Nervous System Development

Development of the Nervous System

• The nervous system's development is a complex and regulated process from a simple neural plate.
• The neural plate folds and creates the neural tube, which develops into the brain and spinal cord.
• Gene expression patterns and chemical signals drive early development, guiding cells into neurons, glia, and various brain regions.
• Key steps include neurogenesis (new neurons), migration (neuron movement), and differentiation (neuron/glia specialization).
• Later in development, synaptogenesis (synapse formation), myelination (axon insulation), and pruning (unused connection removal) refine the network.

Neural Induction & Patterning

• Neural Induction & Patterning begins around day 18 of embryonic development.
• The notochord secretes signals, such as Sonic Hedgehog (Shh), inducing the ectoderm to form the neural plate.
• The neural plate folds into the neural tube, giving rise to the central nervous system.
• Dorsoventral patterning specifies motor (ventral) versus sensory (dorsal) regions.
• Rostrocaudal patterning establishes the forebrain, midbrain, and hindbrain.

Neurogenesis and Migration

• Neural progenitor cells divide asymmetrically in the ventricular zone.
• New neurons migrate radially (upward) or tangentially (horizontally), based on their type and destination.
• Migration errors can lead to disorders like lissencephaly or polymicrogyria.

Synaptogenesis, Myelination, and Pruning

• After reaching their final location, neurons grow axons and dendrites, guided by growth cones.
• Synapses form, initially in abundance.
• Postnatal myelination increases conduction speed, which continues into adulthood.
• Pruning removes excess or weak synapses in an activity-dependent manner, to shape efficient neural networks.

Molecular Mechanisms

• Transcription factors such as Pax6, Emx2, and Otx2 control spatial identity.
• Signaling molecules like BMPs, Wnts, FGF, and Shh coordinate regional identity and cell fate.

Neurodevelopmental Timing

• Certain developmental milestones have critical periods.
• Disruption during these periods can result in permanent deficits like vision loss in amblyopia.
• Neural development timing varies; the spinal cord develops before the cortex, and visual areas myelinate earlier than the prefrontal cortex.

Disorders Linked to Development

• Neural tube defects include spina bifida and anencephaly.
• Genetic disorders include Rett syndrome (MECP2 mutation) and Fragile X syndrome.
• Environmental factors such as fetal alcohol syndrome can disrupt migration and synapse formation.

Cellular Organization of the Nervous System

• Neurons and glial cells are the two main cell types in the nervous system.
• Neurons are signaling cells that transmit information electrically and chemically.
• Glial cells support, protect, and nourish neurons.
• Neuron structure has dendrites (input), a soma (integration), and an axon (output).
• Organization differs between the central nervous system (CNS) and the peripheral nervous system (PNS).

Neurons

• Neurons classification depends on shape (e.g., pyramidal, bipolar), function (sensory, motor, interneurons), or neurotransmitter type (e.g., glutamatergic, GABAergic).
• Axons are either myelinated or unmyelinated: myelination increases signal speed.
• Each neuron has a resting membrane potential and communicates using action potentials.

Glial Cells in Detail - Astrocytes (CNS)

• Astrocytes maintain ion balance, the blood-brain barrier (BBB), and neurotransmitter recycling.
• These cells take part in tripartite synapses with neurons and the synaptic cleft.

Glial Cells in Detail - Oligodendrocytes (CNS)

• Create myelin sheaths that insulate multiple axons in the CNS.

Glial Cells in Detail - Schwann Cells (PNS)

• Myelinate only one axon each in the PNS.

Glial Cells in Detail - Microglia (CNS)

• Microglia act as the immune cells of the brain.
• These cells prune synapses during development and respond to injury.

Glial Cells in Detail - Ependymal Cells

• Ependymal cells line ventricles and produce cerebrospinal fluid (CSF).

Support and Integration

• Glia regulate synaptic plasticity, guide axon pathfinding, and support repair after injury, but CNS repair is limited.
• The extracellular matrix supports the brain's organization through structural and chemical means.

Neuron-Glia Interactions

• Astrocytes release gliotransmitters, such as glutamate or ATP, affecting nearby neurons.
• Glia help regulate synaptic strength, acting as co-active players in neural computation.

