Week 4 Topic 3 - The effects of activity, experience and deprivation on the nervous system

Question 1

What is week 4 Topic 3 about?

Answer 1

Hello, my name is Sam Cooke. I’m a lecturer, here, at King’s College London and I work on learning and memory,
the processes by which sensory experience and deprivation modify the brain to store information which can
later be retrieved in the appropriate context.

This work is important not just for increasing our understanding of
how the brain works, but as you’ll see at the end of this lecture, it’s also highly relevant to understanding what
goes wrong in disorders of the nervous system and for identifying potential treatments.

In this lecture, we will delve into how neural activity and sensory experience and deprivation can shape brain
function.

We will start with a quick refresher on synaptic plasticity, focusing on Hebbian synaptic plasticity which
you will have already covered in a lecture by Professor Peter Geza.

We will then apply this knowledge to start
thinking about how the selective responses of neurons in the brain to neural activity or to sensory input, which
as we will see – are not necessarily the same thing, can be shaped through Hebbian synaptic plasticity to both
segregate and integrate inputs.

For the purposes of this lecture, we will focus mostly on the visual system.

As this is an important sensory
modality for humans, it’s intuitive to understand and it is probably the sensory modality that we have the
deepest understanding of.

However, it’s also important to note that most of the concepts that we described are
relevant to the postnatal development of other sensory modalities, such as auditory or somatosensory systems
and to higher order functions, such as the development of language faculties or executive function.

Briefly revisit Hebbian plasticity in order to make sure that we have a command of the key
characteristics which will then enable understanding of how activity and experience can shape functional
properties of the nervous system.

Question 2

Whos was Donald Hebb?

Answer 2

Donald Hebb was a Canadian psychologist who used his knowledge of animal learning to identify some
important theoretical criteria for the biological mechanisms that must support this critical faculty. In his famous
text, The Organization of Behavior, Hebb describes many theories that remain influential to this day.

Question 3

What is the process of Hebbian synaptic plasticity:

Answer 3

‘When an axon of cell A is near enough to excite a 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 the efficiency of A, as one of the cells firing B, is
increased’.

Question 4

What does the theory of Hebbain plasticity mean?

Answer 4

The key concept to get hold of here is that existing
chemical synapses on any one neuron arise from many different sources and are independently modifiable in
strength based on the pattern of activity between the two connected cells.

This fact would allow the synapse to
serve as the major unit of information storage in the brain and reflect the history of activity at that synapse.

Question 5

What does bidirectional modification relate to?

Answer 5

Although Hebb never discussed bidirectional modification, it is also important – for the purposes of this lecture – to appreciate that synapses can be strengthened or weakened, depending on whether pre- and post-synaptic cells are correlated in their activity or uncorrelated in activity respectively.

Question 6

What is fire together, wire together not quite right?

Answer 6

Many of you may have come across
the phrase, ‘fire together, wire together’, which was coined as a mnemonic device to understand and
remember the key aspects of Hebbian plasticity.

I would like to point out that, while you may find it useful in some way, this slogan misses the mark and does not
really describe Hebbian plasticity, because it implies that this plasticity is occurring between cells that are not
already connected.

A critical component of Hebbian theory is that synaptic plasticity allows experience to
shape connections that already exist by increasing or decreasing their efficacy.

There are certain examples of rewiring that occur in the nervous system that may actually be critical for
recovery of function after brain damage, or perhaps even aspects of learning and memory, but they are very
different phenomenon from Hebbian plasticity.

Question 7

How are processes of Hebbian plasticity are commonly studied experimentally?

Answer 7

These processes of Hebbian plasticity are commonly studied experimentally using high frequency trains of
electrical stimulation, known as a ‘tetanus’, which is applied to axonal pathways that are afferent to a population
of neurons, whose activity can be recorded using methods known as electrophysiology.
This stimulation allows experimenters to guarantee electrical activation of pre-synaptic terminals at the same
time as producing activation of post-synaptic neurons. The precise conditions that Hebb described as being
necessary for the strengthening of synapses. Some experimental preparations also allow for the isolation of
separate axonal inputs to the same cell, allowing experimenters to test the Hebbian theory that synaptic
plasticity can occur at one synapse without affecting its neighbour – an important property, known as ‘input
specificity’.

Question 8

What is ‘input

specificity’?

Answer 8

the Hebbian theory that synaptic

plasticity can occur at one synapse without affecting its neighbour

Question 9

What is the most commonly studied form of Hebbian plasticity?

Answer 9

The most commonly studied form of Hebbian plasticity, known as ‘long-term potentiation’ or ‘LTP’, relies upon
these electrophysiological stimulations and recording techniques.

Question 10

Who originally discovered and characterised LTP by electrophysiological stimulations and recording techniques and what did they study on and what is it now studied on?

Answer 10

This very well studied phenomenon was
originally discovered and characterised by British neuroscientist, Tim Bliss, and his Norwegian colleague, Terje Lømo, in the hippocampus of anaesthetised rabbits.

LTP is now commonly studied in surgically excised tissue, which helps greatly with positioning, stimulating and recording electrodes and for washing drugs on and off to
determine underlying mechanisms.

Question 11

Describe a common current-day approach to studying LTP.

Answer 11

Here is a slice of human hippocampus, which has been removed from a patient with otherwise intractable
epilepsy as an emergency treatment. The neurons in this transverse hippocampus slice can be kept alive by
maintaining it at the correct temperature in carefully oxygenated solutions that contain all the required ionic
concentrations
and metabolites.

Visualisation of the slice, under a microscope, allows precise positioning of recording
electrodes by the cell bodies of hippocampal neurons and, in this case, the granule cells of the dentate gyrus
where LTP was first recorded by Bliss and Lømo in the early 70s. Two stimulating electrodes are positioned on
either side of these cells to stimulate different afferent pathways, each of which evokes a response in the postsynaptic cells, demonstrating independent synaptic inputs.

On the right is a graph showing the strength of the synaptic response to electrical pulses delivered to each of these pathways at a test frequency, which is delivered at one pulse every minute, and it does not induce
plasticity.

After a half hour baseline, to ensure stability, a high frequency tetanus of 100 Hz is delivered to just
one of these pathways – which is depicted with black circles – while the other pathway continues to receive the very low frequency test pulses. As you can see, the tetanised pathway undergoes potentiation which then lasts for at least an hour without the control pathway being affected.

This is the famous phenomenon of LTP which is
an input-specific, long-lasting Hebbian form of synaptic plasticity.

Question 12

LTP and LTD

Answer 12

Since LTP was discovered, many considered it a theoretical imperative that the reverse phenomenon, ‘longterm depression’ or ‘LTD’, must exist at synapses since activity-dependent potentiation would quickly saturate synaptic strength and lead to hyperexcitability in the nervous system.

After many years of trying it, it was discovered that low frequency tetanus of 1 Hz, still much higher in frequency
than the test pulses that don’t induce plasticity at all, would produce the reverse effect of LTD – in contrast to
the 100 Hz tetanus that induces LTP. Importantly, both forms of plasticity could be observed longitudinally at the same synapses.

