The Ash Twins Blog

Curtis et al (2004) use the following matrix of images

to test the hypothesis that emotional disgust is an evolved psychological device for avoiding disease. From the abstract:

Over 40 000 individuals completed a web-based survey using photo stimuli. Images of objects holding a potential disease threat were reported as significantly more disgusting than similar images with little or no disease relevance. This pattern of response was found across all regions of the world. Females reported higher disgust sensitivity than males; there was a constant decline in disgust sensitivity over the life course; and the bodily fluids of strangers were found more disgusting than those of close relatives. These data provide evidence that the human disgust emotion may be an evolved response to objects in the environment that represent threats of infectious disease.

Wilson et al (1993) found that having to give reasons for one’s preferences seems to cause human subjects to violate their true preferences. In that study, they asked test subjects to evaluate a set of posters, some of which were paintings (van Gogh or Monet) and some of which were humorously themed. In the control group, subjects just gave a generalized rating of the posters. In the test group, subjects were asked to give reasons for why they preferred particular posters. Control-group subjects preferred the paintings, while test-group subjects preferred the joke posters. Apparently, explaining why one likes a humorous poster is easier than explaining why one likes art. At the end of the experiment, subjects selected a poster to take home with them, and again, control-group subjects mostly selected paintings while reasons-giving subjects mostly selected joke posters. Three weeks later, the experimenters contacted test subjects and inquired about the subjects’ contentment with their selected poster. Control-group subjects generally voiced contentment with their selection, while reasons-giving subjects generally expressed discontentment. The requirement of giving reasons for one’s choices served directly to reduce the benefits subjects accrued from participation in the experiment.

A new book on Winston Churchill throws new light on the lionized figure:

As soon as he could, Churchill charged off to take his part in “a lot of jolly little wars against barbarous peoples.” In the Swat valley, now part of Pakistan, he experienced, fleetingly, an instant of doubt. He realized that the local population was fighting back because of “the presence of British troops in lands the local people considered their own,” just as Britain would if she were invaded. But Churchill soon suppressed this thought, deciding instead that they were merely deranged jihadists whose violence was explained by a “strong aboriginal propensity to kill.”

He gladly took part in raids that laid waste to whole valleys, writing: “We proceeded systematically, village by village, and we destroyed the houses, filled up the wells, blew down the towers, cut down the shady trees, burned the crops and broke the reservoirs in punitive devastation.” He then sped off to help reconquer the Sudan, where he bragged that he personally shot at least three “savages.”

The young Churchill charged through imperial atrocities, defending each in turn. When the first concentration camps were built in South Africa, he said they produced “the minimum of suffering” possible. At least 115,000 people were swept into them and 14,000 died, but he wrote only of his “irritation that kaffirs should be allowed to fire on white men.” …

As war secretary and then colonial secretary in the 1920s, he unleashed the notorious Black and Tans on Ireland’s Catholics, to burn homes and beat civilians. When the Kurds rebelled against British rule in Iraq, he said: “I am strongly in favor of using poisoned gas against uncivilized tribes.” It “would spread a lively terror.” (Strangely, Toye doesn’t quote this.)

Of course, it’s easy to dismiss any criticism of these actions as anachronistic. Didn’t everybody in Britain think that way then? One of the most striking findings of Toye’s research is that they really didn’t: even at the time, Churchill was seen as standing at the most brutal and brutish end of the British imperialist spectrum. This was clearest in his attitude to India. When Gandhi began his campaign of peaceful resistance, Churchill raged that he “ought to be lain bound hand and foot at the gates of Delhi and then trampled on by an enormous elephant with the new Viceroy seated on its back.” …

In 1943, to give just one example, a famine broke out in Bengal, caused, as the Nobel Prize-winning economist Amartya Sen has proven, by British mismanagement. To the horror of many of his colleagues, Churchill raged that it was their own fault for “breeding like rabbits” and refused to offer any aid for months while hundreds of thousands died.

