If It Ain’t Broke, Just Replay

Biological basis of Memory and Learning: Part 2 of 4

https://higgsmass.medium.com/against-the-grain-8c1ea757aaad

This is part two in the series. Part one is linked above. The scientific basis of human behavior as revealed by genomics and neuroscience is worth exploring.

Photo by Denise Jans on Unsplash

Interconnected

Many creatures share the web of life. We owe our existence to humble origins of an ancient common ancestor. It occupied a perch on the evolutionary tree long before our arrival. So do our cousins, the sea slugs, fruit flies, honey bees and other creatures. Sea slugs, the marine counterparts to snails, are interesting in particular.

Aplysia Californica: Image Credit — Leonid Moroz Lab

Our Distant Cousin

Sea Slugs (genus: Aplysia, class: Gastropoda) are marine gastropod mollusks. They are also known as a Sea Hares because of protruded tentacles on their head called rhinophores that resemble the ears of a hare. They have a soft body and an internal shell. They feed and rest on seaweeds in shallow tropical and sub tropical tide waters. They have an extremely well-developed sense of smell by following their rhinophores that serve a dual purpose of smelling and tasting. They are hermaphrodites, in which either partner can become male or female in order to reproduce, just like most plants and other invertebrates.

All this sounds pretty mundane. But if one dissects to peek inside its central nervous system (CNS), one encounters the largest nerve cells found in animal kingdom. Discovered in 1955 by the neurophysiologist Angelique Arvanitaki, sea hares make a model organism bar none.


Model Organisms

A model organism is a species that is employed extensively in a laboratory in a well-defined narrow context. During the last few centuries pigs, guinea pigs, frogs, fruit flies, mice, zebrafish, and others were used as model organisms. They helped in expanding our knowledge of diseases, biological processes, genetic mapping, and other phenomena.

Sea slugs, sponges, sea anemones, and annelids are new kids on the block. Technological advancement makes them attractive-additions in diversifying the menu. Scientists pick them based on a specific set of characteristics, broadly categorized into structural, functional, and behavioral traits they share with humans. They also have a short life-cycle and are amenable to gene sequencing, in-breeding, and other transformations.


What have we learned from sea slugs? In what way are they our cousins?

The answer comes in two parts:

  1. genes we share in common with sea slugs (Genomics)
  2. memory, learning and behavior that genes confer in humans and sea slugs (Neuroscience)

Genomics

Phylogeny

One of the core tenets of evolution is the idea of common ancestry. If humans and sea slugs are a pair of twigs on the evolutionary tree, we can trace back along their branches (by gene sequencing methods) and reach a common-branch. Our common ancestor diverged around the Cambrian explosion, over 530 million years ago.

Genetic relationship in organisms using sequencing. Image Credit: (Tatusov et al., 2003). Our proximity (pink-line) to the sea-slug (teal) is closer than that of its genetically close relatives, the honey bee or fruit fly (green)

Over the last two decades, genomic science has made tremendous advances in comparative classification to precisely situate them on the evolutionary tree. The diagram illustrates such a phylogenetic relationship. A speciation event split our common ancestor. The changes to its genome diverged splitting into lineages of sea slugs, honey bees, fruit flies and humans, among others. But a part of the gene sequence of our common ancestor was conserved — copied faithfully across millions of generations in daughter species including humans and sea slugs. Such sequences are called orthologs.

In this sense, sea slugs are our distant, yet close-relatives. The evolutionary distance (measured in the length of gene sequence) from a human (genus: Homo) to the sea slug (genus: Aplysia) is much shorter than the distance to the honey bee (genus: Apis) or the fruit fly (genus: Drosophila). Orthologs can occur in a couple of ways:

  1. Due to convergent evolution: If both species evolved geographically isolated but in similar environments/habitats and therefore evolved similar adaptations, behave similarly, have similar structures or functions although they are unrelated species as is the case for longer-sequence-orthologs. Anteaters, moles, and flying squirrels evolved independently in the Americas and Australia, for instance.
  2. As a result of pure chance: These orthologs are remnants of an evolutionary quirk, as is the case for shorter sequences. This mechanism is more likely to have occurred between humans (genus: Homo) and sea slugs (genus: Aplysia).

