Znz @ Ethz - Introduction To Neuroscience I (Hs11)

Front 1

Main divisions of the nervous system: CNS

Back 1

Includes all structures derived from the neural tube (brain, spinal cord, retina)

Front 2

Main divisions of the nervous system: PNS

Back 2

- Derived from the neural crest (dorsal root ganglia, autonomic ganglia, peripheral nerves)
- Motor, sensory, and auonomic components

Front 3

Main divisions of the nervous system: Enteric nervous system

Back 3

- Derived from the neural crest; controls the gastrointestinal system
- Functionally closely related to the autonomic nervous system
- Often neglected but quantitatively not negligible!

Front 4

Cell types in the CNS?

Back 4

- Neurons: Multiple populations, mainly recognized morphologically, but no simple classification system is possible. Key distinction: Projection neurons versus interneurons
- Glial cells: Astrocytes, Oligodendrocytes (Schwann cells in the PNS), Microglial cells, Polydendrocytes
- Ependymal cells (line the walls of the ventricles and the central
canal)
- Blood microvessels: endothelial cells, pericytes, smooth muscle cells; endothelial cells form the blood brain barrier (they are closely associated with astrocytes); strictly speaking, brain microvessels are outside the CNS

Front 5

Cresyl violet

Back 5

The cresyl violet stain a basic dye, is a common stain used in histology.

• Non-specific staining of cell bodies (mainly rough
endoplasmic reticulum
• Allows to distinguish the cytoarchitecture of the brain
(cortical layers and areas, subcortical nuclei, etc), based on
the differential distribution, size, and shape of neurons (and
glial cells)

Front 6

The Golgi impregnation technique

Back 6

• Silver impregnation of
neurons, discovered by
Camillo Golgi
• It randomly labels small
subsets on neurons,
allowing the detailed
visualization of their
morphology
• Santiago Ramon y Cajal
has used it extensively to
produce the most detailed
and accurate description of
neurons and their
connections in the CNS

Front 7

Defining features of neurons

Back 7

• Neurons are derived from epithelial cells. They are
polarized, with dendrites corresponding to the basolateral
compartment and axons to the apical compartment of
epithelial cells
• They possess all characteristic organelles of eukaryotic cells
(nucleus, endoplasmic reticulum, Golgi apparatus,
mitochondria, cytoskeleton, etc) and have no organelle that
is specific for them
• Typical neurons have one or several dendrites (which
usually receive synaptic input), one cell body, and a single
axon (subdivided into hillock, initial segment, and axon
proper), and multiple axon terminals (which usually form
synapses on other neurons)

Front 8

Neuronal polarization

Back 8

• Neurons are functionally polarized
• The classical view states that incoming synaptic signals are
received by dendrites, propagate passively towards the
soma, where the sum of depolarization/hyperpolarization
determines the change in membrane potential that might
result in the generation of an axon potential in the axon
hillock; along the axon, propagation of axon potentials is an
active process, resulting in a wave of depolarisation in axon
terminals, leading to Ca++-dependent neurotransmitter
release
• It is now well established that dendrites are also capable of
active backpropagation of Na+ and Ca++-dependent axon
potentials

Front 9

Limited regenerative capacity of central neurons

Back 9

• Neurons are postmitotic and terminally differentiated
• The regeneration capacity of axons in the CNS is highly
limited (with the exception of serotonergic and
noradrenergic neurons)
• Neurogenesis in the adult brain occurs at specific locations
(lateral ventricle/rostral migratory stream, subgranular zone
of the dentate gyrus), as well as in the olfactory epithelium

Front 10

What is a postmitotic cell?

Back 10

A mature cell that is no longer capable of undergoing mitosis.

Front 11

Particular neuron types

Back 11

• Special sensory cells (rods and cones, olfactory neurons,
etc)
– Lack dendrites but have specialized compartment involved in signal
transduction
• Dorsal root ganglion cells
– No dendrites, but a bifurcated axon; the central branch penetrates
into the CNS
• Olfactory bulb granule cells
– Axonless neurons; make and receive synapses on their dendrites
• Central noradrenergic neurons
– Extensive axonal arbor across the entire CNS

Front 12

Classification of neurons: Shape of soma and primary dendrites

Back 12

– Pyramidal cells in the cerebral cortex
– Mitral cells in the olfactory bulb
– Purkinje cells in the cerebellum

Front 13

Classification of neurons: Number and morphology of dendrites

Back 13

Stellate, bipolar, multipolar, etc

Front 14

Classification of neurons: Trajectory/postsynaptic target of axon

Back 14

– The axon of interneurons remains in the same region where the soma is
localized
– The axon of projection neurons (principal cells) innervates a different territory
– Some axons target selective subcellular compartments on postsynaptic cells
(e.g. “chandelier cells” innervate the axon initial segment of pyramidal cells)

Front 15

Classification of neurons: Neurochemical profile

Back 15

Expression of a specific protein (e.g. calcium-binding protein, neuropeptide,
transcription factor, etc)

Front 16

Classification of neurons: Functional properties

Back 16

Firing mode, intrinsic excitability, pace-maker properties

Front 17

Ultrastructural features of neuronal somata

Back 17

• Large, pale nucleus
• Abundant endoplasmatic
reticulum
• Numerous mitochondria
• Pale cytoplasm in dendrites,
with characteristic
cytoskeletal elements
• Note the densely packed
“neuropil”, made of dendrites,
axons, axon terminals, spines,
and glial cell profiles, surrounding
neuronal cell bodies and primary
dendrites

Front 18

Ultrastructure of dendrites

Back 18

• Dendrites have a pale
cytoplasm and contain
characteristic cytoskeletal
elements (microtubules and
neurofilaments)
• They receive synaptic
contacts from multiple,
distinct types of axon
terminals

Front 19

Ultrastructure of the synapse

Back 19

• Chemical synapses are highly
specialized organelles ensuring
transmission of information
between neurons
• Presynaptic terminals contain
vesicles loaded with
neurotransmitter, numerous
mitochondria, and a presynaptic
membrane specialization (active
zone), where transmitter release
takes place
• Postsynaptically, a thickening of
the membrane (postsynaptic
density) contains are large array of
proteins (receptors, signaling
molecules, scaffolding proteins)

Front 20

A new technique: Freeze fracture replica labeling

Back 20

After freeze-fracturing, the tissue is coated with a thin
metal layer and digested with SDS, leaving membrane
proteins that stick to the metal in situ. Immunogold
labeling with appropriate antibodies allows detection of
these proteins.
Example here: Distribution of voltage gated sodium
channels on the axon initial segment, soma and dendrites
of CA1 pyramidal cells (Lorincz and Nusser, Science 328,
1010)

Front 21

How do neurons fulfill their functions?

Back 21

• Intrinsic properties
• Transmitter synthesis and release
• Postsynaptic function
• Plasticity

Front 22

Astrocytes

Back 22

Major cell type in the nervous system,
fulfilling multiple functions
• They are intimately linked with blood
vessels, surrounding the blood-brain
barrier by extensive “end-feet”
• They are also intimately linked with
synapses, where they contribute to
neurotransmitter reuptake and
metabolism and maintenance of the
ionic balance
• They play a key role in brain energy
metabolism, providing neurons with
energy substrates (glucose, lactate)
derived from the blood stream
• They react to neuronal damage and
injury, secrete cytokines and
chemokines, and contribute to scar
formation

Front 23

Morphological features of astrocytes

Back 23

• Astrocytes are star-shaped and make
up about 20% of the brain
parenchyma
• Protoplasmic astrocytes predominate
in the gray matter and fibrous
astrocytes in the white matter
• They develop from radial glial cells
(which are formed early in
embryogenesis and guide neuronal
migration)
• Recent evidence indicates, however,
that radial glial cells are pluripotent
progenitor cells that can give rise to
neurons, as well

Front 24

What is "parenchyma"?

Back 24

The parenchyma are the functional parts of an organ in the body. This is in contrast to the stroma, which refers to the structural tissue of organs, namely, the connective tissues.

Front 25

What are the functions of astrocytes

Back 25

• Uptake and metabolism of neurotransmitters
• Metabolic coupling
• Signaling
• Regulation of synaptogenesis
• Response to lesion
• Repair

Front 26

Oligodendrocytes and Schwann cells

Back 26

• Synthesize myelin, which covers
and insulates axons, providing a
support for rapid conduction of
axon potentials
• Each oligodendrocyte or Schwann
cell covers only a small portion of
the axon; they are separated by
nodes of Ranvier (which have a
special complement of membrane
proteins)
• Oligodendrocytes can wrap
several axons, Schwann cells only
a single axon
• Schwann cells provide much more
to the axon than electrical
insulation (complex relationship
during de- and regeneration)
• Mutations in myelin proteins are
major causes for a large variety of
inherited neuropathies

Front 27

Microglial cells

Back 27

• Microglial cells are resident
macrophages in the brain, derived
from bone-marrow monocytes
• They enter the brain early during
development and represent about 2-
5% of the total cell population
• They help phagocytose degenerating
neurons (notably after apopotosis)
• They retain the capacity to divide and
have immunophenotypic properties of
monocytes
• After a lesion or exposure to noxious
stimuli (or proinflammatory factors),
they become activated and change
their shape and function
• Their role is largely unknown

Front 28

Relations with the immune system

Back 28

• The brain is devoid of circulating lymphocytes (B- and T-
cells) and was long-considered to be an immunoprivileged
territory
• However, all major cell types in the CNS can express and
respond to cytokines and chemokines, which have profound
effect on neuronal function and survival
• Microglial cells formally belong the the immune system
• The integrity of the blood-brain barrier is often compromized
during neuroinflammation, allowing entry of immune cells (T
cells, neutrophils, monocytes) into the brain

Front 29

Cytokines

Back 29

Cytokines (Greek cyto-, cell; and -kinos, movement) are small cell-signaling protein molecules that are secreted by numerous cells and are a category of signaling molecules used extensively in intercellular communication. Cytokines can be classified as proteins, peptides, or glycoproteins; the term "cytokine" encompasses a large and diverse family of regulators produced throughout the body by cells of diverse embryological origin.

