Chimpanzees have Alzheimer’s neuropathology including plaques and tangles

Many articles include the premise that Alzheimer’s disease (AD) neuropathology is unique to humans. However, there is a large body of literature suggesting that the characteristic neuropathology of AD, including diffuse amyloid plaques, neuritic amyloid plaques, and abnormally phosphorylated tau, are also seen in some non-human primates.

One of the only exceptions where AD pathology has not been commonly reported is coexisting amyloid plaques and neurofibrillary tangles, although even this has been reported in one chimpanzee.

Coexisting tau and amyloid immunoreactivity in the PFC of a 41-year old chimpanzee; PMC2573460

On the genetic level, tau is identical between chimps and humans, while APP is 99% identical.

It is not that surprising that chimps would have the most similar neuropathology as humans, because chimps (and bonobos) are among the most similar non-human primates to humans.

cladogram based on morphology and genetics from http://anthro.palomar.edu/primate/prim_8.htm

Now, a nice article from Edler et al examines neuropathology from 20 chimpanzees aged 37-62 to directly interrogate the presence of AD neuropathology in a large sample.

The authors scored neuropathology in all 20 chimpanzees in 4 brain regions (PFC, MTG, CA1, CA3) using the following scoring system:

Here were some of their findings:

• All of the chimps had APP/Aβ and Aβ-positive blood vessels, while only 2/3rds had plaques not associated with vessels, suggested that Aβ accumulation near blood vessels may be an early or precursor lesion in chimps.
• Cerebral amyloid angiopathy, which is seen in 80% of AD patients, had a strong association with tau pathology in their chimps, especially pretangle density:

CAA = Cerebral Amyloid Angiopathy; Fig 7B; PMID: 28888720

• On the other hand, Aβ42 levels were not correlated with tau pathology.
• Pretangle and NFT staining in chimps followed the pattern of Braak staging seen in humans.
• In reviewing the literature, they note that only subtle, but not profound, age-related memory decline has been demonstrated in chimps. This may be because chimps have differences in APOE and other factors, but it is also the case that very few studies have directly addressed this question.

Overall, the most important finding from this study confirmed the previous 2008 report from a single chimp that amyloid and tau can coexist species other than humans.

These non-human primate studies shine an important light on the true biology of AD, which is especially important to consider when evolutionary or environmental explanations are invoked to explain the disease.

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No uniformity of cortical microstructure

The sensory cortex contains many columns of vertically arranged neurons that span the width of the cortex, share connectivity, and, importantly, respond to a single peripheral receptive field. This arrangement suggests homogeneity. But that assumption fails upon closer analysis, since cell type, synapse organization, and gene expression differ widely between and within species.

Casanova et al recently reported on their work comparing post-mortem tissue samples of macaques, chimpanzees, and humans in Nissl-stained pyramidal cell columns of the primary visual cortex. They measured the average distance between the central axes of the columns, finding that chimps had the longest average distance (~24-25 micrometers), then humans (~18-19 micrometers), then macaques (~16 micrometers). Also, humans were found to have increased variability in the diameter of their minicolumns as compared to the two other species. There are some evolutionary implications of these findings, namely that the human minicolumns may have been susceptible to reorganization during human evolution.

References

Casanova MF, et al. 2009 Morphometric variability of minicolumns in the striate cortex of Homo sapiens, Macaca mulatta, and  Pan troglodytes. Journal of Anatomy 241:226-234. doi: 10.1111/j.1469-7580.2008.01027

Rakic P. 2008 Confusing cortical columns. PNAS 105:12099-12100. doi: 10.1073/pnas.0807271105

Evolution of peripheral myelin protein 22

The evolution of the protein structure of myelination in jawed vertebrates is fascinating in part because certain vertebrates (i.e., goldfish and zebrafish) have the capability to regenerate myelin. If we could figure out the protein changes underlying this divergence, we could perhaps express genes promoting the expression of these critical proteins in humans and replicate this ability. And even if that lofty goal is not realized, the study of the evolution of myelin protein may yield insight into demyelinating diseases such as multiple sclerosis and leukodystrophy. Of course, none of this is news to those of you who have read my essay on the evolution of myelin proteins in vertebrates!

One of the proteins that I didn’t include due to space constraints and lack of detailed research was peripheral myelin protein-22 (pmp-22). In the peripheral nervous system, this protein interacts with a receptor (the integrin alpha-6 beta-4 subunit) to improve adhesion between the myelin sheath and the basil lamina.

