july 20, 2006—terasem annual workshop on geoethical nanotechnology, lincoln, vermont nancy j....
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July 20, 2006—Terasem Annual Workshop on July 20, 2006—Terasem Annual Workshop on Geoethical Nanotechnology, Lincoln, VermontGeoethical Nanotechnology, Lincoln, Vermont
Nancy J. Woolf, Ph.D.Nancy J. Woolf, Ph.D.
Department of PsychologyDepartment of Psychology
University of California, Los Angeles, CAUniversity of California, Los Angeles, CA
Neuronanotechnology to Cure Neuronanotechnology to Cure Criminality and Mental IllnessCriminality and Mental Illness
In Order to Elucidate Potential In Order to Elucidate Potential Cures a Physically Detailed Cures a Physically Detailed
Model of Mind is NeededModel of Mind is Needed
Neural networks are part of the solution.Neural networks are part of the solution.
Biomolecular and biophysical approaches Biomolecular and biophysical approaches offer the most complete description of mind, offer the most complete description of mind, but are in the early stages of development.but are in the early stages of development.
One biomolecule of interest is the One biomolecule of interest is the microtubule.microtubule.
Current ApproachCurrent Approach
Define the mind as a unique interwoven Define the mind as a unique interwoven collection of thoughts.collection of thoughts.
Understand the biomolecular and Understand the biomolecular and biophysical nature of an individual thought. biophysical nature of an individual thought.
Apply neuronanotechnology to find cures to Apply neuronanotechnology to find cures to mental illness.mental illness.
Thoughts are stored in memory.Thoughts are stored in memory.
Leading to the question: How is Leading to the question: How is memory stored?memory stored?
Arguments for Subsynaptic Arguments for Subsynaptic Storage of MemoryStorage of Memory
Synapses (many on dendrite spines) are transiently Synapses (many on dendrite spines) are transiently plasticplastic; ; most return to baseline.most return to baseline.
Dendrites continue to grow as intellect grows.Dendrites continue to grow as intellect grows.
Microtubule matrices inside dendrites determine synaptic Microtubule matrices inside dendrites determine synaptic strength because they control strength because they control transporttransport and and local protein local protein translationtranslation..
Microtubules store information via patterns of microtubule-Microtubules store information via patterns of microtubule-associated proteins (e.g., MAP2); these patterns are associated proteins (e.g., MAP2); these patterns are determined by determined by tubulin isotypestubulin isotypes. But how does this translate . But how does this translate into a mental state?into a mental state?
What happens inside neurons What happens inside neurons when animals learn? when animals learn?
(e.g. What happens when animals (e.g. What happens when animals perform tasks such as fear perform tasks such as fear
conditioning, avoidance, and conditioning, avoidance, and spatial navigation?)spatial navigation?)
Fear conditioningFear conditioning increases the breakdown of increases the breakdown of MAP2 and tubulin and also alters the MAP2 and tubulin and also alters the phosphorylation state phosphorylation state ((Woolf et al., 1999; Woolf, Woolf et al., 1999; Woolf, 1998; Woolf et al., 19941998; Woolf et al., 1994).).
Knockout studies show MAP2 is essential to Knockout studies show MAP2 is essential to fear conditioning fear conditioning ((Khuchua et al., 2003Khuchua et al., 2003).).
Passive avoidancePassive avoidance affects the distribution of affects the distribution of MAP2-rich modules of cortex MAP2-rich modules of cortex ((Van der Zee et al., Van der Zee et al., 19941994).).
Spatial and working memorySpatial and working memory are enhanced by are enhanced by overexpression of kinesin overexpression of kinesin ((Wong et al., 2002Wong et al., 2002).).
MAP2 and Tubulin Are MAP2 and Tubulin Are Reorganized with Memory TasksReorganized with Memory Tasks
Naïve Control Tone-Shock Paired Tone-Shock UnpairedNaïve Control Tone-Shock Paired Tone-Shock Unpaired
Increased MAP2 immunostaining in hippocampal Increased MAP2 immunostaining in hippocampal CA1 pyramidal cells is due to increased breakdown CA1 pyramidal cells is due to increased breakdown of these proteins (confirmed by immunoblotting).of these proteins (confirmed by immunoblotting).
Woolf et al., 1999Woolf et al., 1999
MAP2 breakdown in select cortical modules MAP2 breakdown in select cortical modules depends on recent experience and learning.depends on recent experience and learning.
During learning, there is activation of…During learning, there is activation of…
acetylcholine and glutamate terminals, acetylcholine and glutamate terminals, therebythereby affecting neurotransmitter release. affecting neurotransmitter release.
actin filaments,actin filaments, microtubules, and MAPs,microtubules, and MAPs, thereby thereby affecting their affecting their conductive signaling conductive signaling properties.properties.
Woolf, 2006
Neurons Have the Largest Variety Neurons Have the Largest Variety of Tubulin Isotypes: Why?of Tubulin Isotypes: Why?
The tubulin dimer consists of The tubulin dimer consists of and and subunits.subunits.
I-tubulin is present in all cells.I-tubulin is present in all cells.