Front 30

Chemokines

Back 30

Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

Front 31

Polydendrocytes (NG2 cells)

Back 31

• Distinct cell type in the CNS
• They are parenchymal cells (present in gray and white
matter), with long and slender neurites, and characterized
by expression of NG2
• They have been considered to be pluripotent cells,
generating oligodendrocytes, astrocyte, and neurons in vivo
• Cell-fate mapping studies indicate that they (exclusively)
generate oligodendrocytes
• They receive synaptic inputs from
neurons
• They are excitable, but do not
fire axon potentials

Front 32

Ependymal cells and choroid plexus

Back 32

• Ependymal cells are ciliated epithelial cells forming the wall
of the ventricles and central canal; the cilia produce
movement of the CSF
• The choroid plexus is a specialized organ, located in the
ventricles and secreting the CSF

Front 33

Brain blood vessels

Back 33

• Capillary endothelial cells form the blood brain barrier (intercellular
spaces are closed by gap junctions)
• They are surrounded by a basal lamina, and astrocytic end-feet
• Active transport mechanisms are required for brain penetration (or
extrusion) of all substances that cannot diffuse freely across membranes

Front 34

Effect of a lesion

Back 34

• Astrocytes and microglia cells monitor the functional and
structural integrity of the brain parenchyma and become rapidly
activated in case of a mechanical or chemical insult
• Astrogliosis is accompanied by increased expression of GFAP,
rapid morphological changes, and proliferation of astrocytes
• Activation of microglial cells also profoundly alters their
morphology and neurochemical repertoire (overexpression of
CD68) and leads to increases motility and proliferation
• Activated astrocytes and microglia cells contribute to the process
of neuroinflammation; depending on the location and
circumstances, they can be beneficial (e.g. phagocytosis of
harmful organisms or cellular debris) or harmful (production of
pro-inflammatory cytokines)
• The astroglial scar clearly limits axonal regeneration in the CNS

Front 35

Membrane transport

Back 35

• Neurons and glial cells are endowed with multiple
transporters in the plasma membrane (and intracellular
organelles, such as synaptic vesicles, Golgi apparatus,
endoplasmic reticulum) to ensure appropriate ion gradients
and uptake/extrusion of metabolites, energy substrates, and
lipids
• Some of these transporters are ATP-dependent (primary
transporters). Others are driven by electrochemical
gradients generated by primary transporters (secondary
transports, synporters, antiporters). Finally, facilitators allow
transmembrane transport along chemical or osmotic
gradients
• The brain uses about 20% of the oxygen consumed by the
body

Front 36

Classification of neuronal transporters

Back 36

• Primary ion transporters (ATP-dependent)
• Secondary active transport
• Facilitators

Front 37

Classification of neuronal transporters: Primary ion transporters (ATP-dependent)

Back 37

– Na,K-ATPase: maintenance of ionic gradients
– Ca pumps: ensure low cytosolic Ca++ concentration (10-8 mol/l)
– VoV1 proton pumps (electrochemical gradient that energizes the
H+ antiporter which loads neurotransmitter into vesicles)
– ATP binding cassettes (large gene family)

Front 38

Classification of neuronal transporters: Secondary active transport

Back 38

– Neurotransmitter reuptake
– Filling of presynaptic vesicles
– KCl exchangers
– Cation antiporters (e.g. Na-Ca, Na-H, Na-H-CO3)

Front 39

Classification of neuronal transporters: Facilitators

Back 39

– Aquaporins
– Glucose diffusion

Front 40

The neuronal and glial cytoskeleton

Back 40

• The cytoskeleton is one of the defining
elements of eukaryotic cells; it
determines the shape and morphology
of cells, which are remarkably diverse
in the CNS.
• Histochemical reactions with the
cytoskeleton have been invaluable to
describe and characterize the cytology
of the nervous system.
• The cytoskeleton serves as dynamic
structural elements and tracks for
organelle transport
• Molecular composition
– Actin microfilaments
– Microtubules
– Intermediate filaments

Front 41

Eukaryotic cell

Back 41

A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear envelope, within which the genetic material is carried.

Front 42

Cytoskeleton in general

Back 42

The cytoskeleton (also CSK) is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton.

Front 43

Major microtubule cytoskeletal proteins

Back 43

• Microtubules exhibit large biochemical diversity, and are associated with
a plethora of proteins
• Tubulins constitute about 10% of neuronal proteins

Front 44

Intermediate filament proteins

Back 44

• Neurofilaments often are modified by phosphorylation
• GFAP is a defining molecular marker for a subset of
astrocytes (and radial glial cells)

Front 45

Gray matter

Back 45

Composed of neurons and their dendrites, glial cells (astroglia and oligodendrocytes, see below), capillaries, and traversing axons.
Nuclei are well-delineated aggregations of neurons. Projection means a bundle of axons terminating in a defined location.

Front 46

White matter

Back 46

Massive bundles of myelinated axons, sparse capillaries, oligodendrocytes producing the whitish myelin, and some astroglia cells
nurturing the axons. Afferent fibers refer to axons reaching a structure, efferent fibers to axons leaving a structure. Fascicle denotes a
visible fiber bundle, alternatively also denoted as tract.

Front 47

Meninges: Dura mater

Back 47

A thick layer of tough connective tissue encapsulating the entire central nervous system. Is pain-sensitive, this pain being perceived as
headaches. Duplications of the dura mater known as sinus draw the venous blood from the brain.

Front 48

Meninges: Arachnoidea

Back 48

Loose connective tissue bridging the liquor-filled space between dura mater and pia mater. Large bridgings are refrred to as cysternae.
All larger blood vessels run in this so-called subarachnoideal space. Smaller vessels then contact the pia mater and dive into the brain.
Ruptured large vessels cause so-called subarachnoideal hemorrhages.

Front 49

Meninges: Pia mater

Back 49

A fine layer of connective tissue covering the entire surface of the central nervous system. Follows blood vesssels for some distance
into the brain. Later on, astroglia covers the vessels with plates, creating a blood-brain barrier.

Front 50

Ventricles and cerebral liquor

Back 50

Large cavities in the brain corresponding to dilations of the lumen of the embryological neural tube. Filled with cerebrospinal liquor. The
walls of the ventricles are covered by ependymal cells with microcilia moving the cerebral liquor. Liquor is produced in organs protruding
into the ventricles, called choroid plexuses. There are 4 ventricles. Two lateral ones within each hemisphere, interconnected by an
opening, the intraventricular foramen located at the rostral end of the third ventricle, which is confined to the diencephalon (see below).
The third ventricle connects to the fourth one by means of the cerebral aquaeduct (see below). The fourth ventricle has two lateral and one dorsal openings to the subarachnoideal space, permitting liquor to flow around the brain and spinal cord. Eventually, liquor is resorbed be veins located in in protrusions of the arachnoidea across the dura mater into the skull called Pacchioni granulations.
Further resorbtion occurs in pouches of the dura mater where spinal nerves emerge. There, liquor is resorbed by lymph vessels. Liquor can be sampled for diagnostic purposes by puncturing a space below the ending of the lumbar spinal cord.

Front 51

Blood supply

Back 51

Originates from the interior carotid arteries crossing the base of the skull, and from the vertebral arteries climbing through holes in the vertebral processes and merging into a common basilar artery ascending along the ventral side of the brain stem. The carotid system branches into the ophtalmic, anterior and middle cerebral artery supplying the eye, medial and lateral side of the hemispheres, respectively. The basilar system gives off arteries to the brain stem, cerebellum, and the posterior cerebral artery supplying the dorsal thalamus and basal and occipital parts of the hemispheres. Carotid and basilar system communicate through small arteries forming the
circle of Willis. Venous blood flows in veins in the subarachnoideal space that abutt into the sinus system of the dura mater. Interruptions of arterial blood supply (by obstruction or rupturing) cause strokes entailing destruction of the target regions. Some
especially long and thin arteries in the human brain form typical predilection sites for strokes, often in white matter such as the internal
capsule (see below).

Front 52

Spinal cord

Back 52

Segmentally arranged gray matter and ascending and descending fiber tracts controlling striate & smooth musculature and sensory
information from skin, viscera, muscles and tendons. Motor fibers leave through ventral roots. Sensory neurons are located in the dorsal root ganglion, one branch of the axon entering the spinal cord as dorsal roots, the other connecting to peripheral sensory cells or ending freely. Neuronal networks coordinate movements, while reflex loops connect sensory input directly to motoneurons. The dorsal parts of the spinal cord are linked to sensory processing and ascending fiber tracts, the ventral portions to motor processing and descending fiber tracts.

Front 53

Medulla oblongata

Back 53

Rostral continuation of the spinal cord within the skull. Contains ascending and descending fiber tracts, a huge computational network (reticular formation, RF). Embedded in it are recognizable clusters of neurons (nuclei) sending and receiving fibers from head organs and viscera. Some ill-defined neuron clusters ("centers") regulate vital automatisms (breathing, blood pressure) by integrating input and
output nuclei.

Front 54

Pons

Back 54

Rostral continuation of the medulla oblongata containing similar structures. In addition, contains the pontine gray nuclei formed by
neurons receiving fibers from all the cortex and relaying the impulses to the opposite (contralateral) cerebellum via the middle cerebellar tract. Harbors, in the floor of the 4th ventricle, the locus coeruleus, a group of noradrenergic neurons innervating large portions of the
brain.

Front 55

Cerebellum

Back 55

Straddles the brain stem, shows two lateral lobes (divided into anterior and posterior lobe), a merging zone between lobes (vermis) and ventrally small appendices (one nodulus, two lateral flocculi). Through the lower cerebellar tract, it receives fibers from the spinal cord carrying sensory and positional information (proprioception) from trunk, neck and extremities, plus information from the vestibular and
oculomotor systems. The middle cerebellar tract (see above) provides information received from descending fibers of the neocortex, plus copies of movement impulses sent to the spinal cord. The bulk of arriving (afferent) fibers are cerebellar mossy fibers; a special connection from the olivary nuclei contains climbing fibers. Integration of the multiple information takes place in the cerebellar cortex formed by many small granule cells and relatively few large Purkinye cells. The latter project (inhibitively) to the so-called deep
cerebellar nuclei that send axons to both motor structures in the contralateral brain stem and to the contralateral motor thalamus, which, in turn, innervates the motor cortex generating movements.

Front 56

Midbrain

Back 56

The phylogenetically old control center of the vertebrate brain controlling body physiology, species-specific behavior and sensori-motor integration.

Front 57

Midbrain: Tectum

Back 57

Contains the colliculus superior (a relay structure for retinal fibers from the eye to brain stem nuclei) and the colliculus inferior (a relay
station for ascending auditory information). Receives also fibers from the neocortex informing the midbrain about cortical activation
zones.

Front 58

Midbrain: Cerebral
aquaeduct

Back 58

Small channel connecting the 3d and 4th ventricle. Causes hydrocephalus if flow of cerebrtospinal liquor is blocked. Is surrounded by the central gray, a region mediating nociception (pain).

Front 59

Midbrain: Tegmentum

Back 59

Formed largely by the reticular formation. Contains the red nucleus (a motor relay structure), the substantia nigra (sending
dopaminergic fibers to the striatum), other dopaminergic cell groups projecting to the forebrain, and serotoninergic neurons at the
midline (raphe nuclei) also innervating the forebrain.By means of these ascending monoamine systems, the midbrain can control activity states (sleep/wake) and generate differentially activated zones in the forebrain (= diencephalon & telencephalon).

Front 60

Diencephalon

Back 60

Extends between optic chiasm and colliculus superior, lining the third ventricle.

Front 61

Diencephalon: Hypothalamus

Back 61

The ventral (lower) part of the diencephalon containing many neurons with receptors for numerous hormones circulating in the
bloodstream. Controls the pituitary gland by sending axons to the neurohypophysis, and by neurohormones delivered into capillaries
(adenohypophysis), and orchestrates concomitantly body physiology including feeding and drinking by sending fibers to the visceral
control centers in the brain stem. Connects reciprocally to the midbrain through the medial forebrain bundle that also extends to the
basal forebrain. The medial hypothalamic zone deals with aversive events and feelings, its lateral zone mediates consummatory
behavior, sex and rewarding emotions. Receives modulating fiber bundles from hippocampus, prefrontal cortex and amygdala.
Contains nuclei controlling activity of the hippocampal formation by means of ascending fibers, and sends fibers to the intralaminar and
limbic thalamus.

