Striatal pathology underlies prion infection-mediated hyperactivity in mice

Although prion diseases are most commonly modeled using the laboratory mouse, the diversity of prion strains, behavioral testing and neuropathological assessments hamper our collective understanding of mouse models of prion disease. Here we compared several commonly used murine strains of prions in C57BL/6J female mice in a detailed home cage behavior detection system and a systematic study of pathological markers and neurotransmitter systems. We observed that mice inoculated with RML or 139A prions develop a severe hyperactivity phenotype in the home cage. A detailed assessment of pathology markers, such as microglial marker IBA1, astroglial marker GFAP and degeneration staining indicate early striatal pathology in mice inoculated with RML or 139A but not in those inoculated with 22L prions. An assessment of neuromodulatory systems including serotonin, dopamine, noradrenalin and acetylcholine showed surprisingly little decline in neuronal cell bodies or their innervations of regions controlling locomotor behavior, except for a small decrease in dopaminergic innervations of the dorsal striatum. These results implicate the dorsal striatum in mediating the major behavioral phenotype of 139A and RML prions. Further, they suggest that measurements of activity may be a sensitive manner in which to diagnose murine prion disease. With respect to neuropathology, our results indicate that pathological stains as opposed to neurotransmitter markers are much more informative and sensitive as markers of prion disease in mouse models.Key words: PrP, neurodegeneration, protein misfolding, home-cage, transmissible spongiform encephalopathy     

Homebase behavior of zebrafish in novelty-based paradigms

Zebrafish (Danio rerio) are emerging as a promising model species in neuroscience research. Many traditional rodent behavioral paradigms may be adapted for zebrafish testing. Exposing zebrafish to three different “open field” tanks for 30 min, we showed that fish display robust homebase behavior, in which one area of the tank is chosen as a preferred point of reference during the test, which the fish frequently return to and spend a longer duration in. This phenotype strikingly resembles rodent homebase behavior, confirming that both species use homebases as “reference points” for their exploration. Our study introduces a simple method for zebrafish homebase phenotyping, and further supports the utility of these fish in neurobehavioral and cognitive research.     

Partner choice creates fairness in humans

Many studies demonstrate that partner choice has played an important role in the evolution of human cooperation, but little work has tested its impact on the evolution of human fairness. In experiments involving divisions of money, people become either over-generous or over-selfish when they are in competition to be chosen as cooperative partners. Hence, it is difficult to see how partner choice could result in the evolution of fair, equal divisions. Here, we show that this puzzle can be solved if we consider the outside options on which partner choice operates. We conduct a behavioural experiment, run agent-based simulations and analyse a game-theoretic model to understand how outside options affect partner choice and fairness. All support the conclusion that partner choice leads to fairness only when individuals have equal outside options. We discuss how this condition has been met in our evolutionary history, and the implications of these findings for our understanding of other aspects of fairness less specific than preferences for equal divisions of resources.     

Partner choice creates competitive altruism in humans

Reciprocal altruism has been the backbone of research on the evolution of altruistic behaviour towards non-kin, but recent research has begun to apply costly signalling theory to this problem. In addition to signalling resources or abilities, public generosity could function as a costly signal of cooperative intent, benefiting altruists in terms of (i) better access to cooperative relationships and (ii) greater cooperation within those relationships. When future interaction partners can choose with whom they wish to interact, this could lead to competition to be more generous than others. Little empirical work has tested for the possible existence of this 'competitive altruism'. Using a cooperative monetary game with and without opportunities for partner choice and signalling cooperative intent, we show here that people actively compete to be more generous than others when they can benefit from being chosen for cooperative partnerships, and the most generous people are correspondingly chosen more often as cooperative partners. We also found evidence for increased scepticism of altruistic signals when the potential reputational benefits for dishonest signalling were high. Thus, this work supports the hypothesis that public generosity can be a signal of cooperative intent, which people sometimes 'fake' when conditions permit it.     

HLA and mate choice in humans.

