Why did the Brain develop in the front in most organisms?

I was wondering: why most, well, pretty much all organism with a brain have it right in front of their bodies or at the top.

TL;DR Visual and auditory systems are crucial for survival, especially in higher animals. Also, visual/auditory systems have great number of cells. For processing to be effective, it should be performed closer to data acquisition (eyes).

First of all, for example, in mouse or human, central nervous system includes brain and spinal cord. Since spinal cord is extremely important at regulating different physiological processes as well as in performing complicated motor tasks, it would be unjust to not think about CNS as a whole.

If you talk only about brain part of CNS, it makes sense to locate important processing pathways near sensitive organs for two reasons. First, it saves material on running long axons from many sensory cells. Secondly, longer axons deliver information slower. If there is a sense that is important for survival, than information in that modality must be delivered and processes as quick as possible.

In comments to the question @anongoodnurse mentioned that "butterflies 'taste' with their feet". I would argue that a) taste in butterflies is not vital for immediate survival and b) number of taste buds is very limited, whereas retinal cells are count up to more than thousand per eye.

But what about humans? We also able to "taste with our feet", e.g. feel temperature. For survival it is crucial to be able to escape hot surface as fast as we can. And we do, thanks to a direct reflex arc going from sensory cells to spinal cord and motor neurons. Which brings back point about CNS as a whole system. Crucial information and immediate decisions are made closer to sensitive organs.

I was wondering: why most, well, pretty much all organism with a brain have it right in front of their bodies or at the top.

I believe you're confounding origins. Complex brains -- like those in us and other mammals -- are situated in the position that has been the best-protected over millions of years of evolution.

Evolution did not decide where the front of the animal should be and then put the brain there. Rather, evolutionary pressures resulted in the brain being an excellent survival tool, and the species that could protect it best kept its benefits. It just so happened that, since complex brains require an enormous amount of resources and are quite fragile, wherever the organism could best protect the brain became its "front".

In mammals that became a skull. In some insects it's in the thorax or abdomen. In sea slugs… well, there really isn't a complex brain in sea-slugs… so the difference between their front-end and back-end is pretty minimal. Same with worms and other very simple creatures.

So think of it like this:

Brain = Good for Survival, but Fragile --> Brain Needs Protection --> Wherever Protection is Best = Where the "head"/"front" has evolved

How Many Brain Cells Does a Child Have

A baby is born with roughly 86 billion neurons 𔁯​ , almost all the neurons the human brain will ever have 𔁰​ .

Although a newborn has about the same number of neurons as an adult, it has only 25% of its adult brain volume.

That&rsquos because infant&rsquos neurons are connected by only some 50 trillion neural connections, called synapses, whereas a grownup has about 500 trillion of them 𔁱​ .

This network of synaptic connections will ultimately determine how a child thinks and acts.

What Is Synaptic Pruning in Early Brain Development

Synaptic pruning is the process in which unused neurons and neural connections are eliminated to increase efficiency in neuronal transmissions.

The network of synapses grows rapidly during the first year and continues to do so during toddlerhood.

By age 3, the synaptic connections have grown to 1000 trillion.

But not all of the synapses will remain as the child&rsquos brain grows.

Life experience will activate certain neurons, create new neural connections among them and strengthen existing connections, called myelination.

Unused connections will eventually be eliminated. This is called synaptic pruning 𔁲​ .

Synaptic pruning is the process in which unused neurons and neural connections are eliminated to increase efficiency in neuronal transmissions.

Building massive connections, creating and strengthening them through life experiences and pruning unused ones is a remarkable characteristic of human brains.

This experience-based plasticity allows babies to adapt flexibly to any environment they&rsquore born into without the constraint of too many hardwired neural connections 𔁳​ .

For more help on calming tantrums, check out this step-by-step guide

The Use It Or Lose It Brain Sculpting Property

The benefits of developing a baby&rsquos brain this way are enormous, but so are the costs and the risks 𔁴​ .

First, children require a lot of care, i.e. life experiences, before they can be independent.

Second, what parents do or don&rsquot do during the formative years can have a profound impact on the child&rsquos mental health and life.

Here&rsquos a synaptic pruning example. Let&rsquos say a parent consistently shows a toddler love and care, then the &ldquolove-and-care connections&rdquo will develop or strengthen over time. But if the parent constantly punishes or is harsh to the child, then the &ldquopunitive-and-harsh connections&rdquo will be stronger instead. And because the love-and-care experience is missing, those corresponding brain cells will wither and eventually be removed from the child&rsquos brain circuits. As a result, the child grows up lacking the love-and-care understanding that is essential to create healthy, meaningful relationships in his future life 𔁵​ .

Why The Early Years Matter in Baby Brain Development

Early years of life is a period of unique sensitivity during which experience bestows enduring effects 𔁶​ .

Although this experience-based brain plasticity is present throughout one&rsquos life, a child&rsquos brain is a lot more plastic than a mature one.

Brain cell pruning also occurs most rapidly during a child&rsquos preschool years.

The density of these connections during adulthood will reduce to half of that in a toddler at age two.

This is why nurturing and positive parenting are so important.

Things can go seriously wrong for children deprived of basic social and emotional nurturing.

Critical Periods and Sensitive Periods in the Developing Brain

Within early childhood, there are also windows of time when different regions of the developing brain become relatively more sensitive to life experiences.

These periods of time are called critical periods or sensitive periods.

During a critical period, synaptic connections in those brain regions are more plastic and malleable. Connections are formed or strengthened given the appropriate childhood experiences. After the critical period has passed, the synapses become stabilized and a lot less plastic.

For example, a young child can learn a new language and attain proficiency more easily before puberty. So the sensitive period for language skills mastery is from birth to before puberty.

Another example is emotional regulation. Emotional self-regulation forms the foundation of the brain architecture. It&rsquos a person&rsquos ability to monitor and regulate emotions.

Emotion regulation is not a skill we&rsquore born with. Yet it&rsquos an essential skill in a child&rsquos healthy development 𔁷​ .

The sensitive period of learning this crucial life skill is before a child turns two. Critical or sensitive period is another reason why early life experiences matter so much.

Brain Cells for Socializing

There was little chance of missing the elephant in the room. About a dozen years after Simba died at Cleveland Metroparks Zoo, a half-inch slab of her yellowish, wrinkled, basketball-size brain was laid out before John Allman, a neuroscientist at the California Institute of Technology in Pasadena.

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Preserved in formaldehyde, it looked like half a pancake, frozen solid on a misting bed of dry ice. Allman carefully sliced it using the laboratory equivalent of a deli meat cutter. Taking well over an hour, he carved off 136 paper-thin sections.

Allman was searching for a peculiar kind of brain cell that he suspects is a key to how the African elephant—like a human being—manages to stay attuned to the ever-shifting nuances of social interplay. These spindle-shaped brain cells, called von Economo neurons—named for the man who first described them—are found only in human beings, great apes and a handful of other notably gregarious creatures. Allman, 66, compares the brains of people and other animals to gain insight into the evolution of human behavior.

"Neuroscience seems really reluctant to approach the question of what it is about our brains that makes us human, and John is doing exactly that," says Todd Preuss, a neuroanatomist and anthropologist at the Yerkes National Primate Research Center in Atlanta. "We know very, very little about how our brains differ from other animals', except that our brains are bigger."

The von Economo neurons are the most striking finding of recent years in comparative brain research, in which scientists tease out fine differences among species. Neuroanatomist Patrick Hof and his colleagues at the Mount Sinai School of Medicine in Manhattan first stumbled across the neurons in human brain specimens in 1995, in a region toward the front of the brain called the anterior cingulate cortex. Most neurons have cone- or star-shaped bodies with several branching projections, called dendrites, that receive signals from neighboring cells. But von Economo neurons are thin and elongated, with just one dendrite at each end. They are four times bigger than most other brain cells, and even in species that have the cells, they are rare.

The Manhattan team, it turned out, had rediscovered an obscure cell type first identified in 1881. Hof named the cells after a Vienna-based anatomist, Constantin von Economo, who precisely described the neurons in human brains in 1926 afterward the cells slipped into obscurity. Hof began looking in the brains of deceased primates, including macaque monkeys and great apes—chimps, bonobos, gorillas and orangutans—donated by zoos and sanctuaries. He contacted Allman, who had a collection of primate brains, and asked him to collaborate. In 1999, the scientists reported that all great ape species had von Economo cells, but lesser primates, such as macaques, lemurs and tarsiers, did not. That meant the neurons evolved in a common ancestor of all the great apes about 13 million years ago, after they diverged from other primates but well before the human and chimp lineages diverged about six million years ago.

Although Allman is renowned as a neuroanatomist, it's not surprising to find him delving into larger questions of what it means to be human. His doctorate, from the University of Chicago, was in anthropology, and he has long been fascinated with how the primate brain evolved. He conducted landmark studies with his colleague Jon Kaas, ident­ifying the parts of the owl monkey brain that analyze visual information and make sight possible. In 1974, Allman moved to Caltech, where he studied vision for 25 years. But he also itched to uncover how the basic workings of the human brain shape social behavior. The von Economo neurons immediately captured his interest.

Allman, who is divorced, lives in a 150-year-old brick house in San Marino that he shares with two Australian shepherd dogs, Luna and Lunita. Sepia-toned photographs of his suffragist grandmother hang on the living room wall. Being "notoriously nocturnal," as Allman puts it, he rarely gets to the lab before 1 p.m., leaves in the evening to continue working at home and usually stays up until 2 a.m. His Caltech office is dimly lit by a single window and a small desk lamp it looks like a cave overrun with books and papers. Down the hall, glass slides of gorilla, bonobo and elephant brain tissue, stained blue and brown, lie drying on tables and counters.

From von Economo's work, Allman learned that the unusual cells seemed to reside only in the anterior cingulate cortex (ACC) and one other niche of the human brain, the frontal insula (FI). Brain-scanning studies have established that the ACC and FI are particularly active when people experience emotion. Both areas also seem to be important for "self-monitoring," such as noticing bodily sensations of pain and hunger or recognizing that one has made a mistake. The ACC seems broadly involved in nearly every mental or physical effort.