Front 62

Diencephalon: Thalamus

Back 62

The ventral (lower) part of the diencephalon containing many neurons with receptors for numerous hormones circulating in the
bloodstream. Controls the pituitary gland by sending axons to the neurohypophysis, and by neurohormones delivered into capillaries
(adenohypophysis), and orchestrates concomitantly body physiology including feeding and drinking by sending fibers to the visceral
control centers in the brain stem. Connects reciprocally to the midbrain through the medial forebrain bundle that also extends to the
basal forebrain. The medial hypothalamic zone deals with aversive events and feelings, its lateral zone mediates consummatory
behavior, sex and rewarding emotions. Receives modulating fiber bundles from hippocampus, prefrontal cortex and amygdala.
Contains nuclei controlling activity of the hippocampal formation by means of ascending fibers, and sends fibers to the intralaminar and
limbic thalamus.

Front 63

Diencephalon: Subthalamus

Back 63

Essentially a rostral extension of the midbrain reticular formation forming the so-called zona incerta and the fields of Forel. Contains
also the subthalamic nucleus belonging to the basal ganglia,

Front 64

Hemispheres

Back 64

Originate embryologically from two vesicles emanating laterally from the rostral end of the neural tube, and contain the lateral ventricles.
The tissue of the vesicles overgrows rostrally and caudally the rostral part of the neural tube. In primates, this process results in
cerebral hemispheres with various lobes representing the bulk of the telencephalon, leaving visible only the brain stem and cerebellum.

Front 65

Basal forebrain

Back 65

A group of nuclei extending along the medial base of the forebrain. Boundaries of cell groups are often ill-defined. Includes the septal
nuclei (in lower mammals), the preoptic area, the diagonal band of Broca (DB), the substantia innominata and the basal nucleus of
Meynert (BM). Medial septum, DB and BM send cholinergic fibers to hippocampus, limbic and associative cortex.These projections are
important for maintaining cognitive functions. Degeneration of the BM is a hallmark of Alzheimer's disease. The basal forebrain
connects reciprocally to the hypothalamus through the medial forebrain bundle.

Front 66

Basal ganglia

Back 66

A mass of gray substance to the left and right of the lateral ventricles. Largely developed beneath the frontal cortex, tapering off along the posterior course of the ventricles. The basal ganglia form an interconnected system by which topographically ordered activity from various cortical regions is communicated to subcortical structures, being progressively condensed and ending, still topographically ordered, in the motor thalamus and motor control regions of the midbrain. In this way, ongoing overall activity of the neocortex is
blended into the ongoing motor activity handled by motor cortex, midbrain, spinal cord and cerebellum. This connective design underlies the so-called "motor planning function" of the basal ganglia.

Front 67

Basal ganglia: Caudoputamen

Back 67

A large mass of relatively uniform GABA-ergic cells receiving descending excitatory fibers from corresponding overlying cortex regions.
In humans, the mass is divided by the fibers of the capsula interna into an inner portion, the putamen, and an outer portion forming a
nucleus lining the lateral ventricle, the caudate nucleus with a bulky rostral head and a tapering tail along the ventricle, almost reaching
the amygdala. In rodents, descending cortical fibers penetrate the the cell mass everywhere, therefore the term striatum. Although
uniform in appearance, the caudoputamen possesses a complicated inner chemoarchitecture caused by differential distribution of
neuromediators. Hereditary degeneration of striatal neurons is the hallmark of Huntington's disease.

Front 68

Basal ganglia: Nucleus accumbens
septi

Back 68

A portion of the striatum beneath the anterior commissure and receiving fibers from limbic structures such as hippocampus and
amygdala. Sends GABA-ergic fibers to the ventral pallidum.

Front 69

Basal ganglia: Globus pallidum

Back 69

Also simply known as pallidum. A wedge-like nucleus containing GABA-ergic cells targeted by converging GABA-ergic axons from the
caudoputamen. Is divided into an external (outer) pallidum (GPE) and an inner part (GPI). GABA-ergic fibers from the GPI inhibit the
motor thalamus and with this, the flow of impulses from the cerebellar dentate nuclei. They also inhibit species-specific motor
automatisms orchestrated by the midbrain. Note that impulses from the caudoputamen reaching directly the GPI cause actually a
disinhibition of the tonically active target structures of the GPI!

Front 70

Basal ganglia: Ventral pallidum

Back 70

Receives fibers from the nucleus accumbens septi, its inhibitory GABAergic axons also reach the anterior (limbic) thalamus and
intralaminar thalamic nuclei. This is the most important non-motor output from the basal ganglia.

Front 71

Basal ganglia: Subthalamic nucleus

Back 71

Receives inhibitory GABA-ergic fibers from the external pallidum (GPE). The STN neurons are excitatory and connect to the inner
pallidum (GPI) which thus receives a double innervation, excitatory from the STN, and an inhibitory one directly from the
caudoputamen. Therefore, the final inhibition level at the the motor thalamus can be carefully tuned. Lesions of the STN result in
overshooting movements (ballism or hemiballism).

Front 72

Basal ganglia: Substantia nigra

Back 72

Visible to the naked eye in the unstained brain because of a high content of melatonin in neurons. Contains two parts. One portion
corresponds functionally to the inner pallidum (GPI) and has similar connections, and is named the substantia nigra pars reticularis. The
other, the substantia nigra pars compacta, is formed by dopaminergic neurons that receive direct inhibitory fibers from the
caudoputamen, and send back dopaminergic axons to the striatal neurons. Striatal neurons have dopamine receptors (D1, D2, D3 etc)
that either reinforce or inhibit the synaptic transmission of cortical descending fibers. Degeneration of dopaminergic cells causes
Parkinson's disease by ultimately increasing the pallidal inhibition of motor impulse transmisson in the thalamus .

Front 73

Claustrum

Back 73

A mass of gray substance between the basal ganglia and neocortex, more voluminous in the frontal forebrain. Connects reciprocally with the overlying cortex. Functions unknown or speculative.

Front 74

Neocortex general

Back 74

Contains pyramidal neurons (excitatory) and granule cells. The latter include excitatory interneurons (stellate cells) or inhibitory ones (basket cells). Other neuron types are less frequent. Glia cells include astroglia intertwining with neurons and oligodendrocytes
wrapping axons into myelin sheets. Dendrites of neurons and glia cells, traversing axons and many capillaries form the the so-called neuropil where most synaptic actions take place. Cortical neurons are arranged in layers containing differential proportions of pyramidal and granule cells. The neocortex is characterized by 5-6 layers, archi- and paleocortex by 1-3 layers. Local variations of these
proportions have been used to create a cytoarchitectonic map characterizing different cortical regions, named and numbered after Brodmann. The functional division of the neocortex is imposed by subcortical input conveyed and distributed by the thalamus. Most
axons in the neocortex are short and connect reciprocally to neighbored regions. Long axons originate from larger pyramidal cells and travel either downwards (subcortical), over long distances in the same hemisphere, or to the opposite (contralateral) hemisphere.

Front 75

Neocortex general: Primary sensory and motor neocortex

Back 75

Denotes cortical areas receiving specific input from sensory organs (mostly through the thalamus except for olfaction), or from the
contralateral cerebellar dentate nucleus through the motor thalamus. The fibers arriving from the thalamus generally preserve the
topographical organization of the peripheral sensory organs (skin, eye). Thus, information from fibers sensing touch is reflected in
activation of a cortical zone resembling a little (distorted) human, a "sensory homunculus". The motor cortex contains a so-called
"motor homunculus" since the pyramidal cells send axons to motoneurons and spinal cord clustered topographically according to the
body scheme. Note that these homunculi stand upside down in the brain.

Front 76

Neocortex general: Associative neocortex

Back 76

Denotes cortical areas receiving specific input from sensory organs (mostly through the thalamus except for olfaction), or from the
contralateral cerebellar dentate nucleus through the motor thalamus. The fibers arriving from the thalamus generally preserve the topographical organization of the peripheral sensory organs (skin, eye). Thus, information from fibers sensing touch is reflected in
activation of a cortical zone resembling a little (distorted) human, a "sensory homunculus". The motor cortex contains a so-called "motor homunculus" since the pyramidal cells send axons to motoneurons and spinal cord clustered topographically according to the body scheme. Note that these homunculi stand upside down in the brain.

Front 77

Neocortex general: Associative neocortex

Back 77

Associative cortex denotes regions that transfer and analyze impulses originating and spreading from the primary input and output zones. Neighboured regions are defined as unimodal association cortex. Cortical regions that receive input from different modalities are said to be multimodal (or higher-order) association cortex. The latter characterize cortical regions subserving merely cognitive
processes. Lesions of associative cortex areas do often not result in overt neurological symptoms.

Front 78

Frontal lobe

Back 78

All cortex rostral to the central sulcus dividing motor and sensory neocortex.

Front 79

Frontal lobe: Motor cortex

Back 79

The motor output region (named area 4) lies in the precentral gyrus, bordered rostrally by motor association cortex orchestrating
smooth output activity. Area 43 (Broca's area) is a motor association cortex orchestrating neurons in area 4 that activate motoneurons for tongue and layrnx. Its destruction destruction causes aphasia

Front 80

Frontal lobe: Pefrontal cortex

Back 80

Rostral and medial portions of the frontal lobe. Can be considered as a higher-order motor association cortex orchestrating so-called executive functions. Is activated from limbic and dorsomedial thalamus and thought to set directionality and intentions. Also important for organisation and recall of memory, and control of impulsivity.

Front 81

Parietal lobe

Back 81

Includes the postcentral sulcus containing a sensory body map (area 1, 2, 3), and extends caudally to the occipital lobe. Contains large areas with multimodal association cortex blending somatosensory, auditory and visual information with information from the brain stem
conveyed through the nuclei of the posterior dorsal thalamus. Important for many cognitive functions. Depending on lesion sites, neuropsychological symptoms may include agraphia, acalculia and the inability to interprete internal (egocentric) and external
(allocentric) spatial relations. Important gyri serving as landmarks: gyrus angularis, gyrus supramarginalis.

Front 82

Occipital lobe

Back 82

Includes the caudal pole of the hemispheres including the medial surface. Receives, via the lateral geniculate body of the thalamus,
topographically ordered fibers representing the activated spots of the retina in the eye. The termination zone denoted as area 17 is surrounded by unimodal associative areas 18 and 19. Landmark: calcarine sulcus.

Front 83

Temporal lobe

Back 83

Curves downwards and forwards (rostrally). Ist upper and inner portions contain the primary auditory cortex (gyri of Heschl), and unimodal association cortex for auditory information (planum temporale). Blends caudally into multimodal association areas shared with the parietal and occipital lobe. One of them is Wernicke's area whose destruction causes sensory aphasia. Large fiber bundles connect these regions with the motor associative speech area of Broca. The ventral and rostral portions of the temporal lobe are considered as part of the limbic system (see below)

Front 84

Steps of cell development in the brain

Back 84

- Proliferation
- Differentiation (cell migration)
- Connectivity (axonal pathfinding, synapse formation, circuit formation)
- Maturation (from development to function, synapse elimination, cell death)

Front 85

Gatrulation

Back 85

Formation of germ layers

Front 86

Neurolation

Back 86

Formation of the nervous system

Front 87

Fill in the gaps: "Cleavage of the _________ results in the formation of the _______"

Back 87

Cleavage of the fertilized egg results in the formation of the blastula

Front 88

How does a party attack a W's bad character for truthfulness?

