Sexy neurogenesis

Animal communication is wonderfully diverse, ranging from the dance of a bee, to written language, to a dog urinating on a tree. For many (all?) animal species, the majority of animal communication is strategically targeted with one goal in mind: sex. Most species lack our oratory competence, yet seem to be procreating rather successfully, able to wordlessly identify and attract mates with desirable genetic backgrounds.

Although sight and sound dominate human communication, many animals use smell to exchange information, able to convey age, social status, sexual receptivity, gender, and health with the chemicals released by their bodies. In fact, many species can recognize individuals by their olfactory "signature" alone, allowing, for example, a mother to recognize her young, and preventing siblings from mating with each other.

This type of communication is mediated, in part, by poorly understood chemicals called pheromones. Mammalian pheromones can elicit immediate behavioral responses, such as aggression (when a male mouse detects the urine of another male mouse) or sexual behavior (when a female mouse detects the same). Of course, the behavioral effects of pheromones are context-dependent; in fact, the fiercest, most aggressive mouse fights I’ve ever witnessed arise when lactating females catch a whiff of a novel male mouse, upon which she unleashes a bloody, ferocious attack on his genitals.

Mammalian pheromones can also elicit long-lasting effects that alter the physiological state of the animal. For example, the detection of male pheromones by a juvenile female mouse may result in an advance in the onset of puberty. If, however, a pregnant female mouse detects the pheromones of a novel male mouse (e.g. one who has dueled and defeated her current suitor and the “father” of her embryos), she will terminate her pregnancy. The latter is an act of mercy--if she did not abort her pups, the male mouse would have killed them upon birth, ensuring that his chosen mate devotes her time and efforts solely to his genetic material.

Crucial to these pheromone-elicited behaviors is the ability to recognize and discriminate between pheromones. Such social recognition thus requires olfactory memories; just as the evanescent taste of a madeleine cookie evokes the Belle Époque world of Proust’s childhood, a female mouse can associate the scent and taste of a “special” male mouse’s urine with the protection he offers her and her pups. Such olfactory memories may require not only the olfactory bulb (the neural structure involved in perceiving odors), but also the hippocampus (a structure crucial for certain types of memory formation).

These structures happen to be the two primary locations where new neurons continue to be born into adulthood (a process called adult neurogenesis). Since I began research on adult neurogenesis, I have been captivated by the myriad of factors (e.g. running, stress, pregnancy, cognitive stimulation, a multitude of drugs…) that affect the birth, survival, and functionality of new neurons. Given that such modulation must be functionally advantageous, this plasticity has fascinating implications for the evolution of adult neurogenesis, as well as the impact these neurons may have on neural circuits and behaviors.

One matter that has always intrigued me is that the modulators of neurogenesis affect either hippocampal or olfactory bulb neurogenesis, but not both. Thus, I was excited to see an advance online publication in Nature Neuroscience that sought to link neurogenesis in both structures to mating behavior. The research, performed by Sam Weiss at the University of Calgary, focused on female mice, and the olfactory memories endowing them with the ability to identify and select prospective mates.

The researchers found that week-long exposure to male mouse urine simultaneously increased the birth of new neurons in the hippocampus and a region called the subventricular zone (SVZ, the birthplace of neurons destined for the olfactory bulb). Congruent with female preference for powerful men, this response was specific for the urine of dominant males; exposure to urine of subordinate did not result in enhanced neurogenesis.

Two weeks after exposure to either dominant or subordinate male urine, the females were placed in a test cage, in which they could smell and see, but not contact, both the dominant and subordinate male. Females primed with the dominant male pheromones had a preference for the dominant male (determined by quantification of “sniffing time”), whereas females exposed to the subordinate male did not show a preference. When neurogenesis was inhibited by a chemical treatment, however, the females did not show a preference regardless of the male with which she was "primed," implicating that male pheromone-induced neurogenesis was necessary for olfactory recognition and/or discrimination.

The results imply that the exposure to a dominant male may provide the impetus for a female to form a new olfactory memory, mediated by the birth of new neurons. Her olfactory system, constantly barraged with olfactory signals, lies in wait for a whiff of something enchanting and unique, which calls it to attention and prompts it to take action. These specialized olfactory memories allow her to distinguish the males with the greatest genetic gifts from the undesirables.