Cellular Layers and Circuits

• Cortical neurons arrange in six layers with input-output patterns.
• The hippocampus has well-defined laminar organization, including CA1, CA3 pyramidal cells, and dentate gyrus granule cells.
• Inhibitory interneurons (e.g., parvalbumin-positive cells) and excitatory principal neurons are involved in Local circuits.

CNS vs. PNS Differences

• The CNS lacks robust regeneration due to inhibitory molecules and glial scarring.
• The PNS has greater regenerative capacity because of Schwann cell plasticity and a growth-permissive environment.

Neuroanatomy

• Neuroanatomy studies the nervous system's structure and spatial organization.
• The central nervous system (CNS) consists of the brain and spinal cord.
• The peripheral nervous system (PNS) includes cranial/spinal nerves and ganglia.
• Major brain divisions include the forebrain, midbrain, and hindbrain.
• These divisions derive from embryonic vesicles: prosencephalon, mesencephalon, and rhombencephalon.

CNS Regional Breakdown - Cerebral Cortex

• Frontal, parietal, temporal, and occipital lobes divide the cerebral cortex.
• The cerebral cortex is organized into six layers (neocortex).
• Sensation, movement, language, decision-making, and memory are controlled by the cerebral cortex.

CNS Regional Breakdown - Subcortical Structures

• Basal Ganglia: motor planning, reward learning.
• Hippocampus: spatial memory, encoding long-term memories.
• Amygdala: emotional processing.

CNS Regional Breakdown - Thalamus and Hypothalamus

• Thalamus: relay center for sensory/motor information to the cortex.
• Hypothalamus: controls autonomic functions and hormones via the pituitary gland.

CNS Regional Breakdown - Brainstem

• Midbrain: auditory/visual processing and movement.
• Pons: connects the cerebrum and cerebellum.
• Medulla: autonomic control like breathing and heart rate.

CNS Regional Breakdown - Cerebellum

• Coordinates fine motor control, balance, and motor learning.

CNS Regional Breakdown - Spinal Cord

• Spinal cord segments consist of cervical, thoracic, lumbar, and sacral segments.
• The spinal cord transmits information to and from the body/brain.

Functional Pathways

• Sensory (afferent) and motor (efferent) systems are topographically organized.
• Major tracts include the corticospinal tract (motor commands from cortex to spinal cord), spinothalamic tract (pain/temperature from periphery to brain), and dorsal columns (fine touch/proprioception).

Connectivity & Circuitry

• White matter tracts (myelinated axons) connect distant brain regions.
  • Commissural fibers (e.g., corpus callosum) connect hemispheres.
  • Association fibers connect regions within the same hemisphere.
  • Projection fibers link the cortex to the lower brain/spinal cord.
• The limbic system is a network including the hippocampus, amygdala, and cingulate gyrus.
• This system is critical for emotion and memory.

Functional Localization

• Early studies (e.g., Brodmann) mapped the cortex by cytoarchitecture.
• Modern neuroimaging supports functional specialization like the visual cortex in the occipital lobe or Wernicke's and Broca's areas for language.

Ventricular System and CSF

• The brain has four ventricles filled with cerebrospinal fluid (CSF).
• Choroid plexus produces CSF, which flows through the ventricles, around the brain/spinal cord, and is reabsorbed by arachnoid granulations.
• CSF cushions the brain and removes waste.

Blood Supply

• The brain receives blood via internal carotid arteries and vertebral arteries.
• These arteries join to form the Circle of Willis (an important collateral pathway).
• Disruption of blood supply can lead to strokes or transient ischemic attacks.

Neural Communication

• Neurons communicate with electrical signals (action potentials) within a neuron.
• Neurons communicate with chemical signals (neurotransmitters at synapses) between neurons.
• An action potential is a rapid, temporary change in membrane voltage along the axon.
• At the synapse, the electrical signal makes neurotransmitters releases in the synaptic cleft.
• These chemicals bind to receptors which effects the electrical activity on the postsynaptic neuron.