Back 88

A party may attack a W (the “target W”) by calling another W (the “character W”) to testify to target W’s bad character for veracity

Front 89

Landmarks of embryonic neural development?

Back 89

- proliferation: birth from stem cell precursors
- differentiation
- migration
- axonal pathfinding
- synapse formation
- circuit formation
- maturation: from development to function, synapse elimination (learning)

Front 90

All bilaterian animals at an early stage of development form a _______.

Back 90

All bilaterian animals at an early stage of development form a gastrula.

Front 91

The gastrula has the shape of a _____ with three layers of cells, an inner layer called the ________, a middle layer called the _________ and an outer layer called the _________.

Back 91

The gastrula has the shape of a _____ with three layers of cells, an inner layer called the endoderm, a middle layer called the mesoderm and an outer layer called the ectoderm.

Front 92

Formation of germ layers.

Back 92

Gastrulation.

Front 93

Formation of the nervous system

Back 93

Neurulation.

Front 94

_________ of the fertilized egg results in the formation of the ________.

Back 94

Cleavage of the fertilized egg results in the formation of the blastula.

Front 95

Is blastula preceeded by gastrula or the opposite?

Back 95

Morula -> blastula -> gastrula.

Front 96

Blastula is the ________ of the gastrula.

Back 96

Blastula is the precurso of the gastrula.

Front 97

The gastrula is _________, with one end called the ________ ___ and the other the __________ ___.

Back 97

The gastrula is polarized, with one end called the animal pole and the other the vegetal pole.

Front 98

The ectoderm gives rise to _________, and to the _____ _____ and other tissues that will later form the _______ ______.

Back 98

The ectoderm gives rise to epidermis, and to the neural crest and other tissues that will later form the nervous system.

Front 99

The mesoderm is found between the ________ and the ________ and gives rise to ______, which form ______; the _________ of the ribs and vertebrae; the ______, the _________, ______ and blood ________, ____, and __________ _______.

Back 99

The mesoderm is found between the ectoderm and the endoderm and gives rise to somites, which form muscle; the cartilage of the ribs and vertebrae; the dermis, the notochord, blood and blood vessels, bone, and connective tissue.

Front 100

The endoderm gives rise to the __________ of the _________ system and ____________ system, and organs associated with the _________ system, such as the ______ and _________.

Back 100

The endoderm gives rise to the epithelium of the digestive system and respiratory system, and organs associated with the digestive system, such as the liver and pancreas.

Front 101

Induction of neural tissue requires ___________ of the gene for a so-called ____ ___________ _______, or BMP.

Back 101

Induction of neural tissue requires inhibition of the gene for a so-called bone morphogenetic protein, or BMP.

Front 102

Two ________ called Noggin and Chordin, both secreted by the __________, are capable of ____________ BMP4 and thereby inducing ___________ to turn into ______ ________.

Back 102

Two proteins called Noggin and Chordin, both secreted by the mesoderm, are capable of inhibiting BMP4 and thereby inducing ectoderm to turn into neural tissue.

Front 103

Neurulation is the stage of organogenesis in vertebrate embryos, during which the _______ ____ is transformed into the primitive structures that will later develop into the _______ _______ ______.

Back 103

Neurulation is the stage of organogenesis in vertebrate embryos, during which the neural tube is transformed into the primitive structures that will later develop into the central nervous system.

Front 104

Formation of the neural tube.

Back 104

In the developing vertebrate, the neural tube is the embryo's precursor to the central nervous system, which comprises the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, and ultimately the folds meet and coalesce in the middle line and convert the groove into a closed tube, the neural tube or neural canal (which strictly speaking is the center of the neural tube), the ectodermal wall of which forms the rudiment of the nervous system.

Front 105

Primary neurulation divides the _________ into three cell types, the ______ ____, which is internally located, the __________, which is externally located, and the ______ _____ _____, which develop in the region between the ______ ____ and _________ but then migrate to new locations.

Back 105

Primary neurulation divides the ectoderm into three cell types, the neural tube, which is internally located, the epidermis, which is externally located, and the neural crest cells, which develop in the region between the neural tube and epidermis but then migrate to new locations.

Front 106

Primary neurulation begins after the ______ _____ has formed. The _____ of the neural plate start to _______ and ____ upward forming the ______ _____. The center of the _____ _____ remains grounded allowing a U-shaped ______ ______ to form. This _____ ______ sets the boundary between the right and left sides of the embryo. The neural folds ______ __ towards the midline of the embryo and ____ together to form the ______ ____.

Back 106

Primary neurulation begins after the neural plate has formed. The edges of the neural plate start to thicken and lift upward forming the neural folds. The center of the neural plate remains grounded allowing a U-shaped neural groove to form. This neural groove sets the boundary between the right and left sides of the embryo. The neural folds pinch in towards the midline of the embryo and fuse together to form the neural tube.

Front 107

In secondary neurulation, the cells of the ______ _____ form a ________ structure that __________ inside the embryo and ________ to form the tube.

Back 107

In secondary neurulation, the cells of the neural plate form a cord-like structure that migrates inside the embryo and hollows to form the tube.

Front 108

Development of both the central and the peripheral nervous system start with ____________.

Back 108

Development of both the central and the peripheral nervous system start with neurulation.

Front 109

The cell cycle consists of four distinct phases: __ phase, __ phase (__________), __ phase (collectively known as _________) and _ phase (_______).

Back 109

The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis).

Front 110

Cell cycle: G1 phase.

Back 110

Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.

Front 111

Cell cycle: S phase.

Back 111

DNA replication occurs during this phase.

Front 112

Cell cycle: G2 phase.

Back 112

During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.

Front 113

Cell cycle: M phase.

Back 113

Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.

Front 114

Cell cycle: G0 phase.

Back 114

A resting phase where the cell has left the cycle and has stopped dividing.

Front 115

Before a cell can enter cell division, it needs to take in _________. All of the preparations are done during the ___________. __________ proceeds in three stages, G1, S, and G2. Cell division operates in a cycle. Therefore, interphase is preceded by the previous cycle of ________ and _____________. Interphase is also known as _____________ phase, in this stage ________ and ____________ division does not occur. The cell prepares to divide.

Back 115

Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during the interphase. Interphase proceeds in three stages, G1, S, and G2. Cell division operates in a cycle. Therefore, interphase is preceded by the previous cycle of mitosis and cytokinesis. Interphase is also known as preparatory phase, in this stage nucleus and cytochrome division does not occur.The cell prepares to divide.

Front 116

Asymmetric cell division?

Back 116

Produces two daughter cells with different cellular fates.

Front 117

In Drosophila melanogaster, asymmetric cell division plays an important role in neural development. __________ are the _________ cells which divide asymmetrically to give rise to another __________ and a ______ ________ _____ (GMC).

Back 117

In Drosophila melanogaster, asymmetric cell division plays an important role in neural development. Neuroblasts are the progenitor cells which divide asymmetrically to give rise to another neuroblast and a ganglion mother cell (GMC).

Front 118

Two proteins play an important role in setting up the asymmetry in the neuroblast of the Drosophila, which ones?

Back 118

Prosepro and Numb.

Front 119

Areas of the nervous system where proliferation occurs.

Back 119

- ventricular zone
- subventricular zone
- external germinal/granule layer

Front 120

________ __________ defines the number of neuronal cells.

Back 120

Lateral Inhibition defines the number of neuronal cells.

Front 121

Activation of _______ signaling changes the pattern of ____ ___________.

Back 121

Activation of Notch signaling changes the pattern of gene expression.

Front 122

The patterning of the neural tube occurs _______ in development and results from the activity of several secreted _________ _________. _______ __________ (___) is a key player in patterning the ________ axis, while ____ ____________ _________ (___) and Wnt family members play an important role in patterning the _______ axis.

Back 122

The patterning of the neural tube occurs early in development and results from the activity of several secreted signaling molecules. Sonic hedgehog (Shh) is a key player in patterning the ventral axis, while Bone morphogenic proteins (Bmp) and Wnt family members play an important role in patterning the dorsal axis

Front 123

Cell types are specified by the secretion of Shh from the __________ (located __________ to the neural tube), and later from the ______ ______ cells. At the ________ end of the neural tube, _____ are responsible for neuronal patterning. ___ is initially secreted from the overlying ________. A secondary signaling center is then established in the _____ _____, the _______ most structure of the neural tube. BMP from the _______ end of the neural tube seems to act in the same ____________-___________ manner as Shh in the ________ end.

Back 123

Cell types are specified by the secretion of Shh from the notochord (located ventrally to the neural tube), and later from the floor plate cells. At the dorsal end of the neural tube, BMPs are responsible for neuronal patterning. BMP is initially secreted from the overlying ectoderm. A secondary signaling center is then established in the roof plate, the dorsal most structure of the neural tube.[1] BMP from the dorsal end of the neural tube seems to act in the same concentration-dependent manner as Shh in the ventral end.

Front 124

French-flag model.

Back 124

Each cell has the potential to develop as blue, white or red. The position of each cell is defined by the concentration of morphogen. The positional value is intepreted by the cells which differentiate to form a pattern.

Front 125

In the French-flag model the poisition of each cell is defined by the concentration of ___________.

Back 125

In the French-flag model the poisition of each cell is defined by the concentration of morphogen.

Front 126

Two opposing gradients pattern the dorso-ventral axis of the neural tube, which ones?

Back 126

BMPs gradient and Shh gradient.

Front 127

The concentration of Shh determines what?

Back 127

Cell type.

Front 128

Shh represses ________ genes but induces ________ genes.

Back 128

Shh represses class I genes but induces class II genes.

Front 129

What produces sharp boundaries?

Back 129

Mutual repression.

Front 130

The notochord is a _________, rod-shaped body found in _________ of all chordates. It is composed of cells derived from the _________ and defines the _________ _____ of the ________. The notochord is found ________ to the neural tube.

Back 130

The notochord is a flexible, rod-shaped body found in embryos of all chordates. The notochord is found ventral to the neural tube.

Front 131

The notochord arises from the __________ _________ ____.

Back 131

The notochord arises from the bilaminar embryonic disk

Front 132

The notochord forms during ___________ and soon after induces the formation of the neural ______ (_________), synchronizing the development of the neural tube.

Back 132

The notochord forms during gastrulation and soon after induces the formation of the neural plate (neurulation), synchronizing the development of the neural tube.

Front 133

By transplanting and expressing a second notochord near the _______ neural tube, 180 degrees opposite of the normal notochord location, one can induce the ________ of ___________ in the ______ ____. Motoneuron formation generally occurs in the ______ neural tube, while the ______ tube generally forms ________ cells.

