Notes

Why is this Topic important?

• Biological plasticity might provide a different angle to understand the training procedures in DNNs.
• Given the effectiveness of human brain learning bio-plasticity might provide inspiration/new ideas for improved DNN training algorithms.
• Understanding biological plasticity might help to better understand how (hierarchical) learning is organized in the brain (Learning&Memory).
• Many neural disorders such as dementia relate to a disturbance in neuronal plasticity that cause neuronal networks to become dysfunctional.

Content of the Lecture

• Why Do We Need Plasticity?
• Synaptic Plasticity
  • Time Scales of Synaptic Plasticity (Short Term, LTP/LTD).
  • Homeostatic Plasticity.
  • Hebb's Idea and STDP.
  • Heterosynaptic Plasticity.
• The Hippocampus as a Model System to Study Neural Plasticity
  • LTP and LTD Induction in the Hippocampus.
  • Molecular Basis of Synaptic Plasticity.
• Non-Synaptic Plasticity
  • Neuronal Excitability and Spike Generation.
  • Axonal Modulation (Shunting, Frequency Filtering).
  • Alterations of Dendritic Excitability.

Synaptic Plasticity

Defining Learning, Memory and Plasticity

• Plasticity, it allows the acquisition of knowledge/information and the formation of a memory through experience.
• Memory, it is a storage of information that can be recalled at a later stage in time.
• Note, learning results in memory - which has a further outcome - it can change future behavior.

Time - Scales of Synaptic Plasticity

Synaptic Plasticity - A Short Recap of Synaptic Function In the presence of a presynaptic action potential, Calcium channels open allowing an increase of calcium, such that glutamate in vesicles fuses with the synapses and crosses them. Then AMPA are activated and neurotransmitters attach to the receptors. EPSP happens.

Amplitude increases with the number of receiving AMPA channels, hence with LTP the amplitude of EPSP increases due to an increase of neurotransmitters released and received.

Synaptic Plasticity Alters the Intern-Neuron Connection Strength

1. Synaptic Density Size Changes (short term).
2. AMPA/NMDA ratio changes (short term).
3. Number of spines changes (long term).

Note that NMDA stays constant!

Timescales of Neuronal Plasticity

Homeostatic Plasticity, Hebb's Idea & STDP

Necessity of Homeostatic Plasticity Homeostatic plasticity is a mechanism that ensures that the activity of neurons among levels remains constant. It is the process by which the brain adjusts the strength of its synapses to maintain a consistent level of activity. This process helps to balance the overall activity of the brain and maintain a stable internal environment. For example, LTP may occur in response to a particularly strong or meaningful stimulus, resulting in an increase in synapse strength. This increase in strength may be necessary for the formation of a new memory. However, if the increased strength of the synapses were to persist indefinitely, it could lead to an imbalance in activity in the brain. Homeostatic plasticity can help to restore balance by adjusting the strength of other synapses in response to the LTP-induced increase. In this way, LTP and homeostatic plasticity can work together to support the formation of long-term memories while also maintaining the overall stability of the brain.

Papers: "Homeostatic Plasticity in the Developing Nervous System" & "Homeostatic Synaptic Plasticity: Local and Global Mechanism for Stabilizing Neuronal Function".

Homeostatic & Hebbian Plasticity From The Organization of Behavior by Donald Hebb, 1949. "When an axon of cell A is near enough to excite cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased".

Hebb postulated that this behavior of synapses in neuronal networks would permit the networks to store memories. A Hebbian Synapse is a "coincidence detector".

The first real demonstration of this paradigm can be found in STDP.

Examples of Hebbian Learning - Spike Timing Dependent Plasticity (STDP) STDP represents a form of neural plasticity, it refers to the process by which the strength of a synapse is modified based on the timing of action potentials in the neurons. According to the STDP rule, if an action potential in one neuron (the presynaptic neuron) occurs shortly before an action potential in a second neuron (the postsynaptic neuron), the synapse between the two neurons becomes stronger. On the other hand, if the action potential in the presynaptic neuron occurs after the action potential in the postsynaptic neuron, the synapse becomes weaker.

