T DEVELOPME OF THE ERVOUS SYSTEM (Chapter 9.1)
Early phases of neural development (FIG. 9.1).
Embryos consit of three layers: ectodem, mesoderm and endoderm.
Induction of neural plate (ectodermal tissue) by underlying mesoderm (week 3 after
conception).
Cells of the neural plate are referred to as embryonic stem cells ( neural and
glial stem cells):
They have unlimited capacity for self-renewal
They have the ability to develop into diferent types of mature cells.
The neural plate leads to the formation of the neural tube, from where
forebrain, midbrain and hindbrain develop (by 40 days after conception).
The inside of the neural tube will eventually become the cerebral
ventricles and sopinal canal.
Growth and Development of euron
Proliferation: cells lining the ventricles divide and form neurons and glial cells.
Migration: Movement of cells from ventricular zone to final destination.
Radial migration. From the ventricular zone to the to the surface of the neural
tube. (Fig. 9.2).
Tangential migration. Parallel to the wall of the neural tube (Fig. 9.2).
Migration can occur by
Somal translocation (caterpillar-like movement, Fig. 9.3, top
panel), or
Glia-mediated migration (radial glial cells, Fig. 9.3, bottom
panel)
Cortex develops inside out
Aggregation. Cells accumulate in certain areas forming nuclei (singular: nucleus).
Differentiation Neurons take their adult morphology.
Myelination. In humans, starts in spinal cord and progresses toward forebrain.
eural crest.
Located dorsal to the neural tube (Fig. 9.1).
Neural crest cells develop into the neurons and glial cells of the PNS.
Axon Growth and Synapse Formation.
How do axons make correct connections with appropriate targets?
Growth cones and filopodia (Fig. 9.4)
Three major mechanisms can guide the process of target finding and synapse formation:
1. Blueprint hypothesis.
This hypothesis proposes that there are preformed pathways and tunnels.
Pioneer growth cones, guidepost cells.
Fasciculation
Role of cell-adhesion molecules (NCAMs)
Evidence against blueprint hypothesis:
Cells with altered locations (transplants) still find targets
2. Chemoaffinity hypothesis: connections are highly specific.
Sperrys eye-rotation experiments (1943). (Fig. 9.5)
After cutting optic nerves and rotating eyes 180 deg, the axons of retinal
ganglion cells regenerated back to original target regions in the optic tectum
(mesencephalon).
Frogs whose eyes had been rotated, but without cutting the optic nerves,
responded in the same way.
How specific are the connections?
If half of the retina was distroyed, remaining axons project in an orderly way
on the entire tectum (Fig. 9.6, middle panel).
If half of the tectum was destroyed, all of retinal axons accomodated in the
remaining tectum and formed appropriate map (Fig. 9.6, bottom panel).
These observations support the Chemical Gradient Hypothesis
(Fig. 9.7).
3. Fine-tuning of connections by spontaneous and experience-evoked neural activity
Neural activity can lead to a strengthening of some synapses and a weakening of others.
The Hebb postulate: eurons that fire together wire together.
Role of glutamate receptors. Respond to glutamate.
MDA receptors, are glutamate receptors that are
also stimulated by N-methyl-D-aspartate (NMDA)
Detect correlated activity between
presynaptic and postsynaptic cells.
non- MDA receptors. are glutamate receptors that
do not respond to NMDA
Role of spontaneous and evoked activity
Critical or sensitive periods in development.
euron Death and Synapse Rearrangement
Regulation of cell numbers
During normal development, many neurons die. It is believed that they fail to compete
successfully for life-preserving chemicals.
Among these chemicals are the neurotrophins or trophic factors, such as Nerve growth
factor (NGF), and brain derived neurotrophic factor (BDNF).
Lack of trophic factors triggers Apoptosis, or active, programmed cell death (different from
ecrosis, or passive cell death)
Why does the CNS produce more neurons that it needs?
To compensate for failure of some axons to find target.
To compensate for target variability in size
Synapse Rearrangement.
Synapses that are "wrong" are likely to disappear (Fig. 9.8).
The vulnerable developing brain
Many factors can go wrong during development
More than 200 genetic mutations associated with mental retardation
The developing brain is more vulnerable than the mature brain to the effects of malnutrition, toxic
chemical and infections.
For instance, impaired function of the thyroid gland (endocrine gland) in infancy produces
mental retardation that can be permanent. In the adult, thyroid impairment produces
lethargy and other symptoms, but not mental retardation.