Back 133

By transplanting and expressing a second notochord near the dorsal neural tube, 180 degrees opposite of the normal notochord location, one can induce the formation of motoneurons in the dorsal tube. Motoneuron formation generally occurs in the ventral neural tube, while the dorsal tube generally forms sensory cells.

Front 134

The notochord secretes a ________ called _______ ________ ________ (___), a key _________ regulating organogenesis and having a critical role in __________ the development of motoneurons. The secretion of ___ by the notochord establishes the ______ pole of the dorsal-ventral axis in the developing embryo.

Back 134

The notochord secretes a protein called sonic hedgehog homolog (SHH), a key morphogen regulating organogenesis and having a critical role in signaling the development of motoneurons. The secretion of SHH by the notochord establishes the ventral pole of the dorsal-ventral axis in the developing embryo.

Front 135

The notochord is ________ and _________ for ________ the formation of a the ______ plate and ____________.

Back 135

The notochord is required and sufficient for signaling the formation of a the floor plate and motoneurons.

Front 136

________ and ___________ cannot be separated in neural _____ development.

Back 136

Migration and differentiation cannot be separated in neural crest development.

Front 137

The _______ half of somites is ________ for neural crest ________.

Back 137

The caudal half of somites is inhibitory for neural crest migration.

Front 138

Neural crest cells migrate through the ________ half of the ______.

Back 138

Neural crest cells migrate through the anterior half of the somite.

Front 139

____________ can be used for lineage analysis.

Back 139

Retroviruses can be used for lineage analysis.

Front 140

A retrovirus is an ___ virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce ___ from its ___ _______. The ___ is then incorporated into the host's ______ by an integrase enzyme. The virus thereafter replicates as part of the host cell's ___.

Back 140

A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA.

Front 141

Steps of use of retroviruses for lineage analysis.

Back 141

- retrovirus infects a single progenitor cell
- viral genes integrate into cell DNA
- viral genes are expressed, marking the infected cell and all of its progeny
- cells are traced at different times during development

Front 142

Cortical neurons are born in the ___________ zone.

Back 142

Cortical neurons are born in the ventricular zone.

Front 143

Where are cortical neurons born?

Back 143

Cortical neurons are born in the ventricular zone.

Front 144

The cerebral cortex develops from the most ________ part of the neural plate, a specialized part of the embryonic _________. The neural plate folds and closes to form the neural tube. From the cavity inside the neural tube develops the _________ system, and, from the __________ cells of its walls, the ________ and ____ of the nervous system. The most ________ (______) part of the neural tube, the ____________, gives rise to the cerebral hemispheres and cortex.

Back 144

The cerebral cortex develops from the most anterior part of the neural plate, a specialized part of the embryonic ectoderm. The neural plate folds and closes to form the neural tube. From the cavity inside the neural tube develops the ventricular system, and, from the epithelial cells of its walls, the neurons and glia of the nervous system. The most anterior (frontal) part of the neural tube, the telencephalon, gives rise to the cerebral hemispheres and cortex.

Front 145

Cortical neurons are generated within the __________ zone which, at first, contains "__________" cells. These divide to produce ______ and _________ cells.

Back 145

Cortical neurons are generated within the ventricular zone which, at first, contains "progenitor" cells. These divide to produce glial and neuronal cells.

Front 146

The first pyramidal neurons generated migrate out of the __________ zone, together with ______-_______ cells from the preplate.

Back 146

The first pyramidal neurons generated migrate out of the ventricular zone, together with Cajal-Retzius cells from the preplate.

Front 147

Next, a cohort of neurons migrating into the ______ of the preplate divides this transient layer into the ___________ _________ zone, which will become layer ___ of the mature neocortex, and the ________, forming a _______ layer called the __________ plate. These cells will form the deep layers of the mature cortex, layers ____ and ___.

Back 147

Next, a cohort of neurons migrating into the middle of the preplate divides this transient layer into the superficial marginal zone, which will become layer one of the mature neocortex, and the subplate, forming a middle layer called the cortical plate. These cells will form the deep layers of the mature cortex, layers five and six.

Front 148

Later born neurons migrate ________ into the cortical plate past the deep layer neurons, and become the _______ layers (___ to ____). Thus, the layers of the cortex are created in an ______-___ order.

Back 148

Later born neurons migrate radially into the cortical plate past the deep layer neurons, and become the upper layers (two to four). Thus, the layers of the cortex are created in an inside-out order.

Front 149

Neurons migrate ________ along processes of radial ____ cells.

Back 149

Neurons migrate radially along processes of radial glia cells.

Front 150

_______ ____, whose fibers serve as a scaffolding for migrating cells, can itself ______ or __________ to the cortical ____ and differentiate either into _________ or _______. Somal translocation can occur at any time during development.

Back 150

Radial glia, whose fibers serve as a scaffolding for migrating cells, can itself divide or translocate to the cortical plate and differentiate either into astrocytes or neurons. Somal translocation can occur at any time during development.

Front 151

Axons reach their targets in _ _______ __ ________ ______.

Back 151

Axons reach their targets in a series of discrete steps.

Front 152

Growth cone

Back 152

A growth cone is a dynamic, actin-supported extension of a developing axon seeking its synaptic target.

Front 153

Morphology of growth cone

Back 153

- filopodia
- lamellipodium

Front 154

Proteins in the growth cone

Back 154

- actin (surface)
- tubulin (microtubules, central domain mainly, are polymers of tubulin)
- acetylated microtubules

Front 155

Model of cone-mediated axon-guidance

Back 155

- cues from extracellular matrix can be attractive or repulsive
- attractive cues promote actin assembly (involves stabilizing proteins), i.e. polymerization
- specific microtubules are targeted on the attrative side and stabilization is favoured
- opposite effect of repulsive cues

Net effect is cone turning and moving towards positive cues.

Front 156

Examples of axon guidance cues.

Back 156

Netrin, Slit, Ephrins, and Semaphorins. It has more recently been shown that cell fate determinants such as Wnt or Shh can also act as guidance cues. Quite interestingly, the same guidance cue can act as an attractant or a repellent, depending on context.

Front 157

Growth cone extension on a permissive surface: steps.

Back 157

- Filopodium contacts an adhesive substance.
- Vescicle fusion adds membrane to the leading edge of the filopodium.
- Actin polymerization pushes cone forward.

Front 158

How do long- and short-range interaction for axonal guidance manifest?

Back 158

Long range: chemical repulsion/attraction.
Short range: contact repulsion/attraction.

Front 159

List signaling molecules for axonal guidance.

Back 159

Netrins: Netrins are secreted molecules that can act to attract or repel axons by binding to their receptors, DCC and UNC5.

Slits aka Sli: Secreted proteins that normally repel growth cones by engaging Robo (Roundabout) class receptors.

Ephrins: Ephrins are cell surface molecules that activate Eph receptors on the surface of other cells. This interaction can be attractive or repulsive. In some cases, Ephrins can also act as receptors by transducing a signal into the expressing cell, while Ephs act as the ligands. Signaling into both the Ephrin- and Eph-bearing cells is called "bi-directional signaling."

Semaphorins: The many types of Semaphorins are primarily axonal repellents, and activate complexes of cell-surface receptors called Plexins and Neuropilins.

In addition, many other classes of extracellular molecules are used by growth cones to navigate properly:
- Developmental morphogens, such as BMPs, Wnts, Hedgehog , and FGFs
- Extracellular matrix and adhesion molecules such as laminin, tenascins, proteoglycans, N-CAM, and L1
- Growth factors like NGF
- Neurotransmitters and modulators like GABA

Front 160

Categorize signaling molecules for axonal guidance: long- VS short-range.

Back 160

Chemorepulsion: Semaphorins (secreted), Netrins
Chemoattraction: Netrins
Contact repulsion: Eph ligands, Semaphorins (transmembrane), ECM (e.g. tanascins)
Contact attraction: Ig CAMs, Cadherins, ECM (e.g. laminins)

Front 161

Guidance cues can be _________ or __________. Explain.

Back 161

Guidance cues can be constructive or permissive.
Instructive: determine the direction of growth.
Permissive: allow the axon to grow if instructed.

Front 162

The four canonical families of instructive guidance cues.

Back 162

Listed as "ligand (receptor)":
1. Netrin (DCC/neogenin, UNC-5), can be attractive or repulsive, dual function in axon guidance. Its function is evolutionary conserved.
2. Slit (ROBO), mostly repulsive,
Robo receptor member of IG superfamily
3. Semaphorin (neuropilins, plexins)
4. Ephrin (EPH receptors), are important for map formation, act mostly as gradients.

Recently morphogens (Wnt, shh) have been added to the list.

Extracellular matrix proteins are intimately involved in guidance as well.

Front 163

Sperry‘s Chemoaffinity Theory.

Back 163

As described above, topographic maps occur when spatial relationships are maintained between neuronal populations and their target fields in another tissue. This is a major feature of nervous system organization, particular in sensory systems. The neurobiologist Roger Sperry proposed a prescient model for topographic mapping mediated by what he called molecular "tags." The relative amounts of these tags would vary in gradients across both tissues. We now think of these tags as ligands (cues) and their axonal receptors. Perhaps the best understood class of tags are the Ephrin ligands and their receptors, the Ephs.
- Axons and tectal target cells display matching labels
- chemical labels should be deposited as gradients
(solution to coding problem)

Front 164

Summary of axon guidance.

Back 164

- Axons find their targets in discrete steps
- The growth cone contains the pathfinding machinery
- Guidance cues can be repulsive or attractive
- Canonical guidance cues are:
netrins, semaphorins, slits, and ephrins
plus recently discovered morphogens (Wnt, shh)
- Map formation involves molecular gradients

Front 165

Types of synapses in the nervous system.

Back 165

Chemical and electrical.

Front 166

Features of electrical synapses.

Back 166

- continuity between cells via gap junctions
- direct coupling of ions
- bidirectional signal
- quick reflexes, synchronising of neural ensembles

Front 167

Describe a gap junction.

Back 167

A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells.

One gap junction channel is composed of two connexons (or hemichannels) which connect across the intercellular space. Gap junctions are analogous to the plasmodesmata that join plant cells.

Front 168

Features of chemical synapses.

Back 168

-pre- and postsynapse divided by synaptic cleft
-transmission via neurotransmitters
-unidirectionale signal
-time delay (0.3 to 5 ms)
-signal amplification and modification

Front 169

The presynaptic terminal, or synaptic _________, is a specialized area within the ____of the _____________ cell that contains _______________ enclosed in small membrane-bound spheres called synaptic _________.

Back 169

The presynaptic terminal, or synaptic bouton, is a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles.

Front 170

Pre-synaptic parts of a neuromuscular junction (NMJ).

Back 170

- Motor nerve fiber
- Myelin
- Axon terminal
- Schwann cell
- Synaptic vesicles

Front 171

Post-synaptic parts of a neuromuscular junction (NMJ).

Back 171

- Active zone
- Basement membrane
- Synaptic cleft
- Sarcolemma
- Junctional folds
- Nucleus of muscle fiber

Front 172

Neurotransmitter of a neuromuscular junction (NMJ)?

Back 172

Acetylcholine.

Front 173

Development of neuromuscular junction.