On the right is a modification curve, which is a graph mapping the effects of different stimulus frequencies on
the strength of synapses. As you can see, a range of low frequency stimuli will induce LTD while higher
frequencies induce LTP. There’s also a frequency of around 10 Hz that induces no change at all, which is known as the modification threshold.

Much work has been conducted to show that the frequencies which result in LTP do so by ensuring strongly correlated pre- and post-synaptic activity, just as Hebb had originally described, while the lower frequency stimuli that induce LTD do so by ensuring explicitly uncorrelated activity between pre- and post-synaptic cells.

As we shall see later in the lecture, this bidirectional plasticity, the direction of which reflects the recent history of activity at the synapse, is a perfect system to shape the functional response of neurons in the brain to
activity and to sensory input.

The phenomena of LTP and LTD have been observed at most synapses throughout the nervous system. This
slide shows work in ex vivo slices taken from rat hippocampus, rat visual cortex and cat visual cortex. All
showing very similar degrees of LTP and LTD when assessed with electrophysiology. This fact will be highly
relevant to most of the remainder of this topic, which will focus on activity-dependent plasticity in the primary
visual cortex.

Question 13

What are critical mechanisms, at the heart of many forms of LTP and LTD?

Answer 13

Critical mechanisms, at the heart of many forms of LTP and LTD, are the AMPA and NMDA subclasses of
ionotropic glutamate receptors.

Question 14

What does the AMPA receptor do?

Answer 14

One of these receptors, the AMPA receptor, is opened by glutamate and is an ion channel that allows the flow of positively charged ions, mostly sodium ions, into a neuron.

This receptor carries the majority of synaptic current and is responsible for much excitatory fast synaptic transmission.

Changes in the properties or number of AMPA receptors are a major expression mechanism of both LTP and LTD.

Question 15

What does the NMDA receptor do?

Answer 15

The NMDA receptor is also an ion channel that allows positively charged ions to flow into neurons.

However, it’s more complex than the AMPA receptor because, as well as glutamate-binding, it is also voltagedependent.

Meaning that the channel will only open when glutamate is bound and the post-synaptic neuron is
also depolarised, or active.

This property arises from a magnesium ion that blocks the channel pore unless the
post-synaptic membrane is depolarised.

The NMDA receptor, therefore, has the ideal properties to serve as a critical coincidence detector for the
Hebbian criterion of pre- and post-synaptic coactivity.

And the key ions that flow through the NMDA receptor,
and indicates that Hebbian conditions have been met, are calcium ions.

Question 16

What does AP5 (APV) do and why is it important to Hebb’s theory?

Answer 16

This slide shows the original experimental evidence that AP5 (or APV), the specific NMDA receptor antagonist, blocks the induction of both LTP and LTD.

This was ground-breaking work as it demonstrated how biology serves Hebb’s theory.

This experiment also demonstrates an invaluable experimental advantage of the ex vivo slice – which not only allows drugs to be washed on at the appropriate time but also washed off to demonstrate
the synapses are not irreparably altered by drug delivery and the LTP can still be induced subsequent to
washout.

Question 17

How can it be that the same receptor serves opposing directions of synaptic change?

Answer 17

The answer is in the conduction of calcium ions through the NMDA receptor.

Because of the different dynamics of post-synaptic
activation, produced by high- and low-frequency stimulation, the concentration of post-synaptic calcium is very different – as it summates to high concentrations for high-frequency stimulation while remaining elevated, but considerably lower in concentration, as a result of pulsatile, non-summating increases in calcium ion
concentration.

This result in activation of different types of calcium-sensing enzymes, some kinases that will phosphorylate
targets – such as AMPA receptors – to change their properties and some phosphatases which
dephosphorylate and have the reverse effect.

We will not go into the details of the particular signalling systems that play, as Professor Peter Geza has already discussed this to some degree previously, but it is important to understand how LTP and LTD can coexist at the same synapses and share many key mechanisms.

Question 18

Summarise a brief overview of Hebbian plasticity in 9 points.

Answer 18

So, to summarise this brief overview of Hebbian plasticity,

1. Hebbian plasticity is an activity-dependent
   strengthening of synapses between coactive neurons or a weakening of synapses between neurons with
   uncorrelated activity.
2. Hebbian plasticity is modelled experimentally in vitro and in vivo through electrical stimulation to produce longterm potentiation, LTP or long-term depression, LTD which respectively strengthen or weaken synapses.
3. The frequency of stimulation is a major determinant of the direction of change – high for LTP and low for LTD.
4. LTP and LTD occur at most synapses in the nervous system.
5. Hebbian plasticity is input-specific, as it occurs only at synapses that have undergone activity and does not
   occur at neighbouring inactive synapses on the same neuron.
6. It is also long-lasting.

7.  The NMDA subclass of glutamate receptor is often a key mechanism in the induction of LTP as it is an ion
channel that conveys calcium ions only when two coincident events occur: glutamate-binding and post-synaptic depolarisation. 

8. Thus, it serves as the detector of the defining events in Hebbian LTP: correlated pre- and postsynaptic activity. It’s also a key mechanism for many forms of Hebbian LTD.
9. Hebbian plasticity is not accurately described by the statement ‘fire together, wire together’. Hebbian plasticity can only change existing synapses. It does not involve the formation of new synapses.

Question 19

Part 2 of 5
Now, let’s move on to thinking about how Hebbian plasticity could explain the effects of activity on the nervous system during postnatal development.

Answer 19

Now, let’s move on to thinking about how Hebbian plasticity could explain the effects of activity on the nervous system during postnatal development.

Question 20

Part 3 of 5
Now, let’s consider a very different event in the postnatal development of the nervous system, that
nevertheless requires Hebbian synaptic plasticity. This is the integration of inputs on to shared post-synaptic
targets, to create more complex receptive fields. For this purpose, we’re going to focus on the postnatal
development of binocular vision. As we shall see, this process requires visual experience.

Answer 20

Now, let’s consider a very different event in the postnatal development of the nervous system, that
nevertheless requires Hebbian synaptic plasticity. This is the integration of inputs on to shared post-synaptic
targets, to create more complex receptive fields. For this purpose, we’re going to focus on the postnatal
development of binocular vision. As we shall see, this process requires visual experience.

Question 21

Part 4 of 5
Now, let’s turn our attention to a related developmental process that introduces a major permissive factor to
this deprivation-induced plasticity – the critical period.

