Synapses and Networks

Flow of Information

• Input Zone: Neurons collect and integrate information from the environment or other cells (dendrites, cell body).
• Integration Zone: Decision to produce a neural signal is made.
• Conduction Zone: Information is transmitted over great distances (axon).
• Output Zone: Neuron transfers information to other cells (axon terminals).
• Action Potential Recap
  • Membrane potential changes over time (ms).
  • Phases: Rising, falling, overshoot, undershoot.
  • Key values: Resting potential, voltage threshold.

Overview of Synapses and Networks

• Types of synapses.
• Signal transmission in the synapse.
  • Neurotransmitters.
  • Receptors.
  • Excitatory or inhibitory signals.
• Networks.
  • Spatial and temporal summation.

Historical Context

• Camillo Golgi (1843-1926):
  • Developed histological silver stainings of neurons using potassium chromate and silver nitrate solution.
• Santiago Ramón y Cajal (1853-1934):
  • Considered the 'father of neuroscience'.
  • A brilliant neuroanatomist and artist who drew microscopic brain structures.
• Nobel Prize: Golgi and Cajal shared the Nobel Prize in Medicine and Physiology in 1906.
• Neuron Doctrine:
  1. Brains are composed of separate neurons and other cells.
  2. Cells are independent.
  3. Neurons are polarized cells.
  4. Information is transmitted from cell to cell across tiny gaps.

Synaptic Transmission

• Signals are transmitted from a presynaptic cell to a postsynaptic cell at a synapse.
• Components:
  • Presynaptic cell (axon).
  • Postsynaptic cell (dendrites, nucleus, cell body).
  • Synapses.
• Signal direction: From axon of presynaptic neuron to dendrites/cell body of postsynaptic neuron or to a muscle

Types of Synapses

• Axo-dendritic: Axon to dendrite (frequently found).
• Axo-somatic: Axon to soma (frequently found).
• Axo-axonic: Axon to axon (frequently found).
• Dendro-dendritic: Dendrite to dendrite (rare).

Chemical vs. Electrical Synapses

• Chemical Synapses (common):
  • Involve a synaptic cleft.
  • Presynaptic terminal releases neurotransmitters.
  • Postsynaptic neuron has receptors.
  • Glial cells are often nearby.
• Electrical Synapses (rare):
  • Involve connexons, which are composed of six connexin subunits.
  • Connexons of two membranes associate to form a complete channel.
  • Pore connects the cytoplasm of two neurons.
  • Gap of ~3.5 nm between membranes, and the channel is ~20 nm.

Visualizing Axonal Inputs

• 3D reconstruction using stacks of serial EM images.
• Electron microscopy used to visualize and study axonal inputs onto a small segment of an apical dendrite.

Information Coding

• Information is coded through the interaction of neurons.
• Action potentials (spikes): Depolarization events.
• Single neuron's function: Transmit or not transmit a neuronal signal.

Signal Transformation

• Presynaptic Neuron:
  • Depolarization of the axonal terminal membrane opens $Ca^{2+}$ channels.
  • $Ca^{2+}$ ions enter the terminal.
• Increase in $Ca^{2+}$ concentration:
  • Stimulates the release of neurotransmitter stored in vesicles.
  • Vesicles fuse with the presynaptic membrane.
  • Neurotransmitter diffuses into the synaptic cleft.
• Postsynaptic Neuron:
  • Ionotropic receptors are embedded in the membrane of the dendrite or soma.

Ionotropic Receptors

• Ligand-gated ion channels (fast).
• Mechanism:
  1. Neurotransmitter binds directly to the channel protein.
  2. Channel opens immediately.
  3. Ions flow across the membrane for a brief time.

Metabotropic Receptors

• Neurotransmitter interacts with metabotropic receptors.
• Mechanism:
  1. Action potential arrives in the axon terminal, opening $Ca^{2+}$ channels.
  2. $Ca^{2+}$ triggers vesicle fusion and transmitter release.
  3. Neurotransmitter can bind to metabotropic G protein-coupled receptors (GPCRs) that activate G proteins.

Details on Metabotropic Receptors

• Coupled to a G protein (guanine nucleotide-binding protein), consisting of three subunits (also known as G protein-coupled receptors, GPCRs).
• Slower than ionotropic receptors.
• Control ion channels indirectly (from the inside).
• Control different enzymes within the cell using second messenger molecules.

Mechanism of Metabotropic Receptor Action

1. Neurotransmitter binds G protein-coupled receptor.
2. G protein activated.
3. Activated G protein subunit moves to an adjacent ion channel, causing a brief delay.
4. Channel opens, ions flow across membrane for a longer period of time.

Synaptic Components

• Postsynaptic:
  • Ionotropic receptor.
  • Metabotropic receptor.
• Presynaptic:
  • Reuptake transporter.
  • Autoreceptor.
  • Hetero-receptor.
• Synapse:
  • Enzymes (for degradation).

Synapse Overview

1. Action potential propagates over the presynaptic membrane.
2. Depolarization of the presynaptic terminal leads to influx of $Ca^{2+}$.
3. $Ca^{2+}$ promotes exocytosis, the fusion of vesicles with the presynaptic membrane, which releases transmitter into the cleft.
4. Binding of transmitter to receptor molecules in the postsynaptic membrane opens channels, permitting ion flow and initiating an excitatory or inhibitory postsynaptic potential (EPSP or IPSP).
5. EPSPs or IPSPs spread passively over dendrites and the cell body to the axon hillock.
6. Other processes:
   • Enzymes and precursors for synthesis of transmitter and vesicle wall are continually transported to the axon terminals.
   • Transmitter binds to autoreceptors in the presynaptic membrane.
   • Enzyme present in the extracellular space breaks down excess transmitter.
   • Reuptake of transmitter slows synaptic action and recycles transmitter for subsequent transmission.