Will a raw vegetarian diet make you dumber?

Well, no, but according to a recent news article in Science, the addition of meat and cooked foods to the Homo erectus diet may have led to the dramatic expansion of our ancestors' brains and cognitive abilities.

Between 1.9 million and 200,000 years ago, the brains of our ancestors tripled in size (from 500 cc in Australopithecus to about 1500 cc in Neanderthals), a feat that required a massive increase in energy supply. Brains are rather greedy structures, utilizing 60% of a newborn baby's energy expenditure, and 25% of a resting adult's. In contrast, the average ape brain uses only 8% of the animal's total energy expenditure, despite similar basal metabolic rates. So what led to this glorious caloric upsurge?

One well-supported theory proposes that calorie-dense meat provided the necessary fuel. The high caloric return (not necessarily the high protein content) of meat made it a far more efficient fuel, capable of supporting a 35-55% increase in caloric needs. Moreover, a diet with a greater proportion of meat permits a smaller gut, allowing the allocation of energy saved from digestion and tissue maintenance to feeding the voracious brain. One line of evidence that supports this hypothesis stems from correlational primate studies: capuchin monkeys, which eat an omnivorous diet and have small guts, are considered the most intelligent New World monkeys.; in contrast, Howler monkeys, while bereft of significant brainpower, have large guts to accompany their vegetarian diets.

According to Harvard primatologist Richard Wrangham, "a diet of wildebeest tartare and antelope sashimi alone isn't enough." By breaking down collagen and starches, cooking is a form of pre-digestion, thus lightening the load for the GI tract and allowing greater energy expenditure elsewhere. In one study, pythons fed cooked, ground meat spent 23.4% less energy digesting relative to those which ate raw meat; in another, mice raised on cooked meat gained 29% more weight than mice fed raw meat.

Theoretically, cooking and meat could have provided a great enough surge in calories to fuel the major expansion of our ancestors' brains and cognitive abilities, but the idea is still controversial. Back then, cooking required fire, and evidence for the earliest controlled fires is a bit ambiguous. The earliest such evidence is from about 800,000 years ago, and the earliest evidence for cooking (e.g. hearths) is from no earlier than 250,000 years ago, with questionable evidence dating to 300,000 to 500,000 years ago.

Nevertheless, it's an intriguing explanation for this feature of our evolutionary history. Of course, as we are no longer subjected to the same evolutionary pressures, it's not exactly a recipe for intelligence in modern society. It's possible, according to Wrangham, that "Western food is now so highly processed and easy to digest that...food labels may underestimate net calorie counts and may be another cause of obesity." That said, I love a good barbecue, and in the land of "raw foodies" and "fake stake [sic]," it's refreshing to see meat and cooking receive some due recognition for their delicious role in our natural history.

*For those without a Science subscription, Jake at Pure Pedantry has some key excerpts from the article

Estrogen and the aging brain

As women advance in age, pregnancy and childbirth become increasingly dangerous and destructive. Perhaps to protect us, we women have evolved to be infertile later in life: our ovaries stop producing estrogen, causing our reproductive systems to gradually cease operations. Thus rendered barren, we can devote our maternal resources to mentoring and supporting our children and grandchildren. The rosy "grandmother hypothesis" is, however, not the only theory for the evolutionary origin of menopause.

The cessation of estrogen production also results in a number of debilitating symptoms, such as hot flashes, loss of short-term memory, and declining abilities to concentrate and learn new tasks, which would have put older women at greater risk for predation. Accordingly, some have hypothesized that menopause evolved as a way to "thin the herd," eliminating non-reproductive members of society and leaving food and other resources for the young. (Love you, Gumma!)

[This "culling agent" theory receives little support; the predominant theory as to why cognitive abilities decline is that conditions manifesting later in life (especially after reproductive age) are simply not subjected to the pressures of natural selection.]

Regardless of prehistorical reality, humans have evolved the propensity to thwart nature, creating the pharmaceutical industry and one of its many gifts: hormone replacement therapy (HRT). HRT does not rescue infertility, but is intended to mitigate the other lamentable effects of menopause, such as those impacting cognitive function.