Answer 21

Another Nobel laureate, who really crystallised the concept of the critical period, was the Austrian ethologist,
Conrad Lorenz. Lorenz conducted many fascinating experiments on the phenomenon of imprinting, in which he
became the major parental figure to numerous different bird species.
If he served as the primary provider and carer for chicks, goslings or cygnets during a critical period of postnatal
development, they formed a powerful, unbreakable attachment to him that could not be superseded by a
member of their own species. Importantly, this attachment persisted if he took on this role during and beyond
the close of the defined period, which was termed a critical period.
This concept of the critical period – a relatively brief window during which defining plasticity was permitted –
has become influential throughout education, psychology, psychiatry and neuroscience and it’s highly relevant to
the effects of visual experience in deprivation on the neocortex of mammals.
Slide 5:
This is illustrated by a series of experiments in kittens and cats of various ages. The first key observation is that
the effects of monocular deprivation are highly reversible if the deprivation occurred during an early critical
period. In five-week-old kittens, monocular deprivation would not only result in the ocular dominance shift in the
response of layer 2/3 neurons, as we’ve discussed already, but after un-suturing the deprived eye, a reverse
suture of the opposite eye would result in an equivalent shift in the opposite direction.
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Week 4 @ King’s College London 2.
Slide 6:
If this experiment were carried out in the same way with monocular deprivation during the critical period of 5
weeks of age, but then un-suturing and reverse suturing occurred much later, at 14 weeks of age, then not only
did the reversal of ocular dominance in Layer 2/3 not happen, but recovery from the initial shift did not occur.
Slide 7:
Similarly, the ocular dominance plasticity does not occur at all if eyelid suture occurs in the adult animal,
demonstrating very clearly that the capacity of the cortex for plasticity is lost after the critical period.
Slide 8:
A key question, of course, is whether this permanent shift not only compromises response in layer 2/3 of visual
cortical neurons but also actually impairs vision itself.
In humans, we would test vision with a Snellen chart, which many of you may be familiar with. The Snellen chart
is a test of visual acuity, and it asks you to resolve lines that are different distances apart and this is known as
varying spatial frequency. At some point, a threshold can be found beyond which you cannot differentiate the
letters ‘M’, ‘W’, ‘E’ and the number ‘3’, which is the determinant of your visual acuity. 20/20 vision just means
that your vision at 20 feet matches normal vision at 20 feet.
Slide 9:
One classic test of vision teaches a cat to associate a specific orientation of lines with a reward – say vertical
stripes but not horizontal stripes. Once this association is formed then one can just assess vision by changing
the spatial frequency and determining how often the cat chooses to jump to the rewarding orientation.
If one eye or other is covered during this test, then vision can be tested independently through each eye. Here
you can see work from Canadian vision scientists Donald Mitchell and Kevin Duffy, in which monocularly
deprived kittens show normal binocular vision a week or so after the eye is open post-critical period.
However, vision limited to the deprived eye never recovers and the animals remain functionally blind through
this eye even though the eye, itself, is fully operational. Thus, if visual experience does not return to normal until
after closure of the critical period, then there is no functional recovery.
Slide 10:
The visual cortical critical period varies in time and longevity from one species to another. Rather conveniently,
this roughly lines up in weeks for cats, months for monkeys and years for humans, as shown in this graph, with
closure of the critical period occurring around eight to nine weeks, months or years depending on the species.
Slide 11:
Much work has now been done by several laboratories, notably including those of Mark Bear and Takao Hensch
in the US, to demonstrate that a key determinant of both the opening and the closing of the critical period is the
degree of cortical inhibition.
Inhibition develops late in the cortex, relative to excitation circuits, and we now know that the critical period
really represents a sweet spot between too little and too much inhibition.
Slide 12:
So, how can inhibition be a key determinant in whether Hebbian plasticity occurs or does not?
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Week 4 @ King’s College London 3.
Here, we can see a schematic of how a simple feed-forward circuit in the visual cortex looks, with tick marks
representing action potentials. As the schematic shows, cortical inhibition after the eyes open, but before the
critical period opens, is too low to really impact the activity of cortical circuits resulting from visual input.
This means that Hebbian plasticity cannot operate to integrate signals because there’s too much noise in the
system. After inhibition has started to develop, during the critical period, conditions are optimised so that only
the strongest visual inputs will drive enough cortical activation to modify synaptic strength through Hebbian
plasticity. It is during this period that the cortex is primed to be modified by visual experience and deprivation.
The closure of the critical period appears to arise once inhibition is so powerful that it suppresses the
propagation of activity through cortical circuits for all but the very strongest sensory input.
Slide 13:
Thus, the critical period is closed once inhibition in the cortex is matured. However, it is important to note that
the capacity for change still exists in cortical circuits if inhibition can be modified. The opening of the critical
period can be advanced by positively modulating GABA receptors with benzodiazepines. The critical period can
be reopened with treatments that reduce inhibition, such as a genetic knockdown of the key enzyme for
synthesising GABA or, interestingly, by grafting immature inhibitory neurons into the visual cortex of mature
mice. In the next section, we will consider some of the therapeutic implications that this work gives rise to.
Slide 14:
So, in summary for this section on critical periods:
Critical periods define the time window during which the effects of sensory experience or deprivation on the
nervous system are most pronounced, usually occurring quite early in post-natal development.
Critical periods vary for brain regions and sensory modalities, for example, the critical period for plasticity in
somatosensory cortex opens and closes earlier than for visual cortex. Higher order regions of cortex, such as
prefrontal cortex, have even later critical periods.
Critical periods vary from species to species, for example, the critical period for ocular dominance plasticity
closes much earlier for mice than cats, and earlier for cats than primates.
Several lines of evidence indicate that inhibitory neurons play a key role in critical period duration, with
development of inhibition opening the critical period of maturation and maturation of cortical inhibition closing it.
Increasing inhibition can prematurely open the critical period and reducing inhibition can re-open the critical
period after it has closed.
Inhibition is believed to serve as a permissive factor for Hebbian plasticity by reducing overall activity at the
opening of the critical period, thereby reducing ‘noise’ and allowing differentiation of correlated and
uncorrelated activity. However, too much inhibition can prevent enough post-synaptic activity to allow Hebbian
plasticity to occur, thereby closing the critical period.

Question 22

• Part 5 of 5

Now, let’s complete our topic by considering the therapeutic possibilities that exist, because of all this
fundamental neuroscience work. How might we treat sensory deprivation, and are there further reaching
implications for psychiatric disorders? A major focus in this regard is asking whether we could re-open the
critical period in mature patients in order to recover developmental disruptions that may have arisen from
deprivation during childhood.

