Nanoneuroscience

Nanoneuroscience is a new emerging discipline that seeks to solve certain hitherto intractable problems in the neurosciences using nanoscientific perspectives and tools. These state–of–the–art methods stand to meet some of the most challenging feats in neuroscience, such as finding better means of diagnosis, treatment, and prevention for various neurological, neurodevelopmental, and neuropsychiatric disorders. Nanotechnology is arguably one of the most optimal ways currently available to address the core essence of higher cognitive functions. A nanoscale emphasis on the mechanical interactions of biomolecules is uniquely capable of demonstrating the multiple ways in which neurons communicate and transmit signals, ranging from the traditional means of interneuronal and intraneuronal communication to novel modes of biomolecular computation. Notable milestones in nanoscience include the development of instruments and techniques enabling interactions with small surfaces or individual molecules, such as scanning tunneling microscopy (STM), atomic force microscopy (ATM), and nanotweezers. These tools operate in the nanometer size range and have the potential to reveal details about molecular events and subcellular operations within neurons. Nanoscientists have also developed a wide variety of nanomaterials – carbon nanotubes, nanoparticles, nanowires, and quantum dots, among others – that can be used to probe and stimulate neurons or parts of neurons. Nanoparticle–based drug delivery systems (or gene therapy delivery systems) showing enhanced ability to cross the blood–brain barrier could potentially be used to treat a number of neurological, neurodevelopmental, and neuropsychiatric diseases. Nanomaterials, used alone and in hybrid combinations with other materials, can be used to diagnose nervous system disorders, to measure neurotransmitter levels or electrical activity in discrete brain sites, to stimulate discrete brain sites, and finally, to build potential nanoscale prosthetic devices that restore normal neural activity patterns and cognitive function.

Neurons contain many structurally diverse nanoscale components, which individually carry out a well–defined function, or as is increasingly found to be the case, multiple functions. Nanoscale proteins are organized as systems. The neuronal membrane – embedded with multiple ion channels and receptors connected to scaffolding and effector proteins – represents a key information processing system in the neuron. In addition to receptors that mediate electrophysiological responses, there exist distinct membrane receptor populations that respond to neurotrophins and play critical roles in neural growth during development and in neural plasticity during adulthood. Despite their being touted as the main neuronal information processing system, membrane – embedded receptor systems operate relatively slowly, on the order of milliseconds to seconds. This has led researchers to probe other neuronal components in search of faster information processing speeds. DNA strands, which are well known to be the physical substrate of genes, act as semi–conductive wires when isolated outside the cell and are capable of transmitting and processing information analogously to the way a computer circuit might. Yet there is no evidence that DNA strands act as anything other than genes in situ. Cytoskeletal proteins form long strands that fill the entire interiors of neurons. Cytoskeletal proteins include neurofilaments, actin filaments, and microtubules. Traditional roles for the cytoskeletal proteins are mediating cell division, providing cell structure, and serving as a matrix for intracellular transport. Like DNA, microtubules are semiconductive and may transmit and process information, not only when isolated outside the cell, but also in situ. Nanotechnology provides new methods to investigate individual neuronal compartments and to manufacture small products ranging from mimetic molecules that interact with receptors to neural prosthetics that restore function following neural degeneration. Both recent breakthroughs and challenges relevant to creating effective interfaces between neurons and nanodevices are outlined.

One of the major goals of nanotechnology is to advance the field of information processing. The central processing units of the future are likely to be quite different from those currently used. While biomolecular processors are unlikely to displace semiconductor processors for speed and accuracy, certain proteins may offer solutions to problems confronting logical processor design, including self–assembly and emergent computation. Cytoskeletal proteins may prove useful as biomolecular processors or may inspire hybrid designs. Actin filaments and microtubules, for example, have highly charged surfaces that enable them to conduct electric currents and process information. The biophysical properties of these filaments relevant to the conduction of ionic current include a condensation of counterions on the filament surface, the non–linear complex physical structure, and in the case of microtubules, nanopores that allow ions to pass between the outer environment to the microtubule lumen. Possible roles for cable–like, conductive filaments in neurons include intracellular information processing, regulation of developmental plasticity, and mediation of transport. Operating as an interconnected matrix, cytoskeletal proteins form a complex network capable of emergent information processing; moreover, they stand to intervene between inputs to and outputs from neurons. The cytoskeletal matrix receives information from the neuronal membrane and its intrinsic components (e.g., ion channels, scaffolding proteins, and adaptor proteins), especially at sites of synaptic contacts and spines, and in turn affects the output of the neuron. An information-processing model based on cytoskeletal networks is described, which may underlie certain types of learning and memory.

