1. Reflex
Circuits
With
Inter-neurons
Flexor-
Crossed
Extensor
Reflex
(Sheridan
1900)
Painful Stimulus

2. Flexor-cross Extensor reflex
described by Sir Charles Sherrington in early 1900s
its action is to withdraw a limb from a noxious stimulus
it involves both excitation of synergistic muscles and inhibition of antagonist muscles, say, in your legs
action -- noxious stimulus, activate pain sensitive sensory neurons, excite motor-neurons to flexors on pain side and extensors on opposite side, but also inhibit extensor on pain side and flexors on opposite side -- leg is withdrawn without falling down
the excitation of synergists and inhibition of antagonists is coordinated by inter-neurons

3. A Simple model or Minimum Circuit:
HIGHER LEVEL CONTROL
Pain Stimulus
MotoNeuron + + +
Sensory
Neuron
Inter
Neuron
Inter
Neuron
Flexor
MotoNeuron - -
Inter
Neuron
Inter
Neuron
Extensor

4. Flexor-crossed Extensor (Sheridan 1900)

7. Gaits of the cat: an informal computational model

8. Neural Development CS182/CogSci110/Ling109 Spring 2007 Jerry Feldman

9. Lecture Overview Summary Overview Development from embryo
Initial wiring
Activity dependent fine tuning
Additional information/details
Principles of Neural Science. Kandel, Schwartz, Jessell, Mcgraw-Hill (2000).

10. How does this happen
Many mechanisms of human brain development remain unclear, but
Neuroscientists are beginning to uncover some of these complex steps through studies of
the roundworm, fruit fly, frog, zebrafish, mouse, rat, chicken, cat and monkey.
Many initial steps in brain development are similar across species, while later steps are different.
By studying these similarities and differences, we can learn how the human brain develops and hopefully how brain abnormalities, such as mental retardation and other brain disorders, can be prevented or treated.

11. Summary Overview The Amoeba (ref. book) uses
complex sensing molecules penetrating its cell membrane to trigger
chemical mechanisms that cause it to move its blobby body towards food and away from harmful substances.
Neurons are also cells and,
in early development, behave somewhat like Amoeba in approaching and avoiding various chemicals.
But rather than the whole cell moving, neural growth involves the outreach of the cell’s connecting pathway (axon) towards its downstream partner neurons.

12. Summary Overview
The basic layout of visual and other maps is established during development by millions of neurons
each separately following a pattern of chemical markers to
its pre-destined brain region and specific sub-areas within that region.
For example, a retinal cell that responds best to red light
in the upper left of the visual field will connect to cells in the brain that are tuned to the same properties and
these cells, in turn, will link to other cells that use these particular properties giving rise to specific connectivity and cell receptive field properties (topographic maps).

13. Summary Overview In the course of development,
detector molecules in the growing neuron interact with
guide molecules to route the connection to the right general destination, sometimes over long distances as in the connection from the spinal cord to the knee.
This process will get neural connections to the right general area, but
aligning the millions of neurons in visual and other neural maps also involves
chemical gradients, again utilizing mechanisms that are very old in evolutionary terms.

14. Summary Overview
When an axon tip gets to an appropriately marked destination cell, the contact starts a process that develops rudimentary synapses.
Local competition among neural axons with similar marker profiles produces some further tuning at the destination.

15. Summary Overview: Activity Dependent Tuning
In fact, the initial wiring is only approximate and leaves each neuronal axon connected to several places in the neighborhood of each of its eventual partner neurons.
A second, activity dependent, mechanism is required to complete the development process.
The initial chemical wiring actually produces many more connections and somewhat more neurons than are present in adult brains.
The detailed tuning of neural connections is done by eliminating the extra links, as well as the strengthening functional synapses based on neural activity.

16. Summary
Neural development and learning is moving from a mystery to routine science.
We know enough to shape theories of how our brains learn skills, including language, and how we acquire and use knowledge.
Contemporary theories of learning are also heavily influenced by psychological experiments, some of which are described next week.

17. Lecture Overview Summary Overview Development from embryo
Neural tube development
Cell division and neuronal identity
Mechanisms for cell type formation and communication
Initial wiring
Activity dependent fine tuning
Plasticity and Learning

18. Development from Embryo
The embryo has three primary layers that undergo many interactions in order to evolve into organ, bone, muscle, skin or neural tissue.
The outside layer is the ectoderm
(skin, neural tissue),
the middle layer is the mesoderm
(skeleton, cardiac) and
inner layer is the endoderm
(digestion, respiratory).

