Intro to Neuroscience & Neuroembryology

[NEUROSCIENCE I] November 7, 2013

Introduction to Neuroscience & Neuroembryology Page 1 of 6

Neuron doctrine

the nervous system is made up of individually signalling elements called neurons which contact each other only at specialized points of interaction we call the synapses

the basic functional unit of the nervous system is the neuron. It is an excitable cell specialized to receive stimuli and to conduct a nerve impulse

Neuron

Three components: o dendrite – receives impulse o cell body o axon - transmits the impulse away from the cell

body towards its terminal From there it will go to the next neuron SYNAPSE - communication between two

neurons PATHWAY - a chain of communicating

neurons

Impulse travels from the dendrite to the cell body and then to the axon

The transmission of impulse in a single neuron is electrical, while from one neuron to another is chemical by means of neurotransmitters (secreted from the presynaptic terminal binding to receptors in the post synaptic terminals)

CNS PNS

Collection of nerve cell bodies

Nucleus Ganglion

Group of axons Fiber tracts/Lemniscus/Fasciculus

Peripheral nerve

Location Centrally located (Neuraxis) Peripheral

Function correlation, integration, and processing of nervous information

Conduit between the CNS and the organ systems of the body*

Components Brain and spinal cord Peripheral nerves and their associated ganglia, receptors, and effectors

*The peripheral nerves can either conduct impulses from the organ systems to the CNS or the other way around.

Sensory (function) or afferent (direction) – from organs to CNS

Motor or efferent – from CNS to organs

PNS

3 types of peripheral nerves: o cranial nerves – associated with cranial ganglia o spinal nerves – associated with spinal ganglia or

Dorsal Root Ganglion o autonomic nerves (peripheral nerves that course

through cranial and spinal nerves and root to visceral organs)

Foramen Magnum

Junction of the brain and spinal cord

Spinal Cord

Divided into 31 spinal cord segments (8 CV, 12 TV, 5 LV, 5 SV, 1 C), and thus the 31 pairs of spinal nerves as well

Brain

Cerebral hemisphere o largest o divide into right and left hemispheres o deep inside of which are structures belonging to the

diencephalon as well as the basal nuclei (formerly known as the basal ganglia).

Brainstem o Found below the diencephalon o divided into three in rostrocaudal order:

midbrain pons medulla

found immediately above the foramen magnum

Cerebellum – found behind the brainstem

Nervous system starts to form at the 3rd

week of life.

3rd

week of life – formation of notochord

o Source of inducer substance Seep into the overlying ectoderm and

stimulate it to thicken and form a structure called the neural plate -> neural

Calibri – Lecture Notes

Arial narrow – from powerpoint

INTRODUCTION TO NEUROSCIENCE

NEUROEMBRYOLOGY



groove, while the lateral structure will be the neural fold.

The two edges of the neural fold will start to approximate each other, and then separate with the overlying ectoderm to form the neural tube.

Before it separates from the overlying ectoderm, a portion of the neural folds will also separate from the surface ectoderm that will not move with the neural tube; rather it would position itself dorsolateral to the neural tube, and will be called the neural crest.

All these events will constitute the primary neurulation.

o Defines the long axis of the embryo o Determines orientation of vertebral column o Produces cell adhesion molecules so that cells in

the overlying notochord will move as a single unit

Primary neurulation

Formation of the neural tube from neural plate giving rise to the brain

and spinal cord up to lumbar levels

Day 18 – day 25

Neural tube – primordial of CNS o Rostral 2/3 gives rise to the brain o Caudal 1/3 gives rise to the spinal cord up to lumbar

levels o Caudal eminence gives rise to sacral and coccygeal

segments

Neural crest – PNS o Schwann cells o Cranial nerve ganglion o Dorsal root ganglion o Autonomic ganglion o Chromaffin cells of Adrenal medulla o Pia and arachnoid of meninges o Melanocytes

Induction process o Proper development of a structure would require

the proper development of the surrounding structures as well

Neural tube formed in primary neurulation will give rise to the CNS up to the Lumbar portion only

Secondary neurulation

Formation of sacral and coccygeal segments of cord from caudal eminence ; from day 20-42

Gives rise to the sacral and coccygeal portions

Several small tubules coalesce in CT matrix and then they form a mass called te caudal eminence

o Acquire a lumen, and fuse with the neural tube formed by primary neurulation to form the spinal cord of coccygeal and sacral segments

It is in the neck region where the neural fold start to approximate each other and form the neural tube during primary neurulation. It then proceeds rostrally and caudally along the length of the embryonic disc.

