neurons in the visual cortex, the count rises from about 9 million at birth to a peak of about 14.5 million at 2 weeks, then falls to about 13.7 million at 3 years, 10.8 million at 5 years and 9 million at 11 years.

Changes in synapse number with age

Synapse density in human visual cortex: low before birth, a steep rise in infancy to a peak at 8 months after birth, then a decline through childhood to age 10.

Just like the number of neurons, the number of synapses peaks after birth and then declines, and this decline is due to pruning of synapses. In the human visual cortex (data from Huttenlocher, 1984), synapse density is low in the prenatal period, climbs steeply during infancy to a peak at 8 months after birth, and then declines through childhood to 10 years old. A drawing beside the graph shows a single neuron contacted by many incoming axons; at each later stage fewer of those contacts remain.

Synapse maturation: strengthening and refinement

  • Synapse stabilization requires neuronal activity.
  • Correct connections get strengthened.
  • Incorrect connections get removed (pruned).
Three motor axons and three muscle fibres: at birth every axon branches onto every fibre, while in maturity each fibre is innervated by a single axon.

The slide shows this refinement in two places. At birth, each target neuron is contacted by thin branches of several different axons, and each muscle fibre receives endings from several motor axons. In maturity, each neuron is innervated by a single axon that has spread a dense set of branches over it, and each muscle fibre receives a single axon ending. The figure above redraws the muscle case.

Is plasticity always good?

Is plasticity, and the strengthening of connections, always good? Cocaine induces plasticity of dendrites, in particular of their spines, and this increased plasticity may be part of the basis for addiction.

Dendritic spines are the small protrusions along a dendrite where presynaptic axons form synapses. The slide’s drawing of a neuron labels its dendrites, the spines covering them, a synapse between a presynaptic axon and a spine, and the axon; a fluorescent image shows a real neuron whose dendrites are studded with spines. Images of single dendrites from animals given daily cocaine or daily saline (scale bar 10 μm) show the cocaine dendrite carrying more, and bulkier, spines.

Bar chart of dendritic spine density: about 7.8 spines per 10 micrometres in controls and about 8.3 after cocaine, a 6.4% increase.

Counted, spine density was about 7.8 spines per 10 μm in controls and about 8.3 in cocaine-treated animals, an increase of 6.4% (the graph’s vertical axis starts at 7.5).

Learning and sensitive periods

Definition 4.4 (Perineuronal nets). Perineuronal nets (PNNs) are net-like structures that physically surround neurons and their synapses. They “stabilize” synapses by preventing new connections from being made and existing connections from breaking off.

PNNs mediate sensitive periods in development: the windows of time in which experience shapes the brain most easily. The slide’s drawing contrasts a consolidated (mature) neuron, wrapped in a dense net, with a plastic one, in which the net has been loosened (“dematuration”). Below it are two stained tissue sections (scale bars 50 μm) and fluorescence images of a single neuron (green) enclosed by its net (red), shown separately and merged. The next slide shows two more fluorescence micrographs of labelled neurons, without labels.

The mesolimbic reward system

The reward system is called mesolimbic because its dopamine neurons run from the midbrain to limbic regions such as the nucleus accumbens.

Reward circuit diagram: dopamine from the ventral tegmental area to the nucleus accumbens, prefrontal cortex, amygdala and hippocampus; glutamate into the nucleus accumbens; GABA from the nucleus accumbens to the ventral pallidum and between the nucleus accumbens and the ventral tegmental area.

The slide’s diagram of the reward circuit shows the regions involved and the transmitters linking them:

  • Dopamine (DA): neurons in the ventral tegmental area (VTA) project to the nucleus accumbens, the prefrontal cortex, the amygdala and the hippocampus.
  • Glutamate (GLU): the nucleus accumbens receives input from the prefrontal cortex, the hippocampus and the amygdala.
  • GABA: the nucleus accumbens sends output to the ventral pallidum and to the VTA, and GABA neurons in the VTA project back to the nucleus accumbens.

Memory formation

  • Memory formation involves synaptic strengthening and neurogenesis (the birth of new neurons) in the hippocampus.
  • The hippocampus regulates memory encoding, storage, and retrieval.

The slide’s drawing shows the hippocampus as a curved structure deep in the temporal lobe, with the amygdala at its front end; its caption reads: “Hippocampus plays a crucial role in the formation of new memories and in the detection of new surroundings, stimuli and occurrences.” Below it, a micrograph shows hippocampal neurons, each labelled in a different colour, packed into a curved band.

Check yourself

Question 4.5 (Memory test). Which principle of synaptic plasticity best describes each of the following?

  1. Consuming cocaine increases the density of synapses on dopamine neurons.
  2. Consuming cocaine decreases natural dopamine release.
  3. Consuming cocaine affects dopamine synapses, but not vasopressin synapses.

Principles: use it or lose it; use it to improve it; regional and functional specificity.

Show solution
  1. Use it to improve it: cocaine is a particularly strong stimulus, and strong stimulation strengthens synapses (as in the 6.4% rise in spine density).
  2. Use it or lose it: this is a weakening, and weakening of synapses that are used less is the “lose it” side of plasticity.
  3. Regional and functional specificity: the changes happen only in the dopamine system that cocaine acts on.

Question 4.6 (Memory test). Which principle of synaptic plasticity best describes each of the following?

  1. If you haven’t practiced a skill in a few years, you’ve likely lost some of your ability to do so.
  2. Learning Latin will probably not make you good at basketball.
  3. Following neurological damage, people often have to re-learn skills.

Principles: use it or lose it; use it to improve it; regional and functional specificity.

Show solution
  1. Use it or lose it: synapses that are not used are not maintained.
  2. Regional and functional specificity: practicing Latin changes synapses only in the regions that serve language.
  3. Use it to improve it: the skill is rebuilt by repeated practice (repetition of stimulation), which strengthens the connections that remain.

Question 4.7 (Exit discussion). We often view neural plasticity as a positive foundation for learning, but it also plays a critical role in the development of addiction and mental health disorders. Discuss how neural plasticity may

  1. cause an individual to develop drug dependency;
  2. cause the onset of a stress disorder.
Show solution
  1. A drug such as cocaine is an intense stimulus that, used repeatedly, strengthens synapses in the dopamine reward system (LTP, more dendritic spines), so the drug-related connections become strong and lasting; LTP underlies drug addiction, and un-learning it depends on LTD.
  2. An intense or repeated stressful experience can strengthen the synapses that encode it, so the stressful memory becomes strong and lasting (LTP underlies most mental health disorders); overcoming fears depends on LTD, and loss of beneficial synapses raises the risk of mental health disorders.