The Far Corner Cafe: January 2022

We humans like to think of ourselves as self-aware but we really aren’t. Even people who accept a deterministic model of mind don’t usually consider how our existing laws, freedoms, and customs are anachronistic since all are predicated on a notion of free will that is well past its sell by date. This is one of the reasons we are vexed as to how otherwise ‘intelligent’ people can end up believing some really stupid shit. All this free will nonsense hampers our ability to reconsider some of our most cherished beliefs, and our attitudes toward the future role and regulation of information technology and media in our society.

If you want to take the first step in understanding our brains you have to set aside a classic analogy. A computer, with separate hardware and associated software is not really analogous to the human central nervous system (CNS). Changes to the CNS don’t come about from loading new software onto an existing hardware matrix. There is no clear distinction between hardware and software. In the CNS it’s the hardware itself that is plastic or subject to modification. We create, store and modify memory very differently from computers.

Neurophysiology is some pretty heady stuff, so don't think for a second that what follows is anything but a toe in the water. All it is is a simplified view of some of the processes involved in creating memory in the brain. (How it’s actually stored in the brain is another gray matter.) Some important actors have been omitted for clarity and certainly not all of the pathways involved are represented. This isn’t a textbook on neuroscience.

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For simplicity consider the basic unit of memory in the central nervous system (CNS) as a neuron, associated glial cells and a capillary blood supply. At the center is the neuron with its forest of dendrites able to receive inputs from a host of other neurons via connections to their axons. An individual neuron in the CNS may have hundreds (or even a thousand) of input connections to its dendrites or cell body (soma) from other neurons as well as additional ones from nearby astrocytes.

All the credit usually goes to the neurons but the family of glial cells (only 2 of which are illustrated here) that support them do far more than just service the metabolic needs of neurons. Oligodendrocytes (it's Schwann cells in the peripheral nervous system) provide the axon’s insulating myelin sheath that’s so important to the efficient and targeted propagation of an axon’s electrical impulses Astrocytes pass nutrients to the neuron, provide the ‘blood brain barrier’ that determines what elements in the blood can even reach the neurons, police synaptic clefts of expended neurotransmitters, restore the proper ionic state between firings, and modulate the delivery of the long-ranged transmitters (hormones) to the neurons.

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Neurons respond to both local and global stimuli from an array of cells that are networked to them. Local stimuli generally come in the form of direct, very short ranged, neurotransmitter-mediated interactions across a synapse involving a particular axon on the communicating neuron communicating with a particular dendrite on the target neuron. Long distance or hormonal communication appears to be mediated via the astrocytes. The action of hormones released by the endocrine system have more general effects on populations of neurons and appears to be one of the ways that emotion can influence brain function and plasticity.

Keep in mind that as busy as that last image may appear it only represents 0.05 to 0.07% of the average number of connections that a real neurons has. Neurons are often thought of as simple binary switches. While it’s true that neuronal stimulation either results in no activation or propagation of an impulse though an electrical action potential along the neuron’s axon, each neuron is subject to an astonishing number of input patterns that define and control that binary behavior.

It’s well worth repeating: individual neurons may only behave in an all or none fashion, but each neuron is influenced by hundreds of other neurons and a population of glia through its dendrite and astrocyte connections. Each one of those connections influences the circumstances that govern impulse propagation. It may be deterministic chemistry but the sheer number of combinations of positive and negative influences that determine whether that little switch closes or not is vast.

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And it's even more complex than that because impulses large enough to trigger the neuron to fire may promote the firing of the target neuron or, conversely, suppress it (+/-). Some combination of these factors determines whether the neuron just sits there, fires and transmits a short duration impulse, or whether additional plastic changes occur that affect future impulse propagation.

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So what are some of the things happening within those synaptic connections between neurons? Below is a rendition of an excitatory synapse in the CNS with some of its critical components displayed in their ‘resting state’ Resting state is a misnomer since a great deal of energy is required to maintain the baseline charge gradient of these cells against diffusion. Separated by the synaptic cleft, the axon is the input to the synapse and the dendrite is the receiver and output. As mentioned earlier, Astrocytes provide critical support to this process but are omitted for simplicity.

There's a lot going on down here. In this example the axon terminus contains vacuoles filled with glutamate (glutamic acid or Glu). Glutamate is the most common neurotransmitter in the CNS. The synaptic cleft is actively maintained with a resting excess of sodium (Na+) and Calcium (Ca++) ions relative to the interior of the cells.