By contrast, the frontal insula may play a more specific role in generating social emotions such as empathy, trust, guilt, embarrassment, love—even a sense of humor. According to experiments that measure the workings of various brain regions, the area becomes active when a mother hears a crying baby, for instance, or when someone scrutinizes a face to determine the other person's intentions. The FI is where the brain monitors and reacts to "gut feelings" from bodily sensations or interactions within a social network, Allman says. It's the link between self-monitoring and awareness of others that makes it possible for us to understand the feelings of other people. "The basic proposition that I'm advancing," he says, "is the notion that self-awareness and social awareness are part of the same functioning, and the von Economo cells are part of that."

Allman thinks that the neurons expedite communication from the ACC and FI to the rest of the brain. The cells are unusually large, and in the nervous system, size often correlates with speed. "They're big neurons, which I think do a very fast read of something and then relay that information elsewhere quickly," he says. He speculates that as our primate ancestors evolved bigger and bigger brains, they needed high-speed connections to send messages across greater distances. "Large brain size necessarily carries with it a slowing down of communication within the brain," he adds. "So one way of dealing with that is to have a few specialized populations of cells that are pretty fast."

Given that the neurons live in the brain's social hot spots, Allman theorizes that the von Economo cell system allows a rapid, intuitive read on emotionally charged, volatile situations. The neurons "would enable one to quickly adjust to changing social contexts," he speculates. In the ancient past, this neural wiring might have conferred a survival edge to our ancestors by enabling them to make accurate, split-second judgments, especially about whom they could trust or not.

Allman, Hof and their colleagues have looked for von Economo neurons in more than 100 animal species, from sloths to platypuses. Only a few of them, other than primates and elephants, are known to have the cells: humpback whales, sperm whales, fin whales, orcas and bottle-nosed dolphins. The cells presumably evolved in now extinct species that gave rise to those marine mammals some 35 million years ago.

As I watched him section the elephant brain at Caltech, Allman, with colleagues Atiya Hakeem and Virginie Goubert, finally reached the FI of Simba's left hemisphere. Three days later, microscope examination of the brain slices revealed it to be dotted with the distinctive spindle-shaped cells. That confirmed their previous sighting of similar neurons in the FI of Simba's right hemisphere. The elephant cells are larger than human and primate ones, about the size of whale neurons, but the size and shape are unmistakably von Economo neurons.

From counting the von Economo cells in 16 slides—an eye-glazing chore—Hakeem and Allman estimate that there are roughly 10,000 of them in the postage-stamp-size FI on the right side of the elephant brain, or about 0.8 percent of the FI's 1.3 million neurons. Von Economo neurons are more plentiful in the human FI, averaging about 193,000 cells and accounting for about 1.25 percent of all neurons there. In absolute numbers, the human brain has roughly half a million von Economo neurons, far more than the brains of elephants, whales or great apes. Allman and his colleagues have found none in the elephant's closest kin: the anteater, armadillo and rock hyrax. The cells' absence in these species supports Allman's theory that the neurons are a feature of big brains.

Allman speculates that such cells readily evolve from a small set of neurons in the insular cortex that are found in all mammals and regulate appetite. He thinks that while von Economo cells likely evolved to speed information around a big brain, they got co-opted by the demands of social interactions. If he's right, smart, social animals such as whales and elephants might have the same specialized wiring for empathy and social intelligence as human beings.

Whales and elephants, like people and great apes, have large brains and a prolonged juvenile stage during which they learn from their elders. They recognize one another and develop lifelong cooperative relationships. Killer whales hunt in groups and protect injured pod mates. Elephant society is anchored by matriarchs that guide their herds to watering holes they know from previous visits. (And there may be some truth to the belief that elephants never forget: when Allman, Hof and Hakeem made the first high-resolution 3-D image of an elephant brain, in 2005, they found an enormous hippocampus, the brain region where memories are formed.) The sensitive beasts identify each other by their rumblings and trumpet calls, come to each other's aid and seem to mourn their dead.

Allman likes to show a clip from a documentary about a group of African elephants that adopted an orphaned calf. When the baby elephant falls into a water hole, the matriarch quickly marches in, followed by the others. Together she and a second female use their tusks, trunks and legs to free the calf from the muck. Another animal paws at the steep bank with its foot, building a ramp the youngster uses to climb to safety. "It's really remarkable," says Allman of how the elephants rapidly sized up the crisis and worked together to save the baby. "It's a very high sort of functioning that very few animals are able to do. And," he adds with a chuckle, "humans can do it only on good days." The rescue, he says, "captures the essence of really complex, coordinated social behavior."

The idea of the neurons' centrality to social intelligence is gaining ground. Yerkes primatologist Frans de Waal says Allman's "extremely exciting" research dovetails with some of his own investigations of pachyderm intelligence. Two years ago, de Waal and two collaborators reported that a Bronx Zoo elephant named Happy could recognize herself in a mirror. Some scientists theorize that the ability to recognize one's own reflection indicates a capacity for self-awareness and even empathy, useful skills in a highly social species. De Waal points out that only animals that have von Economo neurons can do so.

Yet de Waal also cautions that "until someone establishes the exact function of those cells, it remains a story, basically."

Allman's thoughts about von Economo cells are still evolving. As new data comes in, he discards initial concepts and integrates others. Unlike the stereotypical cautious scientist, he doesn't hesitate to put forward bold hypotheses based on a few observations. The theory that von Economo neurons underlie social cognition is audacious. And it's tempting to seize upon the cells as a simple explanation for the basis of our species' complex social nature. But Allman knows that's a stretch.

His theory has its skeptics. Anthropologist Terrence Deacon, of the University of California at Berkeley, questions whether the neurons are truly a different type of brain cell or are simply a variation that arises in large brains. He says that the differences in our brains that make us human are more likely to have arisen from large-scale changes than from subtle changes in neuron shape. "I don't think it's a very big part of the story," he says of Allman's idea. Yet, he adds, when it comes to understanding the human brain, "so long as we recognize that we have so little to go on, under those circumstances all hypotheses should be entertained."

Point taken. But it's hard not to be seduced by Allman's theory when some of the most compelling evidence comes not from the animal pathology lab but from the medical clinic.

William Seeley, a neurologist at the University of California at San Francisco, studies a poorly understood neurodegenerative disease called frontotemporal dementia. Patients suffer a breakdown in their character, losing social graces and empathy, turning insensitive, erratic and irresponsible. Marriages and careers implode. Many patients seem to lack physical self-awareness: when diagnosed with other illnesses, they deny having any problems. Brain imaging studies of patients with the dementia have uncovered damage to frontal areas of the brain.

In 2004, Seeley heard Allman lecture about von Economo neurons. As Allman clicked through his PowerPoint slides, Seeley saw that the cells were clustered in the same brain regions that the dementia targeted, the ACC and FI. "It was kind of like, Eureka," Seeley recalls. He thought the cells might help researchers figure out why those areas were vulnerable to destruction. "Also, I thought, what an interesting way to learn something about human nature. Maybe the deficits that patients develop might be in things that are uniquely human. So there was a big rush of ideas."

Afterward, over coffee, Seeley and Allman agreed to team up to find out whether von Economo neurons were damaged in people with frontotemporal dementia. Analyzing brains from deceased patients, the scientists discovered that, in fact, about 70 percent of von Economo neurons in the ACC had been destroyed, whereas neighboring brain cells were largely unaffected. "It is very clear that the original target of the disease is these cells, and when you destroy these cells you get the whole breakdown of social functioning," says Allman. "That's a really astounding result that speaks to the function of the cells about as clearly as anything can."

This unusual neural system seems to underlie a lot of what makes us human. But the fact that elephants and whales apparently share the same neural hardware opens the mind to a tilt in perspective: our brains may be more similar to those of other smart, social animals than we thought.

Ingfei Chen lives in Santa Cruz, California.
Photographer Aaron Huey lives in Seattle.

Alcohol Research & Health. 200327(2): 125-133.

Marlene Oscar–Berman, Ph.D., and Ksenija Marinkovic, Ph.D.

Marlene Oscar–Berman, Ph.D., is a professor in the Departments of Anatomy and Neurobiology, Psychiatry, and Neurology, Boston University School of Medicine, and a research career scientist at the U.S. Department of Veterans Affairs Healthcare System, Jamaica Plain Division, Boston, Massachusetts.

Ksenija Marinkovic, Ph.D., is a research scientist at the Athinoula A. Martinos Center for Biomedical Imaging, instructor in the Radiology Department at Harvard Medical School, and assistant in Neuroscience at the Massachusetts General Hospital, Boston, Massachusetts.

This work was supported by National Institute on Alcohol Abuse and Alcoholism grants R37–AA�, K05–AA�, K01–AA�, and by the Medical Research Service of the U.S. Department of Veterans Affairs.

Alcoholism can affect the brain and behavior in a variety of ways, and multiple factors can influence these effects. A person’s susceptibility to alcoholism–related brain damage may be associated with his or her age, gender, drinking history, and nutrition, as well as with the vulnerability of specific brain regions. Investigators use a variety of methods to study alcoholism–related brain damage, including examining brains of deceased patients as well as neuroimaging, a technique that enables researchers to test and observe the living brain and to evaluate structural damage in the brain. Key words: neurobehavioral theory of AODU (alcohol and other drug use) alcoholic brain syndrome brain atrophy neuropsychological assessment neurotransmission risk factors comorbidity disease susceptibility neuroimaging treatment factors survey of research

The brain, like most body organs, is vulnerable to injury from alcohol consumption. The risk of brain damage and related neurobehavioral deficits varies from person to person. This article reviews the many factors that influence this risk, the techniques used to study the effects of alcoholism 1 on the brain and behavior, and the implications of this research for treatment. ( 1 Alcohol dependence, also known as alcoholism, is characterized by a craving for alcohol, possible physical dependence on alcohol, an inability to control one’s drinking on any given occasion, and an increasing tolerance to alcohol’s effects [American Psychiatric Association (APA) 1994].)