Another example is early exposure to alcohol: fetal alcohol syndrome (mental retardation,
motor problems, hyperactivity, decreased alertness, heart defects and facial abnormalities.
Dendrites tend to be short, with few branches. (see Movie).
Rett Syndrome: Anomaly of brain development with mental retardation affecting mainly girls older
than 1-2 years.
Associated with lack of dendritic development, perhaps due to deficit of neurotrophic
factors
Epilepsy
OTE: sections 9.2, 9.3, 9.4, 9.5 are not included.
LEAR I G, MEMORY, and AM ESIA (Chap 11)
What is learning?
The study of learning focuses on the changes in the nervous system that are induced by experiences,
whereas the study of memory focuses on how these changes are maintained over time, and expressed
(recalled).
Learning is impossible without memory, and memory is impossible without learning: memory and
learning are inseparable.
The study of learning is difficult. It probably occurs in large areas of the brain, and trying to find the
changes that occur during learning in a brain as complex as ours is a big challenge.
Amnesic effects of bilateral medial temporal lobectomy
Amnesia: condition characterized by the incapacity to remember
Bilateral medial temporal lobectomy: removal of the medial portion of the temporal lobe in both sides
of the brain (Fig. 11.1).
Lobectomy: removal of a cerebral lobe
Patient HM underwent bilateral medial temporal lobectomy to alleviate severe epilepsy (in 1953).
The tissue removed on both sides included the hippocampus, amygdala and adjacent cortex
(rhinal cortex).
His epileptic condition improved, but he suffered devastating amnesic effects.
He had some degree of retrograde amnesia (backward-acting).
He could remember his childhood well but less well those episodes within the last two years
before surgery.
However, he suffered a severe antrograde (forward-acting) amnesia.
Short-term memory was within normal range (digit span of 6 digits).
But he could not form new long-term memories.
He could not consolidate new memories (process of transferring short-term memories into
long-term memories).
Testing anterograde amnesia with objective tests:
Digit span + 1 test. HM could remember about 6 digits; normal can remember about 15.
Block-tapping memory-span test. HM could follow 5 blocks, within the normal range.
However, HM s memory for sensorimotor tasks was preserved:
Mirror drawing test (Fig. 11.2), and Rotary-pursuit test (Fig. 11.3). HM could improve by
training, although he could not remember that he had practiced.
He also improved in some non-sensorimotor tasks, such as the Incomplete-picture test (Fig. 11.4), but
could not recall previously performing the task.
He also learned a Pavlovian conditioning task. Eyeblink response: pairing sound with air puff on the
eye.
Scientific Contributions of HMs case.
HM symptoms suggested that individual brain structures could be related to specific
memory (mnemonic) processes.
HMs specific problem was a difficulty with memory consolidation.
Also, he was the first patient to suggest that that there are two parallel memory systems:
One for explicit memories (conscious memories), and
One for implicit memories, memories that are expressed by improved test
performance, but without conscious awareness.
Tests to assess implicit memory are called Repetition priming tests.
Examples are the incomplete-picture test and test that involve
memory for words. Amnesiacs can improve at recognizing word
fragments if they see the complete words beforehand, even if they
do not recall seeing the words.
Two kinds of explicit memories:
Semantic memories are explicit memories for general facts or information, for example,
what one would learn in school, language, grammar and facts.
Episodic memories are explicit memories for events and experiences in ones life (seeing a
particular movie).
Patients with medial temporal lobe amnesia mainly have deficits in episodic memories.
Why are there two parallel memory systems: one for explicit memories (conscious memories), and one
for implicit memories?
The conscious (explicit) system may have evolved to confer flexibility: ability to use implicit learning in
different ways or contexts.
Studies showed that although amnesic patients were able to learn an implicit task, they
could not use this knowledge in a different context.
Amnesia after Concussion: Evidence for Consolidation.
Posttraumatic amnesia. Amnesia resulting from nonpenetrating blows to the head that cause
concussion (temporary disturbance of consciousness) or coma (loss of consciousness).
When patients regain conciousness, there is a period of confusion during which the patients
have short-term memory and appear reasonably lucid, but they fail to consolidate these
memories into long-term memories.
Also, they show a permanent retrograde amnesia for the events that led to the blow. (Fig.
11.6).
Gradients of Retrograde Amnesia and Memory Consolidation
The fact that concussions disrupt recent memories suggests that the of storage older
memories is protected by a process of consolidation.