Papers: "Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type" & "Gain in Sensitivity and Loss in Temporal Contrast of STDP by Dopaminergic Modulation at Hippocampal Synapses".

Hebb's Idea How Neurons Can Learn Associations

Hebbian LTD and LTP are Input Specific

1. Cooperativity (induction threshold).
2. Input/Synapse Specificity.
3. Enables Associative Learning.

The weight update is a function H that evaluates time pre and post.

Papers: "Neural Ensemble Dynamics Underlying a Long-Term Associative Memory" & "The Ups and Downs of Hebb Synapses" & "Neuromodulated Spike-Timing-Dependent Plasticity, and Theory of Three-Factor Learning Rules".

What is Geoffrey Hinton's Problem with Hebbian Learning?

One Solution: Three Factor Hebbian Learning Rules The three-factor Hebbian learning rule adds two additional factors to the original Hebbian learning rule:

• Coincidence: the strength of a synapse is only modified if the activity of the two neurons is correlated in time.
• Repetition: the more often the activity of the two neurons is correlated, the greater the effect on the strength of the synapse.
• Intensity: the stronger the activity of the two neurons, the greater the effect on the strength of the synapse.

According to the three-factor Hebbian learning rule, the strength of a synapse is increased when the activity of the two neurons is correlated in time, is repeated, and is strong. Conversely, the strength of a synapse is decreased when the activity of the two neurons is not correlated in time, is not repeated, or is weak.

Heterosynaptic Plasticity

Non-Hebbian Plasticity - Heterosynaptic Plasticity Heterosynaptic Plasticity refers to the process by which the strength of one synapse is modified in response to activity at a different synapse.

Papers: "Is Heterosynaptic Modulation Essential for Stabilizing Hebbian Plasticity and Memory" & "Heterosynaptic Plasticity Underlies Aversive Olfactory Learning in Drosophila".

Homosynaptic vs Heterosynaptic Plasticity There are two broad categories of synaptic plasticity, generally referred to as homosynaptic and heterosynaptic plasticity.

• Homosynaptic plasticity is what we have been discussing with the Hebbian synapses: a synapse-specific strengthening (facilitation) or weakening (depression) based on the activity of pre- and post-synaptic neurons. In fact, the three characteristics: homosynaptic plasticity, associativity and input specificity form the modern definition of the Hebbian synapse.
• Heterosynaptic plasticity refers to synaptic weight adaptation (facilitation or depression) based on the firing of a third modulatory interneuron. It is therefore referred to as non-hebbian plasticity.

In the previous figure: homosynaptic and heterosynaptic mechanisms for long-term plasticity. a) The plastic changes that underlie long-term memory follow a homosynaptic rule, i.e., the events responsible for triggering synaptic strengthening occur at the same synapse as is being strengthened. These changes can result in an increase in synaptic strength or a decrease. b) Synaptic strengthening between a presynaptic and a postsynaptic cell can occur as a result of the firing of a third neuron, a modulatory interneuron, whose terminals end on and regulate the strength of the specific synapse. These changes can result in an increase or in a decrease in synaptic strength.

The Hippocampus as a Model System to Study Neural Plasticity

The Hippocampus as Model System to Study Plasticity Hippocampus is a model system of learning and memory. The role of Hippocampus in learning and memory has been shown with rat experiments with the Morris Water Maze (MWM). MWM is a large pool of opaque water where the rates are placed. The rats were trained to find and escape onto a platform which was hidden. Authors show that chronic infusion of an NMDA antagonist leads to impairment in place learning.

Neural Plasticity in the Hippocampus Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophos-phonovaleric acid (AP5) does not affect synaptic transmission in the hippocampus, but prevents the LTP following brief high-frequency stimulation.

Non-Hebbian Plasticity - Towards the Behavior Timescale Hippocampus neurons learn spatial representations.

Paper: "Behavioral time scale synaptic plasticity underlies CA1 place fields".