About half of the nearly 20 million alcoholics in the United States seem to be free of cognitive impairments. In the remaining half, however, neuropsychological difficulties can range from mild to severe. For example, up to 2 million alcoholics develop permanent and debilitating conditions that require lifetime custodial care (Rourke and Löberg 1996). Examples of such conditions include alcohol–induced persisting amnesic disorder (also called Wernicke–Korsakoff syndrome) and dementia, which seriously affects many mental functions in addition to memory (e.g., language, reasoning, and problem–solving abilities) (Rourke and Löberg 1996). Most alcoholics with neuropsychological impairments show at least some improvement in brain structure and functioning within a year of abstinence, but some people take much longer (Bates et al. 2002 Gansler et al. 2000 Sullivan et al. 2000). Unfortunately, little is known about the rate and extent to which people recover specific structural and functional processes after they stop drinking. However, research has helped define the various factors that influence a person’s risk for experiencing alcoholism–related brain deficits, as the following sections describe.


Alcoholism’s effects on the brain are diverse and are influenced by a wide range of variables (Parsons 1996). These include the amount of alcohol consumed, the age at which the person began drinking, and the duration of drinking the patient’s age, level of education, gender, genetic background, and family history of alcoholism and neuropsychiatric risk factors such as alcohol exposure before birth and general health status. Overall physical and mental health is an important factor because comorbid medical, neurological, and psychiatric conditions can interact to aggravate alcoholism’s effects on the brain and behavior. Examples of common comorbid conditions include:

Medical conditions such as malnutrition and diseases of the liver and the cardiovascular system

Neurological conditions such as head injury, inflammation of the brain (i.e., encephalopathy), and fetal alcohol syndrome (or fetal alcohol effects)

Psychiatric conditions such as depression, anxiety, post–traumatic stress disorder, schizophrenia, and the use of other drugs (Petrakis et al. 2002).

These conditions also can contribute to further drinking.


Some of the previously mentioned factors that are thought to influence how alcoholism affects the brain and behavior have been developed into specific models or hypotheses to explain the variability in alcoholism–related brain deficits. The accompanying table lists the prevailing models (Oscar–Berman 2000). It should be noted that the models that focus on individual characteristics cannot be totally separated from models that emphasize affected brain systems because all of these factors are interrelated. Several of the models have been evaluated using specialized tests that enable researchers to make inferences about the type and extent of brain abnormalities.

Hypotheses Emphasizing the Personal Characteristics Associated With Vulnerability


Premature aging hypothesis: Alcoholism accelerates aging. Brains of alcoholics resemble brains of chronologically old nonalcoholics. This may occur at the onset of problem drinking (“accelerated aging”) or later in life when brains are more vulnerable (“increased vulnerability” or “cumulative effects”).

Alcoholism affects women more than men. Although women and men metabolize alcohol differently, it is not yet clear if women’s brains are more vulnerable than men’s brains to the effects of alcoholism.

Alcoholism runs in families thus, children of alcoholics face increased risk of alcoholism and associated brain changes.

Thiamine deficiency can contribute to damage deep within the brain, leading to severe cognitive deficits.

Hypotheses Emphasizing the Vulnerability of Brain Regions or Systems


Vulnerable to cerebral atrophy.

Limbic system, thalamus, and hypothalamus

Vulnerable to alcohol–induced persisting amnesic disorder (also known as Wernicke–Korsakoff syndrome).

More vulnerable to the effects of alcoholism than other brain regions/systems.

More vulnerable to the effects of alcoholism than the left hemisphere.*

Neurotransmitter systems (e.g., gamma–aminobutyric acid [GABA], glutamate, dopamine, acetylcholine, and serotonin systems)

Several neurotransmitter systems are vulnerable to effects of alcoholism.

*The right hemisphere is also believed to be more vulnerable to the effects of normal aging than the left hemisphere, which is taken as support for the premature aging hypothesis listed above.

NOTE: These hypotheses are not mutually exclusive some are interrelated. Supporting data for these models come from neurobehavioral and electrophysiological studies, brain scans, and post mortem neuropathology.

Models Based on Characteristics of Individual Alcoholics

Premature Aging Hypothesis. According to this hypothesis, alcoholism accelerates natural chronological aging, beginning with the onset of problem drinking.

An alternate version suggests that older patients (age 50 and older) are especially susceptible to the cumulative effects of alcoholism, and aging is accelerated only later in life. The preponderance of scientific evidence suggests that although alcoholism–related brain changes may mimic some of the changes seen in older people, alcoholism does not cause premature aging. Rather, the effects of alcoholism are disproportionately expressed in older alcoholics (Oscar–Berman 2000).

Gender. Although it has been hypothesized that women’s brain functioning is more vulnerable to alcoholism than men’s, studies of gender differences have not consistently found this to be true (see Wuethrich 2001 for a review), even though women and men metabolize alcohol differently (i.e., women achieve higher blood alcohol contents [BACs] than men after consuming the same amount of alcohol). However, it is not known whether this comparison between men and women holds among older populations (Oscar–Berman 2000).

Family History. Family history of alcoholism has been found to be important because it can influence such things as tolerance for alcohol and the amount of consumption needed to feel alcohol’s effects. Also, studies examining brain functioning in people with and without a positive family history of alcoholism have shown that there are clear differences between the groups on measures of brain electrical activity (Porjesz and Begleiter 1998).

Vitamin Deficiency. Research on malnutrition, a common consequence of poor dietary habits in some alcoholics, indicates that thiamine deficiency (vitamin B1) can contribute to damage deep within the brain, leading to severe cognitive deficits (Oscar–Berman 2000). The exact location of the affected parts of the brain and underlying neuropathological mechanisms are still being researched (see the next section).

Models Based on Vulnerable Brain Systems

The outer, convoluted layer of brain tissue, called the cerebral cortex or the gray matter, controls most complex mental activities (see figure 1). Just beneath it are the nerve fibers, called the white matter, that connect different cortical regions and link cortical cells with other structures deep inside the brain (subcortical regions).

Figure 1 Schematic drawing of the human brain, showing regions vulnerable to alcoholism–related abnormalities.

Areas of the brain that are especially vulnerable to alcoholism–related damage are the cerebral cortex and subcortical areas such as the limbic system (important for feeling and expressing emotions), the thalamus (important for communication within the brain), the hypothalamus (which releases hormones in response to stress and other stimuli and is involved in basic behavioral and physiological functions), and the basal forebrain (the lower area of the front part of the brain, involved in learning and memory) (Oscar–Berman 2000). Another brain structure that has recently been implicated is the cerebellum (Sullivan 2000), situated at the base of the brain, which plays a role in posture and motor coordination and in learning simple tasks.

Alcohol–Related Brain Atrophy. According to one hypothesis, shrinkage (i.e., atrophy) of the cerebral cortex and white matter, as well as possible atrophy of basal forebrain regions, may result from the neurotoxic effects of alcohol (Lishman 1990). Furthermore, thiamine deficiency may result in damage to portions of the hypothalamus (perhaps because blood vessels break in that region). According to this hypothesis, alcoholics who are susceptible to alcohol toxicity 2 may develop permanent or transient cognitive deficits associated with brain shrinkage. ( 2 Some people may have better immunity than others to alcohol’s toxic effects.) Those who are susceptible to thiamine deficiency will develop a mild or transient amnesic disorder, with short–term memory loss as the salient feature. Patients with dual vulnerability, those with a combination of alcohol neurotoxicity and thiamine deficiency, will have widespread damage to large regions of the brain, including structures deep within the brain such as the limbic system. These people will exhibit severe short–term memory loss and collateral cognitive impairments (Oscar–Berman 2000).

Frontal Lobe Vulnerability. Although alcoholics have diffuse damage in the cerebral cortex of both hemispheres of the brain, neuropathological studies performed on the brains of deceased patients as well as findings derived from neuroimaging studies of living brains point to increased susceptibility of frontal brain systems to alcoholism–related damage (Moselhy et al. 2001 Oscar–Berman 2000 Sullivan 2000). The frontal lobes are connected with all other lobes of the brain (i.e., the parietal, temporal, and occipital lobes on both halves of the brain see figure 1), and they receive and send fibers to numerous subcortical structures. Behavioral neuroscientists have determined that the anterior region of the frontal lobes (i.e., the prefrontal cortex) is important for engaging in ordinary cognitive, emotional, and interpersonal activities. The prefrontal cortex is considered the brain’s executive—that is, it is necessary for planning and regulating behavior, inhibiting the occurrence of unnecessary or unwanted behaviors, and supporting adaptive “executive control” skills such as goal–directed behaviors, good judgment, and problem–solving abilities. Disruptions of the normal inhibitory functions of prefrontal networks often have the interesting effect of releasing previously inhibited behaviors. As a result, a person may behave impulsively and inappropriately, which may contribute to excessive drinking.

There is evidence that the frontal lobes are particularly vulnerable to alcoholism–related damage, and the brain changes in these areas are most prominent as alcoholics age (Oscar–Berman 2000 Pfefferbaum et al. 1997 Sullivan 2000) (see figure 2). Other studies of frontal lobe function in older alcoholics have confirmed reports of a correlation between impaired neuropsychological performance (e.g., executive control skills, as noted above) and decreased blood flow or metabolism (energy use) in the frontal lobes, as seen using neuroimaging techniques (Adams et al. 1998).

Figure 2 Brain MRI scans of age–equivalent men with different histories of alcohol use. The image shows clear evidence of brain shrinkage in the alcoholic compared with the control subject. The graph on the right shows that older alcoholics have less cortical tissue than younger alcoholics, and that the prefrontal cortex is especially vulnerable to alcohol’s effects. The location of the temporal, parietal, and occipital regions of the brain can be seen in figure 1.

*Z–score is a mathematical measure that is useful for showing the difference between the recorded value and a “normal” value.

SOURCE: Pfefferbaum et al. 1997.

Vulnerability of the Right Hemisphere. Some investigators have hypothesized that functions controlled by the brain’s right hemisphere are more vulnerable to alcoholism–related damage than those carried out by the left hemisphere (see Oscar–Berman and Schendan 2000 for review). Each hemisphere of the human brain is important for mediating different functions. The left hemisphere has a dominant role in communication and in understanding the spoken and written word. The right hemisphere is mainly involved in coordinating interactions with the three–dimensional world (e.g., spatial cognition).