Consolidation has been studied with electroconvulsive shocks (ECS) to test the hypothesis
that disrupting neural activity with the shocks would erase those memories that had not yet
consolidated.
The idea is that the length of the period of retrograde amnesia would correlate
with the time needed for memory consolidation.
Hebb postulated that prior to consolidation, memory is held in reverberating
circuits that are susceptible to disruption of neural activity, such as that caused
by ECS.
Results from one experiment in rats suggested that consolidation
took less than one hour (Fig. 11.7).
Electric shocks applied later than one hour after the training did
not erase what the rats had learned (the location of a water spout).
However, experiments in humans that were treated with ECS for depression suggested that
shocks could erase memories up to 3 years old (Fig. 11.8).
Thus, consolidation may be an ongoing process, which makes Hebbs
hypothesis unlikely.
Reconsolidation
Recent studies suggest that each time a memory is retrieved from long-term stirage, it is
again stored in short-term memory, being therefore susceptible to posttraumatic amnesia.
The Hippocampus and Consolidation
There are some studies suggesting that the hippocampus may be involved in the
consolidation process.
It has been proposed that memories are temporarily stored in the hippocampus
until they are transferred to a more stable cortical storage.
euroanatomy of Object-Recognition Memory
Monkey Model of Object-Recognition Amnesia: The Delayed onmatching-to-Sample Test
Monkeys with bilateral medial temporal lobe lesions had deficits in the delayed
nonmatching-to-sample test (Figs. 11.9 and 11.10).
These deficits were similar to those of HMs (explicit, episodic memories).
Monkeys could show short-term memories, but had difficulty
consolidating them into long-term memories (Fig. 11.10).
In fact, humans with bilateral medial temporal lobe lesions
behaved similarly in the delayed nonmatching to sample tests.
One problem with monkeys is that lesions aimed at hippocampus also lesioned the rhinal cortex (cortex
adjacent to the hippocampus) (Figs. 11.11 and 11.12) .
Therefore, researchers could not be sure whether memory deficits in monkeys were due to
lesion of the hippocampus or rhinal cortex.
The Delayed onmatching-to-Sample Test for Rats
However, the rat model presented the advantage that lesions could be restricted to the
hippocampus (Fig. 11.12).
The version of the delayed nonmatching-to-sample task in rats is the Mumby
box (Fig. 11.13). This box has 3 compartments.
In one compartment, the rat is exposed to the sample object
concealing the food.
In the middle compartment, the rat is made to wait through the
delay.
In the third compartment, the rat was presented with the sample
object that had to be rejected in favor of the new one that now
conceals the food.
Rats performed as well as monkeys with delays up to one minute.
euroanatomical Basis of the Object-Recognition Deficits Resulting from Medial Temporal
Lobectomy
The rodent model revealed that the hippocampus and amygdala were not involved in
deficits of object-recognition memory tested with delayed nonmatching-to-sample tasks.
Instead, these experiments found that the rhinal cortex was important for object recognition
memory (Fig. 11.15).
The hippocampus and memory for spatial location.
The hippocampus does play a key role in memory for spatial location.
Hippocampal Lesions Disrupt Spatial Memory
Damage of the hippocampus result in severe deficits in spatial memory tested in mazes like
the Morris water maze and the radial arm maze tests.
In the radial arm maze, each day rats quickly learn the position of the arms with
food (reference memory for the general principles and skills needed in the
task) and refrain to visit an arm more than once during the day (working
memory: ability to maintain relevant memories while a task is being
performed). Both reference and working memories are deficient after lesion of
the hippocampus.
Hippocampal Place Cells
When rats familiarize themselves with the environment, many cells in the
hippocampus acquire a place field, that is, they fire when the rats is in a
particular place in the environment.
Comparative Studies of the Hippocampus and Spatial Memory
Species of birds that remember where they store seeds have larger hippocampuses than
birds that do not store seeds, supporting the idea that hippocampus is important for spatial
memory in many, if not all, species.
Experiment with humans in virtual-reality towns (show activity in hippocampus using
positron emission tomography, PET) and with taxi drivers (bigger hippocampuses measured
with magnetic resonance imaging, MRI) also support this idea.
Theories of Hippocampal Function
The hippocampus may use sensory input to form an allocentric map of the environment
(space represented by the relation between external landmarks).