Embedded into the cell membrane of the dendrite are a number of protein complexes that span its lipid bilayer. Among these are AMPA (Alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) both of which are ionotropic receptors for glutamate (Glu). An ionotropic receptor is one that selectively admits ions to the cytoplasm of the cell when activated (in this case by Glu). Though not shown here, there are also metabotropic receptors that bind with neurotransmitter. Metabotropic receptors are those that activate intracellular second messenger cascades within the cell. Huh? When the transmitter binds to the external portion of the metabotropic complex, it causes a conformational change in the portion of the complex that extends into the cytoplasm. Once this happens this usually results in a configuration of the protein that allows it to catalyzes some important reaction to create an intercellular messenger that communicates with structures within the cytoplasm. The most famous metabotropic complex is the one associated with adenyl cyclase (the Western Union of eukaryotic cells). This metabotropic complex catalyses a reaction that converts ATP into the ubiquitous intracellular messenger, cyclic AMP (which will play a roll in the discussion of the late phase of LTP).

To rehash, ionotropic receptors allow ions to pass into the cell, while metabotropic receptors switch on some intracellular machinery. You should also note in this diagram that not all of the AMPA receptors are located within the synapse. This will be of some importance after a bit.

This is pretty much the state of things until an action potential makes its way to the synapse as a wave of membrane depolarization moves toward the terminus of the axon.

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Once the terminus deploraizes, the vacuoles containing Glutamate (Glu) bind with the cell membrane and discharge Glu into the synaptic cleft (space between axon end terminus and the dendrite). Glutamate binds to AMPA which opens these ion channels to the cytoplasm allowing Sodium ions (Na+) to rush into the cell. This changes the electrical potential of the dendritic cell membrane.

The ionic changes caused by all this may not be enough to stimulate an action potential in the target dendrite. Or it may be sufficient to stimulate the target neuron and trigger propagation of the impulse through the dendrite. Even if it is strong enough to trigger a response that alone doesn't cause any permanent changes to the synapse.

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But what if repeated stimuli arrive with such frequency that the synaptic machinery doesn’t have time to return to baseline? Things get more interesting. There are a number of mechanisms that can result in permanent changes (neuro-plasticity) to neurons and the brain but here we're only covering synaptic or activity-oriented plastic changes. The first of these plastic changes is called early phase long-term potentiation (e-LTP).

e-LTP is a plastic process independent of protein synthesis that can result in increased sensitivity across an individual synapse for hours, weeks, or even months. How does it work?

The electrical charge changes are sufficient to dislodge magnesium ions (Mg++) that normally block the ion channels of NMDA.
Glutamate binds to NMDA and Calcium ions (Ca++) enter the cell.
Surplus Glu binds to those metabotropic receptors in the synapse to activate second messengers in the cytoplasm. (not shown)
Calcium ions in conjunction with the second messengers activate a number of intracellular cascades including Protein Kinase (PKC) and Calmodulin kinase II (CaMKII).

The activated PKC/CaMKII complex does a couple of things. First, it phosphorylates AMDA receptors which dramatically improves each molecule's ability to transmit Sodium ions to the cytoplasm. This change can persist for some time even if no other changes occur. The enhanced ion channels are far more sensitive to future stimulation and may even promote neuron depolarization at signal frequencies that previously would have been below the threshold for response.

The second effect is that AMPA receptors outside of the synapse are drawn into it. The result is more available receptors without the need for additional protein synthesis further strengthening the synapse's responsiveness to future stimulation.

To rehash because this is important stuff, axonal action potentials of a sufficient frequency (as in number of depolarizations in a given time interval) trigger plastic effects on the target dendrite in addition to the usual depolarizations associated with nerve conduction. Glutamate released by the axon acts across the synaptic cleft to activate ionotropic receptors (AMPA) in the dendrite cell membrane that cause Sodium ions (Na+) to enter the cell and alter its baseline polarity which may trigger an action potential in the target cell. In addition, the repetitive stimulation prevents the dendrite’s potential from returning to baseline before the next stimulation, resulting in a stacking of charges until a critical threshold is exceeded. Once this threshold is exceeded, changes in the dendrite membrane and glutamate binding to NMDA receptors flushes magnesium ions (Mg++) out of the receptors allowing Calcium ions (Ca++) to enter the cell. The Calcium activates PKC and Calmodulin kinase (CaMKII) to phosphorylate the AMPA receptors making them more efficient at sodium transport. This lowers the threshold of the cell to future stimulation. Additional AMPA receptors already bound to the dendrite’s cell membrane are recruited into the synaptic cleft, completing the early (independent of protein synthesis) phase of Long Term Potentiation (e-LTP). Clear as mud, right?