From Baker and George, forthcoming:

We examine whether advertising increases household debt by studying the initial expansion of television in the 1950′s. Exploiting the idiosyncratic spread of television across markets, we use micro data from the Survey of Consumer Finances to test whether households with early access to television saw steeper debt increases than households with delayed access. Results indicate that exposure to television advertising increases the tendency to borrow for household goods and the tendency to carry debt. Television access is associated with higher debt levels for durable goods, but not with the total amount of non-mortgage debt.

The following is an extended excerpt from Floyd Bloom’s Feb 2010 review “The catecholamine neuron: Historical and future perspectives” from Progress in Neurobiology. It provides the best summary I’ve read on the physiology of the noradrenergic modulatory neurotransmitter system. Note that deficits in this neurotransmitter system are hypothesized to underlie attention deficit hyperactivity disorder (ADHD), and the mechanism of action of Ritalin (methylphenidate) and Adderol (amphetamine/dextroamphetamine) is to increase norepinephrine release from noradrenergic neurons. At a visiting-professor lunch, Dr. Aston-Jones told me that, non-intuitively, treatments for ADHD probably work by decreasing stimulus-induced norepinephrine release. A tonic increase of synaptic norepinephrine produced by the drug binds presynaptic alpha-2 autoreceptors and downregulates neurotransmitter release in response to unexpected stimuli. The consequence is a decreased likelihood of breaking one’s attention in response to unimportant environmental stimuli, and an improved ability to focus on the task at hand.

When do LC–NE neurons fire?

Although it was known that the locus ceruleus (LC) was the source of NE axonal projections across most of the neuraxis except the hypothalamus, direct electrophysiological observation of the firing patterns of these neurons was delayed until the mid-1970s, first in anesthetized rodents (Korf et al., 1974) and then in unanesthetized, freely behaving rats ([Aston-Jones and Bloom, 1981a] and [Aston-Jones and Bloom, 1981b]) and monkeys (Foote et al., 1980). The observations in the freely behaving animals greatly refined the anticipated functional repertoire of the LC neurons. In the anesthetized animal recordings, an early common feature was responsiveness to nociceptive stimuli, such as pressure on a paw or the tail; in fact, this nociceptive response was employed as one of the identifying electrophysiological parameters of LC neurons. From this response pattern, investigators predicted that LC discharge, and release of norepinephrine would generate anxiety as a functional consequence. However, when the discharge patterns of LC neurons were repeated in freely behaving rats and monkeys, these response patterns could be re-interpreted: instead of responding only to painful stimuli, LC neurons exhibited a more general and subtle pattern of activity: a slow, tonic, basal discharge rate, but with brief phasic responses to novel sensory stimuli of all kinds—visual, auditory, somato-sensory and gustatory. Furthermore, these neurons showed an interesting correlation between neuronal firing rate and wakefulness, with progressive diminution of already slow basal activity as the animals engagement with its environment decreased, and complete silencing of activity as the animal entered rapid eye movement sleep.

Just as the functional significances of the firing patterns of the DA neurons was refined from a simple ‘firing with reward’ concept to a more refined and biologically more profound functional consequence of error prediction, so has the insight into the behavioral consequences of the LC firing patterns been refined: from an initial, nociceptive-anxiety prediction, to more a general sensory events-alerting, with an attentional prediction.

(Aston-Jones and Cohen, 2005a) and (Aston-Jones and Cohen, 2005b) have taken these observations to a further refined interpretation with an integrative theory of locus coeruleus-norepinephrine function, that they term ‘adaptive gain and optimal performance’ invoking a more complex and specific role in the control of behavior than was previously thought. In their view, phasic LC activation is driven by the outcome of task-related decision processes and is proposed to facilitate ensuing behaviors and to help optimize task performance (exploitation). When the subject’s engagement in the task wanes, LC neurons revert to a slow tonic firing. They further note that in the non-human primate (and presumably also in man) the LC receives substantive inputs from the anterior cingulate cortex and the orbitofrontal cortices. As mentioned earlier, in the now-classic immunohistochemical mapping studies of Lewis and Morrison (see [Lewis et al., 1986] and [Lewis and Morrison, 1989]), these are precisely the forebrain regions with the most dense innervation by LC fibers, and are forebrain regions later shown by (Aston-Jones and Cohen, 2005a) and (Aston-Jones and Cohen, 2005b) and their co-workers that also send direct afferent connections to the LC neurons.