Evidence from studies in rodents suggests that mate selection is influenced by major-histocompatibility-complex haplotypes, with preferences for dissimilar partners. This study was initiated to determine whether avoidance of a mate with the same HLA haplotype as one's own might be occurring in the Hutterites, a North American reproductive isolate of European ancestry, notable for their large sibships, communal lifestyle, and limited number of five-locus HLA haplotypes (HLA-A, -B, -C, -DR, and -DQ). HLA haplotypes were known for 411 Hutterite couples. The number of couples expected to match for a haplotype was calculated in two ways: first, from population genotype frequencies, with account being taken of the nonrandom mating pattern with respect to colony lineages, and, second, from computer simulations using conservative founder assumptions and the exact genealogy of the 411 couples. We observed fewer matches for HLA haplotypes between spouses than expected (first method, P = .005; second method, P = .020-.067). Among couples who did match for a haplotype, the matched haplotype was inherited from the mother in 29 cases and from the father in 50 cases (P = .018). These results are consistent with the conclusion that Hutterite mate choice is influenced by HLA haplotypes, with an avoidance of spouses with haplotypes that are the same as one's own.     

Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans

We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1^Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans.     

Reward context determines risky choice in pigeons and humans

Whereas humans are risk averse for monetary gains, other animals can be risk seeking for food rewards, especially when faced with variable delays or under significant deprivation. A key difference between these findings is that humans are often explicitly told about the risky options, whereas non-human animals must learn about them from their own experience. We tested pigeons (Columba livia) and humans in formally identical choice tasks where all outcomes were learned from experience. Both species were more risk seeking for larger rewards than for smaller ones. The data suggest that the largest and smallest rewards experienced are overweighted in risky choice. This observed bias towards extreme outcomes represents a key step towards a consilience of these two disparate literatures, identifying common features that drive risky choice across phyla.     

Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons

Striatal dopamine plays key roles in our normal and pathological goal-directed actions. To understand dopamine function, much attention has focused on how midbrain dopamine neurons modulate their firing patterns. However, we identify a presynaptic mechanism that triggers dopamine release directly, bypassing activity in dopamine neurons. We paired electrophysiological recordings of striatal channelrhodopsin2-expressing cholinergic interneurons with simultaneous detection of dopamine release at carbon-fiber microelectrodes in striatal slices. We reveal that activation of cholinergic interneurons by light flashes that cause only single action potentials in neurons from a small population triggers dopamine release via activation of nicotinic receptors on dopamine axons. This event overrides ascending activity from dopamine neurons and, furthermore, is reproduced by activating ChR2-expressing thalamostriatal inputs, which synchronize cholinergic interneurons in vivo. These findings indicate that synchronized activity in cholinergic interneurons directly generates striatal dopamine signals whose functions will extend beyond those encoded by dopamine neuron activity.     

Non-random mate choice in humans: insights from a genome scan

Little is known about the genetic factors influencing mate choice in humans. Still, there is evidence for non-random mate choice with respect to physical traits. In addition, some studies suggest that the Major Histocompatibility Complex may affect pair formation. Nowadays, the availability of high density genomic data sets gives the opportunity to scan the genome for signatures of non-random mate choice without prior assumptions on which genes may be involved, while taking into account socio-demographic factors. Here, we performed a genome scan to detect extreme patterns of similarity or dissimilarity among spouses throughout the genome in three populations of African, European American, and Mexican origins from the HapMap 3 database. Our analyses identified genes and biological functions that may affect pair formation in humans, including genes involved in skin appearance, morphogenesis, immunity and behaviour. We found little overlap between the three populations, suggesting that the biological functions potentially influencing mate choice are population specific, in other words are culturally driven. Moreover, whenever the same functional category of genes showed a significant signal in two populations, different genes were actually involved, which suggests the possibility of evolutionary convergences.     

The parental investment model and minimum mate choice criteria in humans

Trivers' parental investment model states that individuals facinghigher levels of parental investment will become increasinglychoosy in their choice of mates. For humans, this leads to twopredictions. First, both males and females will be choosierin relationships more likely to lead to the production of children.Second, females will be choosier than are males, because theirminimum risk of parental investment is higher. Previous studiesof human mate choice found support for these predictions, withone curious exception: male choosiness was lower for short-termsexual relationships involving no relationship commitment (one-nightstands) than for short-term relationships involving no sexualactivity (single dates). Because the risk of parental investmentwould be higher in a one-night stand, this suggests that truerisk of parental investment was not the underlying factor governingchoosiness levels, either because study subjects assigned differentlevels of sexual activity to the relationships than were intendedby the investigators of the study or because perceived riskis more important in human mate choice than real risk. To confirmthat male/female differences in choosiness criteria exist inhumans, and to evaluate the effect that different expected levelsof real or perceived parental investment may have on choosiness,we studied mate choosiness in the context of five types of relationshipsthat reflected explicitly defined, increasing levels of riskof parental investment for both males and females. The subjectswere 468 undergraduate students, mostly between the ages of18–24. By using questionnaires, male and female participantsrated their minimum requirements in a potential mate for 29personal characteristics with respect to level of relationship.Our results confirm the major predictions of the parental investmentmodel for humans but suggest that sex differences in choosinessare better explained by perceived rather than real risk of parentalinvestment.     