If It Ain’t …

Ontogeny recapitulates phylogeny — Ernst Haeckel, 1866

Exactly how long orthologs are and what traits they encode in the organism is a fascinating discovery in and of itself. It turns out sea slugs share 104 orthologs out of 146 genes found in humans³. It is a whopping 71% overlap and is not just any old sequence but the holy-moly-we-struck-gold sequence implicated in 168 neurological diseases (some of them are listed at the end of this post). We (sea slugs and humans) inherited these disease-rife genes from our common ancestor! It makes one wonder why in the world we needed them.

Photo by Markus Spiske on Unsplash

The engine of evolution, being conservative and blind, does not tailor new organisms from whole cloth. If earlier iterations of a trait stick, they are passed on by virtue of their sticking.

Unless random mutations occur or other selection pressures cause a different trait to evolve, the same old genetic-sequence (that ain’t broke), like a movie-reel, just replays in making the new organism (including you, me, the honey-bee, the sea slug and others). Complexity is perhaps newer clips, clipped on to the same reel, in later iterations of the movie.

A new system — a structure, function or behavior as instructed by this gene sequence may make the organism more (or less) susceptible to diseases. Or make them more complex like a human brain, but retain these susceptibilities intact. All systems in any organism have evolved in the service of maximizing its chances of meeting two basic needs.

  1. surviving long enough (to pass on the genes)
  2. keeping out of harm’s way long enough (to pass on the genes)

Evolution facilitated new features in organisms that arrived later, as it did in mammals like us. It is just a bonus — an icing of complexity on the humble cake of genetic sequence we all largely share. We cannot be the handiwork of any Intelligent Design. A simpler, albeit more plausible explanation is that of a blind, unintelligent evolutionary engine at work — powered by free energy, governed by law of entropy and trundling away towards an inevitable equilibrium.


Neuroscience

Biological Spherical Cow

Physics is the simplest of all branches of science. Spherical cow approximation works out, more or less, to illuminate the inner workings of reality. It is not an exaggeration to say we are enjoying the fruits of the fourth industrial revolution due to quantum leaps in solid-state and quantum physics. Nature does not stop at simple. Free energy allows complex molecules to combine into self-organized, replicating structures called cells. It gets exponentially hard as the complex organisms made of trillions of cells interact with their environment and with each other in innumerable ways. Ecology, civilization, global economy, and social networks are some examples of complex systems. This feature makes the studies of Biochemistry, Economics, Social Sciences, and Psychology extremely challenging pursuits. But, I digress.

Spot the Cow: Image Source: Wikimedia

The human brain is a complex system, no doubt. It is a testament to the evolution of the complexity of life on earth. If evolution posits human brains to have evolved from simpler precursors, we must be able to find them in our biodiversity — a figurative biological-spherical-cow. It turns out the sea slug is precisely that which makes for an excellent experimental model. Its neural circuitry is simpler to understand using a classic reductionist approach. With any luck, we may be able to extrapolate and hope to discover more of our mammalian brain, its complex structure, and functions.

Roughly, that was what on Eric Kandels mind as he took a detour from studying the human brain and embarked on understanding the simple nervous system of Aplysia Californica instead. It was in the 1960s as others warned him of career suicide. Yet, he went against the grain. In hindsight, this was indeed a brilliant idea. Forty years later, it paid huge dividends, fetching him the Nobel prize in Physiology or Medicine in 2000 that he shared with Arvid Carlsson and Paul Greengard.


Nervous System

You do not re-learn to ride the bike each time you get back on it. The more you use, the more efficient your motor skills and memory recall get. Practice makes perfect. You need only watch LeBron James or Yo-Yo Ma in action. Eventually, you flex that memory-muscle with alacrity and on-demand. As you age, it may still be accessible, but you may also gradually lose them.

The brain and its neural circuitry form the Central Nervous System (CNS) and drive our lives until our very last breath. The basic unit of this circuitry is a specialized nerve cell called a Neuron. A neuron can express itself by generating a signal to trigger an action. The nerve impulse is called an action potential. It is in response to external or internal stimuli. A signaling neuron may be met with a metaphorical cold-shoulder by its neighbors or, by contrast, its signal may be embraced and bolstered. If the resulting signal is strong, something usually happens, like salivating for that cheesecake. A signal emanates from a neuron and enters the narrow gap (synapses) separating a pair. Chemical ions called neurotransmitters bidirectionally transmit them in these synaptic gaps. Changes to the gap over time are analogous to the information-storage, which is not rigid. Neuroplasticity is the ability that allows neurons to reorganize to form new connections or rewire existing ones as we experience our lives.

