Sunday, October 12, 2014

Rat Tickling and the Neuroscience of Emotions


Image: Patterns of emotionally-induced arousal and inhibition. Inhibition (purple) and arousal (red/yellow) within the lateral (outer region-top image pair) and medial (inner region-bottom image pair) regions of both brain hemispheres while human subjects experience emotions produced by personal memories. As indicated by changes in blood flow, inhibition is primarily arising from the outer (neocortical "self-control") regions - downward arrows, while excitation is primarily occurring in deep inner (subcortical "emotion-generating") regions. It is within these regions that Dr. Panksepp has traced seven neural pathways that, when stimulated, generate consistent emotional behaviors in all mammals. Source: Dr. Antonio Damasio/PLOS One. 
Within the dim, red-lit laboratory, a gentle, avuncular man in a white coat reaches into a glass tank and begins studiously tickling its inhabitant. His free hand holds a microphone, which amplifies and records the response - a high-pitched chortling which is, says the good doctor, the joyful giggling of a laboratory rat.

Meet Dr. Jaak Panksepp, colloquially referred to as the Rat Tickler. Here at Bowling Green State University, he has been pioneering the relatively new field of affective neuroscience.

For over five decades, Dr. Panksepp has meticulously mapped out neural circuits responsible for emotions, deep within the brains of humans and other animals. His findings may revolutionize psychiatry - providing powerful new tools to fundamentally alter the deepest instinctual drives and mental states shared by mammals and other animals, including birds, and perhaps to a lesser extent, reptiles, amphibians, fish and even crustaceans and insects.

He has discovered that these primary process systems arise from deep, ancient limbic brain structures, rather than from higher-order cognitive pathways of the neocortex - the brain's outer surface, where conscious thought, planning and judgements are processed.

These emotion-generating primary process systems are found within the same inner brain regions which regulate hormonal control of the body, via the brain's "thermostat" - the hypothalamus and pituitary gland.

The human brain, explains Dr. Panksepp, can be thought of as a nested hierarchy. Visualizing it in this way allows us to understand its layered organization and evolutionary development. His research shows that we have evolved a uniquely human cognitive (computational) mind atop a widely-shared affective (emotional-physical arousal states) mind. In general, the cognitive system uses neurotransmitters to process incoming sensory data, while the affective system uses neuromodulators to control overall brain states.

Unlike a neurotransmitter, a neuromodulator doesn't directly signal a single target neuron; instead, it spreads across a wide region, altering the activity of several neurons at once. Functionally, neuromodulators are thus able to act like chemical spigots - valves controlling the flow of neural signalling, altering the sensitivity of post-synaptic (signal-receiving) neurons or muscles to neurotransmitters, and thus altering signal strength, rhythm and timing.

The most abundant and powerful known neuromodulators include serotonin, dopamine, norepinephrine and acetylcholine. Because they circulate in the cerebrospinal fluid - the liquid bathing the brain and spinal cord, they can remain active for up to several minutes after release, altering widespread brain regions, including the cerebral cortex and deep neural hubs called the basal ganglia, central to learning and behavior. In this way, neuromodulators appear to underlie long-term effects upon mental and physical states - such as moods.

Higher up the heirarchy,  the basal ganglia produce secondary processes - learning, or creating memories, which can link sensory perceptions with emotional evaluations - feelings. This is the basis of conditioned learning - the formation of useful, survival-guiding memories.

At the third, topmost level, the neocortex uses life experiences to execute tertiary processes - higher-level computations which including thinking, ruminating, and planning. Here too, the forebrain and medial (middle) frontal cortex ideally provide control over emotional reactivity.

Certain neurochemicals and hormones produce highly predictable emotional-behavioral responses, by acting globally upon the brain, bringing several regions and various network functions under the "orchestration of one emotional conductor".  Among them are corticotropin releasing hormone (CRH) , which the hypothalamus secretes to start the chemical cascade of the stress response - more commonly known as the fight or flight response.

Three major neuromodulator systems are central to primary process circuitry, affecting the entire human brain and nervous system:

1. The ventral tegmental area (VTA), which supplies dopamine in the brain's "motivation circuit" - the medial forebrain bundle. This deep brain circuit provides pleasant sensations in the form of an excited expectancy - thus acting as a motivation center. Here, dopamine stimulation increases arousal in animals, which become more eager and inquisitive, engaging in exploratory behavior.

The MFB is part of the much larger mesolimbic system, running from the hypothalamus through the basal ganglia and medial frontal cortex. This is the brain's most important circuit for motivation, learning, and, pathologically, addictions. It's this pathway which is hijacked in addictions to drugs such as cocaine and amphetamines, which artificially increase dopamine levels in the synaptic clefts, the gaps between neurons, across which the chemical messengers known as neurotransmitters are delivered.

2. The dorsal raphe nucleus (DRN), a neural cluster in the midbrain and brainstem, which primarily supplies serotonin to the forebrain and limbic system. The serotonergic system is one of the brain's oldest neuromodulatory systems, primarily engaged in inhibition, opposing other neuromodulators, and thus inhibiting both sensory input and behavioral output. Serotonin is key to controlling impulsivity - behavior without forethought.

Laboratory animals low in serotonin are unable to restrain themselves from responding inappropriately. In humans, serotonin system dysfunction has been linked to an inability to suppress aggression. Serotonin is also critical for modulating and coping with stress, and emotional behavior in general. Impairment of the serotonergic system interferes with one's ability to deal with stressful situations.

3. The locus coeruleus (LC), a neural cluster located in the pons of the brainstem, is a region of the reticular activating system, with neurons that project into several regions of the limbic system - including the VTA - and cortex. The LC synthesizes the neuromodulator norepinephrine, used to regulate wakefulness, attentiveness and physiological responses to stress. It sends projections to the VTA (motivation), amygdala (fear, anger and other emotional processing, as well as salience discrimination - determining what specifically is important enough to our future survival for storing in memory), hippocampus (memory generation), thalamus (sensory processing and relaying) cerebral cortex (conscious thought, planning, sensory interpretation, self control) spinal cord and cerebellum (movement and balance coordination, possibly involved in language and learning), and thus also plays a significant role in learning.

Because of its wide effects, the LC system is central to attention, behavioral and cognitive control, memory, emotions, sleep cycles, and posture and balance. In conjunction with the hypothalamus, it also helps control responses to stress, specifically the fight or flight response. Increased sensitivity among neurons running from the LC to the amygdala is thought to be at the heart of learned fear disorders, such as post-traumatic stress disorder (PTSD).

While the dopamine system may induce general exploratory behavior, the LC-NA (noradrenaline is the older name for norepinephrine) system seems to promote goal-directed behavior, by influencing attentiveness.

Cognition - thought - is fed by accumulated life experiences, encoded as memories and factual knowledge. However, the primary processes - ancient affective states - are necessary to help generate these memories. New memories are encoded with the help of affective states, which enable animals to subjectively evaluate their life experiences.

In The Archaeology of Mind: Neuroevolutionary Origins of Human Emotions, Dr. Panksepp explains that these primary-process affects are "...ancient brain processes for encoding value - heuristics* of the brain for making snap judgements as to what will enhance or detract from survival, with rewarding or punishing effects."

"These brain functions provide selective advantages in that they effectively anticipate universal, future survival needs. Animals that had these capacities survived and bred with greater success.... Just imagine how useful pain is."

Dr. Panksepp's life work has been the discovery of seven such primary-process pathways - circuits which trigger distinct mental, physiological and behavioral patterns, including SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF, and PLAY. Because these pathways and their effects are both ubiquitous and fundamental (what evolutionary psychologists call evolutionarily homologous experiences), equivalent across different species of mammals, Dr. Panksepp spells them in capital letters.