Answer 22

Slide 4:
As well as the various invasive treatments that we discussed for reopening the critical period – including
genetic modifications in mouse to reduce GABA synthesis and the grafting of inhibitory neurons, precursors into
visual cortex – considerable work has been done to develop non-invasive means to influence inhibition and,
thereby, extend or re-open the critical period.
These non-invasive approaches would be much more palatable as potential treatments in humans than genetic
modifications or surgical grafts – although nothing can be discounted if the condition is severe enough and the
patients are willing. Among treatments tested in rodents, that show promise in returning the cortex of adults to
critical period levels of plasticity, include environmental enrichment, dark exposure, caloric restriction, physical
exercise and perceptual training. In addition, certain drugs that are already available for use in humans, such as
Selective Serotonin Reuptake Inhibitors – or ‘SSRIs’ – which are used as antidepressants, appear to influence
cortical inhibition and return it to a critical period-like state.
Slide 5:
Focusing on one of the most promising of these treatments in the visual domain, we can look at some work
revealing that dark exposure for several days in rodents alters inhibition within the visual cortex and, as a
result, alters the modification threshold for synaptic plasticity.
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Week 4 @ King’s College London 2.
On the left are direct measurements of cortical inhibition, using intracellular electrophysiological recordings,
from slices of visual cortex, taken from rodents that have either been raised under normal lighting conditions,
or raised in this manner but, then, briefly exposed to extended dark over several days. The top panel shows
that dark exposure has no effect on cortical inhibition if it occurs during the critical period and is compared to
critical period mice on a normal light cycle.
However, if the same experiment is conducted in adult animals, in which the critical period is closed and
inhibition is fully matured, the dark exposure substantially reduces the amplitude of inhibitory, post-synaptic
currents – ‘IPSCs’ – relative to controls. This effect reveals the capacity of dark exposure to recover cortex to
critical period levels of inhibition.
In the right panels, we can see that if animals are raised in the dark, the direction of Hebbian synaptic plasticity
can be altered in primary visual cortex, reflecting altered inhibition and a shifted modification threshold. Low
frequency stimulation produces less LTD in dark-reared animals than their littermate controls, raised under
normal lighting, and higher frequency stimulation, of around 40 Hz, induces more LTP.
Thus, the expectation would be that dark exposure could either reduce the impact of monocular deprivation –
remembering the important fact that binocular deprivation does not induce a shift in ocular dominance in the
brain – or, more dramatically, recover lost visual function in adult animals after extended monocular
deprivation.
Slide 6:
If we return to cats and the behavioural measure of their visual acuity carried out by Donald Mitchell’s
laboratory, we can see a stunning experimental result that is highly relevant to the treatment of human
disorder. Here you can see the kittens that underwent monocular deprivation through the critical period –
around one month of age – retain major visual deficits long after that eye is open. These deficits, in visual acuity,
are akin to almost complete blindness through the deprived eye for months after the eye has been opened and
in contrast to the open eye, which exhibits normal visual acuity. The amazing thing is that exposing the animals
to 10 days in the dark, at three months of age, leads to a complete recovery of function through the deprived
eye over just a few days of further visual experience. The weight of evidence, therefore, points towards dark
exposure as being a strong candidate for recovery of function in the visual system by modifying inhibition.
Slide 7:
Monocular deprivation in animals is, essentially, a model of a not uncommon human condition, known as
‘amblyopia’ – in which monocular deprivation occurs during childhood as a result of several possible ocular
conditions. Sometimes, this deprivation is not detected early enough during childhood and it extends beyond the
critical period, to ages eight and upwards. Meaning, that the visual cortex is slowly dedicated to responding to
the fully functional eye and cannot be recovered for binocularity even with good treatment of the eye in
adulthood.
The condition of amblyopia is colloquially described as ‘lazy eye’. Amblyopia reduces visual acuity to varying
extents resulting in almost no depth perception, this affects around 2% of the UK population and, even in the
subtlest of cases, prevents those people from entering certain professions that require depth perception, such
as being a pilot or a fireman or a firewoman. In more extreme cases, it results in complete cortical blindness
through that eye and would prevent you from driving. It would also reduce your quality of life in many ways and
potentially also lead onto some mental health issues. In the developing world, such as countries in Asia and
Africa, the problem is more prevalent – as easily treated ocular problems, such as cataracts, are often not
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Week 4 @ King’s College London 3.
tended to at all or until it is too late. In these countries, amblyopia also has a more dramatic effect on one’s
ability to earn a living and can, therefore, be a catastrophic condition.
Slide 8:
Of the causes of amblyopia, some are very easy to detect, such as cataracts or strabismus, due to an obvious
physical manifestation. These conditions would likely be remedied early in life, in the UK, and a child can go on to
have perfectly normal vision. In the developing world, these dysfunctions may not be attended to, due to a lack
of money or facilities.
In countries like the UK, amblyopia can occur due to less noticeable conditions, such as anisometropia – in
which the two lenses are of different refractory indices, and one provides a clearer view of the world than the
other. It is obviously critical to have good tests of visual function when children are young, to give them the best
chance of recovery prior to closure of the critical period.
Slide 9:
The current best clinical practice is to use surgery to return the ‘bad’ eye back to normal before dealing with
residual ocular dominant shift during the critical period. This recovery can be accelerated by performing the
equivalent of a reverse suture experiment, either by patching the good eye or by using eye drops of belladonna
extracts – or atropine – which prevent muscles in the good eye from working properly. This punishment of
vision through the good eye is not ideal, given that the visual system is still developing in numerous other ways.
Development of novel treatments for amblyopia, especially in adults – in which function cannot currently be
recovered, would have a major societal impact. The work on dark exposure and related, non-invasive
treatments is, therefore, extremely important. The therapeutic implications of the fundamental neuroscience
that we have discussed extends way beyond the visual system, however. The work on the effects of visual
deprivation on the visual cortex provides deep insight into the likely consequences for deprivation in other
sensory systems and in higher order systems.
Slide 10:
Insight into the development of inhibitory systems in the neocortex and how that can influence the effects of
experience and deprivation on the nervous system is likely relevant to a slew of conditions, including
neurodevelopmental psychiatric disorders: such as epilepsy, intellectual disability, autism spectrum disorders
and schizophrenia – where dysfunctions in the postnatal development of balanced excitation and inhibition is
heavily implicated.
This so-called ‘E-I balance’ has been studied in the context of these neurodevelopmental disorders. Highly
penetrant genetic causes of these conditions often target synaptic proteins, such as ‘neurexins’ and ‘neuroligins’
– which are transsynaptic signalling molecules that are critical for either normal inhibition of excitatory neurons
or normal excitation of excitatory neurons.
Mutations in the genes that encode these proteins often result in E-I imbalance and intellectual disability, autism
spectrum disorders or schizophrenia. Critical receptors for Hebbian plasticity, such as the NMDA receptors or
associated signalling systems, appear to be risk factors for schizophrenia and there is ample evidence, in this
condition, that inhibitory neurons in the cortex are reduced in number and in the production of GABA –
indicative of E-I imbalance.
Another major risk factor of neurodevelopmental disorder is Fragile X Mental Retardation Protein – ‘FMRP’ –
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Week 4 @ King’s College London 4.
which regulates activity-induced protein synthesis required for many synaptic processes, notably including
lasting Hebbian synaptic plasticity. Disruption of FMRP function, as its name suggests, results in one of the more
common forms of intellectual disability – ‘Fragile X Syndrome’ – which is often comorbid with epilepsy and
autism spectrum disorders and exhibits a clear E-I imbalance at various stages of development.
Other risk genes encode transcription factors, such as MeCP2 – which is the protein that is mutated to cause
the debilitating neurodevelopmental disorder known as ‘Rhett’s syndrome’ and which appears to play a critical
role in the production of enzymes necessary for GABA production in inhibitory neurons, thereby resulting in
major E-I imbalance.
Slide 11:
As we have seen, critical periods reflect the normal development of E-I balance in the cortex, but the timecourse
of critical periods is very different from region to region of the cortex, reflecting the different functions
of these regions. While the sensory critical periods that affect plasticity in primary sensory areas occur early,
around and after birth, similar developmental windows are extended much later into life, for language
development or socialisation. It’s possible that these later critical periods are affected in autism spectrum
disorders. Executive function or context/rule-dependent behavioural control, which arises from higher order
cortical regions in the frontal lobe may not be fully developed until late into adolescence.
Disrupted development of these faculties may contribute to numerous psychiatric disorders, including
schizophrenia. It is a relatively new concept that lost, delayed or exaggerated critical period plasticity – or that
deprivation or aberrant experience that occurs during the relevant critical period – may be causal factors in a
range of neurodevelopmental disorders. Much further work is now required in this domain.
Slide 12:
To summarise this section, non-invasion means to manipulate inhibition may re-open the critical period,
returning the brain to peak plasticity and maximising the therapeutic effects of sensory experience.
Promising methods include environmental enrichment, sensory deprivation, dietary restriction and exercise.
Placing animals in the dark for an extended period greatly reduces the level of inhibition in the visual cortex.
Mature cats, that have previously undergone monocular deprivation as kittens and have severe loss of vision
through the previously deprived eye, can show dramatic visual recovery after being placed in the dark for 10
days.
This approach holds promise for a debilitating condition, known as ‘amblyopia’, which results in a visual cortical
deficit due to childhood deprivation, that persists even after the eye is rendered fully functional through surgery
later in life. Amblyopia affects around 1 to 2% of people in the UK, but many more in the developing world –
where treatment of fixable ocular conditions is less likely to occur, in a timely fashion, and where poor vision
carries more severe consequences.
Work on the visual system also provides general insight into how cortical function is shaped by deprivation and
experience and how altered critical period plasticity may contribute to a wealth of neurodevelopmental
disorders, including intellectual disability, autism spectrum disorders and schizophrenia.