Itou et al recently over-expressed this protein in medaka fish, with approximately 2-fold higher levels of transcription. These fish are relatively normal but have slightly diminished fitness due to diminished nerve conductance velocity and reduced ability to swim against the current. Moreover, the authors found that the sequences coding for pmp-22 have been well preserved throughout jawed vertebrates, even in non-coding motifs. This suggests that it is important to normal function and lowers the probability that differences in myelin phenotype will be due to changes in this protein.

Reference

Itou J, et al. 2009 Functional and comparative genomics analyses of pmp22 in medaka fish. BMC Neuroscience 10:60. doi:10.1186/1471-2202-10-60.

Electromagnetic receptors in humans?

The ability of animals to sense weak magnetic fields is a fascinating ability that as of yet does not have a fully elucidated mechanism. One model has been proposed based on findings from the glass catfish, by Kolomytkin et al. In their model, glycoprotein molecules (which may consist of negatively charged oligosaccharide side chains) are tethered to an ion channel gate in electrorecepting cells. The glycoprotein molecules each contain many negative charges, and the applied electrical and/or magnetic field would exert a force on these glycoprotein molecules. If substantial enough (i.e., if it is greater than the thermal energy associated with one degree of freedom), it would mechanically cause the ion channel to open because they are covalenty bonded to the glycoproteins. If enough of these channels opened, they could sum to an action potential in the sensory neuron.

Using EEG, Marino et al evaluated the likelihood of a magnetic stimuli evoking a post-transduction action potential in ten human subjects. Even with only a 10 ms rise time and a 0.2 ms fall time, field potentials during the onset of the magnetic field occured 100% of the time, and field potentials in the offest of the magnetic field occured 60% of the time. They were able to rule out the possibility that the field potentials resulted from interactions between the field and the scalp electrodes based on other preliminary tests. The fact that the receptor was able to detect such a rapid change (0.2 ms) suggests that the signal transduction process may indeed be initiated by a mechanical force. So although their location has not been pinpointed, it appears that humans also have electromagnetic receptors and that they act through a phylogenetically conserved mechanism.

Reference

Kolomytkin OM, et al. 2007 Glycoproteins bound to ion channels mediate detection of electric fields: A proposed mechanism and supporting evidence. Bioelectromagnetics 28:379-385.

Marino AA, et al. 2009 Evidence that transduction of electromagnetic field is mediated by a force receptor. Neuroscience Letters. doi:10.1016/j.neulet.2009.01.051.

The Adapted Mind book notes, part 2

Here was the first installment, and here are the rest of my notes. As always unless there are brackets please assume that it is a direct quote:

• Women who make more money tend to value monetary and professional status of mates more than those who make less money.
• Those individuals who rise to the top of organizations tend to be bright, initiating, self-assured, decisive, masculine, assertive, persuasive, and ambitious.
• In comparison to high-dominance people, low-dominants smile more often (a gesture of appeasement), are less likely to infringe on another’s personal space, and are more likely to look away from the gaze of others, eyes downcast. Whereas submissives tend to exhibit a drawn-in, slouching posture, dominants tend to have an upright bearing, shoulders straight and head thrown back, and to move with a general ease and freedom of body movements.
• Man’s view of woman as “proprietary” is more than a metaphor: some of the same mental algorithms are apparently activated in the marital and mercantile spheres.
• Women, unlike our nearest relatives, the chimpanzees, have no conspicuous signal of ovulation and relatively little cyclicity of sexual activity. [Possibly because]… the evolving human female was not strictly monogamous.
• Men’s testes are substantially larger, relative to body size, than those of gorillas, a species in which males are polygynous but females mate monogamously so that “sperm competition” within the female reproductive tract is absent. The idea is that such sperm competition selects for high sperm counts and ejaculate volumes and that men evolved in a sexual selective milieu where sperm competition was more extreme than in gorillas.
• Our best guess about the sort of reproductive system in which the human psyche evolved, and to which it is adapted, is one in which mateships were predominantly but not exclusively monogamous, paternal investment was significant, and the variance in reproductive success was slightly greater among men than among women.
• Pregnancy sickness appears to be a lowering of the threshold on the mother’s normal food aversion system, which causes her to avoid or expel previously acceptable foods that can be tolerated by her body but that are too high in toxins for the developing embryo.
• Current hunter-gatherer feeding ecology (although an imperfect model) is characterized by experimentation with a diverse array of food sources.
• Human sensory mechanisms may use toxic diversity as a cue to dietary diversity, so that adding spices to foods mimics the sensation of dietary diversity. Dietary diversity not only ensures adequate nutrition, but prevents overexposure to any one toxin.
• The invention of cooking, which occurred in the middle Pleistocene, expanded the range of plants that could be made edible and thus the range of toxins that humans could include in their diets.
• Nursing and/or carrying twins alone are impossible tasks in many traditional societies; one twin infant is often killed at birth. Usually, either the male or the healthier twin is permitted to live.
• Since the vertebrate eye initially evolved in water, it is sensitive only to a narrow band of wavelengths of electromagnetic radiation, the “spectrum of visible light,” which is transmitted through water without significant attenuation.
• Four features increase the reliability of signal detection in noisy environments: 1) redundancy, 2) conspicuousness, 3) small repertoires, and 4) alerting components.
• [What is the evolutionary reason for play fighting? Interesting explanations are offered.]
• The vocal-auditory channel has some desirable features as a medium of communication: It has a high bandwidth, its intensity can be modulated to conceal the speaker or to cover large distances, and it does not require light, proximity, a face-to-face orientation, or tying up the hands. However, it is essentially a serial interface, lacking the full two-dimensionality needed to convey graph of tree structures and typographical devices such as fonts, subscripts, and brackets.
• In the evolution of the language faculty many “arbitrary” constraints may have been selected simply because they defined parts of a standardized communicative code in the brains of some critical mass of speakers… It is highly adaptive for each member of a community of speakers to be forced to learn to do it the same way as all the other members.
• In different organisms [the brain] has evolved the ability to perform the computations necessary for pollen-source communication, celestial navigation, Doppler-shift echolocation, stereopsis, controlled flight, dam building, sound mimicry, and face recognition.
• There is no reason to think that if you simply pile more and more neurons into a circuit or more and more circuits into a brain that computationally interesting abilities would just emerge. It seems more likely that you would end up with a big random pattern generator. Neural network modeling efforts have suggested that complex computational abilities require either extrinsically imposed design or numerous richly structured inputs during learning or both.
• Mutant fruit flies can have a full leg growing where an antenna should be, and the evolution of new taxa with different numbers of appendages from their ancestors is often attributed to such homeotic mutations.
• [Don’t underestimate the complexity of the life or the linguistic necessities of hunter gatherers, hunting, tracking, and foraging are non-trivial tasks.]
• Although the red and violet spectral colors differ the most widely in physical wavelength, these colors appear more similar to each other than either does to the green of an intermediate wavelength, [this leads to Newton’s color circle.]
• Sex differences for incidental learning of locations in a naturalistic setting were most striking, however; female’s mean scores exceeded males’ by 60 to 70%, for both measures of recognition and recall.
• Water is the one resource that is relatively scarce and unpredictably distributed on the African savannas.
• [Freud] unflinchingly documented the selfish, aggressive, and sexual impulses he found at the root of human motivation.
• Women are better than men at decoding body language, but men are better at noting discrepancies between communication channels that may indicate deception.
• We do not seek reciprocity relationships that involve the mere trading of favors. Instead, we seek relationships based on apparently irrational emotional bonds. Because friends allow debts beyond the available collateral, they provide help when times are hard, which is, of course, when it is needed most.
• [Most of our species’s history was characterized by egalitarianism among males.] Stratification mus therefore be relatively recent. If we assume that our species is on the order of 200,000 years old, then it is likely that stratification has been typical of our societies for less than 10% of that period.
• Whenever a society achieves a relationship among its population density, environment, and technology such that surplus production of food and other goods reliably results, the psychology of our species makes it very likely that social inequality, and, eventually, social stratification will soon follow. [Social exchanges lead to dominance by a few which leads to nepotism.]

You can find the book on Amazon here. Even if some of the topics are not necessary to know in and of themselves, they are useful practice in thinking and reasoning evolutionarily.

Genes coding for neurotrophins in Drosophila

Neurotrophins are growth factor proteins that induce the survival and function of neurons, in large part prenatally but maintained to an extent through the rest of the lifespan as well. Major neurotrophins in vertebrates are nerve growth factor (sensory and sympathetic neurons), brain derived neurotrophic factor (mainly found in the PNS but also the hippocampus and cortex), neurotrophin-3 (activates a diverse set of neurons because of its action on receptor tyrosine kinase in the cell), and neurotrophin-4.