To the pet owner, veterinarian or farmer, the notion that non-human animals cannot experience these emotions is patently absurd. Virtually all domesticated animals - dogs, cats, horses, pigs, cows, goats and even birds - display distinct personalities, temperaments and moods, including affection, loyalty, jealousy, fear, shame, pride, peevishness, anticipation, and many more. And mammals emit essentially the same emotionally expressive vocalizations as humans, including howls of rage, wails of grief, hoots or squeals of joy, and growls of anger. The generation of these sounds originates from the same brain region in every mammalian species. Despite all this, however, many modern scientists and corporate interests see animals as nothing more than simple stimulus-response boxes.

Dr. Panksepp's work is destined to permanently dispel such utilitarian illusions. He has been using a three-pronged approach to tracing these networks, homologous throughout the mammalian world: through direct electrical and chemical stimulation; through the rigorous study of instinctual behavior patterns; and through comparing human reports to (non-human) animal responses when these regions are stimulated, via electrodes or chemical injections.

He first became inspired to study neural correlates of emotions at the University of Massachusetts during the 1960s, while studying under Dr. Jay Trowill, who was experimenting with a new technique first introduced by Peter Milner and James Olds of McGill University - the insertion of electrodes into rat brains to create pleasant or unpleasant effects. In these experiments, after an electrode has been surgically implanted, a test rat is able to switch the electrical stimulation on or off with the press of a lever.

In one variation of such experiments, when a rat presses the control lever, the electrode stimulates regions of the medial forebrain bundle. After experiencing just a single stimulation, the experimental rats would immediately begin to repeatedly press the lever, stimulating their reward centers till they literally dropped from physical exhaustion.

However, activating the neural circuitry of the MFB through dopamine administration produces excited exploratory behavior similar to a search for food. Thus, this pathway seems to function as an instinctive motivation system, generating enthusiasm or expectancy, prompting animals to explore their environment for rewards. Amazingly, emotions can be switched on and off with a tiny electrical current.

In these experiments, since animals can activate or deactivate stimulation of each affect-generating regions, they indicate very clearly and consistently that they all dislike rage, fear, panic and grief, but they enjoy seeking, lust, care and play. And even invertebrates show some primitive affective responses: crayfish, for example, show an extreme liking for addictive substances like morphine and amphetamines, and bees display irritation when given inferior ingredients for their honey-making activities.

The primary process circuits are far more ancient than the earliest humans, who first emerged about two and a half million years ago, during the Pleistocene age.

They are at least as old as the divergence of the first mammals from their reptile ancestors.

These deep subcortical circuits encode the brain's basic emotional operating systems - a form of evolutionary memories.

Evolution tends to be parsimonious (stingy). Biological organisms don't constantly develop in radically new directions, or pass along traits which confer no survival value - natural selection ensures such wasteful development quickly fades out of existence. But features which do promote survival are passed on, as new species emerge from existing ones.

From an engineering standpoint, nearly all multicellular animals are basically tubes, optimized for food-harvesting, with a mouth at one end, and an anus at the other. Add wings, flippers, arms or legs, and you've simply created an eating machine that can harvest calories more quickly. Aside from one major apparently failed global experiment, the basic body plan hasn't changed.

Before the advent of modern genetic comparative analyses, scientists primarily used homologous traits - structures shared by diverse species - such as the jointed wings of a bat, the pectoral fins of a whale and the fingers of a human - to build phylogenic trees (ancestral charts). Such homologous traits are said to have been conserved - genetically preserved and passed down through the course of evolution. Among such conserved traits are a number of brain regions shared among vertebrates, particularly mammals.

Across the entire mammalian class, specific neural clusters and neurochemicals are shared, performing identical or nearly identical functions, depending upon each species' environmentally-determined survival needs. (There is greater detail available here for the particularly curious.)

These neural homologies began to emerge among the first chordates - half-a-billion-year-old creatures from which we descended, and among whose family we count ourselves. The first chordates (like the recently-rediscovered Pikaia) evolved in ancient Earth's oceans, and were so successful that some survive nearly unchanged to the present day. Among these living fossils are 32 known species of lancelets, which live half-buried in the sand of temperate and tropical shallows the world over. These segmented marine animals have "lance-shaped" bodies with sturdy, flexible notochords extending from head to tail, and a recognizable mouth for harvesting plankton.

The notochords would eventually evolve into into central nervous systems, which would branch out in ever-growing complexity from spinal cords. These would come to be encased in spinal columns, as animals incorporated the ancient oceans' abundant calcium salts into skeletal backbones.

Over time, the survival advantage of sense organs for sight, (and later taste, hearing and smell) required a concentration of neurons called ganglia in the creatures' foremost body region. As these early marine animals swam, this neural cluster could interpret incoming sensory data as efficiently as possible, enabling rapid navigation and food-harvesting.

As the stresses of environmental change reshaped their genes, ever more sophisticated chordates emerged - fish, amphibians, reptiles, birds and mammals. And as their sensory organs and locomotor systems grew in sophistication, so did their computational organs - their brains.

However, the parsimonious nature of evolution meant that certain features would get reused, rather than being re-engineered out of whole cloth. Because of this, humans share neural and neurochemical homologies with all mammals, including modern rodents, which superficially resemble our earliest mammalian ancestors.

But we share more than mere anatomical features with all Earth's mammals. In The Archaeology of Mind, Dr. Jaak Pansepp outlines what his five decades of experimentation have revealed: that we share our core emotions and drives with all mammals, and to a lesser extent, birds, reptiles and many other creatures.

We've inherited these traits for a good reason: emotions evolved to ensure survival. They serve as behavioral guides. Coupled with (and guiding the formation of) learned behaviors gleaned through experience, emotions prompt behaviors that bring comfort and reduce discomfort, increasing the odds of survival and reproduction. At heart, "affects" - the raw neural-hormonal responses and states which require cognition to be interpreted as emotions - produce the most basic behavior patterns - approach or avoidance.

The ancient circuitry which creates these affective states lies in the deepest, most evolutionarily ancient and conserved regions of the human brain, sprouting from atop the brainstem, which controls our most vital life functions, such as breathing, heartbeat swallowing and sleep-wake states. We know that these affects are limbically generated, because the behaviors continue even after decortication - the surgical removal of an animal's cortex.

These primal instinctive-emotional circuits are altered by experience, becoming more responsive (sensitization) or less so (habituation), depending upon both our experiences and our mental evaluations of them.

Dr. Panksepp's contribution to our understanding of affective neuroscience has been in charting how these seven emotional-behavioral circuits, when stimulated, produce virtually identical affects (though often differing effects) across every mammal species studied to date.

These seven neural systems lie deep below the level of the human cortex - the most recently-evolved, wrinkly outer layer - the seat of conscious thought, planning, evaluation, calculation and consideration. The primal drives and emotions to which they give rise are distinct from the homeostatic (biochemical balance-maintaining) affects such as hunger and thirst, and the purely sensory affects, which include disgust and various types of pain.

Says Dr. Panksepp, the infinite variety of subtle emotional shades we experienced are produced from a combination of these seven core affects, coupled with the unique melange of memories, cognition and bodily sensations each of us uses to interpret and shape them.

The seven core affective systems he has discovered to date are seeking, fear, rage, lust, care, panic/grief and play. Each of these seven primary-process emotional systems interacts with the others, with inhibitory or synergistic effects, as well as with the arousal systems, moderated by acetylcholine, norepinephrine, dopamine and serotonin, in special neural centers common to all vertebrates.

These neural attention/arousal subsystems are shared - primarily the circuitry concentrated in the brainstem - and are modulated by the neurohormones serotonin, norepinephrine, dopamine and acetylcholine - but overall, each affective circuit follows a distinct, specific path and neurochemistry, and each is shared by all mammalian brains.