Back 173

At the embryonic stage, ACh receptors are homogeneously distributed along the muscle fiber. In the adult nerve, ACh receptors are clustered in a region adjacent to the synaptic cleft.
Expression of ACh receptors is also regulated and increases near the synaptic cleft, while decreases in more distant regions.

Front 174

The synaptic basal lamina contains ________ for
pre- and postsynaptic ______________.

Back 174

The synaptic basal lamina contains signals for
pre- and postsynaptic differentiation.

Front 175

Is deposited by the nerve into the synaptic
basal lamina and leads to clustering. What is it?

Back 175

The proteoglycan agrin is deposited by the nerve into the synaptic
basal lamina and leads to clustering.

Front 176

Development of neuromuscular junction.

Back 176

During development, the growing end of motor neuron axons secrete a protein known as agrin.

This protein binds to several receptors on the surface of skeletal muscle.

The receptor which seems to be required for formation of the neuromuscular junction is the MuSK protein (Muscle specific kinase).

MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the release of phosphate molecules to particular tyrosines on itself, and on proteins which bind the cytoplasmic domain of the receptor.

Upon activation by its ligand agrin, MuSK signals via two proteins called "Dok-7" and "rapsyn", to induce "clustering" of acetylcholine receptors (AChR).

In addition to the AChR and MuSK, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the NMJ.

Front 177

Signals the clustering of ACh receptors. What is it?

Back 177

Agrin, a protein which is secreted at the growing end of the motor neuron axons.

Front 178

Nerve activity ___________ AChR expression in non-synaptic regions.

Back 178

Nerve activity represses AChR expression in non-synaptic regions.

Front 179

There is evidence of ___-_________ of AChR prior to ___________ onto the neuromuscular junction.

Back 179

There is evidence of pre-pattern of AChR prior to innervation onto the neuromuscular junction.

Front 180

Summary of neuromuscular junction.

Back 180

1. Agrin mediates postsynaptic clustering via MuSK, LPR4 and Rapsyn
2. AChR expression is locally stimulated by neuregulin
3. Neuronal activity represses global AChR transcription

Front 181

Two examples of synapse elimination.

Back 181

- Ganglion cells
- Muscle cells

Front 182

Synapse elimination is likely ____________ via __________-mediated signals.

Back 182

Synapse elimination is likely regulated via activity-mediated signals.

Front 183

Synapse elimination: Competition in vitro has been shown to involve a limited ____________ substance that is released, or that neural activity infers advantage to strong post-synaptic connections by giving ____________ to a toxin also released upon nerve _______________. In vivo it is suggested that muscle fibers select the strongest neuron through a ___________ signal.

Back 183

Synapse elimination: Competition in vitro has been shown to involve a limited neurotrophic substance that is released, or that neural activity infers advantage to strong post-synaptic connections by giving resistance to a toxin also released upon nerve stimulation. In vivo it is suggested that muscle fibers select the strongest neuron through a retrograde signal.

Front 184

The Neurotrophic Factors (NTF) hypothesis.

Back 184

The survival of neurons is regulated by survival factors, called trophic factors. The neurotrophic hypothesis was formulated by Victor Hamburger and Rita Levi Montalcini based on studies of the developing nervous system. Victor Hamburger discovered that implanting an extra limb in the developing chick led to an increase in the number of spinal motor neurons. Initially he thought that the extra limb was inducing proliferation of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during normal development, and the extra limb prevented this cell death. According to the neurotrophic hypothesis, growing axons compete for limiting amounts of target-derived trophic factors and axons that neurons that fail to receive sufficient trophic support die by apoptosis. It is now clear that factors produced by a number of sources contribute to neuronal survival.

Front 185

The survival of neurons is regulated by survival factors, called ________ factors. Victor Hamburger discovered that implanting an _____ ____ in the developing chick led to an ________ in the number of _______ ______ neurons. Initially he thought that the extra limb was inducing _____________ of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron _____ during normal development, and the extra limb __________ this cell ____. According to the neurotrophic hypothesis, growing axons ________ for limiting amounts of target-derived _______ factors and axons such that neurons that fail to receive sufficient _______ support ___ by _________ . It is now clear that factors produced by a number of sources contribute to neuronal __________.

Back 185

The survival of neurons is regulated by survival factors, called trophic factors. The neurotrophic hypothesis was formulated by Victor Hamburger and Rita Levi Montalcini based on studies of the developing nervous system. Victor Hamburger discovered that implanting an extra limb in the developing chick led to an increase in the number of spinal motor neurons. Initially he thought that the extra limb was inducing proliferation of motor neurons, but he and his colleagues later showed that there was a great deal of motor neuron death during normal development, and the extra limb prevented this cell death. According to the neurotrophic hypothesis, growing axons compete for limiting amounts of target-derived trophic factors and axons such that neurons that fail to receive sufficient trophic support die by apoptosis. It is now clear that factors produced by a number of sources contribute to neuronal survival.

Front 186

The Neurotrophic Factors (NTF) hypothesis (simple formulation).

Back 186

Target cells secrete limited amounts of a neurotrophic substance, sensed by specific cell
surface receptors. Cells compete for these factors. Those that do not receive sufficient.
amounts are fated to die.

Front 187

Target cells secrete limited amounts of a ____________ substance, sensed by specific cell
surface ___________. Cells _________ for these factors. Those that do not receive sufficient
amounts are fated to ___.

Back 187

Target cells secrete limited amounts of a neurotrophic substance, sensed by specific cell
surface receptors. Cells compete for these factors. Those that do not receive sufficient.
amounts are fated to die.

Front 188

Three NGF-related trophic factors.

Back 188

BDNF, NT3, and NT4.

Front 189

Types of Cell Death.

Back 189

- programmed: apoptosis, autophagy, pyroptosis, oncosis

- not-programmed: necrosis

Programmed cell death: regulated death in response to a specific signal.
Apoptosis: cell death mediated by "apoptotic machinery",

Front 190

Describe apoptosis.

Back 190

Apoptosis is an energy consuming, biochemically fine tuned pathway to death.
Features: DNA laddering, membrane blebbing, no inflammation (contrasting necrosis)

Front 191

Changes on cells after apoptosis.

Back 191

Blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, nuclear collapse, chromosomal DNA fragmentation, apoptotic body formation and lysis of apoptotic bodies.

Front 192

Steps of necrosis.

Back 192

Small blebs form, the structure of the nucleus changes.

The blebs fuse and become larger. No organelles are located in the blebs.

The cell membrane ruptures and releases the cell's content. The organelles are not functional.

Front 193

Steps of apoptosis.

Back 193

Small blebs form.

The nucleus begins to break apart and the DNA breaks into pieces. The organelles are also located in the blebs.

The cell breaks into several apoptotic bodies. The organelles are still functional.

Front 194

Process of apoptosis.

Back 194

Apoptosis is a Regulated Multi-Step Process:
1. Initiation. Intrinsic trigger: DNA damage (via p53 pathway), cell damage, radical oxygen species (ROS). Extrinsic trigger: growth factor withdrawal, Death receptor activation, ...
2. Regulation: inhibiting (anti-) and promoting (pro-apoptotic) proteins
3. Execution: executive caspases, DNA fragmentation
4. Phagocytosis

Front 195

Proposed roles for apoptosis.

Back 195

- removal of non-functional cells
- removal of transient populations of cells
- role in pattern formation and morphogenesis
- error correction
- removal of harmful cells (virus infection, cancer)
- ...

Front 196

Functions of ion-channels.

Back 196

- membrane potential (voltage-gated)
- synaptic potentials (ligand-gated = ionotropic)
- action potentials (voltage-gated)
propagation of action potentials (voltage-gated)
- intrinsic neuronal responses

Front 197

Brief description of ion-channels.

Back 197

Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells (see cell potential) by allowing the flow of ions down their electrochemical gradient.

Front 198

Ion channels are pore-forming _________ that help __________ and ________ the small ________ _________ across the plasma ___________ of cells (see cell potential) by allowing the flow of _____ down their electrochemical ________.

Back 198

Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells (see cell potential) by allowing the flow of ions down their electrochemical gradient.

Front 199

Ball-and-chain mode of ion-channel inactivation.

Back 199

The N-terminus of the protein forms a ball that is tethered to the rest of the protein through a loop (the chain). The tethered ball is transiently sucked into the inner porehole, preventing ion movement through the channel.

Front 200

Phototransduction in the retina.

Back 200

In dark conditions, both Na+ and K+ channels are open (dark current, depolarized cell).
In light conditions, Na+ channel closes (hyperpolarized cell).

Front 201

Ion channels: functions in neurons.

Back 201

1. maintaining membrane potential
2. reception (dendrites): epsp/ipsp
3. conduction (axon): action potential
4. transmission (terminal): neurotransmitter release
5. pacemaker and oscillatory responses

Front 202

Nernst equation.

Back 202

E_ion = RT/zF log ([ion]_out / [ion]_in)

@37°C:
RT/zF = 61.54 mV

Front 203

Two features of the action potential.

Back 203

- threshold event
- all-or-none process

Front 204

Sequence of channel activations during action potential.

Back 204

1. Na+ inactivated / K+ inactivated
2. Na+ activated / K+ inactivated
3. Na+ activated / K+ activated
4. Na+ inactivated / K+ activated
5. Na+ inactivated / K+ activated
6. Na+ inactivated / K+ inactivated

Front 205

Time evolution of an action potential.

Back 205

The course of the action potential can be divided into five parts: the rising phase, the peak phase, the falling phase, the undershoot phase, and the refractory period.

Front 206

Ion channels and disease (channelopathies)

Back 206

- mutations in the coding region of ion channel genes (cystic fibrosis: most common Caucasian genetic disease; LQT cardiac arrhythmia, migraine)
- mutations in the promoter region of the gene
- defective regulation of channel activity by cellular constituents or extracellular ligands (K-ATP channels involved in insulin release: diabetes II)
- antibodies to channel proteins (myasthenia gravis)
- ion channels secreted by cells as toxic agents (Staphylococcus aureus hemolytic toxin)

Front 207

Basics of synaptic transmission.

Back 207

Synaptic transmission

- fast and precise information transfer (basis of thinking and behavior)

- SYNAPSE: the functional unit of the nervous system (switches)
- point of information transfer
- 1 mm3 of cortex: 100,000 neurons, but 109 synapses, 4 km axons
- Charles Sherrington (Nobel Prize 1932) coined the words SYNAPSE NEURON

Why do we need synapses?
- passive current flow between neurons: 100 mV -> 10 ~ 100 uV
- gap junction (electrical synapse): 100 mV -> 1 mV
- chemical synapse: 100 mV -> 100 mV

Front 208

Properties of electrical synaptic transmission via gap-junctions.

Back 208

- usually bidirectional transmission -> ideal for synchronized behavior in a syncytium
- very fast
- temperature insensitive
- usually excitatory
- limited amplitude: ~1 mV (or else, giant synapse)
- limited plasticity: connexins can be phosphorylated/dephosphorylated,
1⁄2 life of ~ 3 hrs

Front 209

Control of current of electrical synaptic transmission via gap-junctions.

Back 209

- usually cannot be completely closed -> residual conductance of 40%
- charge carried mainly by K+
- channel conductance controlled by: transjunctional voltage difference, pH, inhalational anesthetics (halothane) block gap junctions

Front 210

Functions of current of electrical synaptic transmission via gap-junctions.