Differences between the two cerebral hemispheres can easily be seen in patients with damage to one hemisphere but not the other (from stroke, trauma, or tumor). Patients with left hemispheric damage often have problems with language patients with right hemispheric damage often have difficulty with maps, designs, music, and other nonlinguistic materials, and they may show emotional apathy.

Alcoholics may seem emotionally “flat” (i.e., they are less reactive to emotionally charged situations), and may have difficulty with the same kinds of tasks that patients with damage to the right hemisphere have difficulty with. New research has shown that alcoholics are impaired in emotional processing, such as interpreting nonverbal emotional cues and recognizing facial expressions of emotion (Kornreich et al. 2002 Monnot et al. 2002 Oscar–Berman 2000). Yet, despite the fact that emotional functioning can be similar in some alcoholics and people with right hemisphere damage, research provides only equivocal support for the hypothesis that alcoholism affects the functioning of the right hemisphere more than the left (Oscar–Berman and Schendan 2000). Impairments in emotional functioning that affect alcoholics may reflect abnormalities in other brain regions which also influence emotional processing, such as the limbic system and the frontal lobes.

Disruption of Neurotransmitter Systems. Brain cells (i.e., neurons) communicate using specific chemicals called neurotransmitters. Neuronal communication takes place at the synapse, where cells make contact. Specialized synaptic receptors on the surface of neurons are sensitive to specific neurotransmitters. Alcohol can change the activity of neurotransmitters and cause neurons to respond (excitation) or to interfere with responding (inhibition) (Weiss and Porrino 2002), and different amounts of alcohol can affect the functioning of different neurotransmitters. Over periods of days and weeks, receptors adjust to chemical and environmental circumstances, such as the changes that occur with chronic alcohol consumption, and imbalances in the action of neurotransmitters can result in seizures, sedation, depression, agitation, and other mood and behavior disorders.

The major excitatory neurotransmitter in the human brain is the amino acid glutamate. Small amounts of alcohol have been shown to interfere with glutamate action. This interference could affect several brain functions, including memory, and it may account for the short–lived condition referred to as “alcoholic blackout.” Chronic alcohol consumption increases glutamate receptor sites in the hippocampus, an area in the limbic system that is crucial to memory and often involved in epileptic seizures. During alcohol withdrawal, glutamate receptors that have adapted to the long–term presence of alcohol may become overactive, and this overactivity has been repeatedly linked to neuronal death, which is manifested by conditions such as stroke and seizures. Deficiencies of thiamine caused by malnutrition may contribute to this potentially destructive overactivity (Crews 2000).

Gamma–aminobutyric acid (GABA) is the major inhibitory neurotransmitter. Available evidence suggests that alcohol 3 initially potentiates GABA’s effects (i.e., it increases inhibition, and often the brain becomes mildly sedated). ( 3 The amount of alcohol needed to cause this effect depends on the person.) However, over time, prolonged, excessive alcohol consumption reduces the number of GABA receptors. When the person stops drinking, decreased inhibition combined with a deficiency of GABA receptors may contribute to overexcitation throughout the brain. This in turn can contribute to withdrawal seizures within a day or two. It should be noted that the balance between the inhibitory action of GABA and the excitatory action of glutamate is a major determinant of the level of activity in certain regions of the brain the effects of GABA and glutamate on withdrawal and brain function are probably interactive (see Valenzuela 1997 for review).

Alcohol directly stimulates release of the neurotransmitter serotonin, which is important in emotional expression, and of the endorphins, natural substances related to opioids, which may contribute to the “high” of intoxication and the craving to drink. Alcohol also leads to increases in the release of dopamine (DA), a neurotransmitter that plays a role in motivation and in the rewarding effects of alcohol (Weiss and Porrino 2002). Changes in other neurotransmitters such as acetylcholine have been less consistently defined. Future research should help to clarify the importance of many neurochemical effects of alcohol consumption. Furthermore, areas amenable to pharmacological treatment could be identified by studying regionally specific brain neurochemistry in vivo using neuroimaging methods such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) (described below). New information from neuroimaging studies could link cellular changes directly to brain consequences observed clinically. In the absence of a cure for alcoholism, a detailed understanding of the actions of alcohol on nerve cells may help in designing effective therapies.


Researchers use multiple methods to understand the etiologies and mechanisms of brain damage across subgroups of alcoholics. Behavioral neuroscience offers excellent techniques for sensitively assessing distinct cognitive and emotional functions—for example, the measures of brain laterality (e.g., spatial cognition) and frontal system integrity (e.g., executive control skills) mentioned earlier. Followup post mortem examinations of brains of well–studied alcoholic patients offer clues about the locus and extent of pathology and about neurotransmitter abnormalities. Neuroimaging techniques provide a window on the active brain and a glimpse at regions with structural damage.

Behavioral Neuroscience

Behavioral neuroscience studies the relationship between the brain and its functions—for example, how the brain controls executive functions and spatial cognition in healthy people, and how diseases like alcoholism can alter the normal course of events. This is accomplished by using specialized tests designed expressly to measure the functions of interest. Among the tests used by scientists to determine the effects of alcoholism on executive functions controlled by the frontal lobes are those that measure problem–solving abilities, reasoning, and the ability to inhibit responses that are irrelevant or inappropriate (Moselhy et al. 2001 Oscar–Berman 2000). Tests to measure spatial cognition controlled by the right hemisphere include those that measure skills important for recognizing faces, as well as those that rely on skills required for reading maps and negotiating two– and three–dimensional space (visuospatial tasks) (Oscar–Berman and Schendan 2000). With the advent of sophisticated neuroimaging techniques (described below), scientists can even observe the brain while people perform many tasks sensitive to the workings of certain areas of the brain.


Researchers have gained important insights into the anatomical effects of long–term alcohol use from studying the brains of deceased alcoholic patients. These studies have documented alcoholism–related atrophy throughout the brain and particularly in the frontal lobes (Harper 1998). Post mortem studies will continue to help researchers understand the basic mechanisms of alcohol–induced brain damage and regionally specific effects of alcohol at the cellular level.


Remarkable developments in neuroimaging techniques have made it possible to study anatomical, functional, and biochemical changes in the brain that are caused by chronic alcohol use. Because of their precision and versatility, these techniques are invaluable for studying the extent and the dynamics of brain damage induced by heavy drinking. Because a patient’s brain can be scanned on repeated occasions, clinicians and researchers are able to track a person’s improvement with abstinence and deterioration with continued abuse. Furthermore, brain changes can be correlated with neuropsychological and behavioral measures taken at the same time. Brain imaging can aid in identifying factors unique to the individual which affect that person’s susceptibility to the effects of heavy drinking and risk for developing dependence, as well as factors that contribute to treatment efficacy.

Imaging of Brain Structure. With neuroimaging techniques such as computerized tomography (CT) and magnetic resonance imaging (MRI), which allow brain structures to be viewed inside the skull, researchers can study brain anatomy in living patients. CT scans rely on x–ray beams passing through different types of tissue in the body at different angles. Pictures of the “inner structure” of the brain are based on computerized reconstruction of the paths and relative strength of the x–ray beams. CT scans of alcoholics have revealed diffuse atrophy of brain tissue, with the frontal lobes showing the earliest and most extensive shrinkage (Cala and Mastaglia 1981).

MRI techniques have greatly influenced the field of brain imaging because they allow noninvasive measurement of both the anatomy (using structural MRI) and the functioning (using functional magnetic resonance imaging [fMRI], described below) of the brain with great precision. Structural MRI scans are based on the observation that the protons derived from hydrogen atoms, which are richly represented in the body because of its high water content, can be aligned by a magnetic field like small compass needles. When pulses are emitted at a particular frequency, the protons briefly switch their alignment and “relax” back into their original state at slightly different times in different types of tissue. The signals they emit are detected by the scanner and converted into highly precise images of the tissue. MRI methods have confirmed and extended findings from post mortem and CT scan studies—namely, that chronic use of alcohol results in brain shrinkage. This shrinkage is most marked in the frontal regions and especially in older alcoholics (Oscar–Berman 2000 Pfefferbaum et al. 1997 Sullivan 2000). Other brain regions, including portions of the limbic system and the cerebellum, also are vulnerable to shrinkage.

Imaging of Brain Function: Hemodynamic Methods. Hemodynamic methods create images by tracking changes in blood flow, blood volume, blood oxygenation, and energy metabolism that occur in the brain in response to neural activity. PET and SPECT are used to map increased energy consumption by the specific brain regions that are engaged as a patient performs a task. One example of this mapping involves glucose, the main energy source for the brain. When a dose of a radioactively labeled glucose (a form of glucose that is absorbed normally but cannot be fully metabolized, thus remaining “trapped” in a cell) is injected into the bloodstream of a patient performing a memory task, those brain areas that accumulate more glucose will be implicated in memory functions. Indeed, PET and SPECT studies have confirmed and extended earlier findings that the prefrontal regions are particularly susceptible to decreased metabolism in alcoholic patients (Berglund 1981 Gilman et al. 1990). It is important to keep in mind, however, that frontal brain systems are connected to other regions of the brain, and frontal abnormalities may therefore reflect pathology elsewhere (Moselhy et al. 2001).

Even though using low doses of radioactive substances that decay quickly minimizes the risks of radiation exposure, newer and safer methods have emerged, such as MRI methods. MRI is noninvasive, involves no radioactive risks, and provides both anatomical and functional information with high precision. The fMRI method is sensitive to metabolic changes in the parts of the brain that are activated during a particular task. A local increase in metabolic rate results in an increased delivery of blood and increased oxygenation of the region participating in a task. The blood oxygenation level–dependent (BOLD) effect is the basis of the fMRI signal. Like PET and SPECT, fMRI permits observing the brain “in action,” as a person performs cognitive tasks or experiences emotions.

In addition to obtaining structural and functional information about the brain, MRI methodology has been used for other specialized investigations of the effects of alcohol on the brain. For example, structural MRI can clearly delineate gray matter from white matter but cannot detect damage to individual nerve fibers forming the white matter. By tracking the diffusion of water molecules along neuronal fibers, an MRI technique known as diffusion tensor imaging (DTI) can provide information about orientations and integrity of nerve pathways, confirming earlier findings from post mortem studies which suggested that heavy drinking disrupts the microstructure of nerve fibers. Moreover, the findings correlate with behavioral tests of attention and memory (Pfefferbaum et al. 2000). These nerve pathways are critically important because thoughts and goal–oriented behavior depend on the concerted activity of many brain areas.