As Dr. Panksepp explains: "Dopamine lies at the heart of... [the SEEKING system], controlling practically everything that organisms do. Its interactions with other brain regions are so extensive that it helps to facilitate most other emotional urges.

"likewise, norepinephrine, an even older system (since the cells are further down in the brain) facilitates attention during every kind of emotional arousal but more heavily so for euphoric feelings. Acetylcholine does the same, but often for more negative emotions."

Dr. Panksepp's work revises and expands upon the somewhat dated theory of Dr. Paul D. MacLean, an American neuroscientist who hypothesized in the 1960s that the modern brain evolved in three stages: a reptilian complex, a paleomammalian (ancient mammary-bearing animal) complex called the limbic system, and a neomammalian (new mammal) complex called the neocortex.

However, according to Dr. Panksepp, the circuitry reasonsible for these seven affective states - the "primary processes" - arise from the deepest, most ancient regions of the mammalian brain. They are hardwired - built into all mammalian brains, and not learned, constituting what he calls "ancestral memories".

The seven primary processes - raw emotional states - in turn control higher-order secondary processes - learning mechanisms such as associations. Both combine with tertiary processes - cognition - to create our conscious mind states. Affective states mix with and in turn moderate memories, complex ideas, reflections and subjective experiences.

Our uniquely individual gene patterns control the makeup of these seven primary-process circuits, leading to variability among us - emotional temperaments - which give rise with the force of habit to distinct personalities (which can, in turn, be altered by experience).

Dr. Panksepp describes these systems as "... SEEKING (expectancy), FEAR (anxiety), RAGE (anger), LUST  (sexual excitement), CARE (nurturance), PANIC/GRIEF (sadness), and PLAY (social joy). He addresses "...the primary-process nature of these systems,  and to a lesser extent, "...the secondary process (inbuilt emotional learning mechanisms) and the tertiary process (emotional thoughts and deliberations that are so evident in human experience)." He gives a brief summary of each of the seven affective systems as follows:
1. The SEEKING, or expectancy, system (discussed in Chapter 3) is characterized by a persistent exploratory inquisitiveness. This system engenders energetic forward locomotion—approach and engagement with the world—as an animal probes into the nooks and crannies of interesting places, objects, and events in ways that are characteristic of its species. This system holds a special place among emotional systems, because to some extent it plays a dynamic supporting role for all of the other emotions. When in the service of positive emotions, the SEEKING system engenders a sense of purpose, accompanied by feelings of interest ranging to euphoria. For example, when a mother feels the urge to nurture her offspring, the SEEKING system will motivate her to find food and shelter in order to provide this care. The SEEKING system also plays a role in negative emotions, for example, providing part of the impetus that prompts a frightened animal to find safety. It is not clear yet whether this system is merely involved in helping generate some of the behaviors of negative emotions, or whether it also contributes to negative feelings. For the time being, we assume it is largely the former, but that the positive psychological energy it engenders also tends to counteract negative feelings, such as those that occur during FEARful flight and the initial agitation of PANIC/GRIEF. For this reason, animals may actually find fleeing to be in part a positive activity, since it is on the most direct, albeit limited, path to survival.
2. The RAGE system (see Chapter 4), working in contrast to the SEEKING system, causes animals to propel their bodies toward offending objects, and they bite, scratch, and pound with their extremities. Rage is fundamentally a negative affect, but it can become a positive affect when it interacts with cognitive patterns, such as the experience of victory over one’s opponents or the imposition of one’s own will on others who one is able to control or subjugate. Pure RAGE itself does not entail such cognitive components, but in the mature multi-layered mammalian brain (Fig 1.4), it surely does.
3. The FEAR system (see Chapter 5) generates a negative affective state from which all people and animals wish to escape. It engenders tension in the body and a shivery immobility at milder levels of arousal, which can intensify and burst forth into a dynamic flight pattern with chaotic projectile movement to get out of harm’s way. If, as we surmised above, the flight is triggered when the FEAR system arouses the SEEKING system, then the aversive qualities of primary-process FEAR may be best studied through immobility “freezing” responses and other forms of behavioral inhibition, and reduced positive-affect, rather than flight.
4. When animals are in the throes of the LUST system (see Chapter 7), they exhibit abundant “courting” activities and eventually move toward an urgent joining of their bodies with a receptive mate (Figure 7.1), typically culminating in orgasmic delight—one of the most dramatic and positive affective experiences that life has to offer. In the absence of a mate, organisms in sexual arousal experience a craving tension that can become positive (perhaps because of the concurrent arousal of the SEEKING system) when satisfaction is in the offing. The tension of this craving may serve as an affectively negative stressor when satisfaction is elusive. LUST is one of the sources of love.
5. When people and animals are aroused by the CARE system (see Chapter 8), they have the impulse to envelop loved ones with gentle caresses and tender ministrations. Without this system, taking care of the young would be a burden. Instead, nurturing can be a profound reward—a positive, relaxed affective state that is treasured. CARE is another source of love.
6. When overwhelmed by the PANIC/GRIEF (also often termed “separation distress”) system (see Chapter 9), one experiences a deep psychic wound—an internal psychological experience of pain that has no obvious physical cause. Behaviorally, this system, especially in young mammals, is characterized by insistent crying and urgent attempts to reunite with caretakers, usually mothers. 
If reunion is not achieved, the baby or young child gradually begins to display sorrowful and despairing bodily postures that reflect the brain cascade from panic into a persistent depression. The PANIC/GRIEF system helps to facilitate positive social bonding (a
secondary manifestation of this system), because social bonds alleviate this psychic pain and replace it with a sense of comfort and belonging (CARE-filled feelings). For this reason, children value and love the adults who look after them. When people and animals enjoy secure affectionate bonds, they display a relaxed sense of contentment. Fluctuations in these feelings are yet another source of love.
7. The PLAY system (see Chapter 10) is expressed in bouncy and bounding lightness of movement, where participants often poke— or rib—each other in rapidly alternating patterns. At times, PLAY resembles aggression, especially when PLAY takes the form of wrestling. But closer inspection of the behavior reveals that the movements of rough-and-tumble PLAY are different than any form of adult aggression. Furthermore, participants enjoy the activity. When children or animals play, they usually take turns at assuming dominant and submissive roles. In controlled experiments, we found that one animal gradually begins to win over the other (becoming the top dog, so to speak), but the play continues as long as the loser still has a chance to end up on top a certain percentage of the time. When both the top dog and the underdog accept this kind of handicapping, the participants continue to have fun and enjoy this social activity. If the top dog wants to win all the time, the behavior approaches bullying. As we will see in Chapter 10, even rats clearly indicate where they stand in playful activity with their emotional vocalizations: When they are denied the chance to win, their happy laughter-type sounds cease and emotional complaints begin. The PLAY system is one of the main sources of friendship.
As Dr. Panksepp points out in his newest publication, "The goal of psychotherapy is affect regulation". Thus, his research is likely to be of enormous benefit in improving such therapeutic goals.

In a similar vein, researchers such as Emory University neurologist Dr. Helen Mayberg, have recently begun using electrical stimulation of targeted brain regions in hopes of helping patients whose depression is resistant to pharmacological treatments.

Dr. Mayberg's Deep Brain Stimulation technique may have alleviated severe depression in several patients, but Dr. Panksepp contends that this treatment is both figuratively and literally off the mark. He and his team are currently studying ways of addressing mood disorders through direct manipulation of the seven affective systems.

For example, Dr. Panksepp defines depression as an underactivated seeking urge, hobbled by excessive psychological pain. By directly altering the primary process neural circuits (such as the MFB), Dr. Panksepp hopes to counteract the psychological pain by strengthening the primitive seeking urge, in effect "amplifying eagerness to live". At this point, however, such technology is still very much in the experimental stages.