The rarerThe rarerII-, II-, III-, III-, IVa- and IVa- and VII-tubulin VII-tubulin isotypes are found in brain.isotypes are found in brain.
Semi-periodic distributionSemi-periodic distribution of rare of rare -tubulin -tubulin isotypes individualizes each neuronal isotypes individualizes each neuronal microtubule. This enables the storage of microtubule. This enables the storage of specific information along the microtubule.specific information along the microtubule.
Microtubules are Microtubules are universal cables when universal cables when dephosphorylated (with dephosphorylated (with MAP2 densities hidden).MAP2 densities hidden).
Specific information is amplified Specific information is amplified upon phosphorylation (with MAP2 upon phosphorylation (with MAP2 density-contours revealed).density-contours revealed).
Bipolar Disorder: Bipolar Disorder: An Opportunity for An Opportunity for
NeuronanotechnologyNeuronanotechnology
Bipolar disorder is an affective disorder that Bipolar disorder is an affective disorder that afflicts as many as afflicts as many as 4%4% of the population. of the population.
Bipolar disorder is characterized by dramatic Bipolar disorder is characterized by dramatic changes in mood (e.g., shifts between changes in mood (e.g., shifts between depression and mania or hypomania, or depression and mania or hypomania, or mixed states).mixed states).
Bipolar Disorder-Related Changes Bipolar Disorder-Related Changes in Cingulate Cortex, Orbitofrontal in Cingulate Cortex, Orbitofrontal
Cortex, Hippocampus and AmygdalaCortex, Hippocampus and Amygdala
Decreased activity in cingulate cortex and Decreased activity in cingulate cortex and increased activity in orbitofrontal cortex of increased activity in orbitofrontal cortex of bipolar subjects and their siblings during a bipolar subjects and their siblings during a sadness task sadness task (Kruger et al., 2006)(Kruger et al., 2006)..
Increased activity in amygdala and Increased activity in amygdala and decreased activity in orbitofrontal cortex decreased activity in orbitofrontal cortex with mania during a facial response task with mania during a facial response task (Altshuler et al., 2005)(Altshuler et al., 2005)..
Bipolar Disorder Associated Bipolar Disorder Associated with Tubulin and MAP2 with Tubulin and MAP2
DeficienciesDeficiencies
-Tubulin is decreased in the anterior -Tubulin is decreased in the anterior cingulate cortex of bipolar patients cingulate cortex of bipolar patients (Beasley et al., 2006).(Beasley et al., 2006).
MAP2 mRNA levels are decreased in MAP2 mRNA levels are decreased in the hippocampus the hippocampus (MacDonald et al., 2006).(MacDonald et al., 2006).
Mood Stabilizers Used to Treat Mood Stabilizers Used to Treat Bipolar Disorder Affect MAPsBipolar Disorder Affect MAPs
Lithium, valproate, and carbamazepine inhibit Lithium, valproate, and carbamazepine inhibit glycogen synthase kinase-3 (GSK3), which glycogen synthase kinase-3 (GSK3), which phosphorylates the two MAPs: tau and MAP2 phosphorylates the two MAPs: tau and MAP2 (Williams et al., 2004; Grimes & Jope, 2001).(Williams et al., 2004; Grimes & Jope, 2001).
By this mechanism, these mood stabilizers By this mechanism, these mood stabilizers alter microtubule dynamics.alter microtubule dynamics.
Meta-Analyses of Genetic Meta-Analyses of Genetic Studies on Bipolar DisorderStudies on Bipolar Disorder
Genomic loci identified for bipolar Genomic loci identified for bipolar disorderdisorder (e.g., (e.g., Hayden & Nurnberger, 2006; Cheng et al., 2006; Segundo et Hayden & Nurnberger, 2006; Cheng et al., 2006; Segundo et al., 2003al., 2003)) overlap with loci for human tubulin proteins overlap with loci for human tubulin proteins ((Entrez Gene,Entrez Gene, NIHNIH))::
IIII-, -, IIII-, and -, and IIC-tubulin, IIC-tubulin, III-III-and and VI-tubulinVI-tubulin
proteins similar to proteins similar to II-tubulin, II-tubulin, -chain-tubulin, -chain-tubulin, I-I-tubulin, tubulin, IV-tubulin, and IV-tubulin, and V-tubulinV-tubulin
pseudogenes for pseudogenes for IVQ-tubulin, IVQ-tubulin, II-tubulin, and II-tubulin, and V-V-tubulin, and tubulin, and IV-tubulin polypeptide.IV-tubulin polypeptide.
In bipolar In bipolar disorder, disorder, thoughts speed thoughts speed up (as in mania) up (as in mania) or slow down or slow down (as in (as in depression) depression) possiblypossibly due to due to altered MAP2-altered MAP2-binding binding dynamics as dynamics as dictated by the dictated by the tubulin isotypes tubulin isotypes expressed.expressed.
A Novel Treatment for Bipolar A Novel Treatment for Bipolar Disorder Is NeededDisorder Is Needed
Certain individuals do not respond to Certain individuals do not respond to mood stabilizers, and while polytherapy is mood stabilizers, and while polytherapy is common, this can be self-limiting because common, this can be self-limiting because of drug interactions.of drug interactions.