The cytoskeleton of neurons is the nanoscale matrix along which organelles, proteins, mRNAs, or signaling complexes are guided to their final destinations inside the cell. Nanotechnology and molecular biology have enabled precision study of these biomolecular machines, in some cases down to the level of single molecules. Motor, linker, and adaptor proteins are essential to the transport process – the three main motors being kinesin, dynein, and myosin, each of which give rise to families of related motor proteins. Neurons are unique in that they possess two distinct transport systems: one in the axon and the other in the somatodendritic compartment. Microtubules are the main tracks for transport in the axon shaft, with neurofilaments (also concentrated within axons) stabilizing the microtubule network. Synaptic vesicles, containing biosynthetic enzymes that are responsible for manufacturing and releasing neurotransmitters, are routinely transported down along axonal microtubules towards actin–rich axon terminals. Endosomes incorporating neurotrophins typically travel in the reverse direction, from axon terminal to the cell body. These transport processes have been tracked with quantum dot nanoparticles attached to single motor proteins or individual cargo molecules. Microtubules also fill the somatodendritic compartments of neurons where they are pivotal to the transport of neurotransmitter receptor subunits and mRNAs from the cell body to postsynaptic sites, in particular to spines – the postsynaptic specializations enriched with actin filaments. Levels of synaptic activity affect the transport of neurotransmitter receptors and mRNA, and permanent changes in synaptic strength partly depend on transport to postsynaptic sites. Alterations in axonal and dendritic transport underlie neuronal responses to injury, regeneration and morphogenesis, as well as learning and memory. Modifications of transport tracks may constitute a subcellular memory mechanism by which the altered intraneuronal connectivity contributes to the memory trace. Elucidation of this mechanism of memory will come with a greater understanding of the biophysics of transport and motor protein mechanics. Biophysical models detailing the nanoscale mechanisms of cellular transport have already increased our understanding of how biological motors operate mechanistically, providing fundamental guiding principles for nanotechnological advancements. Potential nanotechnologies expected to result from biophysical studies of biological transport include bioengineered motors and biomimetic nanocarrier devices, both promising to be useful in biomedicine or as analytical devices. Cytoskeletal and motor proteins, or hybrid designs including these proteins, stand to contribute to a wide variety of potential nanostructured products.

Nanoscience impacts on nervous system diseases in at least two distinct ways. Nanomechanical structures within neurons are fundamentally impaired in multiple nervous system disorders and nanotechnology is instrumental to the development of novel drug and gene therapies and prosthetic nanodevices. A striking number of neurodevelopmental, neurological, and neuropsychiatric disorders exhibit disruption of the nanomechanical properties of the cytoskeleton, affecting subunit proteins, binding proteins, related signal transduction molecules, or indirectly impairing transport mechanisms. The neurodevelopmental disorders such as the fragile X syndrome, Turner syndrome, Williams syndrome, autism, Rett syndrome, and Down syndrome are associated with abnormalities to dendrites and spines, indicating underlying cytoskeletal involvement. Motor neuron diseases, such as amyotrophic lateral sclerosis, and degenerative neurological disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s disease, present with profound disruption of the neuronal cytoskeleton, as well as compromised axonal transport. There is also evidence of cytoskeletal abnormalities in neuropsychiatric disorders, such as schizophrenia, bipolar disorder, and major depression. Identifying the genetic causes of nervous system disorders leads to new treatment targets. The genetic basis for many neurodevelopmental disorders is known, and in many cases expression of a cytoskeleton–related protein is abnormal. The genetic basis for many neurological and neuropsychiatric disorders remains largely undetermined; however, in those sporadic cases that have a gene locus specified, a deficit in a cytoskeleton–related proteins or impaired transport is often noted. Nanotechnological approaches to neurodevelopmental, neurological, and neuropsychiatric disorders include (1) using nanoparticles or nanocarriers to deliver drug or gene therapies, (2) using nanotechnology to reconstruct, reinforce, and/or stabilize the cytoskeletal matrix, (3) using nanofabrication methods to make biohybrid transport devices, and (4) coating electrodes with nanoparticles. Tangentially related to nanotechnological approaches are rational drug design techniques. High throughput scanning of huge molecular databases can be used to identify potential drugs that will target specific proteins in damaged neurons in an effort to restore nanomechanical function.

The human mind is by far one of the most amazing natural phenomena known to man. It embodies our perception of reality, and is in that respect the ultimate observer. The past century produced monumental discoveries regarding the nature of nerve cells, the anatomical connections between nerve cells, the electrophysiological properties of nerve cells, and the molecular biology of nervous tissue. What remains to be uncovered is that essential something – the fundamental dynamic mechanism by which all these well understood biophysical elements combine to form a mental state. In this chapter, we further develop the concept of an intraneuronal matrix as the basis for autonomous, self–organized neural computing, bearing in mind that at this stage such models are speculative. The intraneuronal matrix – composed of microtubules, actin filaments, and cross–linking, adaptor, and scaffolding proteins – is envisioned to be an intraneuronal computational network, which operates in conjunction with traditional neural membrane computational mechanisms to provide vastly enhanced computational power to individual neurons as well as to larger neural networks. Both classical and quantum mechanical physical principles may contribute to the ability of these matrices of cytoskeletal proteins to perform computations that regulate synaptic efficacy and neural response. A scientifically plausible route for controlling synaptic efficacy is through the regulation of neural transport of synaptic proteins and of mRNA. Operations within the matrix of cytoskeletal proteins that have applications to learning, memory, perception, and consciousness, and conceptual models implementing classical and quantum mechanical physics are discussed. Nanoneuroscience methods are emerging that are capable of testing aspects of these conceptual models, both theoretically and experimentally. Incorporating intra–neuronal biophysical operations into existing theoretical frameworks of single neuron and neural network function stands to enhance existing models of neurocognition.