* heuristics are on-the-fly judgements based upon experience - commonly referred to as "best guesses", "common sense" or "rules of thumb".

Sources: Cross-Species Affective Neuroscience Decoding of the Primal Affective Experiences of Humans and Related Animals, Dr. Jaak Panksepp, September 07, 2011, Public Library of Science One; 
Discover Interview: Jaak Panksepp Pinned Down Humanity's 7 Primal Emotions, Pamela Weintraub, May 31, 2012, Discover Magazine; The Archaeology of Mind: Neuroevolutionary Origins of Human Emotions, Jaak Panksepp, Lucy Biven, Norton Series on Interpersonal Neurobiology, WW Norton and Company, 2012;
A Depression Switch? David Dobbs, April 2, 2006, New York Times

Friday, October 10, 2014

Wow. GREAT stuff.


As I prepare my next monster post (trust me, it's a doozy!), I'd like to entrust you to the gentle care of the brothers Green, whose Crash Course series is a marvel to behold.:
https://www.youtube.com/watch?v=kgZRZmEc9j4

Get brilliant, free rollercoaster ride tours of Biology, Chemistry, Psychology, Ecology, World History, US History and Literature:
https://www.youtube.com/user/crashcourse/playlists

Or More Biology, Chemistry or Physics at SciShow:
https://www.youtube.com/user/scishow/playlists

Until we meet again....

Tuesday, October 7, 2014

Ray Bradbury's "There Will Come Soft Rains" as interpreted by a Soviet animator


Director Nazim Tyuhladziev of the former Soviet state of Uzbekistan animated one of the most haunting science fiction short stories of all time - There Will Come Soft Rains, by the brilliant Ray Bradbury, my personal all-time favorite author (with the possible exception of Tolkein). 


The story tells of how, in the distant future, a completely automated house continues functioning, unable to understand that its charges have all died in a nuclear war. 

Friday, October 3, 2014

The cartography of emotion

Image: Finnish researchers have found specific patterns
of body sensations which correspond to each emotion.


Emotions, it is thought, evolved to provide animals with behavioral templates for their survival. They trigger changes in both the mind and body which help humans and other animals instinctively deal with environmental challenges.

Emotions change both our mental and physical states, enabling us to rapidly deal with danger, while also indicating potentially rewarding social interactions or rewards available in the environment.

The physical sensations arising from these biochemical changes are an important aspect of emotions. For example, while romantic love may elicit feelings of warmth and pleasure all over the body, deep sadness might give rise to a feeling of tightness in the chest.

In December 2013, researchers at Finland's Aalto University first attempted to systematically map the effects of emotions in the body.

Over 700 subjects from Finland, Sweden and Taiwan took part in the online study. The research team elicited varying emotional states in their participants, then invited them to use computer software to color regions of the body where they felt increased or decreased activity.

The researchers discovered that the strongest physical sensations come from the most common emotions, and the pattern of body sensations varies according to each emotion. However, these varying body sensation patterns are consistent in both eastern Asian and western European cultures, showing that emotions - and the body sensations to which they give rise - have biological origins distinct from any cultural origins.

Some theories suggest that conscious emotions follow sensations rather than the other way around - that the biochemical changes in our body lead to the conscious recognition that we are feeling a specific emotion.

It's believed that this line of research will have profound implications for our knowledge of the physical aspects of emotions, emotional disorders, and will provide new means of diagnosing such disorders.

Source: "Finnish research team reveals how emotions are mapped in the body", press release, Lauri Nummenmaa, et al, Aalto University, December 31, 2013

Thursday, October 2, 2014

Cracking the Code

RNA polymerases IV (green) and II (red) in the nucleus of an Arabidopsis
(rockcress) plant cell - Image: Dr. Olga Pontes, University of Indiana
 
One of evolution's deepest mysteries has been solved. Indiana University researchers have discovered how the effects of experience - environmental circumstances - can be handed down from parents to their offspring - without changes to DNA sequences.

According to IU biochemist Dr. Craig Pikaard, the secret to such epigenetic ("above the genes") inheritance lies in gene silencing patterns which can be preserved and passed down through generations. Instead of relying upon information hardwired by the DNA sequence, parent cells use chemical tags as guides for switching off the protein-manufacturing capability of specific DNA regions known as genes.

In essence, cells are essentially little more than tiny sacs of chemical reactions, all run by thousands of special proteins called enzymes, which float about the cytoplasm within your cells, conducting all the work these cells require. These molecules are tiny chemical-reaction machines, enabling your cells to conduct rapid chemical reactions every moment of your life, assembling and disassembling molecules when necessary, allowing cell growth and reproduction, among other functions.

In 1999, Dr. Pikaard discovered two gene-silencing plant enzymes: Pol IV and Pol V. These are RNA polymerases,  so-named because they are enzymes (denoted by the -ase suffix) used to create polymers (long chain molecules) of RNA molecules, the universal chemical blueprints which guide the assembly of proteins, the building blocks of life.

Dr. Pikaard's newest findings show how these enzymes shape plant development.

Genes aren't automatically silenced during normal DNA replication, but chemical markers can be added, providing a molecular memory which allows an offspring's cells to recognize which genes should be silenced. This allows modifications to be passed down without altering an organism's natural DNA sequence, just as installing a new program can alter a computer's functions without a change in its components.

Single-carbon (methyl) or double-carbon (acetyl) chemical tags can be added to or removed from DNA strands (chromatin), providing epigenetic information to the DNA sequence, which in turn guides RNA-assembly.

Short-interfering RNAs (siRNA) are tiny RNA molecules which guide methyl group attachment to DNA strands, deactivating specific gene sequences - the process called RNA-directed DNA methylation (RdDM).

This inheritance, called silent locus identity is controlled by two enzymes which work in tandem to control the chemical tagging responsible for epigenetic memory: histone deacetylase 6 (HDA6) which removes acetyl groups from histones (the protein spools around which chromatic strands wrap), and methyltransferase (MET1), used for DNA maintenance.

HDA6 and MET1 control the recruitment of Pol IV, the synthesis of siRNA and finally the process of RdDM, the final step in this form of gene silencing. The effects can be dramatic - sporadically-occurring diseases like cancer often seem to arise from such epigenetic changes to DNA.

Source: "Gene silencing instructions acquired through 'molecular memory' tags on chromatin - New work identifies machinery of epigenetic inheritance, relevant to development and cancer", press release, Stephen Chaplin, March 20, 2014, Indiana University

Sunday, September 14, 2014

Pure Magic

Nikola Tesla in his laboratory, 1899.

When people speak of longevity, I always joke that I intend to live to 200, for one simple reason.

For all its destructiveness, selfishness, and arrogance, the human race is endowed with the most amazing capacity - its creative ability. This unique attribute has given rise to masterpieces like Chartres Cathedral and the Large Hadron ColliderBeethoven's Ninth, and the Hubble Space Telescope.

To our early ancestors, all this would surely seem the fruits of powerful magic. And I, for one, can't wait to see mankind's next magic trick. Here are my favorites:

1. The PC
Since the Dark Age of DOS, a PC has provided me with the means of earning a living, and in the process become my most prized, multipurpose tool - a typesetter, photolab, publicist, accountant, recording studio, publisher, scout and personal secretary.

It's evolved significantly - my current home built PC functions as an alarm clock, fitness coach, interpreter, tutor, stereo, home theater and game center. I use it to design curricula, to write, illustrate, edit and publish books, blogs, brochures, business cards, posters, ads, and even songs and videos. And when the workday is done, it lets me shed my cares like a dusty overcoat, and lose myself in a movie or game. I heart PCs.