Aston-Jones and Cohen further propose that it is the output of these cortical afferent systems, known to monitor task-related utility that confers on the LC’s broad output the capacity to optimize utility on both short and long timescales. Cohen and his co-workers have expanded our views of these LC discharge patterns together with the post-excitatory refractory period attributed to noradrenergic collateral signals within the locus coeruleus to attribute to these neurons a role in attentional blink, a temporary deficit in processing of a target stimulus following successful processing of a previous target (Nieuwenhuis et al., 2005). Those observations, together with analyses of human visual and auditory discrimination tasks have created a very plausible case for attributing the p300 event related potential recorded with scalp electrodes in man to the novelty detection and attention focusing consequences of LC activation. Furthermore, when one considers the relatively short latency with which the LC neurons react to a salient and unexpected sensory stimulus (around 100 ms), the firing of LC axons to the cortex would allow for the synchronous activity at the tempero-parietal junction that is presently thought to be the origins of the P300 (see Aston-Jones and Cohen, 2005a G. Aston-Jones and J.D. Cohen, Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance, J. Comp. Neurol. 493 (2005), pp. 99–110. View Record in Scopus | Cited By in Scopus (53)[Aston-Jones and Cohen, 2005a], [Aston-Jones and Cohen, 2005b] and [Corbetta et al., 2008]).

What does NE do to target neurons?

As has been noted in many prior reviews, the initially reported effects of iontophoretically administered norepinephrine was to suppress the spontaneous activity of cerebellar Purkinje cells, dentate granule and hippocampal pyramidal neurons, and cerebro-cortical pyramidal neurons ([Aston-Jones et al., 1998], [Berridge and Waterhouse, 2003] and [Foote et al., 1983]). More in depth analysis, however, revealed that while basal activity was suppressed, the responses to spontaneous or evoked afferents was enhanced, both for excitatory and for inhibitory inputs; these sorts of modulatory effects help establish in my mind, if not for others, the dynamic synaptic vocabulary for monoamine neurons that I have long envisioned (Bloom, 1973). While we have long attributed most of this ‘enabling’ action to the transductive consequences of the beta-receptor and intracellular generation of cyclic adenosine monophosphate (Bloom et al., 1975), there are also reports that the actions of locally applied NE in cerebellum and hippocampal formation can be better antagonized by systemic alpha blockers than by beta blockers (Staunton et al., 1988). This is clearly an inconsistency that deserves further attention. One possibility for this discrepancy is that alpha-1 adrenergic receptors, like D1 dopaminergic receptors have a higher affinity for the natural ligand and their antagonists than the beta-adrenergic receptor and the D2 receptors (see [Arnsten and Goldman-Rakic, 1987] and Arnsten et al., 1999 A.F. Arnsten, R. Mathew, R. Ubriani, J.R. Taylor and B.M. Li, Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function, Biol. Psychiatry 45 (1999), pp. 26–31. Article | PDF (98 K) | View Record in Scopus | Cited By in Scopus (98)[Arnsten et al., 1999]).

See previous posts on history, symptoms, neurophysiology, genetics, molecular biology, targets of UbE3A , and systems pathophysiology of Angelman Syndrome.

The laughing, happy demeanor with little or no verbalization is the most distinctive, unusual, and interesting aspect of Angelman syndrome. At the current state of the field, neuroscience has no good way to study the neural basis of this fascinating phenotype. Outside the AS field, some attempts have been made to study the happiness circuit. In one functional MRI study, for example, professional actors placed themselves into a happy or sad affect while in the scanner (Pelletier et al 2003). Nonoverlapping loci within the same regions (orbitofrontal, left medial prefrontal, left ventrolateral prefrontal, left uncus, and right pons) were identified for each emotion.