Back 210

- metabolic (diffusional exchange)
- syncytium: heart, embryo, but also CNS: local inhibitory networks

Front 211

Sequence of events in chemical synaptic transmission.

Back 211

Duration = 0.5 – 2 ms

1. action potential conducted down the axon
2. action potential invades terminal, opening of Ca2+ channels
3. fusion of vesicle to membrane, exocytotic release of vesicle contents
(time between influx of Ca2+ and transmitter release: 100 - 200 us)
4. diffusion of transmitter (30 nm in 0.6 us)
5. gating of ion channels
(6) recycling of vesicles

Front 212

Assign to electrical or chemical synapse:

simple primitive system

Back 212

Electrical synapse.

Front 213

Assign to electrical or chemical synapse:

highly developed structure

Back 213

Chemical synapse.

Front 214

Assign to electrical or chemical synapse:

polarized, structurally and functionally

Back 214

Chemical synapse.

Front 215

Assign to electrical or chemical synapse:

large synapse

Back 215

Electrical synapse.

Front 216

Assign to electrical or chemical synapse:

very fast, no synaptic delay

Back 216

Electrical synapse.

Front 217

Assign to electrical or chemical synapse:

thousand of small synapses

Back 217

Chemical synapse.

Front 218

Assign to electrical or chemical synapse:

temperature-insensitive

Back 218

Electrical synapse.

Front 219

Assign to electrical or chemical synapse:

pre: active zone
post: postsynaptic density

Back 219

Chemical synapse.

Front 220

Assign to electrical or chemical synapse:

versatile (excitatory or inhibitory)

Back 220

Chemical synapse.

Front 221

Assign to electrical or chemical synapse:

synchronized activity

Back 221

Electrical synapse.

Front 222

Assign to electrical or chemical synapse.

slower, synaptic delay (~0.5 ms)

Back 222

Chemical synapse.

Front 223

Assign to electrical or chemical synapse.

Ca2+-independent

Back 223

Electrical synapse.

Front 224

Assign to electrical or chemical synapse.

temperature-sensitive

Back 224

Chemical synapse.

Front 225

Assign to electrical or chemical synapse.

specificity (point-to-point communication)

Back 225

Chemical synapse.

Front 226

Assign to electrical or chemical synapse.

gap junction (connexins)

Back 226

Electrical synapse.

Front 227

Assign to electrical or chemical synapse.

often symmetrical, bi-directional

Back 227

Electrical synapse.

Front 228

Assign to electrical or chemical synapse.

very fast, no synaptic-delay

Back 228

Electrical synapse.

Front 229

Assign to electrical or chemical synapse.

highly developed structure

Back 229

Chemical synapse.

Front 230

Transmitter release in synaptic transmission. Describe.

Back 230

Transmitter release is quantal, not variable.

- the elementary unit of transmitter release is the contents of a single vesicle (quantum)
- transmitter is released in quantal units spontaneously (in the absence of a presynaptic action potential = in the absence of Ca2+ influx)
- the response of such a unit is called a mini (mEPSP, mIPSP, mEPP)
- an action potential:
1) increases the probability of quantal release
2) synchronizes quantal release

Definitions:
- quantal content: number of quanta making up an epsp (or ipsp)
- quantal size: amplitude of response induced by transmitter from 1 vesicle

Front 231

Synaptic transmission: evidence for transmitter release from vesicles.

Back 231

1. all chemically transmitting synaptic terminals contain vesicles
2. synaptic vesicles concentrate and store transmitter
3. rapid freezing of NMJ during stimulation (transmitter release) shows vesicle exocytosis
4. intravesicular proteins appear on external surface after release
5. blockers of vesicular filling reduce mEPSP amplitude (quantal size)
6. synaptic vesicles formed by endocytosis fill with extracellular dyes, and the dye is released by subsequent stimulation
7. toxins that block interaction of synaptic vesicle with cellular presynaptic membrane prevent neurotransmitter release

Front 232

Neuromuscular junction (NMJ): properties.

Back 232

- vesicles are clustered behind the active zone
- action potential induces Ca2+ influx, promoting fusion and exocytosis of vesicles
- fusion of vesicle releases 5000 transmitter molecules within 0.5 ms
- ACh achieves a concentration of 1 mM at the receptors
- 5000 transmitter molecules open 1000- 2000 ACh channels (2 molecules must bind to open receptor channel)
- each channel has a 25 pS conductance, open time of 1.5 ms admits charge transfer of 35,000 cations

Front 233

Probability of release (NMJ),

Back 233

- one action potential conducts into a presynaptic junction containing 800 active zones
- 160 vesicles fuse (640 failures) -> 80% failure rate
- epp: ~ 64 mV
- transmission is 1:1 (one axonal action potential -> one muscle action potential)

Front 234

Transmission of CNS synapse.

Back 234

- various neurotransmitters (but mainly glutamate or GABA)
- release at presynaptic axon (boutons)
- each bouton contains only one or a few active zones
- one action potential releases one vesicle at 10% to 50% of active zones
- release of one vesicule elevates transmitter concentration in the cleft to ~1 mM
- activates 30 ion channels giving a glutamatergic epsp of 0.2 mV
- epsp/ipsp in CNS: subthreshold ~ 1 mV

Front 235

The ion channel is regulated by a _____ and is usually very _________ to one or more ions like ___, __, ____, or ___. Such ___________ located at synapses convert the chemical signal of ________________ released neurotransmitter ________ and very _______ into a ___________ electrical signal.

Back 235

The ion channel is regulated by a ligand and is usually very selective to one or more ions like Na+, K+, Ca2+, or Cl-. Such receptors located at synapses convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal.

Front 236

Metabotropic receptors do not form an ion channel ____.
They are __________ linked with ion-channels on the plasma membrane of the cell through ______ __________ mechanisms, often _ _________.
They are a type of _ _______-coupled receptor

Back 236

Metabotropic receptors do not form an ion channel pore.
They are indirectly linked with ion-channels on the plasma membrane of the cell through signal transduction mechanisms, often G proteins.
They are a type of G protein-coupled receptor.

Front 237

Properties of metabotropic receptors.

Back 237

- G protein-coupled receptors, heptahelical receptors,
seven-transmembrane receptors
- 2 – 5% of the vertebrate genome codes metabotropic receptors
- > 400 cloned metabotropic receptors (~ 1200 odorant receptors)
- largest family of cell surface receptors
- ~ 60% of clinically used drugs act via metabotropic receptors

Front 238

Differences between ionotropic and metabotropic receptors.

Back 238

Ionotropic:
- binding site and channel are combined
- doesn't depend on 2nd messenger
- short latency
- rapid response
- mostly post-synaptic

Metabotropic:
- binding site not associated with channel (indirect)
- G protein-coupled mechanism or 2nd messenger
- long latency
- slow response
- pre- or post-synaptic
- largest family of cell surface receptors
- ~60% of clinical drugs acts on metabotropic receptors

Front 239

Mechanism of G protein-coupled receptor.

Back 239

The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein.

Front 240

Criteria for identification of a neurotransmitter (NT).

Back 240

1. NT and synthetic enzymes or transport mechanism present in neuron
2. selective activation of neuronal pathway should release NT
3. exogenously applied NT should mimic the effect of endogenous NT released synaptically
4. antagonists should block both exogenously applied and endogenous NT
5. mechanism to rapidly terminate the action of the NT must be present

Front 241

Properties of cutaneous mechanoceptors.

Back 241

1. direct extensions of the afferent axons (cell body in or near dorsal root ganglion or cranial nerve ganglion)
2. myelin-free nerve endings
3. contact specialized structures (Merkel cell - Merkel disc)
4. the nerve ending is the transducer (mechanical disturbance induced current)
5. specialized receptors -- specialized locations

Front 242

Responses of non‐cutaneous proprioceptors (arm)

Back 242

1. flex arm
2. stimulation or prolong contraction of biceps
3. extend arm
4. perceive larger movement than usual as the baseline firing/sensitivity of the sensor was increased by "1" and "2".

Front 243

Somathosensory system in the CNS: Dermatomes (parts)

Back 243

1. Cervical
2. Thoracic
3. Lumbar
4. Sacral

Front 244

Ian Waterman: the consequence of proprioception absence.

Back 244

The patient could activate muscles but he needed to plan each and every movement carefully such that only after years of training he could perform basic movements of everyday life.

Front 245

Somathosensory system: large fibers.

Back 245

Transmit rapid changes, fast responses to the spinal cord.

Front 246

Two-points-discrimination test.

Back 246

Touch one or two points on the skin and ask the number. The sensitivity is an estimation of density. Perceived dimensions of limbs are related to density of sensors.

Front 247

Muscles sensors: active or passive?

Back 247

Active, they actively produce electric signal induced by mechanical stress.

Front 248

Pair the following terms: contraction and stretching VS motor control and concious perception of movement.

Back 248

contraction -> motor control
stretching -> concious perception of movement

Front 249

Penfield experiment.

Back 249

Induce sensation of touch and movement by direct stimulation of somathosensory cortex => map of the "homunculus"

Front 250

Distribution of receptors on the retina

Back 250

- only cones in the fovea
- blind spot at around 15°-nose
- distribution of rodes is peaked around fovea but more or less they are spread across the retina
- there are 10^8 cones, 5x10^6 rods
- highly packed around fovea, less packed away from fovea

Front 251

Peak absorption wavelength of rods.

Back 251

498nm

Front 252

Dynamic response of retina receptors.

Back 252

- lower intensities: rods, no colors
- higher intensities: cones, color perception

Front 253

Scotopic and photopic vision systems.

Back 253

Scotopic:
- low-light
- receptors: the rods
- pigment: rhodopsin
- sensitivity: high, also by night
- position: outside the fovea
- visual acuity: low

Scotopic:
- low-light
- receptors: the rods
- pigment: rhodopsin
- sensitivity: high, also by night
- position: outside the fovea
- visual acuity: low

Photopic:
- high-intensity light
- receptors: the cones
- pigment: three different pigments, 420 nm (blue), 534 nm (Bluish-Green), 564 nm (Yellowish-Green)
- sensitivity: low, daylight conditions
- position: concentrated on the fovea
- visual acuity: very high in the fovea, low outside (because of density)

Front 254

Network from the retina to the brain.

Back 254

- ganglion cells
- inner plexiform
- inner nuclear layer
- outer plexiform layer
- outer nuclear layer
- layer of photoreceptors
- pigmented epithelium

Functions:
- the ganglion cells conveys information to the brain
- between receptors and ganglion cells there is a densely packed network of vertical (bipolar) and and horizontal (amacrine) cells
- rods and cones project to the corresponding ganglion cell

Front 255

Spatial encoding on the retina.

Back 255

- there are 100 more receptors than ganglion cells
- the retina compresses the information
- the econding mechanism is mainly "lateral inhibition"

Front 256

Center-sorround cells in the retina.

Back 256

There are two types of center-sorround cells, on-center/off-sorround and v.v.

In the on-center structure, the receptors in the geometrical center of the structure excite the corresponding ganglion cell whereas the receptors disposed around the center inhibit the ganglion cell. The total amount of transmitted light is maintained (weight average is zero).