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While all this is taking place across one synapse that's only one little part of the neuron.

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There can also be plastic changes that do involve protein sysnthesis called late phase Long Term Potentiation (L-LTP). (Note that not every intermediary in the process will be illustrated.) Metabotrophic (second messenger) receptors were briefly mentioned in the last installment but are more significant to L-LTP.

Glutamate reversibly binds with the metabotrophic complex (the red bits) which ultimately activate Adenyl cyclase (AC). AC converts ATP from mitochondria into the cytoplasmic second messenger Cyclic AMP (cAMP).

cAMP in combination with a Protein Kinase (PKA) transmits this message to the nucleus of the stimulated neuron. This is but one of a number of cascades available to the cell, including Calmodulin Kinase, growth factors, other neurotransmitters and even cytokines from stress events, that converge within the nucleus to phosphorylate cAMP Response Element-Binding proteins (CREB).

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Phosphorylated CREB binds to specific DNA segments in the promotor regions of genes, which can be transcribed into mRNA strands relevant to the translation of the peptide subunits of additional receptors like NMDA. These promotor regions where CREB binds are called cAMP Response Elements (CRE). Bound CREB, in combination with several other proteins, unfolds a segment of DNA and allows RNA Polymerase II to transcribe the relevant mRNA strands.

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From the nucleus the mRNA is transported to the endoplasmic reticulum (ER) where protein synthesis generally takes place. ER is one of a number of amazing organelles located within eukaryotic cells. It can be argued that the leap from prokaryote to eukaryote was a far larger change in complexity than the evolution of mammals such as ourselves from single-celled eukaryotes. All of our cells are specialized variations on the basic plan of a eukaryote.

Within the ER, transcribed mRNA copies are translated into new receptor proteins through the interactions of Ribosomes, mRNA, and tRNA-bound amino acids. Technically, the subunit peptides of the proteins get produced in the ER and then are assembled in their final form in the Golgi Apparatus (left off of the diagrams which are complex enough already). There is some controversy regarding whether the new receptors are created within the affected dendrite or in the soma, but an observed property of LTP suggest that it is the soma.

It is said that this process exhibits high selectivity: these newly minted receptors are then transported (usually via microtubules) to the synaptic membranes of the specific dendrite that triggered this cascade, not any others. The plastic change is limited to the dendrite that was subjected to high frequency stimulation. This dendrite receives an added boost in its responsiveness (in addition to e-LTP changes) to future stimuli through the addition of new receptors generated through protein synthesis.

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Things get more complicated if another dendrite is being stimulated at the same time - even if the stimulus is, in and of itself, insufficient to trigger depolarization (say your QAnon feed is active or you're watching Fox News...) . In this case, additional receptors migrate to the other synapse in addition to the primary one that triggered L-LTP

That's LTP in a nutshell. LTP results in enhanced receptor response to future stimuli and more receptors. LTP appears to be a key component of the neuroplastic changes that result in the creation of new memories. But as you might expect, there is a lot more to it...

Conversely, Long Term Depression (LTD) is a neuro-plastic phenomenon that involves a series of events that result in a decrease in the sensitivity of synapses. Both LTP and LTD are necessary to modify neural pathways and maintain homeostasis.

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Stepping back further, it should be apparent that these impulses and plastic changes are part of how the brain‘rewires’ itself through a series of discrete plastic changes that enhance some pathways at the expense of others. Triggering new associations amongst a group of variables affected by the frequency, intensity and emotional state present at the time.

So what’s the point of all of this? Well, if this is how brains actually function then WAY to much effort is being expended debating and defending philosophical constructs of mind, the social structures that result, and obsolete customs and laws formulated before any of these discoveries in neuroscience were made. Things like marketing, social media, speech, and information technology need to be assessed in this light.

Even people who claim to be deterministic with regards to the human mind act, govern, and plan as if there’s some of that fuzzy free will stuff still lying around. Again, this is only a fraction of what is known.

What conclusions has your vast array of biochemical processes come up with regarding the significance of all this?