2. The Internet
The Japanese animation Doraimon recounts tales of a blue robotic cat from the future, equipped with an amazing bit of technology - the docodemo doa, or anywhere door. To me, this is a metaphor for the Internet.

Via the Internet's magic, I can now walk the halls of the most magnificent edifices in history, browse the Louvre, speak in tongues, earn a degree from Harvard, Oxford, or Columbia, chat face-to-face with friends across the planet, trace my family history, or order up a gene sequence as easily as a fresh pizza.

I can learn from history's most brilliant minds, and read wisdom as ancient as the earliest Sumerian cuneiform tablets or as fresh as captions streaming in real time across a live CNN broadcast. I can learn to dance, publish a best seller, or attend a conference without ever leaving my apartment, thanks to the doco demo door.

3. Google Maps
Feed it an address, and Google maps will instantly give step-by-step directions for travel on foot, or by public and private transport, with estimated arrival times and links to schedule, fare and route information. It's even possible to virtually walk the entire route via "street view" images, which comes in handy when one is traveling abroad. Access it on a cell phone, and I can track my progress toward my destination in real time. It's a spectacular innovation.

4. Facebook
Facebook is the greatest party in history. I have literally found everybody who ever meant anything to me - from my very first girlfriend to my old school chums and workmates from across the planet. Via Facebook, we can chat any time of day or night, via text, voice or video - or play mindless video games till dawn together, should the mood strike us.

5. The inflatable bicycle tire
To save money, stay in shape and reduce pollution, I ride a bicycle everywhere. It's given me a deep appreciation for something which remained beneath my notice for decades. Now every time I ride, I'm a bit amazed at the ingenuity that went into engineering the simple bicycle tire - mounted upon load-distributing spokes and sporting its clever little auto-sealing valve.

After inflating a flat, it feels oddly marvelous to glide effortlessly across the ground and to feel the tremendous difference in energy expenditure. This wonderful innovation was Irish inventor John Dunlop's 1888 gift to mankind.

6. The electric light bulb
I suspect that when Roald Dahl wrote Charlie and the Chocolate Factory, he was basing his main character, Mr. Willy Wonka, upon the Wizard of Menlo Park, who authored over two thousand patents worldwide, and gave the world its first electric power station, motion picture camera and sound recording.

Thomas Edison's amazing productivity was not just due to his brilliance, but also his Herculean patience. Forbes Magazine tells of how a reporter once asked him how it felt to spend years producing nothing but failed prototypes for a commercial light bulb, and his paradigm-shifting reply was reputedly: “I have not failed 10,000 times. I have not failed once. I have succeeded in proving that those 10,000 ways will not work. When I have eliminated the ways that will not work, I will find the way that will work.”

Perhaps Edison can be forgiven for indulging in a bit of self-aggrandization in the interest of marketing, but historians Robert Friedel and Paul Israel say that actually no less than twenty-two people invented various forms of electric lights before Edison filed his own 1878 patent. Chief among them was John W. Starr, who died shortly after filing an 1845 patent. And, says the Smithsonian, Edison and his team actually tested 1600 filaments of various types (including coconut fiber and human hair) before settling on carbonized fibers extracted from a folding bamboo fan he found in his factory.

7. Direct current
As if merely lighting up the world wasn't enough for Edison, he would soon create an entire electric power system to run his invention. The world's first power station, launched in 1882, would bring direct current power - and light! - to the masses.

Direct current is generally too expensive for large-scale long-distance distribution, so it's now primarily used in electronic devices, including the Integrated Circuit chips which manipulate the on and off states of binary code - the magnificent Lingua franca of the Digital Age.

8. Alternating current
One wonders if Edison's former employee and arch rival Nikola Tesla knew he was destined to reshape the world someday, by inventing the very lifeblood of our civilization. Try to visualize alternating current at work: electrons streaming across atoms, building speed to a climax, then slowing, and switching direction. The cycle repeats endlessly 50 to 60 times every second.

Tesla used AC to power induction motors - essentially the same variety which run most household appliances, such as vacuum cleaners and blenders. AC flows through copper coils wrapped around a cylindrical iron stator. This generates a magnetic field which induces a rotor inside to turn, running machines used by billions worldwide every day.

9. Binary code
The level of profound genius required to convert a machine's simple on or off states into a Lingua Franca capable of conveying everything from the entire works of Shakespeare to the launch control codes for artificial satellites is mind-boggling. Particularly when one realizes its inventor, the rather eccentric hypergenius Gottfried Leibniz, first devised the system over 300 years ago, in 1679 - based, no less, upon ancient Chinese mysticism. Beyond cool.

10. The internal combustion engine
This magic box harnesses the power of explosions to move cars, trucks and motorcycles. I remember first learning its inner workings in elementary school, daydreaming my way through the process - imagining spark plugs igniting oxygenated gasoline, and the explosions forcing pistons through cylinders hundreds of times every minute, rotating a crankshaft whose motion is ultimately transmitted via gears and axles to the wheels, propelling the vehicle forward. All hail the late, great Nikolaus August Otto.

Thursday, September 11, 2014

On the Recent Silence....

Apologies, kind readers. I have been rather busy as of late, because I am trying to enter graduate school at Harvard Extension to earn my masters in psychology.

My original degree is in journalism, with several certifications in IT, but I spent a year preparing for the general GRE, and earned the highest possible score for verbal reasoning (169) and was on the median (151) for quantitative reasoning. On the psychology GRE I scored in the 83rd percentile (90th for experimental psychology).

At any rate, if you're interested and/or able, you can get a tax write off by sponsoring me. Or if you like, you can purchase one or both of my books. Right now, I'm trying to raise the funds to attend the obligatory first semester on campus. My target for the semester is $17,000. After getting my foot in the door, I would then be eligible for federal funding and/or Harvard scholarships and grants.

You can also help by steering me toward any useful information on private funding.

Thanks for your time.

-eric

Monday, September 1, 2014

Welcome to the Connectome


Why does everyone's brain function so differently? Some of us are extroverted, some not; some of us are experts at language, some not; some of us are afflicted with pathologies like schizophrenia, some not; some of us are compassionate, some not. 

According to MIT neuroscientist Dr. Sebastion Seung, author of Connectome: How the Brain's Wiring Makes Us Who We Are, the differences are all due to our neural wiring. Personality, IQ and memories are encoded by our connectomes - the neural wiring which is every bit as individual as a fingerprint, but on a massively more complex scale.

The connectome describes both the brain's overall wiring, and how genes organize and express the proteins that form neural connections.

The brain's architecture gives rise to specific capabilities and tendencies, including perception, evaluation, behavioral selection, and personal traits. Much of it seems to be based upon a hierarchical system. 

For example, neurons related to perception comprise one such hierarchical network. Neurons at the bottom of the visual hierarchy respond to the simplest stimuli - individual spots of light. In your eye, each photoreceptor on your retina responds to a tiny spot of light at a specific location, much like a digital camera's multiple sensors, which detect light in terms of individual pixels. Moving upward in the hierarchy, neurons process progressively more complex data, with those at the top detecting the most complex stimuli, such as a person's identity. The neurons which detect parts send excitatory signals to neurons which eventually perceive the entirety.

UCLA's Dr. Itzhak Fried discovered one such "top neuron" able to respond specifically to images of actress Halle Berry. Interestingly, the subject's Halle Berry neuron also responded to the actress' written name, suggesting this cell participates in both perceiving and thinking about the actress, meaning it corresponds to an abstract representation of her.

According to Dr. Seung, such neurons are interconnected in cell assemblies, which hold the associations used in forming thoughts. These cell assemblies also interconnect and overlap.

Philosophers say specific principles govern how these associations are learned. The main method is through coincidence detection, finding a contiguity (sequence or series) in time or place. For example, since you often see toast eaten with butter, you have learned to mentally connect the two. 

