Learning and Memory

This section of the course deals with learning and memory. I won’t define these terms because this is a lot more difficult to do than you might expect.

This section is organized as follows.1. An overview of the main current concepts of learning and memory.2. Types of memory.3. Specialized learning and memory systems. The definition of: (a) Perceptual learning. (b) Skill and habit learning. (c) Declarative memory.4. I will then concentrate on four systems: sensory cortices and perceptual learning

(brief); the cerebellum and motor learning; the amygdala and emotional learning; the hippocampus and declarative memory.

In each case we will cover the behaviors measured to study learning in these systems, the anatomy of the substrates and the physiological bases of the underlying plasticity.

Overview 1

There have been many heuristic models of learning and memory. One popular model is based on computer memory. A computer stores instructions and data on a hard disk or in RAM; the processor then fetches and manipulates these files. In other words, the memory location is different from the processing location.

The brain works entirely differently. Based on electrophysiological and behavioral studies, there are many regions of the brain involved in learning and memory.It is known that synapses are not fixed but can be changed by neuronal activity, a process known as synaptic plasticity.

A major hypothesis of neuroscience is that synaptic plasticity is an important cellular basis of memory storage.Molecular neuroscience has revealed the molecular basis of many kinds of synaptic plasticity (this material was covered in the NSC 5402: Cellular and Molecular Neuroscience). These molecular substrates of synaptic plasticity are present in most (all?) brain areas although their expression levels vary. This supports the idea that most (all?) parts of the brain can support synaptic plasticity and might therefore be part of a distributed memory system.

Overview 2

There is something of a paradox here: memory is distributed over much of the brain. Yet there are specialized memory subsystems.

We can understand this in the following way:Different parts of the brain are specialized for different functions; in my section you learned about visual processing in primary visual cortex. In Dr. Fortier’s section you learned about motor systems.

Each of these specialized brain regions has its own synaptic plasticity mechanisms and learning/memory involves synaptic changes in the processing regions themselves.

We’ll see many examples throughout these lectures.

Types of Memory

The major subdivision of memory is into Declarative and Procedural memory.

Declarative memory is what humans generally think of as memory. If an event occurs we can describe what happened with some accuracy and related it to other events.

Animals cannot “declare” what they have experienced. So a subtype of declarative memory- episodic memory- is believed to play the same role but without language. Here are two typical examples of episodic memory in the rat:

(a) The rat learns to find food at a specific location in a maze.(b) The monkey learns to select an item different from one presented a brief

time before (delayed non match to sample).

Procedural memory involves improving some perceptual (interpreting micro-photographs of synapses) or motor skill (riding a bike, skiing etc); in humans this is not associated with conscious awareness of what is being learned.

We’ll look at examples of procedural learning next.

Perceptual Learning 1

Adams et al. 2004. Nature Neuroscience

Based on our everyday experience we expect a light source (the sun) to be coming from above. The patches that are brighter on top are seen as convex (bumps) while the patches that are bright at the bottom are seen as concave (dimples) cause of the way light will be reflected from them.This was thought to be “built in” to our visual systems.In this experiment the observation of the images was paired with touch that indicated that what appeared to be a bump was really a dimple and vice versa. The observers then changed their estimation of where the light was coming from. Visual perception was changed by changed by somatosensory input.The site of this learning is not known.

Perceptual Learning 2

Tsodyks and Gilbert (2004) Nature

In these experiments a subject has to decide whether the central line is nearer the left or right line. As you can see the threshold for this discrimination drops over a period of many days. This perceptual improvement is specific to this task- it does not generalize to the vernier discrimination task: are two lines collinear. The authors of this study presented data that suggested that this improvement was occurring in primary visual cortex.Other studies from this group also reinforce the idea that synaptic plasticity in the visual cortices themselves is the basis for this type of perceptual learning.

This type of learning corresponds to an everyday experience. After some time in a new environment, you learn to better “see” what it is your are looking at, e.g. learning to do microscopy.

Perceptual Learning 3

Weinberger, 1993, Current Opinion inNeurobiology.

The perceptual changes seen in psychophysical experiments can be correlated with electrophysiological studies of single neurons.

Here we see a recording from a neuron in auditory cortex. As you remember, the cell here are tuned to specific frequencies: this cell gave the strongest response to frequencies near 9.5 kHz. The animal then underwent classical conditioning with a 9 kHz tone. As you can see the neuron shifted its frequency tuning: its response to 9.5 kHz was decreased and its response to 9 kHz greatly increased.