19. Neural Tissue
The skin and neural tissue arise from a single layer, known as the ectoderm
in response to signals provided by an adjacent layer, known as the mesoderm.
A number of molecules interact to determine whether the ectoderm becomes neural tissue or develops in another way to become skin

20. Early development
Three to four weeks after conception, one of the two cell layers of the gelatin-like human embryo, now about one-tenth of an inch long, starts to thicken and build up along the middle.
As this flat neural plate grows, parallel ridges, similar to the creases in a paper airplane, rise across its surface.
Within a few days,the ridges fold in toward each other and fuse to form the hollow neural tube.
The top of the tube thickens into three bulges that form the hindbrain, midbrain and forebrain.
The first signs of the eyes and then the hemispheres of the brain appear later.

21. Neural Tube formation

24. In humans, during the 3rd week, this mesoderm begins to segment
In humans, during the 3rd week, this mesoderm begins to segment. The neural plate folds to form a neural groove and folds.

25. Other structures
including heart,
Skeleton, etc.
The neural groove fuses dorsally to form a tube at the level of the 4th somite and "zips up” cranially and caudally and the neural crest migrates into the mesoderm (somites differentiate to form vertebrae, muscles).

26. Somite:
block of dorsal mesodermal cells adjacent to the notochord during vertebrate organogenesis. These transient structures define the segmental pattern of the embryo, and subsequently give rise to vertebrae and ribs, dermis of the back, and skeletal muscles of the back, body wall and limbs. 
  Notocord:
block of dorsal mesodermal cells adjacent to the notochord during vertebrate organogenesis. These transient structures define the segmental pattern of the embryo, and subsequently give rise to vertebrae and ribs, dermis of the back, and skeletal muscles of the back, body wall and limbs.   

27. Flat plate  
deepening neural groove  
neural tube formed

28. BRAIN DEVELOPMENT. The human brain and nervous system begin to develop at three weeks’ gestation as the closing neural tube (left). By four weeks, major regions of the human brain can be recognized in primitive form, including the forebrain, midbrain, hindbrain, and optic vesicle (from which the eye develops). Irregular ridges, or convolutions, are clearly seen by six months.

30. Brain Weight

31. Lecture Overview Summary Overview Development from embryo
Neural tube development
Cell division and neuronal identity
Cell communication
Initial wiring
Activity dependent fine tuning
Plasticity and Learning
Development and Infant behavior

32. Neural cell categories
After the ectodermal tissue has acquired its neural fate,
another series of signaling interactions determine the type of neural cell to which it gives rise.
The mature nervous system contains a vast array of cell types, which can be divided into two main categories:
the neurons, primarily responsible for signaling,
and supporting cells called glial cells.

33. Factors/gradients in cell formation
Researchers are finding that the destiny of neural tissue depends on a number of factors, including position, that define the environmental signals to which the cells are exposed.
For example, a key factor in spinal cord development is a secreted protein called sonic hedgehog that is similar to a signaling protein found in flies.
The protein, initially secreted from mesodermal tissue lying beneath the developing spinal cord, marks young neural cells that are directly adjacent to become a specialized class of glial cells.
Cells further away are exposed to lower concentrations of sonic hedgehog protein, and they become the motor neurons that control muscles.
An even lower concentration promotes the formation of interneurons that relay messages to other neurons, not muscles.

34. Cell Cycle and neuron generation
Neurons of the cerebral cortex are generated in the ventricular zone of the neural tube, an epithelial layer of stem cells that lines the lateral ventricles.
Once they have left the cell cycle, the neurons migrate (on glial cells) out of the VZ to form the cortical plate (gray matter for the cortex).
On the cortical plate, neurons become organized into well defined layers.

35. Timing of Cell Differentiation
Remarkably, the final position of the neuron (its laminar position) is correlated exactly to its birthdate
The birthdate is the time of final mitosis
Cells leaving later migrate past the older neurons (in deeper cortical layers) to the outermost cortex.
The layering of the cortex is thus an inside-first outside-last layering.