Repetition is another method for learning associations. As a baby, the first time you saw your parents buttering their toast, perhaps your brain didn't form a permanent association, but after you saw it every morning at the breakfast table, you eventually formed a permanent mental association - and a synaptic connection. 

Sequences are also important for building associations. Reciting the days of the week and the months of the year repeatedly eventually allowed you to learn them by heart. Since each day and each month always followed its predecessor, you learned to associate them in sequence. Episodic memories, for example, involve a sequence of events, the synapses must be activated in one direction, allowing for memories to be recalled in chronological order.

This type of association will be linear, but if you always see two things appearing together, the association will be bidirectional.

Perception may seem effortless, but memory often seems difficult. If your brain only contained one cell assembly with a single memory, recall would undoubtedly be simple, but since a huge number of these cell assemblies overlap, it creates the potential for memory errors. 

Imagine the first time you ever rode a ferris wheel. You were in the fairgrounds surrounded by the cacophony of rides, electronic games and screams of delight, the smells of smoke, cotton candy and hot dogs wafting on the air. 

If you have a second memory which includes hot dogs - perhaps a Fourth of July barbecue with your family - both memories will differ, but the cell assemblies will share hot dog neurons, so when one cell assembly is activated, it can trigger the second. Delighted squeals might trigger a mixup of both memories. Perhaps this is what leads to faulty memory retrieval.

Says Dr. Seung, a high firing threshold might prevent such haphazard activation spread: if a given neuron can't activate without two excitatory inputs, two cell assemblies which only share one neuron would not be able to have such indiscriminate firing. But such a protective measure becomes problematic because it makes memory recall more difficult. To trigger an entire memory would require a minimum of two cell assembly neurons firing, so recalling your ferris wheel ride might require both the ringing of electronic bells and the smell of hot dogs cooking together. 

This means sometimes your memory may not work even when you need it to, because memory requires a delicate balance:  if there's too much activity, your memories may be hazy, but if there's too little, you may not remember at all. 

In forming associations, synapses "reweight" - either strengthening or weakening, and this is the physical basis of memory in the brain. Strengthening (long term potentiation) occurs as synapses grow more neurotransmitter-filled sacs (vesicles) on the transmitting neuron and more neurotransmitter-sensitive receptors on the receiving neuron. Synaptic weakening (long term depression) or dendritic atrophy occurs when neural pathways fall into disuse. Synapses may also be synthesized or eliminated, in the process called reconnection.

When two neurons repeatedly fire in sequence, the connection from the first to the second will strengthen; if they repeatedly fire simultaneously, connections will strengthen in both directions. This strengthening is the long-lasting basis of memory. These "Hebbian principles" of synaptic plasticity are activity-dependent, because the change in synaptic strength (plasticity) is triggered by the repeated firing of neurons. The changes last for weeks or even a lifetime, depending upon repetition and the subjective importance of the information.

A collection of such strengthened synapses acts as a cell assembly, a group of excitatory neurons interconnected together with strong synapses. There will be a number of additional weak synapses, but they aren't part of the cell assembly, having not been fired remained, and thus remaining unaltered. These weak synapses won't affect recollection, because firing will spread among the neurons in the cell assembly, but not to the unrelated neurons, because the synapses are too weak to activate the unrelated neurons.

Dr. Seung summarizes the idea thusly: "Ideas are represented by neurons, associations of idea by connections between neurons, and a memory by a cell assembly or synaptic chain. Memory recall happens when activity spreads after ignition by a fragmentary stimulus. The connections of a cell assembly or synaptic chain are stable over time, which is how a childhood memory can persist into adulthood."

Monday, August 18, 2014

Making Memories




Neuroscience's Holy Grail has long been the engram - a neuron or set of neurons which physically hold a memory. To a large extent, that search has ended, thanks to scientists like Nobel prizewinner Eric Kandel, who won the 2000 Nobel Prize for his discoveries in the neurochemistry of learning.

Dr. Kandel began his groundbreaking work by using Pavlov's dog-conditioning techniques to study neural changes in the California sea snail Aplysia as it learned. Aplysia has only 20,000 neurons, and they are the largest in the animal kingdom, visible to the naked eye. This makes the neural network easy to manipulate and identify, and makes Aplysia to neurobiologists what fruit flies are to geneticists and rats to behavioral psychologists.

He began by stimulating Aplysia’s sensory neurons with electrodes, then used the process of elimination, neuron by neuron, to map out the entire neural circuit controlling gill withdrawal - a simple behavior in which Aplysia adapts and learns from its environment.

Just as you would jerk your hand away after touching a hot stove, Aplysia reflexively withdraws its gills in response to aversive (unpleasant) stimulation. In comparison with yours, its brain is primitive, essentially two neural bundles called ganglia; but just as with more complex animals, it can learn. In Aplysia, just as in humans, "practice makes perfect"; repeating a stimulus converts a short-term memory - lasting minutes - into a long-term one, lasting days, weeks or a lifetime.

In Aplysia, the gill withdrawal reflex is controlled by just 24 sensory neurons which enervate (send signals to) six motor neurons. Between them are "middle managers" - interneurons which act as modulators, either excitatory (dialing up the likelihood of firing) or inhibitory (dialling down the likelihood of firing). Stimulating the tail activates these interneurons, which excrete the neurotransmitter serotonin. This triggers an excitatory response, and the motor neurons fire, causing muscular contractions. The end result is that the animal withdraws its gill in response to a shock.

Aplysia's neurons (like yours) are hardwired - physically and functionally fixed by instructions encoded in DNA - so they aren't capable of significant change, such as increasing in number or changing in function or location. However, the connections between them are extremely flexible. Learning changes their signalling efficiency.

Neurons communicate via these connections, across tiny gaps called synapses, which excrete chemical messengers called neurotransmitters.

Lasting memories are preserved by the growth and maintenance of these synapses. In other words, memories are encoded in the connections between neurons.

Sensitized
Dr. Kandel's early experiments involved training Aplysia in a learned fear response called sensitization, in which repeated exposure to an aversive stimulus makes a creature more sensitive to that stimulus. For example, a war veteran sensitized to sounds like gunfire might jump at the slamming of a car door. Similarly, an Aplysia snail which has become sensitized to shocks on its mouth organ (siphon) will also respond to stimuli applied to its tail. This is because, simply stated, "practice makes perfect" - repeated exposure converts short term memory into long-term memory, via physical growth (protein manufacture).

After tracing the specific neural circuits which control gill withdrawal, Dr. Kandel devised a technique for growing cell cultures in a petri dish from larval snails, creating the absolutely simplest learning circuit - just two live neurons, one sensory, one motor.

He and his colleagues could then substitute tail shocks with a squirt of serotonin, and investigate the specific molecular processes which lead to memory formation.

He discovered there are two separate chemical sequences, one for building short-term, and one for building long-term memories. Short-term memory - which lasts for seconds to minutes - comes from increasing a presynaptic neuron's ability to emit neurotransmitters.

This neurotransmitter increase develops from a six-step chemical sequence called a signalling cascade:
When the snail's tail is given a mild shock, the neurotransmitter serotonin is released by interneurons (intermediate neurons which amplify or dampen sensory neuron input to targets such as motor neurons). This neurotransmitter binds to protein receptors embedded in the membrane of a recipient (postsynaptic) neuron.

These serotonin-activated (serotonergic) receptors prompt the conversion of ATP, the cell's natural "fuel" into a special chemical signal, a secondary messenger called cAMP. cAMP is called a secondary messenger because it transfers an external signal from the membrane to molecular machines inside a cell.

