Nanomedicine, Volume I: Basic Capabilities
© 1999 Robert A. Freitas Jr. All Rights Reserved.
Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999
18.104.22.168 Outmessaging to Neurons
In vivo nanorobots can outmessage to neurons as well. The most direct method is synaptic stimulation. In excitory cholinergic synapses, perhaps the most common type, the arrival of a presynaptic nerve impulse stimulates the release of up to ~105 molecules of acetylcholine (C7H16NO2, MW = 146 daltons) from synaptic vesicles into the synaptic cleft in ~1 millisec, producing a local concentration of ~3 x 10-4 molecules/nm3 (~0.0005 M).531 The acetylcholine molecules diffuse across the cleft to the postsynaptic membrane (Section 22.214.171.124), where they bind to specific receptor proteins (Section 3.3.3), opening ion channels within 0.1 millisec313 and partially depolarizing the cell, increasing local Na+ permeability. When depolarization reaches ~15% of full voltage range (e.g., from 60 mV down to about 40 mV), voltage-activated sodium channels open, making the membrane highly permeable to Na+ ions. These ions rapidly flow into the cell and initiate the ~100 nanoamp799 action potential spike. These channels close spontaneously after a short interval to reduce permeability, thus allowing the membrane voltage to be restored to its normal resting potential (Section 3.3.3).
A sorting-rotor-tipped manipulator (Section 3.4.2) or pressurized nanoinjector (Section 126.96.36.199) placed in the vicinity of the synaptic cleft can emit a puff of ~105 acetylcholine molecules (~20,000 nm3), producing partial depolarization and initiating nerve impulses at will. (This is preferable to the use of unnatural depolarizing agents such as veratridine.) A 1-micron3 storage volume contains ~5 billion molecules, sufficient to induce ~50,000 discharges or ~1 hour of continuous firing at 15 Hz. The initiating mechanism must provoke a discharge in ~1 millisec, a throughput rate of 108 molecules/sec requiring, say, ~100 sorting rotors with total manipulator tool tip area ~104 nm2. At 15 Hz continuous firing, ~106 molecules/sec are consumed. Sorting rotors placed near the cleft can also absorb the two breakdown products (acetate and choline) of acetylcholinesterase activity (~150 microsec turnover time3143) and recycle them into new molecules of acetylcholine. Taking the enthalpy of hydrolysis under physiological conditions* as ~70 zJ/molecule (~10 Kcal/mole) for the acetylcholinesterase-mediated hydrolysis reaction,3142 the power requirement for continuously recycling 106 molecules/sec is ~0.07 pW. A similar rotor transport mechanism may also be used to rapidly extract acetylcholine molecules from the synaptic cleft, thus extinguishing a passing nerve impulse. Note that to exert control over nerve impulses, neurotransmitter injectors must be placed very close to the postsynaptic surface because the effective diffusion radius of acetylcholine is only a few microns, due to the high efficiency of local acetylcholinesterase.803
* Under controlled mechanochemical conditions (Chapter 19) where the effective heat of protonation of the buffering system can be ignored, the net enthalpy of hydrolysis at 298 K and pH 7 may fall as low as ~1.95 zJ/molecule, or ~0.28 Kcal/mole.3142
Many compounds other than acetylcholine may serve as neurotransmitters (Table 7.2), including nitric oxide and possibly carbon monoxide.1125,1129 Catecholamines such as dopamine, norepinephrine and epinephrine, synthesized in the adrenal gland and elsewhere, act as neurotransmitters at adrenergic synapses which are found at the junctions between nerves and smooth muscles in internal organs such as the intestine and in nerve-nerve junctions in the brain. There are also histaminergic neurons found exclusively in the hippocampus.1123 Most tissues in the human body are innervated by several different types of nerve cells, each using a different neurotransmitter, allowing a great diversity of signals and responses. But synaptic-resident nanorobots should be able to monitor, stimulate, or extinguish all of these signals, even given the confusing geometries entailed by synaptic clusters.
While some synapses use excitory neurotransmitters that elicit an electrical signal, others use different neurotransmitters such as GABA, glycine, or the enkephalins that deliver an inhibitory signal, suppressing electrical response. Some molecules work both ways. For example, acetylcholine is excitory at neuromuscular junctions but may be excitory or inhibitory in the central and peripheral nervous system. A nerve cell may receive thousands of these excitory and inhibitory chemical inputs, and their relative number determines the probability of axonal firing. Again, selections from the complete known library of neurotransmitters of all types may be made available for storage, synthesis, absorption or release by properly configured nanorobots.
Neuropeptides, which can act as highly specific triggers for complex patterns of activity in the nervous system (including memory, learning, perception, mood, and behavior) and allow long-term chemical modulation of synaptic sensitivity, add yet another complication to neural outmessaging by nanorobots. Neuropeptides are manufactured by ribosomes on rough endoplasmic reticulum within the neuron cell body and must be transported to axon terminals for release by "fast axonal transport" -- a journey that may take a day or more for a long axon. They are stored in intracellular vesicles from which they are released to the extracellular space of peptidergic neurons. Neuropeptides released into the synaptic cleft serve as neuromodulators (to inhibit the action of excitory neurotransmitters) or neuromediators (to prolong the action of neurotransmitters), both functions easily duplicated by nanorobots. However, neuropeptides released into the bloodstream act as long-range neurohormones, and neuropeptides released into the extracellular space act as paracrines and enter both pharmacodynamic and pharmacokinetic cascades.770 Nanorobot management of these more diffusely distributed tissue neuropeptide concentrations (e.g., by mimicking the action of natural peptidases of broad substrate specificity) is a more difficult, though not intractable, task.
There are many other methods by which in vivo nanorobots can outmessage to neurons:
1. Periodic manipulation of electric (Section 188.8.131.52) and magnetic (Section 184.108.40.206) fields may trigger neural impulses.3328
2. An excess population of Na+ ions outside the myelinated nerve fiber establishes an intra-axonal resting potential of 60 mV. The net movement of Na+ associated with a single neural impulse is ~0.3 ion/micron2 in ~0.5 millisec,526 so the direct injection of a few electric charges should produce local depolarization, initiating a neural impulse. Note that the voltage balance is maintained by differing concentrations of several ions, not just Na+, although the inrush of Na+ is the primary cause of membrane voltage change during the discharge spike.
3. Membrane ionic currents may be pharmacologically manipulated by nanodevices permanently stationed within the cytosol. For example, sodium pumps are completely inhibited by the injection of 10-100 nM of cardioactive steroids such as ouabain and strophanthidin.805 Injection of ~300 nM tetrodotoxin inhibits sodium currents while leaving potassium currents unchanged; inserting tetraethylammonium blocks only the potassium currents, while leaving sodium currents unchanged.804
4. Establishing a localized ~100 mV circumaxonal (external) superexcess of positive charge may present an electrical barrier steep enough to quench a depolarization wave, thus extinguishing a passing nerve impulse. Techniques of electronic anesthesia, such as transcutaneous electronic nerve stimulation (TENS) and cell demodulated electronic anesthesia (CEDETA), involve crude applications of similar principles.3299,3300
5. Longterm electrical stimulation of neurons using electrodes to apply 0.1-Hz pulses for ~105 sec reduced the expression of neural cell adhesion molecule L1 (NCAM) by a factor of ~13.1063
6. Direct ultrasonic stimulation of neurons.3535
Last updated on 19 February 2003