One Brain, Two Computers
The Rationale for Developing a Microglial Modulator : Part 1
Summary of Lessons Learned Since the 2005 "Rediscovery" of Microglia
Copyright 2017 David Mayfield & Blue Bridge :Life Science
- The human brain is composed of two computers rather than one - a neuron-based digital machine built to compute the relevance of experience strictly in terms of what it already knows, and a microglia-based analog machine built to teach the digital machine how to compute differently given novel experiences it can detect but not yet understand.
- What the digital machine knows is stored in the relative strengths of the 100 trillion synapses through which pre-synaptic neurons send signals to their shared post synaptic partner. (The relative weights of the synaptic connections determine which pre-synaptic neurons more or less reliably contribute to the post-synaptic neuron firing an action potential, the brain's digital, yes/no computation of relevance).
- What the digital machine learns is incorporated biologically as the microglial analog machine durably alters the strength of the synaptic input from a particular pre-synaptic partner relative to the strength of inputs from other pre-synaptic partners connected to the same post-synaptic neuron. At the extremes, the dialing of synaptic strength up may involve the physical construction of new synaptic connections (synaptogenesis) between pre and post-synaptic partners, while the dialing of synaptic strength down may involve the complete physical elimination (phagocytic pruning) of existing synaptic connections.
- It turns out that neuro-developmental and neuro-degenerative disease is frequently rooted in the dysregulation of the microglial analog machine, The onset of disease may not, in other words, be a function of diseased neurons or a dysregulation of their capacity to compute whether inputs from their respective pre-synaptic partners sum to meet the biological threshold for relevance: a membrane potential of -55 mV (the depolarizing point at which an action potential fires in the post-synaptic neuron). Rather, the onset of neurological disease may, in many cases, stem from a failure of the brain's microglia-mediated capacity to learn how to compute differently. Or, to put it in biological terms, neurological disease and disorder results from the failure of microglia to correctly and durably modify the relative strength of synapses in light of new firing patterns between neurons induced by novel experience.
- The particular phenotype of neurological disease will vary, of course, depending on the disease in question. However, the variation may not depend on initial causes unique to the disease, but on the particular neurons and circuitry which are disordered because of the microglia-mediated incapacity to learn. and on the timing of the incapacity.
- The mode of microglial dysfunction is the same across the full range of phenotypically diverse disease - from neuro-developmental disease and disorder such as autism, schizophrenia, attention deficit, mood and addiction disorders..., to neuro-degenerative diseases such as Alzheimer's, ALS, MS, Parkinson's, Huntington's, fronto-temporal dementia, and degenerative diseases of the retina; rather than behaving like brain cells whose evolved purpose is to modulate, in analog fashion, the relative strengths of the brain's 100 trillion synaptic connections, dysfunctional microglia mistakenly behave like peripheral tissue macrophages whose evolved purpose is host defense in the face of pathogens, toxins, or other immunological insults.
- The vulnerability of the brain's analog machine to this behavioral error relates paradoxically to the reasons why microglia are so well equipped to act as the educational interlocutors of neurons in the healthy brain. They originate embryologically outside of the brain, in the extra-embryonic yolk sac as primitive tissue macrophages. Early in development (prior to the closure of the blood brain barrier), a subset of these cells migrate to and colonize the brain. And they bring with them all of the epigenetically heritable, immunological machinery of tissue macrophages (in particular, the immunological language of cytokines, chemokines, trophic and toxic factors as well as their receptors, enabling immune cells to converse with other cells about their state).
- In order, however, for microglia ultimately to function as specialized brain cells in constant dialogue with healthy neurons, (rather than tissue macrophages listening to and responding to unhealthy cells infected by pathogens, or damaged by toxins or trauma), a second layer of mitotically heritable, epigenetic programming must be laid down in response to the brain's unique biochemical milieu which the blood brain barrier makes possible. In fact, we can now surmise -- rather heretically -- that the blood brain barrier did not evolve to protect the brain from immunological insult with microglia providing a last line of immune defense should the BBB fail. It evolved, rather. to secure an environment in which immuno-competent microglia could redeploy their inherited immunological tools to perform entirely non-immunological brain functions.
- But before this second layer of epigenetic programming defining the mature form and function of microglia can be enduringly laid down, the developing brain provisionally needs its resident immuno-competent cells (microglia) to retain, somewhat, the form and function of their macrophage cousins in the periphery; and this is because the process of neuronal circuit refinement in the developing brain proceeds through massive regional waves of phagocytosis carried out by microglia -- first to remove over 100 billion superflous neurons whose axons fail to extend to potentially viable post synaptic partners, and secondly to prune 100 trillion supernumerary synapses connecting presynaptic neurons whose action potentials represent noise rather than signal relevant to the firing of their post-synaptic partner. For much of the brain (excluding circuitry which is involved in high level cognitive, emotional and executive functions) this robustly fast paced process of circuit refinement is completed after the third post natal year in humans, at which point most microglia have permanently (epigenetically) adopted their mature morphology and behavior.
- If the animal is subjected to an ill-timed infection or other immune challenge during this window of vulnerability, before the second layer of epigenetic programming is complete, not only will microglia acutely respond in error as if they were tissue macrophages tasked with the responsibility for host defense, but their very response will result in a profoundly altered biochemical milieu within the brain that interrupts the second layer of epigenetic programming. And this interruption will leave affected microglia and their mitotically identical daughter cells in a chronically juvenile state -- with a morphological and functional profile resembling their macrophage cousins in the periphery -- "primed" for life to over-respond to all subsequent immune challenges, rather than steadfastly remaining focused (even in the context of a systemic immune challenges) on their brain-specific, machine-learning responsibilities.
- In some cases, learning challenges themselves -- the consolidation of which requires precise modulation of the relative weights of thousands of synaptic inputs within relevant neuronal circuitry -- will be misperceived by these "primed" microglia as if they were immune challenges requiring a host-defense type of response, with severe consequences for cognition, learning and behavior.
- It is difficult to overstate how promising this rather depressing discovery is regarding the vulnerability of the brain's analog computer to infection and other immune challenges:
One Brain, Two Computers,, the Rationale for Developing a Microglial Modulator
-Copyright, 2017 David Mayfield & Blue Bridge Life Science