The aging brain, while not suffering from notable cell death (except in conditions like Alzheimer's and Parkinson's Disease), is afflicted by significant changes in the connections (synapses) between neurons, within otherwise intact neural circuits. Certain molecules with essential roles in synaptic communication (e.g. glutamate receptors) change in quantity and location. These molecular changes are accompanied by significant structural alterations to the synapses themselves. Two regions display the greatest vulnerability to these changes: the prefrontal cortex (PFC), involved in attention and working memory, and the hippocampus, involved in many types of memory formation. Although these changes are inevitable concomitants of brain aging, they are exacerbated by the drop in estrogen levels experienced by women undergoing menopause, particularly in the PFC.

Estrogen, like all hormones, acts by traveling through the membrane of a cell to the nucleus, where it switches certain genes on or off, thereby regulating protein production. Of the many genes under the direct control of estrogen are the NMDA receptor (a key molecule for synaptic communication, in particular synaptic plasticity), elements of the cholinergic system (involved in attention and working memory), and genes that influence neuronal survival and structure. In particular, estrogen is known to enhance the number and strength of connections in the PFC of female rhesus monkeys which have had their ovaries removed ("ovariectomized," or OVX). The relevance to the human menopausal situation, however, involving both age and estrogen loss, was heretofore unknown.

A new study by John Morrison at Mt. Sinai School of Medicine investigated this issue by OVXing old and young rhesus monkeys, and treating half of each group with estrogen. The group then tested the monkeys on a task of short-term memory (STM), a component of working memory, in which the monkeys had to remember the location of an object after an increasing delay. They found that aged OVX monkeys which had not received estrogen treatment performed significantly worse than any of the other three groups (aged OVX + estrogen (E), young OVX + E, young OVX), indicative of significant cognitive decline. Moreover, the two groups of young animals performed equivalently, regardless of whether they received estrogen treatment, and the aged OVX + E group performed equally well as the former two. This surprising finding indicates that the estrogen treatment in the aged monkeys was sufficient to improve their cognitive function to levels comparable to their younger peers.

After cognitive testing, the researchers analyzed the brains of all monkeys, discovering that, in the PFC, estrogen increased synaptic density in both young and old OVX monkeys. Highest synaptic density was observed in young OVX + E monkeys, followed by comparable levels between young OVX and aged OVX + E, and lowest density in aged OVX without E. Moreover, estrogen treatment resulted in a significant increase in a particular subpopulation of synapses, which exhibit high dynamism and plasticity.

These findings indicate a complex interplay between estrogen and age, by which "young monkeys without [estrogen] can sustain excellent cognitive function against a background of dynamic spine plasticity." The one-two punch of age and estrogen loss, however, may be sufficiently destructive to impair an animal's cognitive function. By promoting the growth of new, dynamic synapses, estrogen may partially compensate for the effects of aging.

The implication with respect to HRT is that the timing of treatment is crucial. It may be important to begin treatment when ovarian hormone levels just begin to fall, at perimenopause, while synaptic plasticity mechanisms are still robust and resilient. Thus, this study contributes to the enormous body of HRT research (which currently consists of heaps of conflicting information). It has been suggested that the timing of hormonal intervention may underlie many of these contradictory data, and this study may lend some credence to this hypothesis and clear these cloudy waters.

Reference: Hao J et al. Interactive effects of age and estrogen on cognition and pyramidal neurosn in monkey prefrontal cortex. PNAS 2007 Jun 25 [Epub ahead of print].

Free Scientific American!

Scientific American, the oldest continuously published magazine in the United States, is unveiling a new, "appealingly bright, colorful design" and giving away the July issue for free (until June 30). Among the highlights of this issue: neuronal codes and memory formation, gravitational waves, and a debate between Richard Dawkins and Lawrence Krauss on the coexistence of faith and science.

Download your free issue of SciAm here.

Sibling rivalry

A new study in Science reports that the eldest children in families tend to have slightly higher IQs than their younger siblings. The report (brought to my attention by, not surprisingly, my older sister) concluded that the small but significant difference (2.3 IQ points) was not a result of biology, but rather social upbringing.