In Aplysia, the cAMP signal activates a protein on-off switch called a kinase (PKA). This kinase migrates back to the membrane and causes a shape change (phosphorylation) in special calcium channels, proteins embedded in the membrane which act like selective gateways.

The shape change temporarily opens these channels to calcium ions, which flow into the synaptic terminals of the neuron.

Calcium ions function as the chemical switch that triggers increased neurotransmitter release. This increased neurotransmitter release is the physical basis of a short-term memory formation.

To convert this short-term memory into a long-term memory, repeating the stimulation triggers an additional chemical cascade which activates physical growth - protein manufacture.

This anatomical change is the sprouting of new synapses and/or synaptic branches called dendrites. Dendrites are tendril-like appendages which reach out to connect with neighboring neurons.

This anatomical change is called long term potentiation, so-called because, over the long term, the potential for a neuron to fire has been enhanced - the postsynaptic neuron has become more sensitive to stimuli and fires more frequently. This phenomenon involves the long-term modification of the synaptic connection.

In 2010, MIT's Gertler Lab created a spectacular film of this growth process in living, cultured mouse neurons. Here you can see the growth of neurites, neural buds which sprout into dendrites.

In Aplysia, repeating the stimulation (mild shocks) creates higher amounts of serotonin release, triggering a release of higher amounts of the secondary messenger cAMP. This more persistently activates the kinase (PKA) switch. Just as in short-term memory formation, this kinase migrates back to the cell membrane and opens protein channels, and calcium ions rush into the synaptic terminals, triggering neurotransmitter release.

However, the repeated stimulation also results in a second action, that ultimately results in physical growth of the neuron, through protein synthesis.

A subunit of the kinase moves into the neuron's cell nucleus, where it activates a special protein called a transcription factor (CREB protein or cAMP Responsive Element Binding protein). This transcription factor binds to specific DNA sequences (genes), activating them to start manufacturing new synapses, from proteins building blocks like neurexin and neuroligin.

Genes are segments of the DNA molecule arranged in specific sequences to guide the synthesis of messenger RNA (mRNA).

mRNA is a molecule which copies the genetic code from DNA and uses it as a template to guide the manufacture of proteins - the most complex molecules on Earth, which carry out virtually all biological functions, from forming tissues to carrying out chemical processes vital for life.

To accomplish this, mRNA peels off from its parent DNA, then travels outside the cell nucleus to a special region of the cell body - a mazelike series of tubes called the endoplasmic reticulum. Here the mRNA is used by mini protein factories called ribosomes as a blueprint for assembling short building blocks (amino acids) into proteins.

Dr. Robert Singer and colleagues at the Albert Einstein College of Medicine developed a means of filming this neural mRNA synthesis. They attached harmless flourescent chemical tags to mRNA molecules so they could be filmed within live mouse neurons. Here is the world's first film of a memory being formed in real-time: https://www.youtube.com/watch?v=6MCf-6It0Zg

Mammals like mice have evolved a special memory-creating and storing brain structure called a hippocampus, named after the Greek word for seahorse, because of its curly shape.

Dr. Singer's team stimulated neurons in the mouse's hippocampus, where "episodic" and "spatial" memories are formed and stored (episodic memories are the conscious mental record of our life events and the sequences in which they occur, while spatial memories constitute navigational guides through an organism's environments).

The hippocampus acts as a sort of amplifying loop, receiving signals from the cortex - the area where conscious thought and ultimate brain control resides - and sending signals back. As memories are consolidated - stabilized into potentially lifelong memories - they are gradually transferred from the hippocampus to the cortex during sleep.

Dr. Singer's team targeted the mRNA which carries the code for a structral protein called beta-actin, central to long-term memory formation. In mammals, beta-actin proteins strengthen synaptic connections by building and altering dendritic spines.

Within 10 to 15 minutes of stimulation, beta-actin mRNA began to emerge, proving their neural stimulation had triggered transcription of the beta-actin gene. The film shows these fluorescently glowing beta-actin mRNA travelling from neural nuclei to their destinations in the dendrites, where they will be used to synthesize beta-actin protein.

Neural mRNA uses a unique mechanism the Einstein team calls "masking" and "unmasking", which allows beta-actin protein synthesis only when and where it is needed. Because neurons are comparatively long cells, the beta-actin mRNA molecules have to be guided to create beta-actin proteins only in specific regions at the ends of dendrite spines.

According to Dr. Singer, just after beta-actin mRNA forms in the nuclei of hippocampal neurons, it migrates out to the cells' inner gel (the cytoplasm). At this point, the molecules are packed into granules whose genetic code is inaccessible for protein synthesis.

Stimulating the neuron makes the beta-actin granules fall apart, unmasking the mRNA molecules, and making them available for beta-actin protein synthesis. When the stimulation stops, this protein synthesis shuts off: after synthesizing beta-actin proteins for only a few minutes, the mRNA molecules abruptly repack into granules, returning once again to their default inaccessible mode.

In this way, stimulated neurons activate protein synthesis to form memories, then shut it down. Frequent neural stimulation creates frequent, controlled bursts of messenger RNA, resulting in protein synthesis exactly when and where it's needed to strengthen synapses.

Of course, the process involves more than just a single gene - in fact a dizzingly huge number are involved. Learning involves large clusters of genes within huge numbers of cells.

Florida U. Neuroscience Professor Leonid Moroz has tracked specific gene sequence expression in Aplysia neurons, and estimates that any memory formation event will alter the expression of at least 200-400 genes. This is out of over 10,000 which are active every moment of the simple marine snail's life.

Moroz's team zeroed in on genes associated Aplysia's feeding and defensive reflexes, and found over 100 genes similar to those linked to every major human neurological illness, and over 600 similar genes which control development. This shows these genes emerged in a common ancestor and have remained nearly unchanged for over half a billion years of both human and sea slug evolution.

Human brains contain about one hundred billion neurons, each expressing over 18,000 genes, at varying levels of expression (protein synthesis rates), with over 100 trillion connections between them. Aplysia has a comparatively much simpler nervous system, with only 10,000 easily identifiable, large neurons. However, it is still capable of learning, and its neurons communicate using the same general principles as human neurons.

According to Dr. Moroz, if genes use a chemical alphabet, there is a kind of molecular grammar, or set of rules controlling the coordinated activity of gene expression across multiple neural genes. To understand memory or neurological diseases at a cellular level, scientists need to learn these grammatical rules.

More sophisticated
Like the Einstein team, Dr. Eric Kandel also went on to study the mouse hippocampus, and found it makes use of a chemical cascade similar to that of Aplysia neurons. But in mouse - and human - hippocampi, the chemical sequence for memory formation is slightly different:

In the hippocampus the changes which lead to memory formation occur in the receiving (postsynaptic) neuron rather than the sending (presynaptic) neuron. This process occurs in two stages:

During Early LTP, the excitatory neurotransmitter glutamate is released. This glutamate acts upon two types of receptors, NMDA (N-methyl-D-aspartate) and AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Normally, only the AMPA receptors respond, but repeated stimulation activates the NMDA receptors as well. These open ion channels in the membrane, allowing calcium ions to flow into the neurons, and this activates a (different) second-messenger kinase, CAMK2A (calcium calmodulin kinase). CAMK2A triggers a chemical cascade that results in the growth of additional AMPA receptors.

In Late LTP, repeated stimulation activates a second system, which releases the modulatory neurotransmitter dopamine.

Like serotonin in Aplysia, dopamine acts upon the hippocampus like a sort of volume switch, dialing up neural activity. (Disruptions in the dopamine system are at the heart of disorders like schizophrenia and Parkinson's disease.)

Dopamine binds to its own receptors on the cell membrane, increasing production of cAMP, activating the PKA-CREB sequence which starts protein synthesis for new dendrite/synapse formation.

