DEVELOPMENT OF THE NERVOUS 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 Neuron
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.
Neural 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.
Sperry’s 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: Neurons that fire together wire together.
Role of glutamate receptors. Respond to glutamate.
NMDA receptors, are glutamate receptors that are also stimulated by N-methyl-D-aspartate (NMDA)
Detect correlated activity between presynaptic and postsynaptic cells.
non-NMDA receptors. are glutamate receptors that do not respond to NMDA
Role of spontaneous and evoked activity
Critical or sensitive periods in development.
Neuron 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 Necrosis, 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
NOTE: sections 9.2, 9.3, 9.4, 9.5 are not included.
LEARNING, MEMORY, and AMNESIA (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 HM’s case.
HM symptoms suggested that individual brain structures could be related to specific memory (mnemonic) processes.
HM’s 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 one’s 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 storage of 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 Hebb’s 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.
Neuroanatomy of Object-Recognition Memory
Monkey Model of Object-Recognition Amnesia: The Delayed Nonmatching-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 HM’s (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 Nonmatching-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.
Neuroanatomical 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.
SYNAPTIC MECHANISMS OF LEARNING AND 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 NMDA receptors, or non-NMDA receptors
The hebbian nature of LTP results from the properties of the NMDA 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 Nitric Oxide (NO) (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