From The New York Times:

Norwegian epidemiologists analyzed data on birth order, health status and I.Q. scores of 241,310 18- and 19-year-old men born from 1967 to 1976, using military records. After correcting for factors known to affect scores, including parents’ education level, birth weight and family size, the researchers found that eldest children scored an average of 103.2, about 3 percent higher than second children and 4 percent higher than the third-born children. The scientists then looked at I.Q. scores in 63,951 pairs of brothers and found the same results. Differences in household environments did not explain elder siblings’ higher scores.

To test whether the difference could be caused by biological factors, the researchers examined the scores of young men who had become the eldest in the household after an older sibling had died. Their scores came out the same, on average, as those of biological first-borns.

Blame your parents:

Social scientists have proposed several theories to explain how birth order might affect I.Q. scores. First-borns have their parents’ undivided attention as infants, and even if that attention is later divided evenly with a sibling or more, it means that over time they will have more cumulative adult attention, in theory enriching their vocabulary and reasoning abilities.
...

Older siblings [also] consolidate and organize their knowledge in their natural roles as tutors to junior. These lessons, in short, could benefit the teacher more than the student.

Another potential explanation concerns how individual siblings find a niche in the family. Some studies find that both the older and younger siblings tend to describe the first-born as more disciplined, responsible, a better student. Studies suggest — and parents know from experience — that to distinguish themselves, younger siblings often develop other skills, like social charm, a good curveball, mastery of the electric bass, acting skills.

I have failed to develop any such skills (although my Wii-curveball is improving), but all is not lost, little ones! There is a glistening, titillating silver lining to this cloud of inferiority:

Younger siblings often live more adventurous lives than eldest siblings. They are more likely to participate in dangerous sports than eldest children and more likely to travel to exotic places, studies find. They tend to be less conventional in general than first-borns, and some of the most provocative and influential figures in science spent their childhoods in the shadow of an older brother or sister (or two or three or four).

Charles Darwin, author of the revolutionary “Origin of Species,” was the fifth of six children. Nicolaus Copernicus, the Polish astronomer who determined that the Sun, not the Earth, was the center of the planetary system, grew up the youngest of four. René Descartes, the youngest of three, was a key figure in the scientific revolution of the 16th century.

First-borns have won more Nobel Prizes in science than younger siblings, but often by advancing current understanding, rather than overturning it, Dr. Sulloway argued. “It’s the difference between every-year or every-decade creativity and every-century creativity,” he said, “between creativity and radical innovation.”

Link to the NYT article.

Working memory and neuronal calculus

The world offers an awesome, indescribably magnificent profusion of sensory riches. For our meager mortal brains, however, trying to process this deluge of information is akin to taking a drink from Iguaçu Falls: it's tremendously inefficient, and you will likely be violently ripped from your precipice and vanish in a ferocious torrent of natural wonder.

Because the world is too rich for our brains to process at once (or even in a lifetime), we are equipped with mechanisms that restrict the avalanche of information to a manageable trickle. At the level of the brain, this restrictive bottleneck is referred to as attention; when we attend to a certain stimulus, we select it for more comprehensive processing, while relegating the rest to a relatively superficial survey. Importantly, attention endows a capacity limitation onto our brains, not our sensory organs, which latter detect a remarkable embarrassment of sensory details. For example, the sensory neurons on the bottom of your feet are well aware of the pressure exerted by the floor, but you were probably not actively thinking about it until this sentence directed your attention to the sensation.

If our processing ended with attention, we would conduct our lives strictly from information received at the present instant, without any internal state of the mind or abstract thought. But instead of flitting whimsically in and out of our brain, information selected from the world by mechanisms of attention gain access to our working memory, which temporarily holds onto this information for detailed evaluation. For example, when ordering a pizza for delivery, you read from the menu "4-1-5, 6-9-5, 1-6-1-5," hold the sequence in your head, and punch it into your phone. In the interim between reading and dialing, the digits were stored in your working memory, and likely quickly forgotten once you heard the first ring and the number was no longer relevant. In more complex situations, the information in our working memory is the basis for decisions and planning of elaborate behavior, and is thus a critical component in many cognitive processes associated with human "intelligence," such as language.