The hippocampus may be important for recognizing spatial arrangements of objects (such as
furniture, pictures, etc, in a familiar room).
Where are memories stored?
In addition to the structures damaged in patients with medial temporal amnesia (hippocampus, amygdala
and adjacent cortex (rhinal cortex)), other brain nuclei also play a role in memory.
Some of these structures, such as the mediodorsal nucleus of the thalamus, and the basal forebrain (a
midline area, rich in Ach, located just above the hypothalamus) (Fig. 11.17) appear to be damaged in
patients suffering Korsakoff syndrome (often due to alcoholism, as we will see later in the course) and
Alzheimer syndrome (a terminal condition including progressive amnesia and dementia).
Other areas implicated in memory are (Fig. 11.17)
The inferotemporal cortex stores memories of visual patterns.
The amygdala plays a role in memory for the emotional significance of experiences. Rats
with amigdala lesion fail to associate shocks with fear.
The prefrontal cortex stores the temporal order of events, affecting jobs that require a
series of responses, such as cooking.
The cerebellum stores implicit sensorimotor tasks such as the eyeblink response.
The striatum, part of the basal ganglia stores implicit sensorimotor tasks such as habit
formation that develop incrementally after many trials.
SY APTIC MECHA ISMS OF LEAR I G A D MEMORY(Chapter 11.8)
In an attempt to study learning, research has focused on simpler systems that show some changes
asociated with learning, with the hope that these changes are similar to those that occur in more complex
brains.
Two main approaches.
-One approach studies the neural bases of learning in a sea snail (marine mollusk), called
Aplysia (sea slug)
-The other approach focuses on a phenomenon that it is thought to be related to learning in
brains like ours. The phenomenon is called long-term potentiation (LTP). We will
concentrate on this approach.
LTP as a model for learning (Fig. 11.19).
LTP in mammalian brains is the most widely studied neuroplastic phenomenon
LTP: Enduring facilitation of synaptic transmission that occurs
following activation of a synapse by intense high-frequency
(100/sec) stimulation (for 1-4 secs) of the presynaptic neuron.
-It is long-lasting: hours or weeks.
Properties that implicate LTP in learning and memory
1) LTP shows cooperativity (spatial effect): Nearly simultaneous stimulation of two or
more axons produces LTP, whereas stimulation of just one is less effective.
If there are several inpus to a cell, only those that cooperate become facilitated,
the others may actually weaken.
2) LTP shows associativity: Pairing a weak input with a strong input enhances later
responses to the weak input.
3) LTP is the kind of synaptic facilitation that Hebb postulated in 1949 as the basis of
learning and memory:
Hebb's postulate for learning: The synaptic efficacy between A and B will increase when A fires B
consistently.
In order to account for associative learning and memory, synaptic facilitation must result
from an interaction of simultaneous presynaptic and postsynaptic activity.
In fact, LTP does not occur if the postsynaptic cell does not fire (only the
presynaptic).
Or when the postsynaptic cell fires alone.
It is the co-occurrence that matters.
Mechanisms of LTP.
Receptors for Glutamate can be MDA receptors, or non- MDA receptors
The hebbian nature of LTP results from the properties of the MDA receptor (Figs. 11.20 - 11.21).
Normally glutamate does not activate NMDA receptors because they are blocked by Mg++
(magnesium).
-In order to repel the magnesium, it is necessary to depolarize the cell by
activating non-NMDA receptors (e.g., AMPA receptors).
-Glutamate can now open NMDA receptors, which let Na+ and Ca++ in.
-Entry of Ca++ in postsynaptic cell induces cellular changes (Fig. 11.21).
Temporarily activate genes and produce certain proteins.
Proteins alter dendrites and potentiates synapse.
NMDA receptors are necessary for inducing LTP, but not for maintaining it.
It is now clear that effects of LTP are both presynaptic and postsynaptic
LTP appears to increase the presynsptic release of glutamate
LTP appears to promote the insertion of increased number of glutamate receptors in the
postsynaptic membrane.
Signal from postsynaptic to presynaptic cell: Changes in the postsynaptic cell may be transmitted to the
presynaptic cell by the soluble gas itric Oxide ( O) (blocking the synthesis of NO blocks LTP),
although other factors may also play a role.
LTP and behavior
-LTP can occur during training in vivo.
-Blocking LTP interferes with learning.
mice with a mutation of a gene controlling NMDA receptors did not have LTP
and could not learn a spatial task