Until recently a fruit fly homologue had not been identified, but Zhu and colleagues recently accomplished just this, which they called drosophila neurotrophin 1 (DNT-1). Just as in vertebrate neurotrophins, DNT-1 promotes cell survival, as its expression in the midline prevents naturally occurring cell death. It has orthologues in many other insects, including mosquitoes, jewel wasp, and honeybees, meaning that it is well-conserved. The authors suggest that there must have been a neurotrophin present in a common ancestor of invertebrates and vertebrates, thus supporting the theory of a common origin for the centralization of the nervous system.

Reference

Zhu B, Pennack JA, McQuilton P, Forero MG, Mizuguchi K, et al. 2008 Drosophila neurotrophins reveal a common mechanism for nervous system formation. PLoS Biol 6(11): e284. doi:10.1371/journal.pbio.0060284

The Adapted Mind book notes, part 1

This primer to evolutionary psychology is really more a tome than a book, as it has many different authors and approaches. Almost all of them are excellent, however. Here are my notes:

• No instance of anything is intrinsically (much less exclusively) either “general” or “particular”–these are simply different levels at which any system of categorization encounters the same world.
• Human architectures are “pre-equipped” (that is, reliably develop) specialized mechanisms that “know” many things about humans, social relations, emotions and facial expressions, the meaning of situations to others, the underlying organization of contingent social actions such as threats and exchanges, language, motivation, and so on.
• [Conscious will]: A belief in beliefs and desires cannot be justified by observations alone, so the fact that it is conventional among humans to “theorize” about others in this fashion is not inexorably mandated by their experience or otherwise required by the structure of the external world. For the same set of nonmandated ideas to have emerged everywhere on earth, our developmental programs or cognitive architectures must impose this way of interpreting the world of other humans on us.
• Why isn’t “flexibility” in the form of content-independence a virtue?… 1) Possibilities are infinite; and 2) desirable outcomes–by any usual human, evolutionary, or problem-solving standard–are a very small subset of all possibilities…. Thus, the property of freely varying behavior in all dimensions independent of conditions is not advantageous: It is evolutionarily and individually ruinous.
• A mechanism unaided by domain-specific rules of relevance, specialized procedures, “preferred” hypotheses, and so on could not solve any biological problem of routine complexity in the amount of time the organism has to solve it, and usually could not solve it at all.
• Over the course of their evolution, humans regularly needed to recognize objects, avoid predators, avoid incest, avoid teratogens when pregnant, repair nutritional deficiencies by dietary modification, judge distance, identify plant foods, capture animals, acquire grammar, attend to alarm cries, detect when their children needed assistance, be motivated to make that assistance, avoid contagious disease, acquire a lexicon, be motivated to nurse, select conspecifics as mates, select mates of the opposite sex, select mates of high reproductive value, induce potential mates to choose them, choose productive activities, balance when walking, avoid being bitten by venomous snakes, understand and make tools, avoid needlessly enraging others, interpret social situations correctly, help relatives, decide which foraging efforts have repaid the energy expenditure, perform anticipatory motion computation, inhibit one’s mate from conceiving children by another, deter aggression, maintain friendships, navigate, recognize faces, recognize emotions, cooperate, and make effective trade-offs among many of these activities, along with a host of other tasks.
• By adding together a face recognition module, a spatial relations module, a rigid object mechanics module, a tool-use module, a fear module, a social-exchange module, an emotion-perception module, a kin-oriented motivation module, an effort allocation and recalibration module, a child-care module, a social-inference module, a sexual-attraction module, a semantic-inference module, a friendship module, a grammar acquisition module, a communication-pragmatics module, a theory of mind module, and so on, an architecture gains a breadth of competences that allows it to solve a wider and wider array of problems, coming to resemble, more and more, a human mind.
• “Learning” is a name given to the unknown agent imagined to cause a large and heterogeneous set of functional outcomes…. We expect that the concept of learning will eventually disappear as cognitive psychologists and other researchers make progress in determining the actual causal sequences by which the functional business of the mind is transacted.
• Other things being equal, men tend to be more strongly sexually attracted to women with whom they have never had sexual relations than they are to women with whom they regularly have sexual relations.
• Is any of the population variance in trait X caused by genetic variance?… [and only if the answer to that is affirmative,] Was trait X per se designed by selection to serve some function; ie, is it an adaptation?
• Human males universally seem to be maximally sexually attracted… to certain physical characteristics indicative of a human female who has recently begun fertile menstrual cycles and who has not yet borne a child…. Women are maximally sexually attracted, other things being equal, to men who exhibit signs of high status.
• Virtually any non simultaneous exchange increases the opportunity for defection, and in nature, most opportunities for change are not simultaneous.
• Generality can be achieved only by sacrificing efficiency.
• [People have specialized mechanisms for detecting cheaters in social contracts but not altruists, this indicates that it is an adaptation based on the need to succeed in the iterated prisoner’s dilemma].
• When the variance in foraging success of the individual is greater than the variance for the band as a whole, band-wide food sharing buffers the variance. This can happen when one individual’s success on a given day is unconnected to that of another. Because it is a relatively high-variance activity, hunting may have been a particularly important driving force in the evolution of cognitive adaptations for social exchange.
• Situations involving threat, social exchange, hazard, rigid-object mechanics, contagion, and so on each activate different sets of functionally specialized procedures that exploit the recurrent properties of the corresponding domain in a way that would have produced an efficacious solution under Pleistocene conditions.
• Human beings in nonagricultural societies devote much time and energy to seeking high-protein food. This takes the form of hunting or fishing, often cooperatively, for vertebrate prey.
• Nowhere do individuals prefer to mate with all members of the opposite sex equally.
• Three classes of cues could provide, in principle, reliable guides to age and hence reproductive capability: (a) physical features (e.g., smooth, clear, and unblemished skin, lustrous hair, white teeth, absence of gray hair), (b) behavioral features (e.g., sprightly and graceful gait, high energy level, alacrity), and (c) reputation (i.e., knowledge gleaned from others regarding the age, health, condition, appearance, behavior, and prior sexual conduct of a female).
• Females are often in the position of relying on cues that are only probabilistically associated with future resources. Two of the best known predictors of economic success in current human populations are sheer hard work (e.g., ambition and industriousness) and intelligence.
• Even in hunting and gathering societies, status variations are substantial. In general, the higher a male is in status (i.e., the higher the level of esteem and influence accorded to him by others), the greater his ability to control resources across many situations.