Electrical Signals

• The resting membrane potential is typically around -70 mV which is maintained by Na+/K+ ATPase pump and K+ leak channels.
• Action potential steps:
  • Depolarization: Na+ channels open, and Na+ floods in.
  • Peak: the membrane potential reaches approximately +30 mV.
  • Repolarization: K+ channels open, and K+ exits.
  • Hyperpolarization: the membrane briefly overshoots below resting potential.
  • Return to resting potential via pumps.
• All-or-none principle: the AP always fires the same way once a threshold is reached.
• Myelination enables saltatory conduction where the action potential "jumps" between nodes of Ranvier, which speeds transmission.

Synaptic Transmission

• The presynaptic terminal contains vesicles filled with neurotransmitters
• There are voltage-gated Ca2+ channels: CA2+ influx triggers vesicle fusion with the membrane.
• The Postsynaptic membrane contains:
  • Ionotropic receptors: direct ion channels (fast, e.g. AMPA, NMDA).
  • Metabotropic receptors: second messengers and G-proteins (slow, modulatory).
• Key neurotransmitters:
  • Glutamate (main excitatory)
  • GABA (main inhibitory) - Acetylcholine (motor and cognitive roles) - Dopamine, serotonin, norepinephrine (modulatory)
• Excitatory postsynaptic potential (EPSP) = depolarization
• Inhibitory postsynaptic potential (IPSP) = hyperpolarization

Synaptic Plasticity

• Synapse strength can change which helps with learning and memory.
  • LTP (Long-Term Potentiation): Increase in synaptic strength for periods.
  • LTD (Long-Term Depression): Synpatic decrease in strength for periods.
  • Mechanisms involve Ca2+ mechanisms, AMPA/NMDA receptor trafficking, and second messengers.

Receptor Mechanisms

• AMPA receptors: Na+ influx → fast excitation.
• NMDA receptors require both depolarization and glutamate critical for plasticity (allow Ca2+ in).
• GABA_A: Cl- influx → inhibition.
• GABA_B: metabotropic indirectly opens K+ channels or closes Ca2+ channels.

Neurotransmitter Clearance

• Neurotransmitter removal occurs via reuptake, enzymatic degradation and diffusion .
  • Reuptake: (e.g., serotonin reuptake by SERT)
  • Enzymatic degradation: (e.g., acetylcholine by acetylcholinesterase)
  • Diffusion

Electrical Synapses

• Neurons connect via gap junctions-ions flow directly between cells.
• These synapses are faster, work in both directions, and sync activity. Seen in early development or reflex circuits.

Channelopathies & Synaptic Disorders

• Mutations in ion channels cause channelopathies (e.g., epilepsy, migraine).
• Synaptic issues can cause autism, schizophrenia, and depression.

Sensory Systems

• Sensory systems translate physical stimuli (light, sound, chemicals, pressure) into neural signals by sensory receptors.
• Each has a specialized receptor, dedicated pathways to the brain (labeled lines) and primary sensory cortices for processing.
• Types of sensory systems: Visual (sight), Auditory (hearing), Somatosensory (touch, temperature, pain, proprioception), Olfactory (smell), Gustatory (taste) and Vestibular (balance)

Visual system

• Receptors such as rods (dim light) and cones (color) in the retina
• The signal travels Retina → optic nerve → optic chiasm → lateral geniculate nucleus (LGN) → primary visual cortex (V1)
• There is a Retinotopic organization in V1 that helps with spatial mapping of the visual field.
• The visual system depends on higher order processing in dorsal stream and ventral stream for sensory input.

Auditory System

• Air vibrations get transduced to mechanical signals, then neural signals.
• The signal flows through Outer ear → middle ear → cochlea → auditory nerve → brainstem nuclei → inferior colliculus → MGN → primary auditory cortex
• The location of frequencies is mapped by the cochlea, base= high freq, apex = low freq

Somatosensory System

• Somatosensory includes touch, vibration, temperature, pain, and body position.
• Receptors are found in skin, muscles, and joints.
• The signal flows through Dorsal column–medial lemniscal: fine touch & proprioception or Spinothalamic tract: pain & temperature.
• VPL nucleus of thalamus --> cortex in a somatotopic organization to the primary somatosensory cortex