LTP and LTD Induction in the Hippocampus

Most Studied Synapse in Hippocampus: CA3 CA1

The main pyramidal cell layers in Hippocampus are the CA1-4 regions (principally CA1 and CA3) and the dentate gyrus. The Schaffer Collateral / Associational Commissural Pathway is derived from axons that project from the CA3 region of the hippocampus to the CA1 region. The axons either come from neurons in the same hippocampus (ipsilateral) or from the other hippocampus (contralateral). These latter fibers are termed commissural fibers, as they cross from one hemisphere of the brain to the other. This pathway is utilized very extensively to study NMDA receptor-dependent LTP and LTD.

To test plasticity in the hippocampus the CA3 to CA1 pathway was modulated and the EPSP in the CA1 was measured, this tells you the activity of the pathway. If the spiked generated overlap it leads to increased spiking strength as there is Residual Ca2+ in the cell. Short-term depression at about 40ms time frame can be observed if the CA3 to CA1 pathway is stimulated at 50hz it leads to a reduction in the EPSP which is dependent on the frequency of activation. LTP is measured in the hippocampus. The CA3 pathway is given a fast stimulus of (range 50 -- 200 hz) 100 hz known as tetanus. This leads to a stronger post tetanic potentiation caused by the accumulation of Ca in the terminals as well as LTP in the long-term. If the cells are stimulated at a lower time frequency 1-10 hz LTD will occur. (Estimated through in-vitro recordings).

Molecular Basis of Synaptic Plasticity

Short-Term Synaptic Facilitation/Depression

Once again, there are two types of short-term plasticity (STD): Short-Term Depression (STD) and Short-Term Facilitation (STF).

• STD is caused by depletion of neurotransmitters consumed during the synaptic signaling process at the axon terminal of a pre-synaptic neuron.
• STF is caused by influx of calcium into the axon terminal after spike generation, which increases the release probability of neurotransmitters.
• STP has been found in various cortical regions and exhibits great diversity in properties.
• Synapses in different cortical areas can have varied forms of plasticity, being either STD-dominated, STF-dominated, or showing a mixture of both forms.

Synaptic Plasticity Strongly Depends on Calcium Levels

1. Level and timing of Ca2+ rise in spine determines LTD or LTP.
2. Low frequency synaptic firing (approx. 5 Hz) produces LTD, high-frequency synaptic firing (approx. 50 to 100 Hz) produces LTP.
3. The same Ca2+ rules may underlie "spike-timing-dependent synaptic plasticity" (STDP).

Intracellular Plasticity Signaling Pathways LTP and LTD are dependent on CREB which controls the level of AMPA receptors in the cell. The level of AMPA receptors will determine how depolarized or hyperpolarized the cell becomes.

• What controls LTP and LTD:
  • CREB is controlled by many pathways that are dependent on Ca ions or directly by dopamine.
  • Ca ion levels can increase as it enters into the cell from the external environment or released from internal stores.
• How Ca levels change:
  • AMPA channel, when glutamate binds it causes depolarization opening voltage gated Ca channels as well as NMDA channels that further depolarize the cells. Dopamine D2 when binds in leads to Ca2+ increase from the ER, which leads to increased Ca.
• How Ca leads to CREB:
  • Positive: High levels of Ca activated Camkinse 1 and 2 that leads to increased CREB and thus AMPA receptors. Dopamine activated internal cell machinery that leads to increased phosphorylation (activation) of CREB these both pathways are known as the LTP pathways.
  • Negative: Low levels of Ca lead to Camkinse 2 and Calmodulin that reduces the phosphorylation (activation) of CREB thus AMPA receptors.

Non-Synaptic Plasticity

Other Forms of Non-Synaptic (Intrinsic) Plasticity

• Researchers have artificially raised the Neuronal excitability below threshold. It leads to a greater number of firings.
• Researchers can modulate the axons with glutamate puffs and this will affect the action potential traveling along the axon.
• Researchers can modulate dendritic excitability. If the volume is smaller, the EPSP will be summed up leading to AP, the synapse location will also modulate the excitability nearer the soma will be higher as there isn't a loss of charge.