Mice are also capable of much more sophisticated memory feats than sea slugs, such as memorizing spatial layouts in a manner much like humans.

In his experiments with mice, Dr. Kandel found three principles at work in learning. First, when two or more neurons converge, stimulating a third neuron, it creates a logic circuit known as a “coincidence detector”. This circuit underlies associative learning - we link A with B, cause with effect, touching a hot stove with pain, etc. Variations of this circuit underlie many forms of mental computation.

Secondly, he found that mice hippocampi use place cells, special pyramidal neurons which fire in response to specific locations. These place cells act as mental markers, firing at the sight of certain landmarks, allowing mice to encode internal navigational maps.

The permanency of spatial memory varies based upon how much attention is applied to navigation, and levels of attention appear to correspond to levels of the neurotransmitter dopamine. In other words, generally speaking, the more attention (and dopamine) that is applied, the more effectively a route will be memorized. Dopamine modulates the effects of learning - acting like a volume knob that controls how much data is converted from short-term into long-term memory.

Thirdly, Dr. Kandel's team studied motor learning, and concentrated their search in the cerebellum (latin for "Little Brain"), known to be the master coordinator of complex movements.

All animals practice complex sets of coordinated movements until they perfect them, from learning to drive a car (for humans) to catching flies with the tongue (for frogs). Their first attempts may be unsuccessful, but with perseverance, eventually there will be mastery. These are procedural memories, a form of motor learning which is central to animal behaviour. And just as with episodic and spatial memory, procedural memory is also dependent upon changes in synaptic strength.

With repeated practice, there will be growth (of new dendrites and synapses) in a "midline" (superior medial) strip atop the brain's outer surface, the motor cortex, which plans and issues commands for voluntary movements - sequences of muscle contractions.

Coordinating the process, the cerebellum sits behind the brainstem at the top of the spine. It acts as a kind of coach, comparing performance - the actual changing positions of limbs, trunk and head in space - with intentions. Through this "feed forward" mechanism, the cerebellum corrects motion, ensuring smooth timing and orchestration of the many muscle contraction signals in complex movements. Learning to orchestrate these movements depends to a large extent upon special Purkinje cells.

Neurons fire when special protein channels embedded in the cell membranes open, allowing electrically-charged ions to flow inward. Among these, the HCN1 ion channel (Hyperpolarization-activated, Cyclic Nucleotide-regulated nonselective cation), is key to motor learning in Purkinje cells of the cerebellum.

To study the role of HCN1 ion channels in motor learning, Dr. Kandel and his team bred mutant mice with neurons that lacked HCN1 channels in different brain regions.

They then ran their mutant mice (along with a control group of normal mice for comparison) through a series of complex motor tests, which included swimming through water mazes and balancing on rods. These tests required complex, repetitive and coordinated motor output. The mice were also conditioned with simpler motor behaviours like eye blinking.

Mice with no HCN1 channels in their Purkinje cells could still perform simple movements like eye blinking, but had extreme difficulty in performing complex behaviours like swimming and balancing. In contrast, mice without HCN1 channels in their forebrain but with normal cerebella had no problem in performing complex behaviours. This shows that HCN1 channels in Purkinje cells are the key to complex motor learning.

When negative currents were applied to Purkinje cells, those lacking HCN1 channels took longer to return to normal firing activity levels than normal Purkinje cells. This means HCN1 channels stablilize Purkinje cells, allowing them to quickly recover from activation and return to normal functioning. In complex, repeated behaviours, Purkinje cells receive repetitive bursts of input, and this ability to recover quickly is vital to influencing motor activity.

In the end, while it is good to understand the principles by which your brain manufactures memory, here is some more practical advice on how to make the most of what you've got:

1. Sleep at least seven to eight hours at a regular time every night

2. Take fish oil supplements

3. Exercise every day

4. Limit or eliminate your intake of alcohol, tobacco, and fatty or sugary foods

5. Pay full attention to what you want to remember

6. Space your learning out; cramming does not help long-term memory retention, especially all-night study sessions.

7. Think of how the information you want to learn relates to you or to things you already know

8. Study a foreign language and a musical instrument

9. Study in the same environment, at the same time every day

10. Keep your study environment free from clutter and distractions

11. Get up and do something different about every 15 minutes before returning to your studies

12. Spend time in mentally stimulating environments where you have new experiences and interact with many different sorts of people from many cultures and backgrounds

13. Reduce your life stresses to a minimum

If you want to read about the Princeton, MIT, Oxford, Harvard, Yale, Tokyo University and other studies upon which these recommendations are based, I invite you to get a copy of my book, The Path Book II. It also explains the different systems of your body, and the science-supported, most effective nutrition, exercise, love, happiness and success advice found in any book to date.

Sunday, August 17, 2014

Learn Physics at Yale, Irvine and MIT for Free!

I teach English to a wide range of students here in Tokyo, from age three to 70, and, while most are elementary, high school and college students,   I also have a few businesspersons and scientists, including medical doctors and theoretical physicists. Since we use textbooks from their particular fields of specialization, it affords me the opportunity to learn a lot on my own.

For one of my PhD candidate students, I have compiled a list of free resources on the Internet for studying physics in English - at the best schools on the planet. Please enjoy:

Fundamentals of Physics 1 - Yale videos:

Course notes:

Fundamentals of Physics 2 - Yale videos:

Course notes:

MIT Quantum Physics I:

MIT Quantum Physics II:

The MIT audio courses are a bit more of a challenge, as they are only audio, with no transcripts:

Physics I: Classical Mechanics:

Physics II: Electricity and Megnetism:

From University of California Irvine. The videos are found by clicking "course lectures" on the left:

Physics I:

Physics II:

Physics III:

Math Methods in Physics:

Classical Physics:

Einstein's General Relativity and Gravitation:

TV series Manhattan (a lot of pop-up advertising you must close to watch):

Monday, August 11, 2014

On the Passing of Robin Williams: A Psychiatric Nurse Explains Suicide

Oregon psychiatric nurse Shauna Hahn shares the following insight into suicide:

RIP Robin Williams.

On the heels of another suicide, the hanging death of a local mother, I feel compelled to share something about the science of suicide. Too often, I have heard or read comments suggesting that the suicide victim was selfish or did not consider her own family, etc. How I educate patients about this serious topic is to liken suicide to having a heart attack. For example, we know the risks for Coronary Artery Disease: smoking, obesity, hypertension, hyperlipidemia, yet a heart attack doubtless feels surprising to its sufferer. Suicide is a lot like this. We know the risks: depression, substance abuse, risk-taking, history of other aggressions, etc yet the great deficiency in serotonin (a happy neurotransmitter or brain chemical implicated in both depression and anxiety) actually happens quite precipitously.

How do we know this? We can measure levels of serotonin metabolites in the cerebral spinal fluid and we find that, in individuals who have completed suicide, their levels are much lower than in individuals simply struggling with depression. And there is no difference in serotonin metabolites of the lightly depressed versus the seriously depressed. These dangerously low levels of serotonin mean that not only do we have despondency and despair but also poor impulse control. What a lethal combination.

Individuals who have survived high lethality suicide attempts (jumping off the Golden Gate bridge, shooting themselves in the head) mostly remark that they "did not know what they were thinking" and allude to being "not in [their] right mind." Obviously, individuals affected by mental illness have serious problems thinking clearly.

Kant believed that suicide was *the* philosophical problem. (He was very punitive and unforgiving in his view). Certainly, I empathize with individuals not being able to "understand" suicide, but what I would definitely encourage would be to at least try.

Do not judge men by mere appearances; for the light laughter that bubbles on the lip often mantles over the depths of sadness, and the serious look may be the sober veil that covers a divine peace and joy. - Edwin Hubbel Chapin, 1845