36. As the brain develops, neurons
migrate from the inner surface
to form the outer layers. Left:
Immature neurons use fibers
from cells called glia as
highways to carry them to their
destinations. Right: A single
neuron, shown about 2,500
times its actual size, moves on
a glial fiber. (10-6 m/hr)
Illustration by Lydia Kibiuk, Copyright © 1995 Lydia Kibiuk.
Improper migration leads to diseases including childhood epilepsy, mental retardation, lack of sense of smell and possibly others.
Hiroshima Nagasaki Effects

38. Lecture Overview Summary Overview Development from embryo
Initial Wiring details
Axon Guidance
Synapse formation
Activity dependent fine tuning
Plasticity and Learning
Development and Infant behavior

39. Axon guidance mechanisms
Axonal growth is led by growth cones
Filopodia (growing from axons) are able to sense the environment ahead for chemical markers and cues.
Mechanisms are fairly old in evolutionary terms.
Intermediate chemical markers
Guideposts studied in invertebrates
Short and long range cues
Short range chemo-attraction and chemo-repulsion
Long range chemo-attraction and chemo-repulsion
Gradient effects

42. Axons locate their target tissues by using chemical attractants (blue) and repellants (orange) located around or on the surface of guide cells. Left: An axon begins to grow toward target tissue. Guide cells 1 and 3 secrete attractants that cause the axon to grow toward them, while guide cell 2 secretes a repellant. Surfaces of guide cells and target tissues also display attractant molecules (blue) and repellant molecules (orange). Right: A day later, the axon has grown around only guide cells 1 and 3.

45. Axonal Guidance Mechanisms

46. Synapse formation The two cells exchange a variety of signals.
Vesicles cluster at the pre-synaptic site
Transmitter receptors cluster at the post-synaptic site.
The Synaptic Cleft forms
When the growth cone contacts the target cell (immature muscle cell in the case of a motor neuron), a cleft (basal lamina) forms.
Multiple growth cones (axons) get attracted to the cleft.
All but one axon is eliminated.
A myelin sheath forms around the synaptic cleft and the synaptic connection is made.

48. Overall Process

49. Basic Process
Neurons are initially produced along the central canal in the neural tube.
These neurons then migrate from their birthplace to a final destination in the brain.
They collect together to form each of the various brain structures and acquire specific ways of transmitting nerve messages.
Their processes, or axons, grow long distances to find and connect with appropriate partners, forming elaborate and specific circuits.
Finally, sculpting action eliminates redundant or improper connections, honing the specificity of the circuits that remain.
The result is the creation of a precisely elaborated child’s network of 100 billion neurons capable of body movement, perception, an emotion or a thought.

50. Nature requires Nurture
Initial wiring is genetically controlled
Sperry Experiment
But environmental input critical in early development
Occular dominance columns
Hubel and Wiesel experiment

51. Sperry’s experiment
Each location in space is seen by a different location on the retina of the frog
Each different location on the retina is connected by the optic nerve to a different location in the brain
Each of these different locations in the brain causes a different movement direction.
In a normal animal, a retinal region which sees in a particular direction is connected to a tectal region which causes a movement in that direction

52. Innervation of the Optic tectum
Ganglion Cells in the retina map systematically to cells in the optic tectum.
The image of the external stimulus is inverted in the retina and the mapping from the retina to the optic tectum reverts to the original image.
The Nasal ganglion cells of the retina map to the posterior region of the Optic tectum and the temporal ganglion cells map to the anterior region of the tectum

53. Sperry’s experiment
Sperry took advantage of the fact that in amphibians, the optic nerve will regrow after it has been interrupted
Sperry cut the optic nerve and simultaneously rotated the eye 180 degrees in the eye socket.
In 'learning’ movements to catch prey, the part of the retina now looking forward (backward) should connect to the part of the brain which causes forward (backward) movement.

54. Sperry’s findings After regeneration,
his animals responded to prey items in front by turning around and
to prey items behind by moving forward. and
kept doing this even though they never succeeded in reaching the prey.

56. Conclusion from experiment
The conclusion from this (and some supporting experiments) is
that the pattern of connections between retina and tectum, and the movement information represented is not based on experience.
It is innate based on the initial distribution of chemical markers in the brain.

57. Lecture Overview Summary Overview Development from embryo
Initial wiring
Activity dependent fine tuning

58. The role of the environment
The development of ocular dominance columns
Cat and later monkey (Hubel and Wiesel)
Retinal input connects to the LGN (Thalamus)
LGN is composed of layers. Each layer receives input (axons) from a single eye
LGN connects to layer IV of the visual cortex
The visual cortex develops ocular dominance columns
Cells that are connected to similar layers in the LGN get stacked together in columns forming stripes.

59. LGN
VISUAL CORTEX

61. Ocular Dominance Columns

62. Monocular deprivation critical period
Hubel and Wiesel deprived one of the eyes of the cat (later macaque monkey) at various times 1 week – 12 weeks (in the monkey case) 4 weeks – 4 months (for the cat).
The found that the ocular dominance cell formation was most severely degraded if deprivation occurred at 1 – 9 weeks after birth.
Deprivation after the plastic period had no long-term effect.