Another type of MRI application, magnetic resonance spectroscopy imaging (MRSI), provides information about the neurochemistry of the living brain. MRSI can evaluate neuronal health and degeneration and can detect the presence and distribution of alcohol, certain metabolites, and neurotransmitters.

Imaging of Brain Function: Electromagnetic Methods. In spite of their excellent spatial resolution—that is, the ability to show precisely where the activation changes are occurring in the brain—hemodynamic methods such as PET, SPECT, and fMRI have limitations in showing the time sequence of these changes. Activation maps can reveal brain areas involved in a particular task, but they cannot show exactly when these areas made their respective contributions. This is because they measure hemodynamic changes (blood flow and oxygenation), indicating the neuronal activation only indirectly and with a lag of more than a second. Yet, it is important to understand the order and timing of thoughts, feelings, and behaviors, as well as the contributions of different brain areas.

The only methods capable of online detection of the electrical currents in neuronal activity are electromagnetic methods such electroencephalography (EEG), event–related brain potentials (ERP), 4 and magnetoencephalography (MEG). ( 4 The ERP method is considered derived from electroencephalography.) EEG reflects electrical activity measured by small electrodes attached to the scalp. Event–related potentials are obtained by averaging EEG voltage changes that are time–locked to the presentation of a stimulus such as a tone, image, or word. MEG uses sensors in a machine that resembles a large hair dryer to measure magnetic fields generated by brain electrical activity. These techniques are harmless and give us insight into the dynamic moment–to–moment changes in electrical activity of the brain. They show when the critical changes are occurring, but their spatial resolution is ambiguous and limited.

ERP and MEG have confirmed that alcohol exerts deleterious effects on multiple levels of the nervous system. These effects include impairment of the lower–level brain stem functions resulting in behavioral symptoms such as dizziness, involuntary eye movement (i.e., nystagmus), and insecure gait, as well as impairment of higher order functioning such as problem solving, memory, and emotion. ERP and MEG are remarkably sensitive to many alcohol–related phenomena and can detect changes in the brain that are associated with alcoholism, withdrawal, and abstinence. That is, these methods show different activity patterns between healthy and alcohol–dependent individuals, those in withdrawal, and those with a positive family history of alcoholism. As shown in figure 3, when brain electrical activity is measured in response to target stimuli (which require the subject to respond in some way) and nontarget stimuli (to be ignored by the subject), the brains of alcoholics are less responsive than the brains of nonalcoholic control subjects. Some of the ERP abnormalities observed in alcoholics do not change with abstinence, and similar abnormalities have been reported in patients who do not drink but come from families with a history of alcoholism. The possibility that such abnormalities may be genetic markers for the predisposition for alcoholism is under intensive scrutiny in studies combining genetic and electromagnetic measures in people with or without a family history of alcoholism (Porjesz and Begleiter 1998).

Figure 3 Brain electrical activity measured as event–related potentials (ERPs) in response to target stimuli (which require the subject to respond in some way) and nontarget stimuli (to be ignored by the subject). The brains of alcoholics are less responsive than the brains of nonalcoholic control subjects. The heights of the peaks are measured in terms of the strength of the electrical signal (volts) recorded from the scalp over time (in thousandths of a second, or mS).

SOURCE: Porjesz and Begleiter 1995.


Because alcoholism is associated with diverse changes to the brain and behavior, clinicians must consider a variety of treatment methods to promote cessation of drinking and recovery of impaired functioning. With an optimal combination of neuropsychological observations and structural and functional brain imaging results, treatment professionals may be able to develop a number of predictors of abstinence and relapse outcomes, with the purpose of tailoring treatment methods to each individual patient. Neuroimaging methods have already provided significant insight into the nature of brain damage caused by heavy alcohol use, and the integration of results from different methods of neuroimaging will spur further advances in the diagnosis and treatment of alcoholism–related damage. Clinicians also can use brain imaging techniques to monitor the course of treatment because these techniques can reveal structural, functional, and biochemical changes in living patients across time as a result of abstinence, therapeutic interventions, withdrawal, or relapse. For example, functional imaging studies might be used to evaluate the effectiveness of drugs such as naltrexone on withdrawal–induced craving. (Naltrexone is an anticraving medicine that suppresses GABA activity.) Additionally, neuroimaging research already has shown that abstinence of less than a month can result in an increase in cerebral metabolism, particularly in the frontal lobes, and that continued abstinence can lead to at least partial reversal in loss of brain tissue (Sullivan 2000). Neuroimaging indicators also can be useful in prognosis, permitting identification and timely treatment of patients at high risk for relapse.

Alcoholics are not all alike they experience different subsets of symptoms, and the disease has different origins for different people. Therefore, to understand the effects of alcoholism, it is important to consider the influence of a wide range of variables. Researchers have not yet found conclusive evidence for the idea that any one variable can consistently and completely account for the brain deficits found in alcoholics. The most plausible conclusion is that neurobehavioral deficits in some alcoholics result from the combination of prolonged ingestion of alcohol, which impairs the way the brain normally works, and individual vulnerability to some forms of brain damage. Characterizing what makes alcoholics “vulnerable” remains the subject of active research.

In the search for answers, it is necessary to use as many kinds of tools as possible, keeping in mind that specific deficits may be observed only with certain methods, specific paradigms, and particular types of people with distinct risk factors. Neuroscience provides sensitive techniques for assessing changes in mental abilities and observing brain structure and function over time. When techniques are combined, it will be possible to identify the pattern, timing, and distribution of the brain regions and behaviors most affected by alcohol use and abuse. Electromagnetic methods (ERP and MEG) specify the timing of alcohol–induced abnormalities, but the underlying neural substrate (i.e., the anatomical distribution of the participating brain areas) cannot be unequivocally evaluated based on these methods alone. Conversely, the hemodynamic methods (fMRI, PET, and SPECT) have good spatial resolution but offer little information about the sequence of events. Drawing on the respective advantages of these complementary methods, an integrated multimodal approach can reveal where in the brain the critical changes are occurring, as well as the timing and sequence in which they happen (Dale and Halgren 2001). Such confluence of information can provide evidence linking structural damage, functional alterations, and the specific behavioral and neuropsychological effects of alcoholism. These measures also can determine the degree to which abstinence and treatment result in the reversal of atrophy and dysfunction.

ADAMS, K.M. GILMAN, S. JOHNSON–GREENE, D. et al. Significance of family history status in relation to neuropsychological test performance and cerebral glucose metabolism studied with positron emission tomography in older alcoholic patients. Alcoholism: Clinical and Experimental Research 22(1): 105�, 1998.

American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: APA, 1994.

BATES, M.E. BOWDEN, S.C. and BARRY, D. Neurocognitive impairment associated with alcohol use disorders: Implications for treatment. Experimental and Clinical Psychopharmacology 10(3):193�, 2002.

BERGLUND, M. Cerebral blood flow in chronic alcoholics. Alcoholism: Clinical and Experimental Research 5:295�, 1981.

CALA, L.A., and MASTAGLIA, F.L. Computerized tomography in chronic alcoholics. Alcoholism: Clinical and Experimental Research 5(2):283�, 1981.

CREWS, F.T. Neurotoxicity of alcohol: Excitotoxicity, oxidative stress, neurotrophic factors, apoptosis, and cell adhesion molecules. In: Noronha, A. Eckardt, M.J. and Warren, K., eds. Review of NIAAA’s Neuroscience and Behavioral Research Portfolio. National Institute on Alcohol Abuse and Alcoholism (NIAAA) Research Monograph No. 34. Bethesda, MD: NIAAA, 2000. pp. 189�.

DALE, A.M., and HALGREN, E. Spatiotemporal mapping of brain activity by integration of multiple imaging modalities. Current Opinion in Neurobiology 11(2):202�, 2001.

GANSLER, D.A. HARRIS, G.J. OSCAR–BERMAN, M. et al. Hypoperfusion of inferior frontal brain regions in abstinent alcoholics: A pilot SPECT study. Journal of Studies on Alcohol 61:32󈞑, 2000.

GILMAN, S. ADAMS, K. KOEPPE, R.A. et al. Cerebellar and frontal hypometabolism in alcoholic cerebellar degeneration studied with positron emission tomography. Annals of Neurology 28:775�, 1990.

HARPER, C. The neuropathology of alcohol–specific brain damage, or does alcohol damage the brain? Journal of Neuropathology and Experimental Neurology 57(2):101�, 1998.

KORNREICH, C. PHILIPPOT, P. FOISY, M.L. et al. Impaired emotional facial expression recognition is associated with interpersonal problems in alcoholism. Alcohol and Alcoholism 37:394�, 2002.

LISHMAN, W.A. Alcohol and the brain. British Journal of Psychiatry 156:635�, 1990.

MONNOT, M. LOVALLO, W.R. NIXON, S.J. and ROSS, E. Neurological basis of deficits in affective prosody comprehension among alcoholics and fetal alcohol–exposed adults. Journal of Neuropsychiatry and Clinical Neuroscience 14:321�, 2002.

MOSELHY, H.F. GEORGIOU, G. and KAHN, A. Frontal lobe changes in alcoholism: A review of the literature. Alcohol and Alcoholism 36:357�, 2001.

OSCAR–BERMAN, M. Neuropsychological vulnerabilities in chronic alcoholism. In: Noronha, A. Eckardt, M.J. and Warren, K. eds. Review of NIAAA’s Neuroscience and Behavioral Research Portfolio. National Institute on Alcohol Abuse and Alcoholism (NIAAA) Research Monograph No. 34. Bethesda, MD: NIAAA, 2000. pp. 437�.

OSCAR–BERMAN, M., and SCHENDAN, H.E. Asymmetries of brain function in alcoholism: Relationship to aging. In: Connor, L.T., and Obler, L.K., eds. Neurobehavior of Language and Cognition: Studies of Normal Aging and Brain Damage. New York: Kluwer Academic Publishers, 2000. pp. 213�.