While it is not totally fused, there will be an opening both rostrally and caudally.

o Rostral opening - anterior neuropore or rostral neuropore. This communicates the neural cavity with the amniotic cavity.

o Caudal opening - Posterior neuropore, which connects the caudal neural cavity with the amniotic cavity.

o The rostral opening will close first because the cervical region/neck is closer to the rostral than to the caudal part of the body. This occurs at day 23-24

o The caudal neuropore closes at about day 25-26.

When the anterior neuropore closes, it forms a membrane called the lamina terminalis.

Normally, both openings should close to form the complete neural tube rostrally and caudally.

DISORDERS of PRIMARY NEURULATION

ANENCEPHALY o “without brain” o Defective closure of anterior neuropore o No neural tube in anterior o Aka Meroanencephaly – with some degree of

neural tissue, but to cerebral cortex o Absence of the skull o 100% mortality – baby will live for at most 1 week o No extraordinary measures, just comfort, warmth,

and baptism (if catholic.)

SPINA BIFIDA OCCULTA o Non closure of spines of vertebra o Tufts of hair at the area o Minimal defect

SPINA BIFIDA CYSTICA o With protruding mass of tissue at the area of

nonclosure which can be just a meningocoele (meningeal tissue) or meningomyelocoele (meninges + neural tissue)

o Graver defect o Functional impairment

MYELORACHISCHISIS o Open neural tube at the back o High mortality o Prognosis varies on degree of defect o Functional impairment

Preventive Measures o 400 ug of Folic acid daily (one month before

pregnancy up to 12 wks of gestation)



Disorders of Secondary Neurulation

Termed as Myelodysplasia o refers to malformation of parts of the neural tube formed

by secondary neurulation

o Site marked with unusual pigmentation, unusual hair

growth, superficial capillaries and prominent dimple

Tethered Cord Syndrome o Abnormality wherein the conus medullaris and filum

terminale are abnormally fixed to the defective vertebral column

o Affects the exiting spinal nerves from the cord o Loss of sensation in legs and feet o Bladder control problems o External: unusual tuft of hair, violaceous prominent

capillaries in the area; prominent dimple o More symptomatic than spina bifida

PRIMARY BRAIN VESICLES

o Occurs during 4th week of life o During the 5th week, primary brain vesicles will

evolve into secondary brain vesicles o Mesencephalon – most primitive segment of the

brain; retained until the secondary vesicle o Myelencephalon + Metencephalon +

Mesencephalon = BRAIN STEM o As the different secondary vesicles are evolving, the

shape and size of the neural cavities change

To fit in the skull, these structures will have to flex or bend o 1st bend/cervical flexure – between spinal cord and hind

brain(rhombencephalon) o Cephalic flexure- between the midbrain (mesencephalon)

and forebrain (prosencephalon ) o Pontine flexure – demarcates the myelencephalon from

the metencephalon o Telencephalic flexure- between the diencephalon and

telencephalon

TRANSVERSE DIFFERENTIATION of PRIMITIVE NEURAL TUBE

Neural tube o Ventricular zone

o Marginal zone

o Intermediate zone –Mantle layer

Alar plate –sensory function

Basal plate- motor function

o initially exists as single layer; pseudostratified columnar epithelium with very intense proliferative activity of the cells destined to become neurons. If they are destined to become neurons, they will form processes (axons and dendrites).

o Outside the ventricular zone is a layer wherein there are no cells but just the processes forming the marginal zone.

o Later, however, this layer would have extensive mitotic activity so that external to that, another layer will form called the intermediate layer, which will lie between the marginal and ventricular layer.

o Both ventricular and intermediate are cellular, while the marginal only contains processes.

INTERMEDIATE ZONE o Aka MANTLE layer o asymmetrical growth o favors dorsolateral and ventrolateral growth o SULCUS LIMITANS - demarcation separating the

proliferating cells from the dorsal half to the ventral half

Dorsal to it will comprise the alar plate Ventral to it - basal plate.

If a structure is derived from the alar plate or dorsal to sulcus limitans, it would perform sensory function.

If derived from the ventral half/basal plate = motor function

Proliferation of the cells in the alar and basal plate will reduce the cavity into a CENTRAL CANAL

o The ventricular zone will become ependymal cells which line the central canal.

o The alar plate will be the dorsal gray horn – sensory in function.

o Basal plate will become the ventral gray horn – motor in function.

o The marginal zone will become the white matter.



Each cord segment will be supplying a specific area of the skin called a dermatome.

As the ventral gray horn is developing, it will form the ventral root of the spinal nerves which would supply a specific group of muscles called the myotome of that specific cord segment. As the cord is forming, the spine is also developing.

1st

trimester - the root of the first sacral nerve exists below S1.