Similar kinds of plasticity experiments have been performed for orientation tuning in primary visual cortex.So the sensory cortex shows synaptic plasticity that underlies perceptual learning. This type of learning is unconscious and does not generalize.

Motor Learning

Motor control finally derives from brainstem or spinal cord motorneurons and the local interneurons that control them. However the complex pattern of muscle activation that underlies posture and movement is controlled by higher brain centers: the motor cortex, the basal ganglia and the cerebellum. Due to lack of time, we won’t discuss the motor cortex or the basal ganglia except to say that the basal ganglia are probably involved in the learning of habitual movements that are “rewarded”. Instead we’ll concentrate on cerebellum just because it has a fairly simple structure.

The cerebellum is hypothesized to be involved in two types of learning: error corrected gain control and motor timing control.

First we’ll briefly review cerebellar anatomy and physiology and then discuss examples of each type of learning: the vestibulo-ocular reflex (VOR) for error correction and eyeblink conditioning for timing control.

Brodal, The Nervous System. Cerebellum 1: Structure

The cerebellum is an ancient structure; its basic form is already evident in sharks and remains basically the same in all vertebrates. It sits dorsal to the medulla and pons and derives embryologically from the rhombic lip.The cerebellum has several subdivisions but they all follow the same basic pattern of connectivity: sensory input (directly from periphery on indirectly from cortex) ends up in the cerebellar cortex. The cerebellar cortex projects down to the cerebellar nuclei and these in turn project to motor control regions (directly or via the motor cortex).The vestibulo-cerebellum receives vestibular input, projects to the vestibular nuclei and regulates eye movements. This pathway is involved in plasticity of the vestibulo-ocular reflex (VOR).

The cerebellar hemispheres receive sensory input from cortex (via the pontine nuclei) and project back to the red nucleus and motor cortex (via thalamus). This pathway is involved in learning of eyeblink conditioning.

Cerebellum 2: CircuitryBear et al.

The principle players in the cerebellar cortex.Granule cells: tiny neurons that receive most cerebellar input (mossy fibers). There axons project up into the molecular layer and make a characteristic T branch to form parallel fibers.Purkinje cells: the output neurons of the cerebellum; the parallel fibers form numerous synaptic contacts on the spines of Purkinje cells. These are excitatory and utilize the glutamate as a transmitter and AMPA + metabatropic receptors.Purkinje cells receive another excitatory input: climbing fibers that emanate from the inferior olivary nucleus of the medulla.

Climbing fibers responsive project to the same input project to small sagittal strips of cerebellar cortex.The Purkinje cells within one strip project to the same cluster of deep cerebellar neurons.These microzones and target DN cells are therefore thought to be the functional subunits of the cerebellum.

Cerebellum 3: Input and Output

More important details: Purkinje cell dendrites have a planar organization; parallel fibers run perpendicular to the Purkinje cell dendrites and contact many P-cells. Each P-cell receives only one climbing fiber input.

Purkinje cells are the only output of the cerebellar cortex. The inhibit the deep nuclear neurons (DN). The DN neurons are excitatory.

Cerebellum 4: Circuit details

A schematic of the cerebellar circuitry. Remember that the parallel and climbing fiber input to the P-cell are excitatory. The P-cell projection to the DN neurons is inhibitory.

There are also inhibitory interneurons in the cerebellum: stellate, basket and golgi neurons.

There are multiple forms of synaptic plasticity in the cerebellum:

1. Parallel fiber synapses onto P-cells have presynaptic LTP and postsynaptic LTD.

2. Mossy fiber synapses onto granule cells potentiate.

3. P-cell synapses onto DN neurons potentiate and depress (complicated).

Cerebellum 5: LTD and LTP

The best studied form of cerebellar plasticity is LTD of parallel fibers. This is induced by pairing stimulation of parallel and climbing fibers. The climbing fiber EPSP in unchanged by this protocol. The parallel fiber EPSP is depressed for >30 minutes. So this is an associate kind of plasticity- this led to the idea that the climbing fiber was a “teacher” or carried an error code; the parallel fiber “learned” from the climbing fiber. The model was that, for any Purkinje cell, a subset of parallel fibers would be functional. Stimulation of parallel fibers without climbing fiber co-activation produces LTP. So PF synapses can go up or down in strength- this is believed to be a key element for cerebellar based learning.