Bipolar disorder affects approximately Bipolar disorder affects approximately 12 million Americans12 million Americans and exhibits co- and exhibits co-morbidities with substance abuse and morbidities with substance abuse and criminality, thereby raising sociobiological criminality, thereby raising sociobiological issues and ethical concerns.issues and ethical concerns.
Increased Incidence of Increased Incidence of Substance Abuse and Criminality Substance Abuse and Criminality
in Bipolar Disorderin Bipolar DisorderFifty-three percent of female and 79 percent Fifty-three percent of female and 79 percent
of male rapid-cycling bipolar subjects with of male rapid-cycling bipolar subjects with co-morbid substance abuse report having co-morbid substance abuse report having been charged with a crime been charged with a crime (Friedman et al., (Friedman et al., 2005).2005).
Many mentally ill end up incarcerated.Many mentally ill end up incarcerated. (In (In 1939,1939, Lionel Penrose noted a consistent inverse Lionel Penrose noted a consistent inverse relationship between the prison population and the relationship between the prison population and the number of inhabitants in mental hospitals at any number of inhabitants in mental hospitals at any point in time.)point in time.)
Repetitive Transcranial Magnetic Stimulation Repetitive Transcranial Magnetic Stimulation (rTMS) (rTMS) delivered to the frontal cortex at 1 – 20 Hz delivered to the frontal cortex at 1 – 20 Hz decreases symptoms of unipolar depression and decreases symptoms of unipolar depression and bipolar disorder bipolar disorder ((Isenberg et al., 2005;Isenberg et al., 2005; Michael & Erfurth, Michael & Erfurth, 2004; Dolberg et al., 2002;2004; Dolberg et al., 2002; Kozel & George, 2002Kozel & George, 2002).).
There is a laterality effect:There is a laterality effect: Right cortical stimulation Right cortical stimulation treats mania and left cortical stimulation treats treats mania and left cortical stimulation treats depression depression ((Li et al., 2004Li et al., 2004; ; Sakkas et al., 2003Sakkas et al., 2003).).
Electromagnetic Treatments Can Electromagnetic Treatments Can Be Effective for Affective Disorders Be Effective for Affective Disorders
Electromagnetic treatments are potentially Electromagnetic treatments are potentially beneficial, but there is no theoretical basis for beneficial, but there is no theoretical basis for how they work, thereby limiting our ability to how they work, thereby limiting our ability to make these treatments any better. make these treatments any better.
Redefining electromagnetic treatments in terms Redefining electromagnetic treatments in terms of how they affect microtubule signaling and of how they affect microtubule signaling and how they correct abnormal signaling patterns how they correct abnormal signaling patterns will enable significant improvements.will enable significant improvements.
Second-harmonic generation microscopy Second-harmonic generation microscopy indicates that indicates that microtubulesmicrotubules are one of a few are one of a few endogenous structures that show intense endogenous structures that show intense doubling of laser excitation in the 760 – 880 nm doubling of laser excitation in the 760 – 880 nm range range (Dombeck et al., 2003; Campagnola et al., 2002). (Dombeck et al., 2003; Campagnola et al., 2002).
Individual Individual microtubulesmicrotubules respond to respond to near infrared near infrared waves waves by destabilizing and moving towards the by destabilizing and moving towards the source source (Albrecht-Buehler, 1998; Albrecht-Buehler, (Albrecht-Buehler, 1998; Albrecht-Buehler, 2005).2005).
Microtubules Respond to Microtubules Respond to Electromagnetic WavesElectromagnetic Waves
Steps to Develop Treatments That Steps to Develop Treatments That Normalize Neuronal Activity Via Normalize Neuronal Activity Via
Stimulation of MicrotubulesStimulation of Microtubules Identify normal and abnormal collective Identify normal and abnormal collective
patterns of patterns of conductive signalingconductive signaling among among microtubules.microtubules.
Use electromagnetic principles such asUse electromagnetic principles such as constructive constructive andand destructive interference destructive interference to to train normal conductive signaling and train normal conductive signaling and inhibit aberrant conductive signaling.inhibit aberrant conductive signaling.
Moreover, since microtubules are both Moreover, since microtubules are both structurally plastic and capable of long-term structurally plastic and capable of long-term storage, permanent functional adaptation may storage, permanent functional adaptation may be possible. (i.e., This approach be possible. (i.e., This approach maymay lead to a lead to a long-lasting cure for affective disorders.)long-lasting cure for affective disorders.)
Future DirectionsFuture DirectionsResearch at the subcellular level:Research at the subcellular level: Studies on Studies on
individual microtubules and their conductive individual microtubules and their conductive signaling properties.signaling properties.
Research at the clinical level:Research at the clinical level: Measuring Measuring abnormal activity associated with mental abnormal activity associated with mental disorders and associated co-morbidities, as disorders and associated co-morbidities, as these relate to microtubule signaling.these relate to microtubule signaling.
Long-term goal:Long-term goal: Retrain microtubule networks Retrain microtubule networks in neurons to behave adaptively.in neurons to behave adaptively.