Signals propagate only a few feet per second in the wetware between our ears and in our bodies because large ions carry them (chemical transport). All this is true unless it gets damaged or deteriorates — interrupted by trauma, age, lack of use, or otherwise afflicted by neurological diseases or disorders. Our mammalian memories are far from perfect, unlike electronic gadgets that have silicon-based hardware. Robotic AI with perfect recall at light-speed will be vastly different beasts someday.


Making Memories

Neuroscience posits that the brain is the organ of The Mind. In psychology, the mind is a modular system with distinct and well-developed functions. It takes multiple modules to perceive a thing. There is an ongoing debate about Mind vs. Matter, but that is hardly our concern in understanding animal behavior.

A game-winning touchdown-pass from a quarterback as the football gets lodged securely in the hands of a wide receiver is a familiar memory that a fan can readily recollect. You may have done it as you read this. The scene may be easily recalled but requires the brain to process the imagery of sound, color, shape, form, and motion relative to the background.

Learning And Memory

Animal behavior depends on two evolutionary leaps — Learning and Memory, which are verbs and represent processes.

  • Learning is the acquisition of new knowledge about the world. Learning as a basis of behavior will be covered in the next post.
  • Memory is the process of retaining learned knowledge over time. The focus of this article is where and how information is stored.

Where? The brain, if an organism has one. Nature equipped organisms to store and organize information by increasing the complexity of the nervous systems. The solution requires two steps:

  1. The Systems Problem (where) got resolved by structural changes to the brain.
  2. The Molecular Problem (how) did not require changes and got propagated intact. In this respect, animal behavior is evolutionarily conserved.

Data are a representation of the world. It gets captured and transformed by our five senses as it enters our brain. Information is the myriad of patterns in the data. From a genetic perspective, our skin separates us (the gene-carrying vessels) from the world. However, from an experiential perspective, we are not independent entities, as we will explore later.


Fig A: Schematic of limbic system in human brain. Fig B: Ganglia forming a rope-ladder nervous system in Aplysia. Fig C: Image of the colossal R2 neuron in Abdominal Ganglion (AG in Fig B) visible to the naked eye. This makes Aplysia’s nervous system extremely suitable for genomic and molecular studies.

Systems Problem

Memory is not a unitary faculty of mind, but it comes in two forms

  1. Implicit or Procedural memory
  2. Explicit or Declarative memory

Implicit memory is required for motor and perceptual skills and involves the Amygdala, Cerebellum, and Reflex pathways in the brain (see Fig. A). The strategy used is the unconscious recall. This strategy is at the center of the bulls-eye to understand animal behavior.

Explicit memory allows us to distinguish faces, recall salient events, and remember facts. It involves the Hippocampus and the Medial Temporal Lobe of the brain (see Fig. A). The mechanism used is a conscious recall.


Molecular Problem

A mollusk like Aplysia has a primitive nervous system, in contrast to that of the mammalian brain. The human brain has 100,000,000,000 (a hundred billion) neurons. Aplysia has 20,000 (twenty thousand). They form ten bundles called ganglia with roughly two thousand neurons per bundle. Ganglia are linked in a rope-ladder nervous system (see Fig. B). But what makes these neurons remarkable is that they are gigantic, the largest in the animal kingdom! A neuron (Fig. C: See R2) in the abdominal ganglion (AG) is a millimeter in diameter. Aplysia exists for the bare necessities of life — survival and hermaphroditic reproduction.

The molecular mechanism in mammals is almost identical to that in Aplysia and humans (mammals).

  1. Learning is a modulation of a pair (or set) of neurons to alter their synaptic strength.
  2. Memory is the synaptic strength between a pair (or set) of neurons.

Mechanisms that govern short-term memory (minutes to hours) differ from those that govern long-term (days to lifetime). Imagine this Logistics analogy. Say packages need delivery from a central warehouse to various fulfillment centers. They then distribute packages in that area. Tollways are placed en-route from the warehouse and zip-code specific centers. Some tollway routes are fast and get heavily utilized than others, needing smoother package-transit logistics.

A similar mechanism occurs in the brain. Neurotransmitters (like dopamine, serotonin among two hundred others) modulate signal transduction pathways (made of neurons). Signals get modulated (toll booths allowing or denial of passage) in synaptic gaps, introducing agency — excitatory signal for amplification or inhibitory one for attenuation along each segment. Major routes (dopamine pathways) are critically more important than others (minor).