Cerebellum 6: LTD mechanism

The cellular mechanism for Purkinje cell postsynaptic associative LTD has been studied extensively. The climbing fiber depolarizes the entire Purkinje cell dendritic tree causing the opening of dendritic Ca2+ channels. Stimulation of parallel fibers results in glutamate binding to metabatropic glutamate receptors causing the activation of PKC. The simultaneous presence of dendritic Ca2+ and PKC causes the endocytosis of the parallel fiber glutamate (AMPA) receptors producing a long lasting decrease in the EPSPs at that synapse.

The Vestibulo-ocular Reflex (VOR)

G- gaze direction, H- head position, E- eye position, T- table velocity.

Animals often need to stabilize their gaze direction while moving. That is, they may need to focus on one object even if their head and/or body is moving. So they use compensatory eye movements to cancel the movement of their head and remain focuses. This is usually studied by rotating the animal horizontally while it focuses on some object and observing the compensatory eye movements- the VOR.

VOR Circuit

The rotation of the head is signaled by the vestibular system (horizontal canals in this case) and eye movements are controlled by the extraocular muscles. The vestibular nuclei provide the link that controls the VOR.This is a very simplified schematic of the VOR circuitry in a frog.

Cerebellar Control of the VOR

The VOR works quite well with just the brainstem vestibular circuit. But it was discovered that the cerebellum (an ancient lobe called the flocculus) recieves vestibular input and project to the vestibular nuclei responsible for the VOR.

Prism

For normal operation of the VOR, the flocculus is not very important. A major discovery was that the VOR could change if the visual input was perturbed. The classic method for perturbing the visual input was to put a pair of prisms over the eyes. When this is done a head rotation will result in an increased (or decreased dependent on the optics) movement of images across the retina. So the the VOR no longer stabilizes the image on the retina. After many hours to days the VOR compensates and again stabilizes the retinal image. This VOR adaptation requires the flocculus. The theory (based on extensive data) is that retinal slip information reaches P cells via climbing fibers and vestibular input via parallel fibers. When the system is OK there is no retinal slip. When visual input is perturbed a head movement results in a moving retinal image activating the climbing fibers. As a result cerebellar plasticity leads to a modified VOR that removes retinal slip. So perhaps the purpose of the cerebellum is to control the timing and/or gain of the VOR.

The Cerebellum as an Adaptive filterDean et al, 2010 NRN

In an adaptive filter the input goes into a bank of filters. For each filter its gain (amplification or reduction of the input) is controlled as is its time constant (how long the output lasts). The outputs of the filters are then added up.The “adaptive” part comes in when the gain can be regulated.In the cerebellum it is assumed that the gain (weight=w) of the parallel fiber synapses are regulated by climbing fiber input. This results in the correct matching of head velocity and stimulus.This model explains a lot of the VOR data.

Eye blink conditioning

When air is puffed onto the eye the animal blinks as a protective mechanism. This is an unconditioned reflex since it happens in an untrained animal. The air puff is the unconditioned stimulus (US) and the eyeblink the unconditioned response.

A. When a tone precedes the air puff the animal learns to associate the tone with the puff: they learn that the tone predicts the air puff and so they will, after many trials, do the eyeblink in response to the tone. In other words the eyeblink will occur before the air puff and the eye will be even better protected. This is “delay conditioning” and the tone is the conditioning stimulus (CS). The eyeblink is now a conditioned response.B. In some cases the CS does not overlap the US; this is trace conditioning. The cerebellum is essential for learning this conditioned response.

The cerebellum and eye blink conditioning

Here is the circuitry for learning to blink in response to a tone. The climbing fibers give the “teaching” US signal of the airpuff while the parallel fibers carry the CS- the tone. The two are associated somewhere in cerebellum via synaptic plasticity.

The cerebellum: Summary

From these two examples we might conclude that the cerebellum is important for controlling the timing of motor responses to sensory input: for the VOR it controls the phase of the eye movement with respect to the vestibular stimulation; for the eyeblink it controls the time of the eyeblink with respect to the tone.

The cerebellum can change this temporal relation. Many, but not all, neuroscientists believe that this form of learning is based on P cell plasticity. It has been very hard to prove this conclusively. Firstly there are many forms of plasticity in cerebellum and it is hard to parse out which one does what.There are models that incorporate more than one form of plasticity and they do make some good predictions, but there is still disagreements. There have been knockouts of essential ingredients of P cell plasticity (PKC isoforms); these knockouts result in animals that lack P cell LTD and also lack adaptation of the VOR.But these are in the mouse and it hardly has a VOR.

So, even in this “simple” system, it is very difficult to relate cellular plasticity to memory and learnng.