So what is the neural manifestation of working memory? What happens in your brain between reading and dialing the pizza delivery number? Working memory is dependent on the prefrontal cortex (PFC), which is the region at the very front of the brain, directly behind the forehead. In the monkey PFC (and presumably in that of humans), there are neurons that seem to exhibit many properties of working memory; that is, they are activated by a specific stimulus, and if the stimulus will soon be relevant, they temporarily remain activated even after the stimulus disappears. For example, if a monkey must remember the location of a flash of light for a period of 4 seconds, a certain population of neurons will experience a surge in action potentials in response to the light, and proceed to fire at this elevated rate through the 4-second delay period. When the animal reports the stimulus location, the latter information is no longer relevant, and the population of neurons shuts down accordingly. Such neurons are said to exhibit persistent activity (also called "delay period" activity). Persistent neural activity is thought to represent information about a stimulus even after it is gone, thus reflecting the temporary storage of information, i.e. our working memory.

Persistent neural activity presents an interesting computational complication: action potentials are brief electrical pulses, so how does the system interpret a tonic, persisting pattern of neural activity? In a process called temporal integration (theoretically similar to mathematical integral calculations), the system accumulates information over a certain window of time and "remembers" the sum as a pattern of neural activity. That is, the network dynamics of the circuit can integrate a flurry of brief electrical pulses, and translate the sum into a persistent change in activity. One fundamental question is how the circuitry of neural integrators accomplishes this computational feat, which appears to be so fundamental to working memory.

Emre Aksay of Weill Cornell Medical College, in collaboration with David Tank at Princeton University, recently published a study in Nature Neuroscience that investigated this issue in the neural integrator that controls eye movements in goldfish (the goldfish "oculomotor integrator"). Although goldfish eye movement is not the most intuitive place to study working memory, the goldfish oculomotor integrator is a particularly tractable neural integrator, and may thus provide a framework for understanding similar mechanisms in, for example, our PFC.

Like most animals, goldfish spontaneously move their eyes around, fixating on items of interest (e.g. my finger on the glass of their tank). In order to keep the eyes in that stable, fixed position, the animal must have a sustained neural representation (i.e. a memory) of its eye position, which guides and maintains the activation of the appropriate eye muscles (even if my finger is briefly removed). The oculomotor integrator generates this internal representation by integrating the action potentials of neurons which signal changes in eye position.

When a goldfish is looking to the right, the neurons on the right side of the integrator increase their firing rates (behavior characteristic of a positive feedback system), while those on the left decrease their firing rates. Presumably, the positive feedback occurring on the right is critical for generating persistent firing, thereby enabling integration. However, the connective logic of the circuit that mediates this positive feedback is unknown.

It is known that the oculomotor integrator is a bilateral circuit, with two populations of excitatory neurons (one on each side of the brain); these populations are connected primarily by inhibitory neurons. In light of this neuroanatomy, there are two feasible mechanisms that may mediate positive feedback: a) disinhibition from (in this example) the left side of the integrator or b) excitatory connections between cells on the right side of the integrator.

By using drugs that targeted either excitatory or inhibitory neurons, Aksay and Tank sought to dissect the circuitry of the integrator and solve this dilemma. They found that the persistent activity of the integrator that underlies eye fixation did not require inhibitory neurons, but did require the excitatory connections. However, the inhibitory connections between the right and left sides of the integrator appeared to be important for coordinating the two sides, ensuring that only one has persistent activity at any one time (and thus that the eye only moves in one direction at a time).

And now for the tantalizing extrapolations to which neuroscience lends itself so wonderfully: although the persistent neural activity of discrete neural integrators, (holding a specific set of information in your working memory), does not require inhibitory pathways, the coordination between different integrator circuits (i.e. representations of different sets of information) does. The cornucopia of information presented by our surroundings may require these inhibitory connections to help liaise our working memory at a local level, lest the mayhem of our welter world prevail.

Neuroscience topics explained in 120 seconds

If you're looking to mix some education into your procrastination, the Society for Neuroscience website has a series of free online newsletters "explaining how basic neuroscience discoveries lead to clinical applications." The articles are brief and quite accessible, and include a wide variety of interesting topics, like narcolepsy, phobias, memory enhancers, pheromones, and artificial vision.