PARSONS, O.A. Alcohol abuse and alcoholism. In: Nixon, S.J., ed. Neuropsychology for Clinical Practice. Washington, DC: American Psychological Press, 1996. pp. 175�.

PETRAKIS, I.L. GONZALEZ, G. ROSENHECK, R. and KRYSTAL, J.H. Comorbidity of alcoholism and psychiatric disorders. Alcohol Research & Health 26:81󈟅, 2002.

PFEFFERBAUM, A. SULLIVAN, E.V. MATHALON, D.H. and LIM, K.O. Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics. Alcoholism: Clinical and Experimental Research 21:521�, 1997.

PFEFFERBAUM, A. SULLIVAN, E.V. HEDEHUS, M. et al. In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism. Alcoholism: Clinical and Experimental Research 24:1214�, 2000.

PORJESZ, B., and BEGLEITER, H. Event–related potentials and cognitive function in alcoholism. Alcohol Health & Research World 19(2):108�, 1995.

PORJESZ, B., and BEGLEITER, H. Genetic basis of event–related potentials and their relationship to alcoholism and alcohol use. Journal of Clinical Neurophysiology 15:44󈞥, 1998.

RNA scientists identify many genes involved in neuron development

Neurons result from a highly complex and unique series of cell divisions. For example, in fruit flies, the process starts with stem cells that divide into mother cells (progenitor cells), that then divide into precursor cells that eventually become neurons.

A team of the University of Michigan (U-M), spearheaded by Nigel Michki, a graduate student, and Assistant Professor Dawen Cai in the departments of Biophysics (LS&A) and Cell and Developmental Biology at the Medical School, identified many genes that are important in fruit flies' neuron development, and that had never been described before in that context.

Since many genes are conserved across species such as between fruit flies (Drosophila), mice, and humans, what is learnt in flies can also serve as a model to better understand other species, including humans. "Now that we know which genes are involved in this form of neurogenesis in flies, we can look for them in other species and test for them. We work on a multitude of organisms at U-M and we've the potential to interrogate across organisms," explains Michki. "In my opinion, the work we did is one of the many pieces that will inform other work that will inform disease," adds Michki. "This is why we do foundational research like this one."

Flies are also commonly used in many different types of research that might benefit from having a more comprehensive list of the fly genes with their associated roles in neuron cell development.

The discovery

Neurons are made from stem cells that massively multiply before becoming neurons. In the human brain, the process is extremely complex, involving billions of cells. In the fly brain, the process is much simpler, with around 200 stem cells for the entire brain. The smaller scale allows for a fine analysis of the neuronal cell division process from start to finish.

In flies, when the stem cell divides, it yields another stem cell and a progenitor cell. When this last one divides, it makes a so-called precursor cell that divides only once and gives rise to two neurons. Genes control this production process by telling the cells either to divide -- and which particular type of cell to produce -- or to stop dividing.

To this day, only a few of the genes that control this neuron development process have been identified and in this publication in Cell Reports, the scientists have characterized many more genes involved. Along the timeline of the neuron development process, the U-M team could precisely record which genes were involved and for how long.

In particular, at the progenitors' stage, the scientists identified three genes that are important at this stage for defining what 'kind' of neuron each progenitor will make these particular genes had never been described before in this context. They also validated previously known marker genes that are known to regulate the cell reproduction process.

When they applied their analysis technique to the other phases of the neuron development process, they also recorded the expression of additional genes. However, it is still unknown why these genes go up in expression at different steps of the neuron development process and what role they actually play in these different steps. "Now that many candidate genes are identified, we are investigating the roles they play in the neuron maturation and fate determination process," says Cai. "We are also excited to explore other developmental timepoints to illustrate the dynamic changes of the molecular landscape in the fly brain."

"This work provides rich information on how to program stem cell progeny into distinct neuron types as well as how to trans-differentiate non-neuronal cell types into neurons. These findings will have significant impact on the understanding of the normal brain development as well as on neuron regeneration medicine," adds Cheng-Yu Lee, a Professor from the U-M Life Sciences Institute who collaborated with the Cai Lab.

The techniques

This study is mostly based on high-throughput single-cell RNA-sequencing techniques. The scientists took single cells from fruit flies' brains and sequenced the RNA, generating hundreds of gigabytes of data in only one day. From the RNA sequences, they could determine the developmental stage of each neuron. "We now have a very good understanding of how this process goes at the RNA level," says Michki.

The team also used traditional microscope observations to localize where these different RNAs are being expressed in the brain. "Combining in silico analysis and in situ exploration not only validates the quality of our sequencing results, but also restores the spatial and temporal relationship of the candidate genes, which is lost in the single cell dissociation process," says Cai.

At the beginning of their study, the scientists analyzed the large data set with open-source software. Later, they developed a portal (MiCV) that eases the use of existing computer services and allows to test for repeatability. This portal can be utilized for cell and gene data analysis from a variety of organs and does not require computer programming experience. "Tools like MiCV can be very powerful for researchers who are doing this type of research for the first time and who want to quickly generate new hypotheses from their data," says Michki. "It saves a lot of time for data analysis, as well as expenses on consultant fees. The ultimate goal is to allow scientists to focus more on their research rather than on sometimes daunting data analysis tools." The MiCV tool is currently being commercialized.

Why did the Brain develop in the front in most organisms? - Biology

The key kinds of symmetry relevant in the study of organismal biology are radial and bilateral symmetry. In studying the evolutionary development of symmetry in plants and animals, one fascinating element that emerges is that symmetry is not easily broken in natural selection. Evidence of this comes primarily from genetic tests conducted with the fruit fly (Drosophila). For more specific information about these experiments, click here. Some scientists believe that the recorded prevalence of bilateral symmetry in organisms is simply a default result of the fact that most cells do not possess any "symmetry breaking" information. Consequently, the study of asymmet ry in organisms is intriguing, but it is a field of study that is relatively hazy due to the lack of information on cellular differentiation or coordinates of differentiation. Two examples of asymmetrical development in animals are revealed in the lobster claw, which is randomly asymmetrical, and in the coiling pattern of snails, which possess fixed asymmetry. The sponge, which is a fascinating organism in just about every aspect, actually possesses no symmetry at all and no formulaic pattern of asymmetry. For more detailed information, a very technical essay entitled, "From symmetry to asymmetry: Phylogenetic patterns of asymmetry variation in a nimals and their evolutionary significance," is available from the Biology department of the University of Alberta.

Kingdom Animalia

Difference in structural symmetry is one of the guiding elements behind animal diversification and the vertebrate/invertebrate split during an animal's evolutionary history. In tracing the history of biological diversity, biologists have now almost unive rsally agreed on the fact that the animal kingdom is monophyletic, meaning that if one could trace the entire evolutionary tree of animals all the way back to the Precambrian era, all of the branches would converge on one single protistan ancestor.

From that single ancestor, one of the earliest branching points in the hypothetical phylogeny of animals is the place at which multicellular beings with true tissues (eumetazoa) split into those possessing radial symmetry and those possessing bilateral sy mmetry.

Radial Symmetry: A radial animal has a top and a bottom (or an oral and aboral side), but has no head end or rear end and no left or right. Examples of animals possessing radial symmetry are: jellyfishes, corals, anemones, and ctenophora.

Bilateral Symmetry: Bilateral (two-sided) symmetry is the most common form of symmetry possible, and it is found throughout the biological and non-biological world. Animals possessing bilateral symmetry have a dorsal (top) side, a ventral (bottom ) side, an anterior (head) end, a posterior (tail) end, and a distinct left and right side. Associated with bilateral symmetry is the phenomenon of cephalization, which is the evolutionary trend towards the concentration of sensory equipment on the anter ior end this means that such organisms are directionally sensitive and mobile. Generally the anterior, or cephalized, end is the first to encounter food, danger, or other stimuli. Before bipedal development (common in humans and apes), cephalization wa s an adaptation for movement such as crawling, burrowing, or swimming. Examples of animals that possess bilateral symmetry are: flatworms, common worms ("ribbon worms"), clams, snails, octopuses, crustaceans, insects, spiders, brachiopods, sea stars, sea urchins, and vertebrates.

The symmetry of an animal generally fits its lifestyle. For example, many radial animals are sessile forms or plankton and their symmetry equips them to meet their environment equally well from all sides. More active animals are generally bilateral. Th e two forms of symmetry, however, are not absolutely separate. A great deal of radial symmetry is proven to emerge secondarily from a bilateral condition (frequently it emerges from animals adapting to a more sedentary lifestyle). Some animals, such as t he sea urchin, are radially symmetrical, but their embryonic development and internal anatomy show that they arose from a bilaterally symmetrical ancestor.

Images of symmetry in the animal kingdom (according to phyla>:

    (no symmetry) (radial) (bilateral)
  • Arthropoda: Dragonfly | Crayfish (bilateral)
  • An example of the "midplane" in bilateral symmetry.
Kingdom Plantae

Bilateral and radial symmetry are also found in the Plant kingdom symmetry in ggeneral, however, is less significant here that among animals. These forms of symmetry have the most significance in the structure of flowers, which are the points of fertili zation for angiosperms. Unlike the animal kingdom in which organisms with radial symmetry developed out of a nascent bilateral structure, the opposite is true for plants. Many plant phyla have gradually evolved from having radial symmetry to having bila teral symmetry. Much of this is a result of form following function: plants possessing bilateral symmetry are capable of signaling a particular pollinator in the direction of the flowers fertilizing organs. A good way to judge floral symmetry is to plac e flowers in the following categories: 1) fused petals - radial symmetry, 2) free petals, fully open, most often radial symmetry, 3) free petals, closed, most often bilateral.

More Images of Symmetry in Flowers:
Other Biological Implications of Symmetry

Symmetry is a pivotal concept in many other areas of biology, particularly in the study of molecular biology. Molecular biology is ultimately more complex than organismal biology, but if you want to learn more, here are some excellent links to molecular biology pages regarding symmetry:

For a comprehensive list of links to articles and analyses about macromolecular symmetry (primarily proteins) click here.