Neural Integration

• A neuron can collect information from few to hundreds of other neurons.
• When and which signal is picked up by a neuron depends on:
  1. Type of synapse and associated neurotransmitter (excitatory or inhibitory synapse).
  2. Number of synapses and spatial position on the dendrites/soma of the input zone.
  3. Duration and synchrony of neurotransmitter release from different synapses.
• Each neuron forms many synapses.

Neurotransmitter Types

• Type of neurotransmitter and receptor defines whether a postsynaptic potential is excitatory or inhibitory.
• Typical transmitters at excitatory synapses: Glutamate, aspartate, nicotinic acetylcholine (nACh), muscarinic Ach (slow EPSPs).
• At inhibitory synapses: GABA, glycine, muscarinic acetylcholine.

Postsynaptic Potentials

• The neurotransmitter and receptors can either cause a depolarization (EPSP) or hyperpolarization (IPSP) at the postsynaptic membrane.
• Excitatory synapse (+).
• Inhibitory synapse (-).

Temporal Summation

• If the neurotransmitter is released for a longer time into the synaptic cleft, then the postsynaptic potential is stronger.

Spatial Summation

• If postsynaptic potentials arrive together in the integration zone, they are summed up.
• Two excitatory synapses (+).
• Two inhibitory synapses (-).

Action Potential Generation

• If the membrane at the integration zone is depolarized above threshold, an action potential will be generated.
• The more excitatory input arrives, the stronger the output signal.

Integration Zone Processing

• EPSPs and IPSPs that arrive at the same time or within a small time window are summed up.
• The more inhibitory input arrives, the weaker the output signal, and the neuron may even not transmit any output signal.

Neural Decision Making

• Excitatory inputs: Cause the cell to fire if the threshold is reached.
• Inhibition: Counteracts excitation, preventing an action potential.
• Integration: The cell integrates excitation and inhibition; additional excitation can overcome inhibition, triggering an action potential.

Neural Networks

• How is information coded in neural networks?
• Spatial and temporal summation at the synapses determines how the signal travels through a network.
• The connectivity of the network (connectome) determines when or where a signal travels faster or slower, is amplified or reduced, or muted.

Network Properties

• .Divergence: Neuron broadcasts to many others.
• Convergence: Neuron listens to many others, has high sensitivity and/or can be a gatekeeper or decision-maker.

Feedback Loops

• Feedback loops (positive, negative) provide direct or indirect input influencing signals and thus information.
• Signal can be amplified soon after reaching the network (positive loop, excitatory feedback synapse) or reduced (negative loop, inhibitory feedback synapse).
• Delay between arrival and feedback amplification or reduction.

Artificial Neural Networks

• Artificial networks for solving AI (artificial intelligence) problems (e.g., navigation, object recognition in images, speech recognition) may not require reference to cognitive mechanisms or neurobiological circuits.
• Do not aim to explain the details of how the brain works.
• Deep Neural Networks (DNNs) have been shown to predict experimental outcomes (e.g., human perceptual similarity judgments, neural activity in primate sensory cortices).

Neural Network Development

• 5-day time-lapse of rat hippocampal neurons showing development of networks and interconnections.
• Contrast enhanced to highlight neurites.

Neuron Types

• Multipolar neuron
  • Input zone: Dendrites and cell body.Integration zone: Cell body.Conduction zone: Axon.Output zone: Axon terminals.
• Bipolar neuron
  • Input zone: Dendritic branches.Integration zone: Cell body.Conduction zone: Axon.Output zone: Axon terminals.
• Unipolar neuron
  • Input zone: DendritesIntegration zone: .Conduction zone: Axon.Output zone: Axon terminals.

Neurons and Neuroglial Cells

• Cultured mouse hippocampal neurons (green) and astrocytes (red).
• Various cell types: Neuron, microglia, oligodendrocytes, astrocytes.
• Myelin sheath covers axon.
• Synapse between neurons.

Signal Transmission Distance

• Spiking neuron: Transmits neural signals over short and large distances.
• Non-spiking neuron: doesn't propagates signal over large distance.

Conduction Velocity

• Conduction velocity increases with increase of diameter and with myelination of axons.
• Myelinated neurons with thin axons can reach similar conduction velocities as those with unmyelinated thick axons.
• Conduction velocity is on log scale.

Key Synapse Points

• Location: Axo-dendritic; Axo-somatic; Axo-axonic; Dendritic-dendritic
• Types: Chemical (common) and Electric (rare) Synapses
• Chemical Synaptic Transmission:
  • Action potential in presynaptic neuron
  • Opening of calcium voltage-gated channels
  • Fusion of neurotransmitter vesicle with membrane
  • Release of neurotransmitters into the synapse
  • Neurotransmitters connect to postsynaptic receptors
    • Ionotropic or Metabotropic
  • Excitatory or Inhibitory Postsynaptic potential (EPSP/IPSP) spreads through dendrites.
  • Temporal/Spatial summation creates an action potential
  • Other processes in the synapse:
    • Reuptake transporter back to presynaptic neuron
    • Auto-receptor and hetero-receptor for the regulations of the presynaptic neuron
    • Enzymes for the degradation of neurotransmitters in the synapse