L20 Plasticity and Regeneration

Question 1

Describe the factors that induce gene expression in individual cells

Answer 1

1) Inducing factors
- Signalling molecules provided by other cells. They can be:

• freely diffusible, exerting their action over a long range, or
• tethered to the cell surface, acting locally
• They can modify gene expression, cell shape and motility. Because cells in different positions in the embryo are exposed to different inducing factors, each cell’s position in early development is critical for its fate.
  2) Competence
• The ability of a cell to respond to inducing factors, which depends on:
• exact set of surface receptors
• transduction molecules and
• transcription factors expressed by the cell

Question 2

define what neurogenesis is and how many weeks it takes

Answer 2

Neurogenesis: the process by which neurons are generated

5th week – 5th month of gestation

Question 3

describe 2 key features of Neural Stem cells / Neural precursor cells

Answer 3

1) Infinitely self –renewing
2) After terminal division and differentiation they can give rise to the full range of cell classes within the relevant tissue, e.g. inhibitory and excitatory neurons, astrocytes, oligodendrocytes.

Question 4

describe 2 key features of neural progenitor cells

Answer 4

1) Incapable of continuing self – renewal
2) Capable to give rise to only one class of differentiated progeny, e.g. an oligodendroglial progenitor cell will give rise to oligodendrocytes until its mitotic capacity is exhausted.

Question 5

describe Protein distribution in precursor cells

Answer 5

• The proteins notch-1 and numb are differentially distributed in the precursor cells of the developing neocortex.
• Vertical cleavage partitions these proteins equally in the daughters= 2 neural stem cells

, but horizontal cleavage does not it results in= a neuroblast from Notch-1 that will migrate away

The Numb part will become a progenitor cell with limited mitotic potential

Question 6

describe the function of the neuroblast

Answer 6

Postmitotic, immature nerve cell that will differentiate into a neuron

Question 7

what factors decide the fate of the migrating neuron

Answer 7

• Age of precursor cell
• Position in ventricular zone
• Environment at time of division

Question 8

describe the inside out development of the cortex

Answer 8

Inside-first, outside-last order.

Differentiation: the process by which structure becomes more functionally specialised during development. It is a consequence of a specific spatiotemporal pattern of gene expression.
Differentiation of the neuroblasts into a neuron will begin with the appearance of neurites sprouting off the cell body; one will become the axon, the other dendrites.

Question 9

describe the 3 ways in which a neuroblast differentiates

Answer 9

Differentiation:

1) Pathway selection-e.g. retinal ganglion cell reaching the correct thalamic location.
2) Target selection-selecting the appropriate thalamic nucleus, LGN.
3) Address selection-which LGN layer.

Question 10

describe the 2 different types of guidance cues

Answer 10

1) Chemoattractants
e. g. netrin
- Axons growing toward a secreted attractive cue preferentially grow toward the source, extending up a concentration gradient

2) Chemorepellents,
e. g. slit
- Axons that encounter a secreted repulsive cue preferentially turn and extend away from the source of the cue.

Question 11

describe the 2 different types of substrate-bound cues

Answer 11

1) Axons that encounter substrate-bound attractive cues preferentially extend along the surface of those cells
2) , Axons that encounter substrate-bound repulsive cues retract their growth cones, resample the environment, and preferentially extend on cells expressing different cues.

Question 12

where is netrin released & what are its effects

Answer 12

The protein netrin is secreted by cells in the ventral midline of the spinal cord. Axons with the appropriate netrin receptors are attracted to the region of highest netrin concentration

Question 13

what type of axons produce the protein Robo

Answer 13

the slit receptor, grow away from the region of highest slit concentration. Up-regulation of robo by axons that cross the midline ensures that they keep growing away from the midline.

Question 14

name a neurotrophic factor

Answer 14

• nerve growth factor-NGF

Question 15

describe the relation between apoptosis and neurotrophic factors

Answer 15

• Apoptosis or programmed cell death: reflects competition for trophic factors and produces the proper match in the number of presynaptic and postsynaptic neurons.

Question 16

describe the process of synaptic elimination

Answer 16

a) Initially each muscle fibre receives inputs from several alpha motor neurons. Over the course of development, all inputs but one are lost.
b) ) Normally, postsynaptic AChR loss precedes the withdrawal of the axon branch. Simply blocking a subset of receptors with α-bungarotoxin can also stimulate synapse elimination.