Question 23

What is the neocortex?

Answer 23

The neocortex is a six-layered structure that exists only in mammals.

It’s highly plastic and is known to be
critical for long-term memory.

Question 24

Why are the primary sensory regions of neocortex by far the best studied and
understood regions of the neocortex?

Answer 24

The primary sensory regions of neocortex are by far the best studied and
understood regions of the neocortex because,

1. first, they receive relatively unprocessed sensory information,
   which is relayed from the relevant sensory operators – usually via very few intermediary structures.
2. Second,
   they potentially provide a general model of neocortical function because they contain all the key circuit and
   molecular elements that are found in higher-order regions, such as prefrontal cortex.

3.  Third, their structure and
function are relatively well understood and often exhibits visible specialisations that reflect its topographical
organisation as a spatial recapitulation of the sensory world.

Question 25

What are whisker barrels and where are they?

Answer 25

The primary visual cortex, known as ‘V1’, the primary auditory cortex, known as ‘A1’, and the primary
somatosensory cortex, known as ‘S1’.

This view reveals particularly striking anatomical specialisations in
somatosensory cortex, known as ‘whisker barrels’, which are columnar organisations that are each dedicated
to input from a single whisker.

Thus, it’s possible to constrain sensory stimulation to a very specific region of
interest and study the plasticity that results.

Question 26

What are ocular

dominance columns and where are they?

Answer 26

For this topic, we’re going to focus on the visual system and the similar specialisations, known as ‘ocular
dominance columns’, that exist in the primary visual cortex V1 of most mammals – including primates, such as
ourselves, and other well-studied species – notably including carnivore species, such as cats and ferrets.

The organisation of ocular dominance layers in the thalamus and columns in the neocortex have been tracked
experimentally using radioactive transsynaptic tracers injected into one eye of an animal.

Question 27

Cat experiment 1

Answer 27

This enabled
autoradiographic tracing of this functional segregation, which is seen here in a cat brain.

On the left, is a section
through the primary visual relay nucleus of the thalamus, the ‘lateral geniculate nucleus’ or ‘LGN’, revealing
layers that are dedicated to the contralateral eye – which is not injected and, therefore, without tracer present
in the thalamus – and the ipsilateral eye – which is injected and, therefore, with tracer in the thalamus.

On the right are two views of primary visual cortex. First, a view from above of visual cortex showing the
interdigitated zones dedicated to one eye across the visible layer 4. And, second, a transverse section
revealing white matter projections up to V1, showing the restriction of these labelled ocular dominance zones to
layer 4 of cortex.
Slide 6:
Here’s a schematic of the segregation of ocular inputs and the maintenance of this segregation through the cat
visual system, up to primary visual cortex. Spatially segregated zones are dedicated to processing visual
information provided through the contralateral eye – in blue – or the ipsilateral eye – in yellow.
The segregation is maintained in the optic nerve and the lateral geniculate nucleus all the way up into V1 where
ocular dominance columns are maintained in layer 4, which is the first layer of neocortex to receive the
thalamic input. If we now look at the laminar organisation in V1, we can see that intracortical connections
integrate these two separated inputs in layers 2, 3, and 5 into binocular representations – which are shown in
green.

Question 28

Definition of ipsilateral.

Answer 28

belonging to or occurring on the same side of the body
. Contralateral is defined as ‘pertaining to the other side’. Ipsilateral is considered the opposite of contralateral and occurs on the same side

Question 29

How can segregation in ocular dominance columns of layer 4 can be initiated by
Hebbian plasticity and how can integration into binocular representations can occur in layer 2/3, also through
Hebbian plasticity.

Still cat experiment…

Answer 29

Let’s start with how ocular dominance columns may arise from activity within the nervous
system.

A key question for neuroscientists has been whether this segregation of function arises from genetic
programming, that determines the organisation of the developing visual system, or whether the activity of
neurons plays a critical role in the development of ocular dominance territories in the brain, as had been
hypothesised by British neuroscientist, David Willshaw.

Question 30

What did British neuroscientist, David Willshaw hypothesise?

Answer 30

the activity of
neurons plays a critical role in the development of ocular dominance territories in the brain, as had been
hypothesised by British neuroscientist, David Willshaw.

Question 31

Lamberto Maffei’s laboratory, in Italy, and Carla Shatz’s laboratory in the US

Answer 31

An important observation came from Lamberto Maffei’s laboratory, in Italy, that retinal neurons produce
spontaneous activity.

And this was followed up by Carla Shatz’s laboratory, in the US, who used calcium imaging
to show that there were, in fact, waves of activity that passed across the retina.

Question 32

Retinal Waves

Answer 32

This slide shows an example of
such a wave which can be recorded in a dish with a calcium imaging dye and reveals the time course of the
progression of a wave of activity across the retina, here taken in time snaps over seconds.

These retinal waves
have subsequently been a major area of investigation.