2nd trimester and at birth, (B & C), the cord is shorter, vertebra seems longer, indicating the vertebra is faster in growth, or the cord slowed down in growth.

There is a discrepancy in the length of the cord and the length of the vertebra so much so that the cord is almost at the level of L2 at this time.

o The first sacral nerve will have to travel a longer way to reach S1.

At birth, it still goes up further up to L1.

In the adult, the tip of the cord is between L1 & L2.

Implications o Tthe discrepancy in the slower growth of the cord

compared to the vertebra will impose a longer distance for the spinal nerves from lower thoracic to the coccygeal segments to exit below the corresponding vertebra

o Lumbar tap in the child – not in the same level as in the adult. The cord might be hit.

DRG being sensory in fxn coming from the alar plate will be receiving processes from the pseudounipolar neuron forming the Dorsal root of the spinal nerve

Ventral Gray Horn sending axons to form the ventral root of the spinal cord to supply a specific myotome level.

*How will the nerve be able to say where to terminate?

This phenomenon is biochemically dictated. Structures derived from the neural crest contain in their surface INTEGRINS, which recognize a specific molecule in the connective tissue at a specific dermatome level, which in turn contains LAMININ/FIBRONECTIN containing is a specific amino acid sequence. This enables the integrins to know where to terminate.

MYELENCEPHALON

Gives rise to the medulla o Has a portion which is similar to the spinal cord

and a portion where the neural cavity opens to become the 4

th ventricle.

o In the portion of the medulla similar to spinal cord, all structures dorsal to the sulcus limitans such as the sulcus gracilis and nucleus cuneatus are alar plate-derived and have sensory function.

o The gracilis is for conscious propioception on the legs, while the cuneautus would be conscious proprioception in the upper extremities and the trunk.

Upper 1/3 of the medulla, the cavity there opens to form the 4

th ventricle.

o Because of the opening of the cavity to become the ventricle, the alar plate becomes rotated dorso laterally and becomes lateral to the sulcus limitans.

o As for the basal plate, it will now become medial to the sulcus limitans. The orientation of the alar and basal changes in the upper medulla.

Lower 2/3 of medulla – alar is posterior/dorsal; basal – ventral

SUMMARY of changes in the Myelencephalon (Medulla)

o Nucleus solitarius (CN 7, 9, 10) – for taste



o Descending nucleus of V (trigeminal) – for pain and temperature (face region)

o CN nerves 12, 11, 10, 9 can be found in the Myelencephalon

METENCEPHALON (Pons and Cerebellum)

Wide cavity

Orientation of alar and basal plate would still be lateral and medial, respectively

At the region of the pons, CN 5, 6, 7, and 8 can be found

Sensory (CN 5, 8) - alar

Motor (6, 7) – basal

RHOMBIC LIP of the ALAR plate– proliferative; as it starts to grow further, it would meet with the rhombic lip of the other side and cover the posterior surface of the 4

th ventricle to

give rise to the cerebellum

DEVELOPMENT OF THE CEREBELLUM

outer gray matter, inner white matter

Cells from the intermediate zone would migrate using the radial glia cells as a scaffold to hold on to while they migrate external to the marginal zone to form the external/granular layer.

From this layer of cells, the granule cells, stellate cells and basket cells will be formed.

From the original intermediate zone, the cells would also migrate but they migrate outward and would give rise to the deep cerebellar nuclei and purkinje cells.

It is the POSTEROLATERAL FISSURE and not the PRIMARY FISSURE that is the 1

st to form in the cerebellum.

MESENCEPHALON (MIDBRAIN)

The orientation of the alar and basal plate reverts back to the usual. Alar – dorsal; basal - ventral

CN 3 & 4 (Oculomotor and Trochlear) – motor; basal plate-derived

CN 1 & 2 (Olfactory and Optic) cannot be found in the brainstem because they are sensory cranial nerves whose ganglion are in the periphery

Inferior colliculus – auditory relay nucleus

Superior colliculus – visual relay nucleus

DIENCEPHALON

Initially, there exists a demarcation between the diencephalon and the telencephalon.

However, during development the telencephalic starts to overhung the diencephalon, and thus the structures of the diencephalon cannot be seen externally. To see this structures, one will have to dissect the brain into sagittal or coronal or longitudinal sections. The diencephalon is covered by the cerebral cortex.

The diencephalon is largely derived from the alar plate.

Gives rise to the epithalamus, thalamus and hypothalamus

Development of thalamus occurs in an “outside-first” sequence (most lateral nuclei develop first, medial nuclei develop last)

Establishment of an orderly map of the sensory world in the thalamic nuclei (retinotopic mapping, tonotopic mapping)

o Ex. In the lateral geniculate nucleus which receives signals from the retina, as the images in the retina are organized, when they are projected to the lateral geniculate, orderly din.