Question 17

describe the how the brain circuits are modified as a result of experience

Answer 17

1) First steps in constructing brain circuitry rely largely on intrinsic cellular and molecular mechanisms (establishment of distinct brain regions, neurogenesis, major axon tracts, guidance of growing axons to appropriate targets, initiation of synaptogenesis).
2) Activity-mediated influence on the developing brain is most consequential in early life, during temporal windows called critical periods

Question 18

describe the critical period concept

Answer 18

Variable time window for different skills/behaviours

e.g. sensorimotor skills, language acquisition, visual perception, emotional functions

Question 19

describe the Two important factors for successful completion of the critical period:

Answer 19

1) Availability of appropriate influences (e.g. exposure to language, or species-specific songs for songbirds)
2) Neural capacity to respond to them

Question 20

describe the proof for Ocular dominance columns, layer IV of V1

Answer 20

1- radioactive amino acids injected in the eye

2- Transynaptic transport through the LGN terminates in layer 4 of the primary visual cortex

3- Terminations are visible as bright bands on the autoradiograph

Question 21

describe the proof for Visual deprivation: development of visual perception requires sensory experience

Answer 21

• the amount of exposure to light is positive correlation to the number of cells activated
• this is true from contralateral and ipsilateral eye exposure

slide 21

Question 22

describe the effect of Effect of monocular deprivation onocular dominance columnsin the macaque monkey

Answer 22

In normal monkeys,ocular dominance columnsseen as alternating stripes of roughly equal width are already present at birth.

(B) The picture is quite different after monocular deprivation. This dark-field autoradiograph shows a reconstruction of several sections through layer IV of theprimary visual cortexof a monkey whose right eye was sutured shut from 2 weeks of age to 18 months, when the animal was sacrificed. Two weeks before death, the normal (left) eye was injected with radiolabeled amino acids. The columns related to the nondeprived eye (white stripes) are much wider than normal, whereas as those related to the deprived eye are shrunken

Question 23

describe the perception to visual deprivation on ocular dominance

Answer 23

• slide 23

Question 24

describe the importance of competitive imbalance

Answer 24

• First evidence of how experience during a critical period changes the way the brain is wired, and how individual neurons respond to stimuli

Question 25

what is the need of early social interactions in humans and which other mammal Is neural development and learning imprinted in

Answer 25

• Early social interaction with other humans is essential for normal social development (René Spitz, 1940s)
• imprinted in birds

Question 26

How are changes in patterns of neural activity translated into changes in neural circuitry?

Answer 26

Hebbian modifications during development-

-Two target neurons in the LGN have inputs from different eyes. Inputs from the two eyes initially overlap and then segregate under the influence of activity. A) The two input neurons in one eye (top) fire at the same time. This is sufficient to cause the top LGN target neuron to fire, but not the bottom one. The active inputs onto the active target undergo Hebbian modification and become more effective.

B) This is the same situation as in part A), except that now the two input neurons in the other eye (bottom) are active simultaneously, causing the bottom neuron to fire.

C) Over time, neurons that fire together wire together. Notice also that input cells that fire out of sync with the target lose their link.

slide 27

Question 27

why do critical periods end

Answer 27

1- Various hypotheses (axon growth, synaptic transmission matures, constraint cortical activation)

Question 28

describe the Somatotopic order in the human primary somatic sensory cortex

Answer 28

Somatotopic order in the human primary somatic sensory cortex.

B) Diagram of somatotopic representation of body parts from medial to lateral.

C) Cartoon of the homunculus constructed on the basis of mapping in B). The amount of somatic sensory cortex devoted to the hands and face is much larger than the relative amount of body surface in these regions.
A similar disproportion is apparent in the primary motor cortex, for the same reasons.

Question 29

describe Plasticity in the adult cerebral cortex upon losing a finger

Answer 29

Image left: functional changes following amputation of a digit. Following amputation the map changes substantially: neurons in the area previously responding to stimulation of digit 3 now respond to stimulation of digits 2 and 4.

Image right: Changes in cortical representation, functional re-mapping, in response to sensory or motor experience. This task used heavily digits 2, 3 and occasionally 4.

Question 30

describe peripheral regeneration

Answer 30

The Schwann cell is essential for this process. Once the macrophages have cleared the debris from the degenerating peripheral stump, the Schwann cells proliferate, express adhesion molecules on their surface, and secrete neurotrophins and other growth-promoting signalling molecules. In parallel, the parent neuron of the regenerating axon expresses genes that restore it to a growth state. The gene products are often receptors, or signal transduction molecules, that allow the cell to respond to the factors provided by the Schwann cell

Question 31

describe central nerve regeneration

Answer 31

Local cellular changes at or near an injured site include the degeneration of myelin and other cellular elements; the clearing of this debris by microglia (CNS phagocytic cells); local production of inhibitory factors by astrocytes, oligodendroglia, and microglia; and glial scar formation.