For an interesting article on dihedral symmetry in cancer cells (warning, this is very technical), go here.

For a great article on the symmetry of the largest macromolecule ever discovered, go here.

For everything you could ever want to know about molecular and structural biology, visit the Nature Magazine Structural Biology site. You will have to logon with a user name, but it's free and seems to have no strings attached.

Mind & Body Articles & More

That’s what Ben’s father says to the camera as we see Ben play in the background. Ben is two years old and doesn’t know that a brain tumor will take his life in a matter of months.

Ben’s father tells us how difficult it is to be joyful around Ben because the father knows what is coming. But in the end he resolves to find the strength to be genuinely happy for Ben’s sake, right up to Ben’s last breath.

Everyone can relate to this story. An innocent treated unfairly, and a protector who seeks to right the wrong—but can only do so by finding the courage to change himself and become a better person.

A recent analysis identifies this “hero’s journey” story as the foundation for more than half of the movies that come out of Hollywood, and countless books of fiction and nonfiction. And, if you take a look, this structure is in the majority of the

Why the brain loves stories

The first part of the answer is that as social creatures who regularly affiliate with strangers, stories are an effective way to transmit important information and values from one individual or community to the next. Stories that are personal and emotionally compelling engage more of the brain, and thus are better remembered, than simply stating a set of facts.

Think of this as the “car accident effect.” You don’t really want to see injured people, but you just have to sneak a peek as you drive by. Brain mechanisms engage saying there might be something valuable for you to learn, since car accidents are rarely seen by most of us but involve an activity we do daily. That is why you feel compelled to rubberneck.

To understand how this works in the brain, we have intensively studied brain response that watching “Ben’s story” produces. We have used this to build a predictive model that explains why after watching the video about half of viewers donate to a childhood cancer charity. We want to know why some people respond to a story while others do not, and how to create highly engaging stories.

We discovered that there are two key aspects to an effective story. First, it must capture and hold our attention. The second thing an effective story does is “transport” us into the characters’ world.

What makes a story effective?

Why do our palms sweat as we watch James Bond fight for his life? Paul Zak is helping find the answer.

Any Hollywood writer will tell you that attention is a scarce resource. Movies, TV shows, and books always include “hooks” that make you turn the page, stay on the channel through the commercial, or keep you in a theater seat.

Scientists liken attention to a spotlight. We are only able to shine it on a narrow area. If that area seems less interesting than some other area, our attention wanders.

In fact, using one’s attentional spotlight is metabolically costly so we use it sparingly. This is why you can drive on the freeway and talk on the phone or listen to music at the same time. Your attentional spotlight is dim so you can absorb multiple informational streams. You can do this until the car in front of you jams on its brakes and your attentional spotlight illuminates fully to help you avoid an accident.

From a story-telling perspective, the way to keep an audience’s attention is to continually increase the tension in the story. Ben’s story does this. How will Ben’s father be able to enjoy his son’s last weeks of life? What internal resources will he draw upon to be strong and support his dying son?

We attend to this story because we intuitively understand that we, too, may have to face difficult tasks and we need to learn how to develop our own deep resolve. In the brain, maintaining attention produces signs of arousal: the heart and breathing speed up, stress hormones are released, and our focus is high.

Once a story has sustained our attention long enough, we may begin to emotionally resonate with story’s characters. Narratologists call this “transportation,” and you experience this when your palms sweat as James Bond trades blows with a villain on top of a speeding train.

Transportation is an amazing neural feat. We watch a flickering image that we know is fictional, but evolutionarily old parts of our brain simulate the emotions we intuit James Bond must be feeling. And we begin to feel those emotions, too.

Stories bring brains together

Emotional simulation is the foundation for empathy and is particularly powerful for social creatures like humans because it allows us to rapidly forecast if people around us are angry or kind, dangerous or safe, friend or foe.

Such a neural mechanism keeps us safe but also allows us to rapidly form relationships with a wider set of members of our species than any other animal does. The ability to quickly form relationships allows humans to engage in the kinds of large-scale cooperation that builds massive bridges and sends humans into space. By knowing someone’s story—where they came from, what they do, and who you might know in common—relationships with strangers are formed.

We have identified oxytocin as the neurochemical responsible for empathy and narrative transportation. My lab pioneered the behavioral study of oxytocin and has proven that when the brain synthesizes oxytocin, people are more trustworthy, generous, charitable, and compassionate. I have dubbed oxytocin the “moral molecule,” and others call it the love hormone. What we know is that oxytocin makes us more sensitive to social cues around us. In many situations, social cues motivate us to engage to help others, particularly if the other person seems to need our help.

When people watch Ben’s story in the lab—and they both maintain attention to the story and release oxytocin—nearly all of these individuals donate a portion of their earnings from the experiment. They do this even though they don’t have to.

This is surprising since this payment is to compensate them for an hour of their time and two needle sticks in their arms to obtain blood from which we measure chemical changes that come from their brains.

How we learn through stories

But it turns out that not all stories keep our attention and not all stories transport us into the characters’ worlds.

We ran another experiment that featured Ben and his father at the zoo to find out why. I should mention that Ben was really a boy with cancer who has now died, and the featured father is really his father. In the zoo video, there is no mention of cancer or death, but Ben is bald and his father calls him “miracle boy.” This story had a flat structure, rather than one with rising tension like the previous story. Ben and his father look at a giraffe, Ben skips ahead to look at the rhino, Ben’s father catches up. We don’t know why we are watching Ben and his father, and we are unsure what we are supposed to learn.

People who watched this story began tuning out mid-way through. That is, their scarce attention shifted from the story to scanning the room or thinking about what to buy at the grocery store after the experiment concluded. Measures of physiologic arousal waned and the empathy-transportation response did not occur. These participants also did not offer much in the way of donations to charity.

This evidence supports the view of some narrative theorists that there is a universal story structure. These scholars claim every engaging story has this structure, called the dramatic arc. It starts with something new and surprising, and increases tension with difficulties that the characters must overcome, often because of some failure or crisis in their past, and then leads to a climax where the characters must look deep inside themselves to overcome the looming crisis, and once this transformation occurs, the story resolves itself.

This is another reason why we look at car accidents. Maybe the person who survived did something that saved his or her life. Or maybe the driver made a mistake that ended in injury or death. We need to know this information.

How stories connect us with strangers

We also tested why stories can motivate us, like the characters in them, to look inside ourselves and make changes to become better people.

Those who donated after watching Ben’s story had more empathic concern of other people and were happier than those who did not donate money. This shows there is a virtuous cycle in which we first engage with others emotionally that leads to helping behaviors, that make us happier. Many philosophical and religious traditions advocate caring for strangers, and our research reveals why these traditions continue to influence us today—they resonate with our evolved brain systems that make social interactions rewarding.

The form in which a narrative is told also seems to matter. The narrative theorist Marshall McLuhan famously wrote in the 1960s that “the medium is the message,” and we’ve found this is true neurologically. The video showing Ben with his father talking on camera is better at both sustaining attention and causing empathic transportation than when people simply read what Ben’s father has to say themselves. This is good news for Hollywood filmmakers and tells us why we cry at sad movies but cry less often when reading a novel.

Does any of this matter to you?

We’ve recently used the knowledge we’ve developed to test stories that seek to motivate positive behavioral changes. In a recent experiment, participants watched 16 public-service ads from the United Kingdom that were produced by various charities to convince people not to drink and drive, text and drive, or use drugs. We used donations to the featured charities to measure the impact of the ads.

In one version of this experiment, if we gave participants synthetic oxytocin (in the nose, that will reach the brain in an hour), they donated to 57 percent more of the featured charities and donated 56 percent more money than participants given a placebo. Those who received oxytocin also reported more emotional transportation into the world depicted in the ad. Most importantly, these people said they were less likely to engage in the dangerous behaviors shown in the ads.

So, go see a movie and laugh and cry. It’s good for your brain, and just might motivate you to make positive changes in your life and in others’ lives as well.


Different human neurons studied at the Allen Institute, part of an effort to chart all the different types of human brain cells.

If you ask Christof Koch, Ph.D., Chief Scientist and President of the Allen Institute for Brain Science, how close we are to understanding our own brains, he scoffs.

&ldquoWe don&rsquot even understand the brain of a worm,&rdquo Koch said.

The lab roundworm, more technically known as Caenorhabditis elegans, houses 302 neurons and 7,000 connections between those neurons in its microscopic body. Researchers have painstakingly mapped and described all those connections in recent years. And we still don&rsquot fully understand how they all work synergistically to give rise to the worm&rsquos behaviors.

We humans have approximately 86 billion neurons in our brains, woven together by an estimated 100 trillion connections, or synapses. It&rsquos a daunting task to understand the details of how those cells work, let alone how they come together to make up our sensory systems, our behavior, our consciousness.

For the 2019 Brain Awareness Week, we asked Koch and his colleagues at the Allen Institute for Brain Science, a division of the Allen Institute, to reflect on how much we still don&rsquot know about the brain &mdash our brain unawareness, if you will &mdash and how these research teams are trying to solve those mysteries.

What is the brain made of?

Reconstructions of human neurons.

The brain consists most obviously of gray matter and white matter, brain tissue and its interconnections or bundles of axons. Look more closely at the former and one can distinguish neurons and glia (the other kind of brain cell). But we&rsquore far from understanding all the types of neurons and other brain cells at the level of what they do.

&ldquoHow can we understand the entire thing if we don&rsquot understand how many different components there are?&rdquo Koch asked.

He and his colleagues sometimes refer to this as discovering the &ldquoperiodic table of brain cell types.&rdquo Chemists have an organized table that describes the 118 known chemical elements &mdash the building blocks of matter &mdash but neuroscientists are lacking such a well-defined categorization of the brain&rsquos building blocks.

It&rsquos human nature, or at least many scientists&rsquo nature, to understand something by categorizing it. When Koch was a kid, the first thing he&rsquod do with a new box of Legos was to sort them into types, he said: &ldquoThe one-by-one, the one-by-two, the two-by-four, etc.&rdquo

Sorting neurons is not as simple. Allen Institute for Brain Science researchers are using several characteristics to define a brain cell type. Different teams at the Institute are sorting cells based on the genes they switch on and off, their detailed shapes, the regions of the brain they connect to, and their unique electrical behavior. Then comes the hard task of putting all that information together to define brain cell types based on all of these attributes.