The retinal waves were found to occur long before the
eyes of many species open, an event that usually happens a considerable time after birth.

Question 33

A first question to address was, what would be the consequence of inactivating the retina and preventing the spontaneous activity from occurring during postnatal development prior to eye opening?

Answer 33

To accomplish this,
experimenters turned to toxins that are extracted from the animal world.

In this case, ‘Epibatidine’, extracted
from the skin of a species of Ecuadorian frog known as ‘Anthony’s poison arrow frog’, and to ‘Tetrodotoxin’ or
‘TTX’, which is taken from the puffer fish and is the active ingredient that numbs the lips of those that eat puffer fish, a delicacy in Japan. These nerve toxins target different molecular mechanisms.

Epibatidine is an antagonist
of many different acetylcholine receptors and TTX blocks voltage-gated sodium channels but both block neural
activity and are commonly used, now, as experimental tools to assess the importance of activity in specific
neural populations.

Question 34

What did Carla Shatz and Michael Striker, in the US, show that application of TTX in the
prenatal cat embryo does?

Answer 34

It had previously been shown by Carla Shatz and Michael Striker, in the US, that application of TTX in the
prenatal cat embryo, prevented normal segregation of ocular dominance zones, indicating that spontaneous
neural activity must play a major role.

However, blockade of activity in the retina of postnatal ferret pups prior to eye opening, thereby preventing
retinal waves, also had a striking effect on the segregation of ocular dominance zones. In the work shown here,
from Andrew Huberman and colleagues in the US, you can see that the boundaries between the zones
dedicated to ipsilateral and contralateral eyes in the LGN – which are, here, marked with different coloured
trans-neuronal dyes delivered to each eye – are significantly blurred if activity is blocked in the retina.

Question 35

What happens when the retinae are inactivated during postnatal development prior to eye opening?

Answer 35

Similarly, when the retinae are inactivated during postnatal development prior to eye opening, ocular
dominance columns in V1 do not segregate at all.

Question 36

How does this lack of synchrony between the activity of the two eyes contribute to segregation of ocular
dominance layers in the thalamus and ocular dominance columns in layer 4 of the neocortex?

Answer 36

The key factor to note, here, is that while the retinae and other parts of the nervous system are exhibiting a
high degree of spontaneous activity at this stage of development, that activity is in no way correlated since the
retinae are not receiving shared sensory input.

That lack of correlation plays a major role in the ability of
Hebbian plasticity to segregate zones of the visual system that are dedicated to input from one eye or the
other.

Question 37

When does Hebbian synaptic weakening occur?

Answer 37

Remember that Hebbian synaptic weakening, as modelled by LTD, occurs when there is a lack of correlation
between activity in the presynaptic neuron and the postsynaptic neuron. Thus, where post-synaptic neurons are
having their activity driven by one eye slightly more powerfully than by the other eye, because these two inputs
are out of synchrony, the slightly weaker input will be further weakened until it eventually is unable to elicit any
activity in the post-synaptic neuron. Thus, the post-synaptic neuron can be said to have a monocular receptive
field, more or less dedicated to processing information from one of the two eyes only.
Subsequently, inputs from this favoured eye will be strengthened even further through Hebbian potentiation, as
modelled by LTP, given the increasingly reliable coincidence between pre-synaptic activity and post-synaptic
response.

Question 38

How can ocular
dominance columns arise from a population of neurons that initially had a largely
binocular response

Answer 38

This overall scenario is depicted in the schematic to explain how highly segregated zones or ‘ocular
dominance columns’ – in blue and yellow – could arise from a population of neurons that initially had a largely
binocular response – shown in green.

All that would be required for this to occur is the prior existence of a very slight bias in one direction or
another.

This bias may arise through chance or it could be that some genetic mechanisms that are not activitydependent
do create some very rough bias before this is hugely refined by activity.

This latter scenario would
explain why, for instance, there’s some vestige of zones dedicated to input from one eye or the other when the
retinas are silenced postnatally.

Question 39

A major question posed by this hypothesis is whether segregation requires the NMDA receptor in cortical
neurons.

Answer 39

Remember, that this ionotropic glutamate receptor acts as a detector of coincidence between pre and
post-synaptic elements and is critical for many forms of Hebbian LTP and LTD.

Question 40

Knock Out Approach.

Answer 40

The mouse is the only
mammalian species in which genetic engineering can easily be used to ablate, or ‘knock out’, a gene and,
thereby, the expression of the protein encoded by that gene.

Although modern technology is changing that – soon we will be able to knock out or manipulate genes in almost
any species.

This knock out approach is critical to determine whether Hebbian plasticity is required for
functional segregation based on spontaneous activity.

Question 41

Using whisker barrels as evidence for a key role played by Hebbian plasticity

Answer 41

This slide shows data from a mouse in which the NMDA
receptor has been functionally ablated from glutamatergic neurons of the cortex.
Mice don’t exhibit ocular dominance columns, unlike most other mammalian species, but they do have
analogous functional segregation in primary somatosensory cortex, known as ‘whisker barrels’ – as we
discussed at the beginning of this section.
On the right, you can see anatomical markers and stains of neural activity that reveal severely ill-defined
whisker barrels in the primary somatosensory cortex of mice that do not express NMDA receptors in the
neocortex. This requirement, for NMDA receptors to achieve functional segregation in primary sensory areas,
is further evidence for a key role played by Hebbian plasticity.

Question 42

summary, ‘ocular dominance columns’ experiments

Answer 42

In summary, ‘ocular dominance columns’ are zones of cortex that only respond to input through one or another
eye. They are present in the primary visual cortex of many species – for example, cats and humans. And
functional segregation also exists in the visual thalamus.
In many species, the eyes open sometime after birth, but ocular dominance columns still emerge during this
period.
Spontaneous neural activity can be recorded in the retina prior to eye opening and these are known as ‘retinal
waves’. Similar spontaneous activity can be detected in the visual thalamus. Retinal waves are not correlated
between the two eyes.
Inactivation of the retinae to prevent retinal waves prevents the formation of discrete ocular dominance
columns. Evidence suggests that blockade of NMDA receptors also prevents segregation of ocular dominance
columns and whisker barrels in the somatosensory cortex.
Hebbian synaptic plasticity is hypothesised to progressively sharpen the boundaries between ocular dominance
columns by weakening connections between neurons that are uncorrelated in activity – ie responsive to
opposite eyes – and strengthen connections between neurons that are correlated– ie those that are responsive
to waves in the same retina.

Question 43

After the eyes open, does visual stimuli

evoke activity in the retinae?

Answer 43

The important starting point for this section is to take into consideration that after the eyes open, visual stimuli
will start to evoke activity in the retinae.

This activity is very different from the spontaneous activity occurring
during retinal waves for the simple reason that it is highly correlated across the two eyes.

Thus, activation of
neurons in the visual system will start to reflect the statistics of the environment, and this activity will be shared
across the segregated zones.