Question 32

describe the zones in which Adult neurogenesis occur

Answer 32

1)Sub Ventricular Zone (SVZ) to olfactory bulb

2)Hippocampus
primarily interneurons
some integrate in functional networks, but most die

Question 33

describe SVZ in neurodegenerative disease

Answer 33

a| The SVZ is located in the wall of the lateral ventricle. It consists of an ependymal layer, a gap region and an astrocytic ribbon, and is seperated from the caudate nucleus and the striatum by a layer of myelin.b| The SVZ contains three different cell types (types A, B and C) that are organized in a specific pattern, with the type A cells closest to the ependymal layer, the type B cells forming the astrocytic ribbon and the type C cells located close to the myelin layer and the striatum. Arrows represent interconversion of cell types.c| The brain of an individual with Huntington’s disease is characterized by striatal cell loss, but increased SVZ thickness. The SVZ has more type A, B and C cells than normal and is enriched in endogenous mitogenic factors, such as neuropeptide Y (NPY), nitric oxide synthase (NOS), certain GABA receptor subunits and the cannabinoid receptor CB1 (d).e| In the SVZ of individuals with Parkinson’s disease (PD) there is a reduction in the dopaminergic input from the substantia nigra (depicted as a dashed inhibitory connection) that leads to the death of D2 and D3 receptor-rich type C cells (shown as red cross). The PD-affected SVZ has fewer progenitor cells.f| In the SVZ of individuals with Alzheimer’s disease, there is a reduction in neurogenesis because there is an imbalance in the ratio ofsecretases, leading to abnormal accumulation of-amyloid and generic cell death in the SVZ.

Question 34

describe the Cortical development and barriers to regeneration

Answer 34

After neurogenesis ceases, gliogenesis commences en force with the conversion of some RG into immature and subsequently mature astrocytes (iACs and ACs, respectively). Also, oligodendrocyte progenitor cells (OPCs) are born and differentiate into myelinating oligodendrocytes (MOs) in the white matter (WM). Other RG transition into subventricular zone neural stem cells (NSCs), and ependymal cells (ECs). NSCs can give rise to INPs, which generate migrating olfactory bulb-destined neurons (mOBNs).(B)In the postnatal and adult brain, significant barriers to regeneration are present. Radial glia are exhausted and become a “lost highway” to any neuronal migration. Similarly, cortical neurons are no longer generated and thus virtually no neurons can be found migrating into the cortex. Neuronal plasticity becomes significantly attenuated, preventing the type of plasticity observed prior to developmental critical periods. Interneuron progenitors and mINs disappear. Parenchymal glia do not cross lineage boundaries and become reactive after injury and degeneration. Moreover, the axon lengths become many fold longer in the adult due to the growth of the organism. For example, a SCPN may reach almost a meter in length while the initial axon started at a few millimeters before progressive lengthening. Finally, in humans there is minimal subventricular zone (SVZ) neurogenesis in the adult, inhibiting strategies which might utilize such cells. Abbreviations: PS, pial surface; IZ, intermediate zone; MGE, medial ganglionic eminence; LGE, lateral ganglionic eminence; Ctx, cortex.

Question 35

describe Neurogenesis in the hippocampus and memory -Computational theories of neurogenesis

Answer 35

a | Without neurogenesis, new events (represented by different
shapes) are limited by the set of sparse ‘codes’ (combinations of active neurons) provided by mature granule cells in the
dentate gyrus. This can lead to the dentate gyrus not having the flexibility to encode new memories well or to
interference between memories formed in the hippocampus (shown as a cluster of memories in a projection of the
high-dimension hippocampal ‘memory space’)

b | New neurons (shown in green) provide new sparse codes for encoding
new information, while older memories are preserved because they are represented by older neurons (shown in red). This
can facilitate the formation of new memories while avoiding catastrophic interference, saving older memories (shown
in the left panel as two separate clusters of memories in a projection of the high-dimension hippocampal memory space).
The three-way arrow indicates that new neurons can change how memories are encoded in the hippocampal network.
Neurons born at different times (shown in green and blue in the right panel) represent different inputs, and the sparse
codes generated at a particular time are clustered together (active neurons in a population are similar in composition to
one another), separately from sparse codes that were generated at a different time, essentially encoding time into new
memories.