Fig. D: Rube Goldberg Device. Source: Pinterest

If a presynaptic neuron needs to transmit a signal, dopamine gets released into the gap, expressing a message-send intention. It propagates across the gap and docks with a receptor in the post-synaptic neuron. Where it docks is crucial. For short term memory, it finds a target receptor on the cell membrane. For long-term memory, it penetrates the cell nucleus and triggers new-protein synthesis by stimulating the target genes in the DNA. A confirmational change (message-received) then triggers a call-to-action cascade inside the post-synaptic neuron, analogous to a Rube Goldberg device (Fig. D).

The signal may then propagate to its neighbor and so forth along the pathway. These pathways are critical for learning, memory, motivation, and reward. The signaling machinery is a fascinating biochemical choreography involving neurotransmitters, proteins, enzymes (PKA), second messenger molecules (cAMP), ion channels, ion pumps, and receptors. Signal transmission is akin to a software layer (slow synaptic transmission) modulating the underlying hardware (fast synaptic transmission). Interested readers can refer to the two seminars for details, the underlying keywords that convey the ideas are in the word-cloud (see Fig. E below).

Fig. E: Word-cloud of seminars by Eric Kandel and Paul Greengard: Image generated by author

Summary

  • A hunch (hypothesis) that the signaling machinery found in liver cells may be similar to that in the nerve cells led to its discovery.
  • Studies first carried out in Aplysia and later in mammals revealed that the signaling machinery is a universal pattern — a recurring theme: If It Ain’t Broke, Just Replay.
  • The dopamine signaling pathway is so critical that any abnormalities in it can lead to psychiatric diseases such as Parkinsonism, schizophrenia, ADHD, and drug abuse. We will explore this in the next installment.
  • Genes we share with Aplysia (yep, the same sea slug) cause neurological disorders such as Down syndrome, OFD syndrome, Lesch Nyhan syndrome, Williams-Beuren syndrome, and diseases such as neuroblastoma, epilepsy (EPM1), muscular atrophy (SMA1), among others.

It is impossible to summarize the molecular mechanisms of memory storage in a few sentences. Voluminous material spanning several decades since the 1960s exist. I have tried my best to condense it into a couple of paragraphs and linked the research material for the interested explorer.

We inherited gene fragments from a distant ancestor that was so strange that we wouldn’t want it as a pet. All organisms in our biodiversity are interconnected — starting from a single cell to bacteria to a sea slug, all the way to complex mammals like us. Genomics and Neuroscience illuminate the nature of our ancestry, genes, and associated molecular machinery and diseases. Common gene sequences point to a tape that ain’t broke that replays. The resulting behavioral traits, disease, and molecular mechanisms are conserved. We will explore the evolutionary psychology of learning and reward in the next post.


PREVIEW of Part 3

Learning

The knowledge of the world out there gets encoded in here, as we experience life — in our brain. A close partner of making memories is the process of learning. If an animal encountered a predator in the African Savanna and survived, it would require encoding the experience. Humans have evolved complexity in both Learning and Memory. On the one hand, say you burned your finger on its first encounter with a hot object. You paid a heavy price in learning not to do it. On the other hand, if you watched someone else experience it, you can learn at zero cost.


References

  1. Neuronal Transcriptome of Aplysia: Neuronal Compartments and Circuitry. Leonid L. Moroz et. al, Cell. 2006 Dec 29; 127(7): 1453–1467
  2. Aplysia. Leonid L. Moroz, Curr Biol. 2011 Jan 25; 21(2): R60–R61
  3. Sequence analysis of the human genome: implications for the understanding of nervous system function and disease. Cravchik A, Subramanian G, Broder S, Venter J.C, Arch Neurol. 2001;58:1772–1778.
  4. https://www.whitney.ufl.edu/people/current-research-faculty/leonid-l-moroz-phd/
  5. https://www.cnn.com/2013/05/14/health/lifeswork-eric-kandel-memory/index.html
  6. https://www.scientificamerican.com/article/human-sea-slug-brains-sha/
  7. https://pubmed.ncbi.nlm.nih.gov/14759257/
  8. https://www.cell.com/current-biology/pdf/S0960-9822(10)01453-3.pdf
  9. https://www.sciencedaily.com/releases/2006/12/061228131329.htm
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434285/
  11. https://www.broadinstitute.org/aplysia/aplysia-genome-project

©️ Venkat Kaushik 2020. All Rights Reserved.