Question 44

Canadian neuroscientist, David Hubel and
Swedish neuroscientist, Torsten Wiesel, who won the Nobel Prize for their ground-breaking work together at
Harvard, in the US, on the development of receptive fields in the visual system.

Answer 44

We’ll now focus on one aspect of the very famous work developed by Canadian neuroscientist, David Hubel and
Swedish neuroscientist, Torsten Wiesel, who won the Nobel Prize for their ground-breaking work together at
Harvard, in the US, on the development of receptive fields in the visual system.

One aspect of the work that
they conducted was in coming to understand how neurons in the brain could take on binocular representations
that are required for such important faculties as depth perception.

They worked in carnivore and primate species, which all have excellent binocular vision, unlike some prey
species such as mice and deer. This is accounted for by their front-facing eyes, which allows both eyes to serve
a match of the same extent of the visual field. One of the species of choice was the cat – the visual system of
which is, again, depicted here.

As we discussed before, ocular dominance columns are maintained as separate for each eye within layer 4 of
visual cortex – shown here in yellow or blue – but cells from each of these columns then make common contact
with other neurons within the cortex, particularly in layers 2 and 3. These neurons then take on a binocular
representation – shown in green – as inputs from each eye drive activity in the same binocular neuronal
population. But, how does this integration occur?
Slide 7:
A very well used, experimental strategy to study the plasticity of ocular dominance and binocularity was to
reversibly close one eye, preventing visual input. This was usually achieved by carefully suturing the eyelids
closed. This may sound like a cruel procedure but, when performed with surgical precision, it allows for careful
reopening of the eye after several days or weeks without any compromise to the function of the eye. And,
assessment of response of the brain to input through that eye compared to the other eye that had remained
open. Thus, ocular dominance plasticity could be measured.
The first thing to note is that the ocular dominance columns in cortical layer 4 undergo dramatic reorganisation
when the contralateral eye of kittens is sutured for several weeks. Here you can see, using the same
radioactive tracer technique described earlier to track ocular dominance columns, that the territory dedicated
to the open, ipsilateral eye has dramatically expanded into the columns previously dedicated to the
contralateral eye.
Slide 8:
Another important technique was developed by Hubel and Wiesel to record the electrical activity of neurons in
visual cortex of anaesthetised cats with tungsten microelectrodes. This revealed an additional striking
functional effect of ocular dominance. As we’ve described in previous slides, neurons in layers 2 and 3 and
further intercortical networks of primary visual cortex exhibit binocularity.
Using Hubel and Wiesel’s electrophysiology approach and masking visual input through one eye or the other, it
could be observed that most neurons in layer 2/3 were either completely or partially binocular in their
response to visual inputs, as shown on the right. Just around 10 to 20% of neurons were monocular in their
response within this layer in kittens, undergoing normal visual experience.
Slide 9:
However, as Hubel and Wiesel showed, as well as others, such as Colin Blakemore, here in the UK. Monocular
deprivation through, lid suture of the contralateral eye, led to a profound shift in these binocular responses so
that neurons in layer 2/3 became almost exclusively responsive to the open ipsilateral eye – here depicted in
shades of yellow – even after the eye had been reopened.
This effect is known as ocular dominance plasticity as a result of monocular deprivation, and it has been a
deeply studied phenomenon – as it likely provides broad insight into how experience and deprivation shape the
nervous system.
Slide 10:
An alternative experimental approach was to create an artificial strabismus in kittens, in which the eyes were
forced to view different parts of the visual field. This was achieved by surgically cutting one of the muscles
around the eyeball. Like monocular deprivation, the strabismus treatment more or less eradicated binocular
receptive fields from layer 2/3 neurons.
Please note that this is a transcript. It is not a learning object. Please refer to topics for visuals and full lecture content.
Week 4 @ King’s College London 3.
However, in contrast to monocular deprivation, strabismus led to equal responsiveness through the two eyes
as each eye was delivering equal amounts of activity. That activity was just not correlated between the two
eyes.
Slide 11:
Importantly, this process of deprivation-dependent plasticity appeared to rely upon Hebbian mechanisms, as
work from Wolf Singer’s lab showed – in which they blocked NMDA receptors in primary visual cortex with a
selective receptor antagonist and prevented the ocular dominant shift resulting from monocular deprivation in
kittens.
Slide 12:
Another dramatic observation was that the ocular dominance shift did not occur if both eyes were sutured for
the same period as the previous monocular deprivation experiments. Thus, more deprivation did not result in
more plasticity or, indeed, much plasticity at all. This was a really important observation because it showed the
ocular dominance plasticity is a competitive process that requires not just deprivation of input through one eye
but, also, experience through the other.
Slide 13:
So, in summary for section 3, binocular vision is critical for depth perception and survival. Once the eyes open,
activity switches from being uncorrelated between the two eyes to being correlated, due to shared visual input
from the outside world over much of the visual field. The visual system integrates inputs from the two eyes
through experience to form binocular representations – ie neurons that respond to shared visual inputs from
both eyes.
In carnivores and primates, intra-cortical synapses originating from segregated ocular dominance columns in
layer 4 converge on neurons in layers 2/3 and 5 of primary visual cortex to form binocular receptive fields.
Ocular dominance plasticity, which results when vision through one eye is deprived or altered, provides insight
into the mechanisms that support binocular integration.
Closure of one eye in kittens or monkeys shifts the response of neurons in layer 2/3 of visual cortex away from
the closed eye and towards the open eye. This shift remains even after the eye is opened. Strabismus, in which
muscles are cut to prevent the eyes from focusing on the same part of the visual field, has a different effect of
forcing neurons in layer 2/3 to become responsive to just one eye or the other.
Hebbian plasticity mediates formation of binocularity. Blockade of the NMDA receptor prevents ocular
dominance plasticity. If both eyes are closed, no plasticity occurs, showing the competition between inputs is
critical for ocular dominance plasticity.

Question 45

What are the three reasons whisker barrels are the best studied and understood?

Answer 45

1. they receive relatively unprocessed sensory information relayed from the relevant sensory apparatus via few intermediaries
2. they provide a general model of neocortical function
3. their structure and function are well understood an they often exhibit visible specializations that reflect spatial recapitulations of the sensory world.

Question 46

Retinal Waves: does functional segregation arise from genetic programming or does neuronal activity play a critical role in development?

Answer 46

calcium Imaging reveals that retinal neurons produce spontaneous activity and that waves of this activity pass across the retina

Question 47

What happens if you inactivate the retina prior to eye opening?

Answer 47

Inactivation of the retina prevents segregation of ocular dominance columns.

Question 48

How does lack of synchronous retinal activity contribute to segregation of ocular dominance layers and columns?

Answer 48

Spontaneous activity is not correlated between the two eyes, forcing Hebbian plasticity to segregate ocular dominance zones.

Question 49

How does Hebbian plasticity result in ocular dominance columns?

Answer 49

Activity-dependent plasticity prior to eye opening segregates inputs with uncorrelated spontaneous acitivity

Question 50

Does segregation require the NMDA receptor in cortical neurons?