How does the brain change in disease?

Allen Institute researchers processing human brain tissue.

A big part of understanding the brain&rsquos parts list is so researchers can better understand which cells in the brain might underlie neurological and psychiatric diseases. Many neuropsychiatric disorders do not affect the entire brain uniformly, but rather start in or are driven by specific classes of neurons or other brain cells.

&ldquoRight now, we don&rsquot understand which cell types are vulnerable in these diseases,&rdquo said Boaz Levi, Ph.D., a neuroscientist at the Allen Institute for Brain Science.

If researchers compile the full list of brain cell types, they could then see which types of cells die, grow out of control or otherwise change their course in diseases of the brain. Researchers could then build better tools to study those disease-triggering cells &mdash and possibly therapies that target a single cell type at the heart of disease.

As part of the Allen Institute&rsquos work studying different human brain cell types, Levi and his colleagues develop molecular tools to isolate and track those specific cells. Those tools could potentially be engineered to deliver specific gene therapies or other treatments directly to a certain cell type. The Allen Institute researchers are now collaborating with a team at Seattle Children&rsquos Research Institute to test whether one of these tools could be used to treat Dravet syndrome, an uncommon but severe form of early-childhood epilepsy that is usually caused by a mutation in a single gene and which affects a specific class of neurons.

How do neurons talk to each other?

Electron microscope, or EM, images of a section of the human brain generated at the Allen Institute. This technique allows researchers to map brain tissue down to the level of its individual connections, or synapses.

Biology textbooks tell us that the brain communicates via synapses, specialized connections between two different neurons.

&ldquoWe believe this is true for many neuron types in the brain,&rdquo said Jack Waters, Ph.D., a neuroscientist at the Allen Institute for Brain Science.

The majority of neurons use one of two common signaling molecules known as neurotransmitters, GABA or glutamate, that are known to pass through specialized synapses. But there are many other types of signaling molecules present in the brain, and it&rsquos not clear how those molecules get their message across.

Take, for example, the molecules that most neurological or psychiatric drugs act on.

&ldquoIf you were to scroll through all the drugs that people have heard of, most of them are not acting on glutamate or GABA,&rdquo Waters said. &ldquoWith drugs like opioids or antidepressants, we actually don&rsquot understand the mechanisms of the underlying molecules those drugs are interacting with.&rdquo

It&rsquos a difficult question to answer because it&rsquos so broad, Waters said. But data gathered through a collaborative project known as the IARPA MICrONS project could help. That work, which is partly conducted at the Allen Institute, is creating the largest ever roadmap of connections in the mammalian brain, mapping a piece of the mouse visual cortex the size of a grain of sand that contains about a billion synapses. Once that&rsquos complete, researchers can start to piece together the puzzle of which molecules go with which synapses, Waters said.

How does the brain compute?

Allen Institute researchers in front of the specialized equipment that allows them to capture real-time activity of neurons in the mouse brain as the animal sees different natural images.

If understanding the brain&rsquos makeup is a challenge, figuring out how those billions of components come together to enable all the brain&rsquos complex behavior is even more difficult. The Allen Brain Observatory team aims to capture a small part of that complexity: how a mammal&rsquos brain represents and processes visual information.

Neuroscientists have been studying the visual part of the mammalian brain for decades, but until very recently technology only allowed them to capture information from a handful of neurons at a time. It&rsquos like if you tried to watch a movie but could only see 1000 pixels out of several million on the screen, Koch said.

&ldquoImagine you have to infer who loves whom, who backstabs whom, what&rsquos going on from just those few pixels,&rdquo he said. &ldquoThat&rsquos the situation you have had in neuroscience until recently. You record from a handful of neurons and try to infer some common principles.&rdquo

Researchers on the Observatory team are now looking at tens of thousands of neurons as they fire in real time. As for those principles of computation? So far, there doesn&rsquot seem to be a simple answer, Koch said.

What will it mean to understand our brains?

When we think about understanding something, we often think about being able to explain it in a relatively simple way. In science, researchers in other fields look to physics as a model of understanding, said Koch, who is himself a former physicist. The physical world lends itself to abstractions that can be boiled down to (relatively) simple equations.

But what if biology doesn&rsquot? The more Koch and others at the Allen Institute study the brain at large-scale, looking at many or most cells in the brain rather than just a few, the more they realize that even the parts of neuroscience they thought the field had nailed down are more complicated than anyone had realized.

&ldquoThere may not be any simple path to understanding complex systems shaped by natural selection,&rdquo Koch said. &ldquoEvolution doesn&rsquot care about elegance. The brain doesn&rsquot care if you understand it.&rdquo

So how can we get to an understanding of the brain that will help feed medical research and satisfy our curiosity about this organ that makes us uniquely who we are? It might take more computational power, Koch said. Computer models can help, but we may need a lot of them to explain each little piece of the puzzle. Or it might just mean embracing the power of big data.

The good news is that technology has advanced to the point where we can gather and store that data in larger and larger amounts. And in recent years, there&rsquos been a growing interest in and funding for neuroscience, thanks in part to the 2013 BRAIN Initiative through the National Institutes of Health.

Recombinant Lentiviruses in Neuroscience

Lentiviral biology has been extensively studied since the early 1980s following evidence that human immunodeficiency virus (HIV) was the causative agent of AIDS. Harnessing aspects of this knowledge, gene therapy researchers developed recombinant viral vectors based on HIV (Verma and Somia, 1997 Naldini, 1998), feline, and equine equivalents. Lentivirus is a member of the Retroviridae family of viruses, named because reverse transcription of viral RNA genomes to DNA is required before integration into the host genome. Unlike other retroviral genra, such as gamma-retroviruses that are also used in gene therapy, lentiviruses are able to infect both dividing and non-dividing cells by virtue of the entry mechanism through the intact host nuclear envelope (Naldini, 1998 Vodicka, 2001). This characteristic makes it an ideal viral vector for neuroscience, where the majority of cells in the postnatal brain do not divide.

Lentiviral genomes are single-stranded RNA with gag, pol and env genes encoding polyprotein components of the capsid, the enzymes reverse transcriptase, protease and integrase, and envelope glycoproteins, respectively. The viral genome is flanked by long terminal repeats (LTRs), required for genome replication and integration (Naldini, 1998). Lentiviruses have additional accessory genes, but these are dispensable in recombinant vectors. Instead, a recombinant lentiviral vector genome contains LTRs flanking a packaging signal, plus an exogenous promoter used to express a transgene that enables identification of subpopulations of cells, overexpression or knockdown of genes or to target cells with a drug- or light-inducible protein to analyze cell function (Dull et al., 1998). The genome capacity is 8� kb for maximal packaging efficiency and viral particles are packaged in human cell lines (usually HEK293 derivatives) by co-transfection of helper plasmids encoding gag, pol, and env (Dull et al., 1998). In post-mitotic cells, lentiviral vectors integrate at random, whereas integration preferentially occurs into active genes in mitotically active cells (Bartholomae et al., 2011). An alternative and additional safety aspect for post-mitotic cell transduction is the development of integrase deficient lentiviral vectors (Liu et al., 2014). Removal of the integrase from the packaging construct prevents integration, resulting in episomal maintenance of the transgene vector in post-mitotic cells. Recombinant lentiviral vectors appear to offer greater safety over gamma retroviral vectors in which activation of oncogenes has been reported (Hacein-Bey-Abina et al., 2003 Zhou et al., 2010). Although lentiviral vectors have some limitations, mainly in respect to limited spread within the brain parenchyma, this provides an additional advantage in some cases. Permanent integration of lentiviral delivered transgenes into mitotic or post-mitotic cells, similar to episomal maintenance of integrase-deficient lentivirus or AAV in post-mitotic cells, should allow stable transgene expression for the life of the organism or cell, preventing the need for repeated vector administration (Linterman et al., 2011). An important advantage of lentiviral vectors over other vector systems, including adeno-associated virus (AAV), is that inflammatory, and immune responses associated with the vector itself are limited (Abordo-Adesida et al., 2005 Annoni et al., 2007).

This review highlights how lentiviral vectors have been used in neuroscience research. We focus on targeting gene expression to selected neuronal phenotypes, both spatially and temporally, to answer specific biological questions surrounding gene function and the anatomy and physiology of neural circuits in the mature brain.


In spite of 50 plus years of experimental anatomical and physiological studies of vertebrate brains, there are still vast gaps in our understanding of how they are organized. We know nothing about the physiology of the cerebral cortices in hagfishes, very little about the forebrain organization of cartilaginous fishes, almost nothing about the biological significance of variation in the cerebellum across vertebrates, and virtually nothing about the organization of higher motor centers in any group of vertebrates except mammals. Any comparative neuroanatomist would be hard pressed to list the neural specializations for feeding in ray-finned fishes or flight in birds. We are so intent on constructing a model of how “the brain” is organized that we forget that each vertebrate radiation has evolved unique suits of neural characters that are responsible, in part, for their being able to interact with the world in unique ways.

If Garstang's hypothesis is correct, it will be possible to understand vertebrate brain evolution only within the context of brain development. If this is true, the vast body of data on the organization of adult vertebrate brains represents only the tip of the ontogenetic iceberg. We know almost nothing about the development of most brain centers and pathways across vertebrates. There is every reason—in fact it is necessary—to assume that there is at least as much variation, if not more, in developing brains as in adult brains. A number of developmental “models” (e.g., zebrafish, clawed frogs, chicks and mice) are proving useful in providing insights into many aspects of neural development, but they do not allow us to address most questions concerning the developmental modifications required for the origin of novel features (e.g., the origin and evolution of electroreception).

Finally we need to focus our attention on how ecological factors alter development and thus phylogeny. Many, perhaps most, unique neural characters will be understood only within the broader framework of life history strategies. In spite of Robert Frost's fantasy that some day our arms and legs might atrophy so that only our beached brains remain with the single wish that the tide will rise to “keep our abstract verse from being dry,” brains do not exist in isolation but as parts of complex organisms changing over time.