I hope that many of these ideas have been as counter-intuitive to you as they were to me. More of these notes to come shortly.

Chronicling the evolution of the neocortex in primates

Jon Kaas (2006) discusses some of the research on the evolution of the neocortex throughout mammals. He notes some interesting facets of this process, such as the “late makes great” rule, where brain regions that form late developmentally are especially large in bigger brains. The inference that humans and other large-brained mammals must have an especially large neocortex follows trivially.

He describes early primates as small, nocturnal creatures that spent most of their time feeding in tree branches. This lends credence to the hypothesis that primate brain size increased initiallly due to an opportunity for animals with improved visual and sensorimotor abilities to thrive. Based on the fossil record of extinct and extant primates, the temporal cortex in particular was expanded, which was probably devoted to vision.

Finally, he speculates that the reason for the especially cognitive success of humans is due to excessive modulation of brain regions that chopped them up into more and more areas. These areas were then forced to become more automonous in order to cut down on the need for anatomically long processing.

Semendeferi et al showed that the volume of the frontal lobes had not changed throughout primate evolution. Perhaps this increased specialization hypothesis could explain how executive functions changed so dramatically without altering the volume of the region.

Reference

Kaas JH. 2006 Evolution of the neocortex. Current Biology 16:910-914. Link to PubMed.

Semendeferi K, Damasio H, Frank R, Van Hoesen GW. 1997 The evolution of the frontal lobes: a volumetric analysis based on three-dimensional reconstructions of magnetic resonance scans of human and ape brains. Journal of Human Evolution 32:375-88.

Myelin sheathing originated in placoderms

Zalc et al published a paper earlier this year in Current Biology hypothesizing that vertebrate myelination developed in the now extinct class placoderms. It is a horrificly concise paper (that is a good thing), and their evidence is simple. As compared to ostreostaci, a class that preceded them, placoderm fossils suggest oculomotor nerves that are 10 times longer, despite having oculomotor foramina of similar diameter.

