How we learn (and forget)

In the last few years, there has been a remarkable advance in the understanding of how we learn as infants.   The mechanisms of learning may also shed light on the nature of neurodegenerative disorders.    Paradoxically, the process of learning might be likened to a starting point of a very weak knowledge of a quasi-infinite number of undistinguished things where over time, the amount of knowledge and the connections gets pared back into a finite number of strong connections.   This is evident in a process called neural paring.

Let me speak to the process of neural paring in learning and also in neurodegenerative disorders. Neural paring is also known by the term synaptic paring.   Both terms mean a process where a relatively large number of neurons are present at birth, with a relatively small number of interconnections projecting from each.   The process of learning appears to be a process where the large initial neuron population gets pared back, and the remaining live neurons are strengthened, and the number of interconnections from these survivors increases.

The process of neural paring has been seen in a number of regions in the nervous system, but I’ll mention two in particular where the process has been observed:  the hippocampus and the neuromuscular system.

The hippocampus is in an older part of the brain called the limbic system – very much in the center.   It  is deeply involved in something called declarative memory, and also cognitive maps.   Declarative memory is the kind of memory that can be consciously recalled, like facts and individuals.   An example of a non-declarative memory might be the motor memory associated with a skill like bike riding.  

A second function of the hippocampus is to store cognitive maps, or a mental map of an individual’s surroundings.   Typically one doesn’t see creation of cognitive maps until an individual has undergone some maturity after birth.  

In a behavioral sense, we can see a distinction between young children and Alzheimer’s Disease victims on the one hand, and healthy mature adults on the other hand.   Much data have been collected on the behavior of lost persons.   Typically, both young children and Alzheimer’s Disease (AD) victims have poorly formed cognitive maps of their surroundings.   When they get lost, the typically are found very close to their last known position, not being able or wanting to wander very far.   Healthy mature adults, on the other hand possess a strong cognitive map, and the strength becomes something of a weakness.   The mature adults will try to find their way out of a situation where they’re lost and end up traveling much farther from their last known position than either young children or AD victims.   This has been born out in a large amount of data accumulated by search and rescue missions.

 Another part of the brain that has been studied in neural pairing is the neuromuscular interface.   Here nerve cells terminate on muscle cells.   When nerve cell fires next to a muscle cell, it releases a chemical across a junction called a synapse.   When the muscle cell senses the chemical, a neurotransmitter, it then reacts by contracting.   There are ways to foil this system.  One example is botox, or botulism toxin, which blocks the transmission of the neurotransmitter signals to the muscles.  

In both the hippocampus and the neuromuscular system, paring appears to occur as part of the maturation process.   One can broadly think of two kinds of interconnections between nerve cells or nerve in muscle cells.  There is one extreme case where there are a lot of neurons but each one has a relatively small number of connections.  In the other extreme case, there are a far smaller number of neurons running the show, but they are larger have a lot of connections projecting to other nerve or muscles cells.

The process of neural “growth” or “learning” appears to be associated with a phase after birth where there are at first lot of small neurons and many connections collectively, but a small number of connections from any individual neuron. As the individual matures, many nerve cells disappear, but the remaining ones are made healthier – larger and create many connections.

In a lot of ways, it’s like a growing forest – one starts out with a lot of weak seedlings, with a limited number of root and limb branches.   As the forest matures, most of the seedlings die, and the remaining ones are empowered to grow more roots and limbs

The process of this paring away of neurons and strengthening the remaining ones requires activation of the neural pathways for the pruning and strengthening process to take place.

You can look at the uncoordinated movements of an infant as a behavioral aspect of this process, where they slowly gain motor coordination over time.  Typically there is a factor of 10 die-off in nerve cells in a newborn, but the overall amount of nerve tissue remains the same or is even slightly increased over time as the surviving nerve cells grow more branches and larger trunks.

Recently, evidence has been found on the mechanism of how nerve cells are pared back during maturation.   It is a variation on the immune system response.   In the immune system outside the brain, there are two subsystems – the innate immune system and the adaptive immune system.   If there is an invading organism, say a bacterium, anti-bodies develop that recognize the foreign proteins on its cell membrane.  The anti-bodies themselves are part of the adaptive immune system, as different antibodies develop in response to different invaders.

The antibodies bond to the membrane of the invader – this triggers the innate part of the immune system, which recognizes the only “back-side” of the antibody, which is not specific to a particular foreign invader – it’s a kind of universal.   The innate system has a cascade of chemical reactions called the complement system where the presence of the antibody on the cell membrane triggers the body to attack the membrane of the invader.   This cascade of interactions eventually leads to a protein complex that creates a hole in the cell membrane of the invader.   Once that hole, or multiple holes open up, the invader dies as pressures across the hole cause the cell to self-destruct.

The recent insight into neuron-paring is the existence of the same immune complement system inside the brain in mammals as they undergo maturation and “learning”.   The chemicals associated with the complement system in immune response are found in large quantities in mammals just after birth when the neural paring is the largest.  

The precise mechanism is unknown as to how a nerve cell gets tagged for destruction, but there is a “punishment” theory that suggests that one nerve cell wins out over another by firing more often than the other.   Then, a kind of immune response cell in the nervous system called a microglial cell tags the nerve cell destined for destruction, which then initiates the complement system cascade that ensures the death and clearance of the tagged cell. 

It appears that a similar neural paring occurs in patients who suffer from Alzheimers and other neurodegenerative diseases.   Rather than a learning process, this is more of an autoimmune response, where cells are pared, but there doesn’t seem to be any maturation and growth of remaining cells.   In Alzheimer’s disease, nerve cells appear to be tagged by the presence of amyloid placques, which initiate the complement cascade system, leading to the cell’s destruction.   As such, it is not part of the entire process of neural paring, but only the destruction part.

Refs:

A. Stephan, B. Barres, B. Stevens, The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease, Ann. Rev. Neuroscience, 2012. 35: 369-89.

J. Tapia et al. Pervasive synaptic branch removal in the mammalian neuromuscular system at birth, Neuron, 2012.  74.5: 816-129

B. Ojo et al.  Age-Induced Loss of Mossy Fibre Synapses on CA3 Thorns in the CA3 Stratum Ludicum, Neuroscience Journal (2013) ID 839535.