Addiction researchers have identified hedonic circuits in the midbrain and striatum and circuits for negative affect in the extended amygdala and insula (Koob & Volkow 2010). In humans, primates, and rodents, similar behaviors are predictably associated with hedonic experience (Berridge & Kringelbach 2008). Although many brain regions demonstrate activity associated with reward, stimulation of only a few small hotspots by themselves increase the probability of these hedonic behaviors.  From stimulation experiments, it appears that only the nucleus accumbens shell, the ventral pallidum, and the pontine parabrachial nucleus are causative areas for pleasure (Berridge & Kringelbach 2008). Humans report that stimulation of the nucleus accumbens causes pleasurable sensations, and rodents will voluntarily stimulate the nucleus accumbens until they die. Infusion of opioids or cannabinoids into these hotspots prior to stimulation multiplies the hedonic reaction. The ventral pallidum may be the most important node in the pleasure circuit, as it is only by lesion to this region that hedonic reactions to pleasurable stimuli can be abolished.  An interesting hypothesis is that in AS, circuit malfunction leads to hyperactivity in these areas. Measuring the fMRI BOLD activity in AS patients or recording electrical activity in the AS mouse model in these pleasure-linked areas would test this hypothesis.

Otherwise, we can philosophize: Do these patients behave this way because they are locked into a perpetual state of joy, or are their behavioral circuits so degraded that the only one that is intact is happy laughter? The subjective feeling of pleasure (mood) and the behavioral signs of pleasure (affect) are dissociable, and it is possible that in AS the latter occurs without the former. Circumstantial evidence that AS patients do experience authentic joy comes from the fact that their laughter and happy affect are not random, but tied to things that a child may find humorous; slap-stick humor, for example, is especially popular among AS patients (Clayton-Smith & Laan 2003). Given the mild neuropathological findings of AS and the rescue of neurological deficits in the AS mouse by a single-amino acid CaMKII mutation, one may be sanguine that drugs targeting these pathways or gene therapy restoring maternally-imprinted UbE3A could significantly ameliorate the symptoms of AS. In this scenario, we would be able to ask cured AS patients about their internal state and determine if they really had been in a permanent state of gaiety. And if that were the case, would a cure be ethical?

Berredge K, Kringelbach M (2008) “Affective neuroscience of pleasure: reward in humans and animals.” Psychopharmacology 199:457–480

Clayton-Smith J, Laan L. (2003) “Angelman syndrome: a review of the clinical and genetic aspects.” J Med Genet. 40(2):87-95. Review.

Koob GF, Volkow ND. (2010) “Neurocircuitry of addiction.” Neuropsychopharmacology. 35(1):217-38.

Pelletier M, Bouthillier A, Lévesque J, Carrier S, Breault C, Paquette V, Mensour B, Leroux JM, Beaudoin G, Bourgouin P, Beauregard M. (2003) “Separate neural circuits for primary emotions? Brain activity during self-induced sadness and happiness in professional actors.” Neuroreport. 14(8):1111-6.

See previous posts on history, symptoms, neurophysiology, genetics, molecular biology, and targets of UbE3A in Angelman Syndrome.

Angelman Syndrome (AS) is a neurological syndrome which causes patients to be excessively cheerful, giggling, and happy, and mentally retarded with very little or no language. AS occurs when the protein ubiquitin E3A ligase (UbE3A) is lost due to abnormal methylation/imprinting of a region of chromosome 15. UbE3A recognizes proteins and attaches a ubiquitin to them, which causes the proteins to be degraded in the proteasome. Loss of UbE3A in Angelman Syndrome would prevent these proteins from being degraded and lead to an excess of them in cells. In the previous post, I described the known functions of the ubiquitination targets of UBE3A. The three most relevant targets are 1) Arc – a protein which regulates synaptic strengths in response to neuronal activity;  2) Ephexin5 – a rho-GEF which regulates cytoskeletal remodeling to restrict synapse number;  and 3)Sacsin – A proteasome-related protein which is important in large neurons of the motor system.