In living animals, a higher ratio of nerve length to diameter is found whenever the nerves are myelinated. This makes sense, because myelin allows action potentials to propagate down nerves faster and with less energy because the potentials can “hop” from one node to the next. Without myelin, another strategy to make nerves longer is to increase axon diameter, which also increases impulse speed, although it comes at the cost of higher energy and space constraints. Therefore, if placoderms are shown to have had a high ratio of nerve length to diameter compared to unmyelinated species, it means that their nerves were most likely myelinated.

Myelin evolution is interesting in particular because some species have the ability to regenerate their myelin when it is damaged (for example, in goldfish), but at some point this ability was lost. If we could figure out the exact mechanism by which myelin sheathing evolved, we could perhaps develop a drug that allowed for myelin regeneration in humans as well.

Reference

Zalc B, Gouget D, Colman D. 2008 The origin of the myelination program in vertebrates. Current Biology (18): 511-512.

The Stuff of Thought book notes

Steven Pinker’s The Stuff of Thought starts off a little bit verbose, but by the end of the book he has really hit his groove, and he uses the architecture that he has built up to make a number of fairly profound points. Here are my notes:

• Linguistics is often studied based on simple intuitions. “Designating a sentence as ‘ungrammatical’ simply means that native speakers tend to avoid the sentence, cringe when they hear it, and judge it as sounding odd.”
• “Language acquisition is an example of the problem of induction — making valid generalizations about the future from limited data available in the present, whether they involve language acquisition by a child, learning by a computer, or theorizing by the scientist.”
• We naturally think about objects geometrically: “when the mind conceptualizes an entity in a location or in motion, it tends to ignore the internal geometry of the object and treat it as a dimensionless point or a featureless blob.”
• Objects are conceptualized as having a certain amount of dimensions; we literally have maps of objects in our brains. He illustrates this fact brilliantly using linguistics.
• On humans trying to do statistics: “It’s as if people heard the statistic that women outlive men on average and concluded that every woman outlives every man. The image of one orb floating above another seems to come more naturally to the mind than an image of two overlapping bell curves.”
• How language works. “We gather our ideas to put them into words, and if our verbiage is not empty or hollow, we might get these ideas across to a listener, who can unpack our words to extract their content.”
• There are two natural systems for keeping track of quantities. “One is an analogue estimation system, in which quantities are gauged in an approximate manner by relating them to some continuous magnitude in the head, such as a vague sense of ‘amount of stuff,’ or the extent of an imaginary line. The second system keeps track of exact quantities, but only up to a small limit, around three or four.” Neither of our innate systems can do complex math, for which you need a number system and language. There is some evidence that the first continuous magnitude one may be on a logarithmic scale–see this post from Columbia’s Statistics blog.
• People report that they “think in” their native language, “but these echoes are not the main event in thinking; most information processing in the brain is unconscious.”
• Enst Poppel believed that “We take life three seconds at a time. That interval, more or less, is the duration of an intentional movement like a handshake; of the immediate planning of a precise movement, like hitting a golf ball….” This is a pretty ambitious theory, but it is interesting. Perhaps the time frame varies a little bit from person to person? Regardless, this should be testable.
• Politeness is about pretending to give the listener options. For example, “would you pass the salt?” is more polite than simply “pass the salt.”
• Evolutionary psychologists believe that aside from language, humans stand out because of their propensity for tools and a talent for cooperation. The former is a manipulation of the physical world, the latter is a manipulation of the social world.
• Evolutionary psychological mechanism for abstract thinking: “Now imagine an evolutionary step that allowed the neural programs that carry out such reasoning to cut themselves loose from actual hunks of matter and work on symbols for just about anything. The cognitive machinery that computes relations among things, places, and causes would then be co-opted for abstract ideas. The ancestry of abstract thinking would be visible in concrete metaphors, a kind of cognitive vestige.”
• Bribing maitre d’s works nearly every time. If you remember one thing from these notes, it is to bribe maitre d’s, you will skip lines in restaraunts nearly every time.
• He deconstructs our courtship patterns brilliantly. Essentially our current practices our built to ensure plausibility deniability for all parties involved. Tactless pick-up attempts are too bold, which is awkward. It’s not about whether the person knows that you’re interested in them, it’s whether they know that you know that they’re interested in you, and whether you know that they know that you know that they’re intersted in you. Seriously.

Pinker’s other work is more famous, but I’d recommend this book wholeheartedly. Just remember to power through those first 100 pages–you’ll be thanking me later.