PROSENCEPHALON

Gives rise to Telencephalon and Diencephalon

Central induction -process of forebrain development

Failure of prosencephalon to undergo cleavage results in holoprosencephaly (alobar and semilobar)

Develop at 2nd month of gestation simultaneous with formation of facial structures from mesoderm

o Ex. Cyclops; multiple facial clefts; proboscis

Infections may predispose to CNS abnormalities- TORCH o TORCH (Toxoplasmosis, Rubella, Cytomegalovirus,

Herpes Simplex, Syphilis) – to test infectious agents which the pregnant woman may have had in the past but can still affect the baby

TELENCEPHALON (CEREBRAL CORTEX)

Outer gray – has 6 layers

“Inside-out pattern”



Formation of cortical plate at interface of marginal zone and intermediate zone

Formation of the subplate, a narrow region internal to cortical plate

Marginal zone gives rise to layer 1 of cerebral cortex

Cortical plate gives rise to layers II-VI

Subplate and intermediate zone gives rise to subcortical white matter

1st

trimester – hallmark of a normal brain to have gyri and sulci/fissures

o Due to limited space in the skull o When it encounters resistance – it would form the

gyri and sulci o More neurons buried inside the sulci and fissures o Main fissures – seen during the 1

st trimester

Interhemispheric fissure Sylvian fissure Central sulcus

o 8th

month – secondary sulci o 3

rd trimester – tertiary or all sulci are formed

Center of critical thinking, imagination, analysis, etc

ABNORMALITIES o Lissencephaly- failure of gyri to form; smooth surfaced

cerebral cortex o Pachygyria- unusually large gyri o Microgyria- unusually small gyri o Schizencephaly- abnormal patterns of sulcal and gyral

development with unilateral or bilateral clefts in cerebral hemisphere

Parameters in brain organization:

Density or Number of neurons o Neurons – terminally differentiated and thus will

not undergo mitosis once formed o 6 months of gestation – overproduction of neurons;

afterwhich, there will be selective apoptosis of neurons that are not good/useful

Pattern of axon and dendrite branching o Age 2-3 y.o – complete neurons with dendritic and

axonal branching

Pattern of synaptic contacts o occurs throughout life o Neurons are always open to new learning

experiences; synaptic contacts can be fashioned/remodeled

Lumosity – website (plasticity of the brain!) haha. May free app na ganito

Factors affecting synaptic stabilization

Critical period refers to time period when these types of plastic changes occur; varies from region to region

o Ex. Baby with congenital cataract or severe myopia of left eye –

o as the baby grows the impulses from the right eye would have to establish synaptic stabilization in the visual centers in the cortex. But since the left eye is severely myopic, whatever stimulation it receives is not enough to send synaptic contact to the cerebral cortex. If this is not treated early, the entire visual cortex will be taken over by the good eye so much

so that if later corrective lenses were given, wala nang pupuntahan na visual cortex kasi kinuha na ng right eye yung buong area. (This clinical condition is called AMBLYOPIA)

PLASTICITY o alterations in selective neuronal death, axonal

simplification and retention of transient axonal branches and synapses that would otherwise be lost

o “When someone tells you PLASTIC NA PLASTIC KA, tanungin mo, “alin, yung brain ko?” and if he/she says Yes, reply with a “Thank you very much” for it is a compliment. Pag sinabi niyang hindi ang brain mo, SAMPALIN MO NA. kasi iniinsulto ka.” (Dra Lumitao, 2013)

Synaptic development parallels cellular proliferation and migration; maximal during six months after birth; vulnerable to perinatal hypoxia, malnutrition and environmental toxins

Myelination from six month of life, peaks from birth to first year; continues into adulthood; motor and sensory tracts mature early; affected by leokodystrophies, phenylketonuria and malnutrition

o Myelin is made of lipid. So defect in metabolism of lipid can affect myelination of nerve tracts.

VENTRICULAR SYSTEM

Normally, should be patent so the CSF can circulate

Any abnormality in the Ventricular system is called HYDROCEPHALUS

o Treated by shunting of the flow of the CSF. Otherwise, the trapped CSF will cause pressure in the developing neurons and then atrophy

o OBSTRUCTIVE NON COMMUNICATING HYDROCEPHALUS

When there is atresia of the cerebral aqueduct, the CSF cannot circulate, there will be dilation proximal to the obstruction

Congenital aqueductal stenosis o NON-OBSTRUCTIVE COMMUNICATING

HYDROCEPHALUS No obstruction but there is abnormality in

the transfer of the CSF from the Sub arachnoid to the venous system

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Intro to Neuroscience & Neuroembryology