Although the advances in our molecular and genetic understanding of Angelman Syndrome (AS) are commendable, what these changes mean for organ systems and the organism is not obvious. This disconnect is not unique to AS pathophysiology. It is problematic for investigators studying all neurobiological diseases to link identified molecular lesions with neural and behavioral dysfunction. To alleviate this situation, investigators study animal models of disease at the systems (in this case, the nervous system) level.

Fortunately for those interested in AS, a heterozygous ubiquitin E3A (UbE3A) knockout inherited from the mother recapitulates a neurodevelopmental disorder approximating AS in mice (Jiang et al 1998). These mice exhibit motor dysfunction, sound-induced seizures, an abnormal EEG (large amplitude 3 Hz spike wave activity), defective contextual fear-conditioning, and impaired hippocampal LTP. The brain appears normal with standard neuroanatomical and histological techniques. P53 levels are very high in the cells of these mice, alluding to the possibility that UbE3A can ubiquitinate p53 even in the absence of the viral E6 protein (see previous, molecular biology). Miura et al noted mostly the same pattern of findings in their independently-generated UbE3A maternal-KO mouse, but did not find increased p53 levels (2002).

Dindot et al engineered mice to express yellow fluorescent protein (YFP) fused to UbE3A in neurons (2008). In these mice, it was shown that UbE3A localizes to synapses and the nucleus, and that while neurons only use the maternal allele, glia use both the paternal and maternal allele of UbE3A (see genetics). Dendritic arbors were simplified in these mice, with abnormally small hypervariable spines and decreased spine density (Dindot et al 2008). Abnormal synchronous (epilepsy-like) oscillations in the cerebellum of these mice are rescued by gap junction blockers, suggesting that UbE3A may regulate the electrical coupling between cells (Cheron et al 2005). It was recently discovered that these mice also have decreased neurogenesis in the dentate gyrus of the hippocampus, which could have implications for the abnormal learning and LTP in these mice (Mardirossian et al 2009).

Yashiro et al analyzed the visual cortex of AS mice in greater detail (2009). In whole cell recordings from L2/3 pyramidal neurons, they noted a decreased frequency of miniature excitatory postsynaptic potentials (mEPSCs) compared to wild-type (WT) with no change in mEPSC amplitude. The authors also noted plasticity abnormalities in several paradigms. Dark rearing (raising animals in darkness), for example, decreased mEPSC frequency in WT but not in the KO. In addition, decreased long-term potentiation (LTP) and long term depression (LTD) were identified at the L4 to L2/3 synapse, a decrease which progressed in adulthood. Interestingly, LTP and LTD could be induced in dark-reared animals; it was not until normal sensory experience occurred that plasticity was impaired. Furthermore, plasticity could be restored by dark-rearing the mice in adulthood. Monocular deprivation experiments like that described in the previous section for Arc KO mice revealed an identical pattern – no ocular dominance reorganization in favor of the spared eye occurred in AS mice.

UbE3A-maternal-KO mice demonstrate increased levels of inhibitory phosphorylation on CaM kinase II in neurons (Weeber et al 2003). Prevention of this inhibitory phosphorylation by mutation of CaMKII’s threonines 305 and 306 rescues the mouse’s neurological deficits (van Woerden et al 2007). This surprising result is especially relevant given the recent finding that the activity-dependent translocation of proteasomes into dendritic spines depends on CaMKIIα acting as a scaffolding protein (Bingol et al 2010). This activity-dependent translocation is abolished by the T305/306 mutation. From these findings we can formulate this model: In AS, proteasomes translocate to the dendritic spine normally, but important degradation targets like Arc and Ephexin5 are not ubiquitinated and do not enter the proteasome. Some proteins are degraded while UbE3A’s targets remain, which by some mechanism leads to the inhibitory phosphorylation of CamKIIα. This phosphorylation encourages more proteasome to enter the spine, which leads to more aberrant degradation. This vicious cycle produces long, thin, abnormal spines (Dindot et al 2008) which cannot change in response to experience (Yashiro et al 2009). Prevention of CaMKIIα’s inhibitory phosphorylation breaks this cycle by suppressing the translocation of proteasomes into synapses. With fewer spine proteasomes, the UbE3A non-targets are protected from degradation relative to UbE3A targets, and a proteomically-balanced synapse is restored.

Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M. (2010) “Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines.” Cell. 140(4):567-78.

Cheron G, Servais L, Wagstaff J, Dan B. (2005) “Fast cerebellar oscillation associated with ataxia in a mouse model of Angelman syndrome.” Neuroscience 130:631–637.

Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL. (2008) “The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology.” Hum Mol Genet 17:111–118.

Jiang, Y., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., & Beaudet, A. L. (1998) “Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.” Neuron 21, 799–811

Mardirossian S, Rampon C, Salvert D, Fort P, Sarda N. (2009) “Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome.” Exp Neurol. 220(2):341-8.

Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes GL, Wagstaff J. (2002) “Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice” Neurobiol Dis 9:149–159.

van Woerden, G.M., Harris, K.D., Hojjati, M.R., Gustin, R.M., Qiu, S., de Avila Freire, R., Jiang, Y.H., Elgersma, Y. and Weeber, E.J. (2007) “Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation.” Nat. Neurosci., 10, 280–282.

Weeber, E.J., Jiang, Y.H., Elgersma, Y., Varga, A.W., Carrasquillo, Y., Brown, S.E., Christian, J.M., Mirnikjoo, B., Silva, A., Beaudet, A.L. et al. (2003) “Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome.” J. Neurosci., 23, 2634–2644.

Yashiro, K., et al., Ube3a is required for experience-dependent maturation of the neocortex. Nat Neurosci, 2009. 12(6): p. 777-783.

Eisenegger et al (Nature, 2010) find that

the sublingual administration of a single dose of testosterone in women causes a substantial increase in fair bargaining behaviour, thereby reducing bargaining conflicts and increasing the efficiency of social interactions. However, subjects who believed that they received testosterone—regardless of whether they actually received it or not—behaved much more unfairly than those who believed that they were treated with placebo. Thus, the folk hypothesis seems to generate a strong negative association between subjects’ beliefs and the fairness of their offers, even though testosterone administration actually causes a substantial increase in the frequency of fair bargaining offers in our experiment.

Yamagishi and Shinada (PNAS 2009) find that

certain players of an economic game reject unfair offers even when this behavior increases rather than decreases inequity. A substantial proportion (30–40%, compared with 60–70% in the standard ultimatum game) of those who responded rejected unfair offers even when rejection reduced only their own earnings to 0, while not affecting the earnings of the person who proposed the unfair split (in an impunity game). Furthermore, even when the responders were not able to communicate their anger to the proposers by rejecting unfair offers in a private impunity game, a similar rate of rejection was observed. The rejection of unfair offers that increases inequity cannot be explained by the social preference for inequity aversion or reciprocity; however, it does provide support for the model of emotion as a commitment device. In this view, emotions such as anger or moral disgust lead people to disregard the immediate consequences of their behavior, committing them to behave consistently to preserve integrity and maintain a reputation over time as someone who is reliably committed to this behavior.

Aharoni et al (2007) find that psychopathic personalities do not experience retributive feelings in response to stories about crimes:

Participants who rated either high or low in psychopathic traits read stories about a homicide. These stories were designed to evoke both retribution and the consequentialist motive of behavior control by varying, respectively, criminal intent and likelihood of recidivism. The participants then recommended a length of confinement for the offender. Individuals high in psychopathic traits were uniquely insensitive to retributive cues, and they were particularly consequentialist in their punishment of criminal offenders.