The spatial averaging and wavelength sensitivity might change: M (magnocellular) ganglion cells respond to sensitivity, P (parvocellular) to colors, i.e. red VS green and yellow VS blue.

Front 257

Visual pathways.

Back 257

- eye, especially the retina
- optic nerve
- optic chiasma
- optic tract
- lateral geniculate body (thalamus)
- superior and pulvinar colliculus
- optic radiation
- primary visual cortex (V1)

Front 258

Retino-thalamical projection.

Back 258

- signals travel from the eye to the thalamus and then to the cerebral cortex
- the region in the thalamus is called LGN
- LGN is structured in 6 layers, alternatively receiving left/right temporal retina signals (left LGN) and left/right nasal retina signals (right LGN)

Front 259

Hubel and Wiesel experiment.

Back 259

- extracellular recording on cat's visual cortex
- stimulating with orientated bars, moving bars, ...
- registered simple and complex cells
- extensive, complete definition of cells "selectivity" (orientation and direction selectivity)
- derived ice cube model, combining orientation selectivity and ocular dominance

Orientation selectivity can be exaplained by combination of on and off cells. Similarly, computer algorithms have been developed to perform edge-detection on images.

Front 260

Ocular dominance.

Back 260

Tendency to prefer information of one eye with respect to the other. Around 2/3 of population are "right-eyed", 1/3 left. Small proportion neither of the two.
In V1, information from right and left eye are combined.

When one eye is kept blind-folded, regions in V1 corresponding to the other eye receive more blood spully, therefore responding differently to light illumination.

Front 261

Pinwheel model in V1.

Back 261

Neurons with similar orientation preferences are grouped in the visual cortex in a pinwheel pattern

Front 262

Columnar organisation of cortex.

Back 262

The column is the basic computational unit in the visual cortex.
In a column, the signals from both eyes are represented for all orientations.
By combining ocular dominance and orientation selectivity maps one obtains a map where:
- orientation selectivity is organized in "pinwheels"
- ocular dominance has a larger spatial scale (regions are larger than orientation selectivity regions)
- orientation selectivity and ocular dominance region borders always cross perpendicularly and, as a consequence, pinwheel centers never lie on ocular dominance borders

Front 263

What and where in the visual cortex.

Back 263

What: ventral stream (object identification, face recognition)
Where: dorsal stream (landmark discrimination).

The two informations seem to split their pathways: ventrotemporal and dorsoparietal.

Front 264

Definition of proteomics and neuroproteomics.

Back 264

Proteomics is defined as the all of the proteins expressed in a biological system under specific physiologic conditions at a certain point in time. Neuroproteomics is a subset of this field.

Front 265

Proteomics is defined as ___ ____ of the proteins __________ in a biological system under specific ____________ ____________ at a certain ______ __ ____.

Back 265

Proteomics is defined as the all of the proteins expressed in a biological system under specific physiologic conditions at a certain point in time.

Front 266

Classical methods to measure proteins in neuroproteomics, and issues.

Back 266

- separation/purifying protein from complex mixture
- identification/quantification

Issues:
time consuming, low throughput, dependent on the availability of suitable antibodies.

Front 267

Technologies for proteomics.

Back 267

Proteomics analyzes:
- sample preparation
- mass spectrometric measurements
- biometric data processing

Front 268

Protein separation in neuroproteomics.

Back 268

Proteins need to be separated in terms of their proteome of origin (e.g. one can be set in normal conditions, an other under diseased conditions).
In order to do so, proteins are passed through a gel (2D PAGE technique). The proteins are then separated by charge and mass. Once they are mapped they need to be correlated with the disease.

Front 269

Protein identification in neuroproteomics.

Back 269

The range of protein size that protein separation techniques can handle (e.g. 2D PAGE) is limited. Mass spectrometry is used in identification techniques to increase the range, even though the protein samples are here limited.

Front 270

Workflow of neuroproteomics for mass spectrometry.

Back 270

1. sample preparation
2. ionization
3. separation
4. detection
5. mass spectrum

Front 271

Methods for ionization in neuroproteomics.

Back 271

- Maldi
- Electrospray
- Nanospray
- Liquid chromatography

Front 272

Methods for separation in neuroproteomics.

Back 272

- time-of-flight
- quadrupole
- ion trap

Front 273

Detection in neuroproteomics.

Back 273

- large molecules
- protein
- DNA
- peptides

Front 274

Microfluidic HPLC peptide separation (ESI - ElectroSpray Ionization).

Back 274

- peptides are separated passing them through Microscale Capillary
High-Performance Liquid Chromatography (HPLC) column
- peptides elute in order of their hydrophobicity

Peptide solutions are sprayed onto the spectrometer. An electric field is applied on the space where sprayed particles fly.
Different physical and chemical properties permit the distinction of proteins based on the data recorded.

Front 275

MALDI technique for mass spectrometry (proteomics).

Back 275

- matrix of analyte is prepared
- laser hits the matrix
- ions leave the matrix
- electric field accelerate the particles
- spectrometer detects particles
- images are reconstructed (proteins VS body parts)

Front 276

Principles of mass spectrometry.

Back 276

- charge molecules and inject into the MS (ionization through Maldi, ESI)
- separate molecules by m/z (isolation through time-of-flight, ion trap, quadrupole)
- detect and analyze by measures of m/z
- spectral matching with known peptides

Proteins undergo digestion (from protein to peptides), than ionization, isolation, fragmentation. The final ions are analyzed (m/z).

Front 277

Mass spectrometry protein identification overview.

Back 277

Protein sample -> enzymatic digestion -> tandem mass spectrometry -> peptide mixture -> peptide identifications -> database search, validation -> peptide grouping, validation -> protein identifications

Front 278

Proteomics: ESI vs MS

Back 278

ESI:
- liquid state ionization
- samples are all consumed
- ion trap/quadrupole

MS:
- solid state ionization
- samples are not entirely consumed
- time-of-flight

Front 279

What can MS-proteomics do?

Back 279

- peptide/protein identification
- analysis of post-translational modifications
- peptide/protein/PTM quantification
- combinations of the above

Front 280

Surfaceome.

Back 280

- determines how cells interact with the environment (communication, interaction, binding to messengers, migration)
- reflects differentiation state
- indicates functional capacity

Front 281

Problems for surfaceome analysis.

Back 281

- isolation of plasma membrane is made difficult by the fact that plasma membrane and intracellular membranes do not differ in physico-chemical properties
- cytoplastmic proteins are more abundant than surface proteins
- 2D PAGE techniques cannot be applied to cell surface proteins

Front 282

Applications of proteomics.

Back 282

1. peptide fragmentation
2. quantitative proteomics (different markers)
3. differential proteomics (normal vs diseased)
4. off-gel fractionation (cell surface proteom for cell type classification)

Classes of neuroproteomics (NP):
- expression NP (identification of proteins in the brain)
- functional NP (PTM analysis of proteins): studies the functional properties of individual proteins, post-translational modifications, organization into structures, networks, complexes (interactomics)
- clinical NP (targeted strategies): identification of disease markers, study of cancer, parkinson, epilepsy, down syndrome, multiple sclerosis, ..., used in pharmacology, drug abuse, neurodegenerative diseases, psychiatric disorders...

Front 283

What is neuromorphic engineering?

Back 283

Electronics that embody computational principles of brain-like systems.

Front 284

Differences between brain and computer.

Back 284

At the system level, brains are at least 1 million times more power
efficient than computers. Why?

Cost of elementary operation (turning on transistor or activating
synapse) is about the same. It’s not some magic about physics.

Computer:
- fast global clock
- bit-perfect deterministic logic state
- memory distant computation
- ADC are fast, constant sample-rate

Brain:
- no clock
- memory and computation in the same place
- information encoding/decoding is unreliable, data-driven

Mobility of electrons in silicon is
about 107 times that of ions in solution.

Front 285

People in the physics of computation.

Back 285

Carver Mead, Feynman, Hopefield

Front 286

"The fact that we can build devices that __________ the same basic ____________ as those the nervous system uses leads to the
inevitable conclusion that we should be able to build entire systems based on the ___________ ___________ used by the nervous
system."

by _______ _____, 19__

Back 286

The fact that we can build devices that implement the same basic operations as those the nervous system uses leads to the
inevitable conclusion that we should be able to build entire systems based on the organizing principles used by the nervous
system.

Carver Mead, 1990

Front 287

Examples of organizing principles.

Back 287

1. using device physics for computation
2. using complementary devices to avoid burning static power
3. averaging over space & time to control noise and find signal context
4. using context to normalize signals
5. representing signed quantities by rectifying into ON and OFF
channels
6. using adaptation to amplify novelty
7. computing locally in analog and communicating remotely using
events

Front 288

Neuromorphic engineering: complementary devices, amplification.

Back 288

- summation on the dendritic tree
- capacitance integrates over time
- synapses multiply/accumulate
- complementary channels push/pull on the membrane voltage
- dendrites do local (analog) computation, axons communicate events over long distances (digital)

Front 289

Transistor/membrane analogy.

Back 289

- channel sensitivity is exponentially related to Vmem
- the current is exponentially related to gate voltage
The organizing principle is: use controlled energy barriers for carriers that show Boltzmann distribution to perform amplification.

Front 290

Simplified dynamic vision sensor.

Back 290

- photoreceptor
- capacitance
- differencing
- comparators
- digital on/off signals (asynchronous, event-driven)

Front 291

Properties of active dendrites.

Back 291

- amplification or dampening of synaptic input
- action potential backpropagation
retrograde signal about neuron state
- local dendritic spikes
- coincidence detection
sensitivity to synchronous, clustered inputs

Front 292

Basics of Neural Networks, summary.

Back 292

- individual neurons are sophisticated computational devices rather than simple
summation units
- microcircuits are established by complicated connections among the diverse, specialized cell
types
- effective connectivity can change dynamically both on the short-term and long-term time scale

Front 293

Dynamic measurements of neural networks activity.

Back 293

- electrophysiology (multi-electrode recording)
- in vivo population imaging (two-photon microscopy, calcium imaging)

Front 294

Methods for measuring the activity of neurons or network in vitro or in vivo.

Back 294

- multi-unit recordings (tetrode, multi-electrode, ...)
- extracellular recordings
- patch clamp
- calcium imaging
- two-photon microscopy
- genetically-encoded calcium indicators (GECI)

Front 295

Phases of Zebra finch's song learning.

Back 295

- sensory: listens to tutor (20d to 55d)
- somathosensory: listen to himself while trying to emulate tutor (subsong, plastic, crystalized) (30d to 90d)

Front 296

Lateral inhibition in embriology.

Back 296

- it is a type of cell–cell interaction whereby a cell that adopts a particular fate inhibits its immediate neighbours from doing likewise.

- the transmembrane proteins Notch and Delta (or their homologues) have been identified as mediators of the interaction.

- neuroblast with slightly more Delta protein on its cell surface will inhibit its neighboring cells from becoming neurons. In flies, frogs, and chicks, Delta is found in those cells that will become neurons, while Notch is elevated in those cells that become the glial cells.

- unregulated lateral inhibition causes disproportion of neural tissue