Neurodevelopment Part I (and a tiny bit of neurophysiology)

Andrew Vosko Assistant Professor, Basic Sciences SCUHS NS Fall 2012

Monoamines--catecholamines
Dopamine D1 (Excitatory) and D2 (Inhibitory) receptors GPCRs Two major areas are from SUBSTANTIA NIGRA and VENTRAL TEGMENTAL AREA (VTA) Substantia nigra is involved with basal ganglia circuit and loss of dopamine here is cause of Parkinsons Disease VTA involved with both addiction and schizophrenia

Monoamines--catecholamines
Norepinephrine Produced in the Locus Ceruleus in the pons All about arousal alertness and attention PNS sympathetic neurotransmitter 2 alpha and 2 beta receptor subtypes Come from DOPA

Dopamine and norepinephrine are both recycled through similar transporters and hydrolyzed by MAO

Other monoamines
Serotonin (5-HT)
Related to depression Raphe nuclei of the brainstem (midbrain) At least 7 different receptor subtypes SSRIs Recycling and degradation also involved MAOIs. This is why for a long time all monoamines were targeted in depression. Now, mix of targets for 5-HT and NE

Other monoamines
Histamine
Predominantly made in the hypothalamus, in the tuberomamillary nucleus Also comes from mast cells in the brain

Related to being conscious

Other neuro-signaling molecules

Neuropeptides
Co-released with other neurotransmitters Packaged in Golgi Complex, Cleaved Slow transport to axon terminal Vesicles not recycled Require higher freq AP More typical to act as neuromodulator Examples are substance p, VIP, CCK, Endorphins

Other neuro-signaling molecules

Adenosine
Another co-released with glutamate Tends to be more sedative Antagonist is caffeine Receptors are GPCRs

Other neuro-signaling molecules

Nitric oxide (NO)
Gaseous neurotransmitter Diffuses quickly across and between cell Implicated in learning and memory Travels in many directions Synthesized immediately before use

Sensory and Motor arms make up different inputs and outputs to the CNS
Sensory
Receptor transduces energy into electrochemical signal Enters through the peripheral nervous system (spinal nerves or cranial nerves) Travels to either/all
Spinal cord Reticular formation Cerebellum Thalamus Cortex

http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/201 2010%20Exam%20Reviews/Exam%204%20Review/reflex%20arc%20diagra -a.bmp

Sensory and Motor arms make up different inputs and outputs to the CNS
Motor
Skeletal Muscles innervated by:
Spinal cord Reticular formation Basal ganglia Cerebellum Motor cortex
http://apbrwww5.apsu.edu/thompsonj/Anatomy%20&%20Physiology/2010/ 2010%20Exam%20Reviews/Exam%204%20Review/reflex%20arc%20diagram -a.bmp

Through spinal and cranial nerves called lower motor neurons

Different levels of CNS function

Spinal cord
Locomotor pattern generation Withdrawal reflex Antigravity reflex Autonomic reflexes

Subcortical brain
Most subconscious activity control

Cortical brain
Make the lower brain and spinal cord execution more precise

Why study neurodevelopment?

An understanding of the development of the nervous system helps make sense of its adult configuration and organization

Better understand congenital malformations

When we are born

Nervous system is already intact 97% of births are without major neurodevelopmental dysfunction 3% probs.
Most of these result in miscarriage

But no 2 nervous systems ever develop the same exact way About half the protein coding genes are also in some way involved in development of the nervous system

Some landmarks
At 10 weeks
Brain and spinal cord formed Can see the brainstem and cerebellum

From 12 to 19 weeks
Lissencephalic brain

At 22 weeks
Gyroencephalic brain

Born relatively precocious

Most neuronal production and migration occurs during the third through fifth months of development
The formation of neural connections (Neuropil) and production of myelin sheaths continue after birth

Critical period of vulnerability is during gliogenesis

Domowicz et al., 2011

It all happened so fast

Totipotent

Pluripotent

Embryonic origins of the human nervous system

Amniotic cavity Epiblast Hypoblast

Yolk sac Before Gastrulation

After Gastrulation - 3 primary germ layers

Gastrulation Is.
Transformation from bilayered to trilayered embryo Produces 3 primary germ layers
Ectoderm - gives rise to nervous system and skin
Mesoderm - gives rise to skeleton and musculature
**and also the notochord**

Endoderm - gives rise to the gut tube (pancreas, liver, spleen, lining of the stomach and intestines)

Next step - neural induction What structures are important?

After neural induction

After gastrulation

 Neurulation involves:
1) Formation of a neural plate 2) Neural plate becomes neural groove surrounded by crests 3) Groove becomes closed tube in highly ordered fashion

Neural Induction
Neural plate

Undifferentiated ectoderm

?
Notochord

Neural Induction
Neural plate

Undifferentiated ectoderm

?
Notochord

Neural crest fate

Neural crest forms the majority of the peripheral nervous system
Autonomic Ganglia Spinal nerves Schwann cells Melanocytes Adrenal medullary cells Pia Arachnoid Facial musculature

Spina Bifida

Anencephaly

http://www.cdc.gov/ncbddd/birthdefects/images/anencephaly-web_small.jpg

 3 Bulges = primary vesicles

Cervical flexure bet. Rhombencephalon and spinal cord Cephalic flexure bet. Mesencephalon and prosencephalon

2 more bulges = 5 secondary vesicles

Rhombencephalon sep. to myelencephalon and metencephalon at level of pontine flexure Prosencephalon sep. to diencephalon and telencephalon

Rostro-caudal development

 Lumen of neural tube becomes ventricular system Choroid plexus is vascular tissue entering
Makes CSF Not in aqueduct nor spinal cord

Future Basal Ganglia

Lamina Terminalis (Future corpus callosum and anterior commissure)

Shaped growth around the insula

 Shaped growth rotates structures beneath neocortex

Corpus callosum Basal ganglia Hippocampus Choroid plexus/ventricular system

Patterning on another axis

Sulcus limitans

Two signaling systems pattern the dorsoventral axis

Sonic hedgehog (Shh) = secreted signaling molecule; initially expressed in the notochord (N) Bone morphogenetic proteins (BMPs) = secreted signaling proteins with a variety of functions; expressed in ectoderm (ECT) S = somite (mesoderm)

Two signaling systems pattern the dorsoventral axis

Shh = ventral; expressed in notochord and floorplate (F) BMPs = dorsal; expressed in epidermis

Two signaling systems pattern the dorsoventral axis

Shh = ventral; expressed in notochord and floorplate BMPs = dorsal; expressed roofplate (R) Neural crest (NC) delaminates at this stage

Two signaling systems pattern the dorsoventral axis

Shh = ventral; expressed in notochord and floorplate BMPs = dorsal; expressed roofplate (R) Dorsal commissural neurons (C) and ventral motor neurons (MN) develop