66. Cat Striate Cortex Layer IV
CLOSED
EYE C I 1 7 5 6 3 4 2
OPEN
EYE
Monkey Striate Cortex Area 17 (V1) Layer IV

67. Critical Periods in Development
There are critical periods in development (pre and post-natal) where stimulation is essential for fine tuning of brain connections.
Other examples of columns
Orientation columns

69. Pre-Natal Tuning: Internally generated tuning signals
But in the womb, what provides the feedback to establish which neural circuits are the right ones to strengthen?
Not a problem for motor circuits - the feedback and control networks for basic physical actions can be refined as the infant moves its limbs and indeed, this is what happens.
But there is no vision in the womb. Recent research shows that systematic moving patterns of activity are spontaneously generated pre-natally in the retina. A predictable pattern, changing over time, provides excellent training data for tuning the connections between visual maps.
The pre-natal development of the auditory system is also interesting and is directly relevant to our story.
Research indicates that infants, immediately after birth, preferentially recognize the sounds of their native language over others. The assumption is that similar activity-dependent tuning mechanisms work with speech signals perceived in the womb.

70. Post-natal environmental tuning
The pre-natal tuning of neural connections using simulated activity can work quite well –
a newborn colt or calf is essentially functional at birth.
This is necessary because the herd is always on the move.
Many animals, including people, do much of their development after birth and activity-dependent mechanisms can exploit experience in the real world.
In fact, such experience is absolutely necessary for normal development.
As we saw, early experiments with kittens showed that there are fairly short critical periods during which animals deprived of visual input could lose forever their ability to see motion, vertical lines, etc.
For a similar reason, if a human child has one weak eye, the doctor will sometimes place a patch over the stronger one, forcing the weaker eye to gain experience.

71. Adult Plasticity and Regeneration
The brain has an ability to reorganize itself through new pathways and connections.
Through Practice:
London cab drivers, motor regions for the skilled
After damage or injury
Release from inhibition
Undamaged neurons make new connections and take over functionality or establish new functions
But requires stimulation (phantom limb sensations)
Stimulation standard technique for stroke victim rehabilitation

72. When nerve stimulation changes, as with amputation, the brain reorganizes. In one theory, signals from a finger and thumb of an uninjured person travel independantly to separate regions in the brain's thalamus (left). After amputation, however, neurons that formerly responded to signals from the finger respond to signals from the thumb (right).

73. Possible explanation for the recovery mechanism
The initial pruning of connections leaves some redundant connections that are inhibited by the more active neural tissue.
When there is damage to an area, the lateral inhibition is removed and the redundant connections become active
The then can undergo activity based tuning based on stimulation.
Great area for research.

74. Phantom Limb Phenomena

75. Hand movement observation by individuals born without hands: phantom limb experience constrains visual limb perception. Funk M, Shiffrar M, Brugger P.
We investigated the visual experiences of two persons born without arms, one with and the other without phantom sensations.
Normally-limbed observers perceived rate-dependent paths of apparent human movement .
The individual with phantom experiences showed the same perceptual pattern as control participants, the other did not.
Neural systems matching action observation, action execution and motor imagery are likely contribute to the definition of body schema in profound ways.

76. Neurogenesis
In 1999, researchers at the Salk Institute in San Diego found evidence of new neuron production in a 72 year old person
They used a chemical marker and found growth in the hippocampus (used for certain types of memory).
Previously, neuron production was found in the rat hippocampus (1970) and in songbirds (1990)
Subsequently, new neuron production was reported in the frontal, ITP, and Posterior Parietal areas of primates.
So, can stem cells with appropriate growth factors (recall SHH) be implanted to generate new neurons?

77. How does activity lead to structural change?
The brain (pre-natal, post-natal, and adult) exhibits a surprising degree of activity dependent tuning and plasticity.
In order to understand the nature and limits of the tuning and plasticity mechanisms we need to study the methods by which
Activity is converted to structural changes (say the ocular dominance column formation)
It is centrally important for us to understand these mechanisms to arrive at biological accounts of perceptual, motor, cognitive and language learning
Biological Learning is concerned with this topic.

78. Summary
Both genetic factors and activity dependent factors play a role in developing the brain architecture and circuitry.
There are critical developmental periods where nurture is essential, but there is also a great ability for the adult brain to regenerate.
Next lecture: What computational models satisfy some of the biological constraints.
Question: What is the relevance of development and learning in language and thought?

79. 5 levels of Neural Theory of Language
Spatial Relation
Motor Control
Metaphor
Grammar
Cognition and Language
Computation
Structured Connectionism
abstraction
Neural Net
SHRUTI
Computational Neurobiology
Triangle Nodes
Biology
Neural Development
Quiz
Midterm
Finals