Answer 50

1. the knockout approach is critical in determining whether Hebbian plasticity is required for functional segregation based on spontaneous activity.
2. Mice that do not express NMDA receptors in the neocortex have severely ill-defined whisker barrels
3. The requirement for NMDA receptors is further evidence that Hebbian plasticity plays a key role in functional segregation of columns.

Question 51

Summary of part 2

Answer 51

1. Ocular dominance columns are zones of the cortex that only respond to input through one eye or the other.
2. They are present in the primary visual cortex of many species including the cat and human.
3. Functional segregation also exists in the visual thalamus
4. In many species, the eyes open some time after birth, but ocular dominance columns still emerge during this period.
5. Spontaneous neural activity can be recoded in the retinas prior to eye opening, known as retinal waves.
6. similar spontaneous activity can be detected in the visual thalamus
7. Retinal waves are not corelated between the two eyes
8. inactivation of the retinas, to prevent retinal waves, prevents the formation of discrete ocular dominance columns
9. evidence suggests that the blockade of NMDA receptors also prevents segregation of ocular dominance columns in visual cortex and whisker barrels in the somatosensory cortex
10. Hebbian synaptic plasticity is hypothesised to progressively sharpen the boundaries between ocular dominance columns by weakening connections between neurons that are uncorrelated in activity (ie responsive to opposite eyes) and strengthen connections between neurons that are correlated [ie responsive to waves in the same retina]

Question 52

Summary of part 3

Answer 52

1. binocular vision is critical for depth perception and survival.
2. Once the eyes open, activity switches from being uncorrelated between the two eyes to being correlated, due to shared visual input from the outside world over much of the visual field.
3. the visual system integrates inputs from the two eyes through experience to form binocular representations (ie neurons
   that respond to shared visual inputs from both eyes). In carnivores and primates, intra-cortical synapses originating from segregated ocular dominance columns in layer 4 converge on neurons in layers 2/3 and 5 of primary visual cortex to form binocular receptive fields.
4. ocular dominance plasticity, which results when vision through one eye is deprived or altered, provides insight into the mechanisms that support binocular integration.
5. closure of one eye in kittens or monkeys shifts the response of neurons in layer 2/3 of visual cortex away from the closed eye and towards the open eye. This shift remains even after the eye is reopened. Strabismus, in which muscles are cut to prevent the eyes from focusing on the same part of the visual field, has a different effect of forcing neurons in layer 2/3 to become responsive to one eye or the other.
6. Hebbian plasticity mediates formation of binocularity. Blockade of the NMDA receptor prevents ocular dominance plasticity. If both eyes are closed no plasticity occurs, showing the competition between inputs is critical for ocular dominance plasticity.

Question 53

Summary of Part 4

Answer 53

1. critical periods define the time window during which the effects of sensory experience or deprivation on the nervous system are most pronounced, usually occurring quite early in post-natal development.
2. critical periods vary for brain regions and sensory modalities, eg a critical period for plasticity in somatosensory cortex opens and closes earlier than for the visual cortex. Higher order regions of cortex, such as prefrontal cortex, have even later critical periods.
3. critical periods vary from species to species, eg the critical period for ocular dominance plasticity closes much earlier for mice than cats, and earlier for cats than primates.
4. several lines of evidence indicate that inhibitory neurons play a key role in critical period duration, with development of inhibition opening the critical period and maturation of cortical inhibition closing it. Increasing inhibition can prematurely open the critical period and reducing inhibition can re-open the critical period after it has closed.
5. Inhibition is believed to serve as a permissive factor for Hebbian plasticity by reducing overall activity at the opening of the critical period, thereby reducing 􀃉noise􀃊 and allowing differentiation of correlated and uncorrelated activity. However, too much inhibition can prevent sufficient post-synaptic activity to allow Hebbian plasticity to occur, thereby closing the critical period.

Question 54

What happens if the visual experience doesn’t return to normal during the critical period?

Answer 54

No functional recovery can occur if the visual
experience does not return to normal prior to
closure of the critical period, without intervention.

Question 55

Summary of part 5

Answer 55

1. non-invasive means to manipulate inhibition may re-open the critical period, returning the brain to peak plasticity
   and maximising the therapeutic effects of sensory experience.
2. promising methods include environmental enrichment, sensory deprivation, dietary restriction and exercise.
3. placing animals in the dark for an extended period greatly reduces the level of inhibition in the visual cortex.
   Mature cats that have previously undergone monocular deprivation as kittens and have severe loss of vision
   through the previously deprived eye can show dramatic visual recovery after being placed in the dark for 10 days.
4. this approach holds promise for a debilitating condition, known as amblyopia, which results in a visual cortical
   deficit due to childhood deprivation that persists even after the eye is rendered fully functional through surgery
   later in life. Amblyopia affects around one per cent of people in the UK, but many more in the developing world,
   where treatment of fixable ocular conditions is less likely to occur in a timely fashion and where poor vision
   carries more severe consequences.
5. work on the visual system also provides general insight into how the cortical function is shaped by deprivation
   and experience and how altered critical period plasticity may contribute to a wealth of neurodevelopmental
   disorders, including intellectual disability, autism spectrum disorder and schizophrenia.

Question 56

Outline of Week 4 Topic 3

Answer 56

1. Hebbian synaptic plasticity: theory and experimental proof
2. Segregating inputs through Hebbian plasticity: how does activity shape the visual system?
3. Integrating inputs through Hebbian plasticity: how does experience and deprivation shape the
   visual system?
4. Critical periods: how does inhibition serve as a permissive factor for Hebbian plasticity?
5. Re-opening the critical period: therapeutic approaches to recovering function in the deprived
   nervous system.

Question 57

Summary of Part 1

Answer 57

1. Hebbian plasticity is an activity-dependent strengthening of synapses between co-active neurons or
   weakening of synapses between neurons with uncorrelated activity.
2. Hebbian plasticity is modelled experimentally in vitro and in vivo through electrical stimulation to produce
   long-term potentiation (LTP) or long-term depression (LTD), which respectively strengthens or weakens
   synapses. The frequency of stimulation is a major determinant of the direction of change 􀃅 high for LTP
   and low for LTD. LTP and LTD occur at most synapses in the nervous system.
3. Hebbian plasticity is input-specific, as it occurs only at synapses that have undergone activity and does
   not occur at neighbouring inactive synapses on the same neuron. It is also long-lasting.

4. The NMDA subclass of glutamate receptor is often a key mechanism in the induction of LTP as it is an ion
channel that conveys calcium ions only when two coincident events occur 􀃅 glutamate binding and postsynaptic depolarisation 􀃅 thus it serves as a detector of the defining events in Hebbian LTP 􀃅 correlated pre- and post-synaptic activity. It is also a key mechanism for many forms of Hebbian LTD!

5. Hebbian plasticity is not accurately described by the statement 􀃉Fi􀁨e together, wire 􀁪oge􀁪he􀁨􀃊. Hebbian
   plasticity can only change existing synapses. It does not involve the formation of new synapses!