Optimal risky choice in humans: effects of amount of variability

The present study investigated whether the predictions of an optimal risk-sensitive foraging model (the energy-budget rule) would extend to humans’ choices between high- and low-variance monetary response options. In Experiment 1, participants were presented with repeated choices between two options that had the same mean values but different variances across positive- and negative-budget conditions. In Experiment 2, a within-subject comparison was conducted to investigate choice under positive- and negative-budget conditions when the options were either (a) a fixed option and a high-variance option, or (b) a low-variance option and a high-variance option. Session-wide choices were analyzed in relation to the predictions of the energy-budget rule and sequential choices were analyzed with dynamic optimization modeling. When both options were variable choice was generally consistent with predictions of the energy-budget rule and was more risk prone under negative-budget than positive-budget conditions. Sequential choices were sensitive to local budget conditions, but choices were less consistent with optimality when both options were variable, possibly because of the greater similarity in expected earnings for optimal and nonoptimal choices in these conditions. Overall, the results provide further evidence that the energy-budget rule may have broad applicability and that it can extend to human risky choice between multiple variable response options.     

Persistent reflection underlies ectopic activity in multiple sclerosis: a numerical study

Ectopic activity in multiple sclerosis (MS) patients has been traditionally attributed to hyperexcitability of the demyelinated axon segments. Here, we propose that the same outcome may be the result of persistent reflection—the continuous reactivation of the axonal nodes that limit a demyelinated internodal segment. Using computer simulations, we studied the patterns of impulse propagation for a wide range of electrophysiological conditions. In uniformly myelinated fibers, increasing the temperature enabled successful propagation with no blocks in more severe conditions of demyelination. Secondary activations that were originated at the paranodes were formed for temperatures lower than T = 305 K, and at the condition of high sodium channel excitability. Non-sustained and persistent reflections appeared in the case of focally demyelinated fibers, and only within a narrow range of parameters of high temperature and membrane excitability. Persistent reflection reached steady state in ionic currents within 4 ms, and was characterized with a very high activation frequency of 1.504 ± 0.039 kHz. We conclude that persistent reflection is a possible mechanism for ectopic activity in MS patients, being more prominent in higher temperatures and severe axonal demyelination. Eliminating these symptoms may be addressed by cooling the body or by applying pharmacological agents to alter excitability properties.     

Striatal adenylate cyclase activity following reserpine and chronic chlorpromazine administration in rats.

Adenylate cyclase activity was assayed in rat striatal homogenates. Dopamine and, to a lesser extent, 1-norepinephrine added $\text{in vitro}$ produced a dose-dependent enhancement of adenylate cyclase activity. Fluphenazine did not alter basal enzyme activity, but prevented both dopamine- and 1-norepinephrine-elicited increases. No significant changes in basal- or dopamine-stimulated adenylate cyclase activity were found in homogenates from rats pretreated with chlorpromazine for 21 days or reserpine for 2 days. It is concluded that the behavioral and neurophysiologic postsynaptic supersensitivities that follow similar pretreatments are not mediated by alterations in the sensitivity of striatal adenylate cyclase to dopamine.     

Mental imaging of motor activity in humans

Motor imagery corresponds to a subliminal activation of the motor system, a system that appears to be involved not only in producing movements, but also in imagining actions, recognising tools and learning by observation, as well as in understanding the behaviour of other people. Recent advances in the field include the use of techniques for mapping brain activity and probing cortical excitability, as well as observation of brain lesioned patients during imaging tasks; these advances provide new insights into the covert aspects of motor activity.     

Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Positron emission tomography studies have revealed a decline in glucose metabolism in the brain of patients with HD by a mechanism that has not been established. We examined glucose utilization in embryonic primary cortical neurons of wild-type (WT) and HD knock-in mice, which have 140 CAG repeats inserted in the endogenous mouse huntingtin gene (HD(140Q/140Q)). Primary HD(140Q/140Q) cortical neurons took up significantly less glucose than did WT neurons. Expression of permanently inactive and permanently active forms of Rab11 correspondingly altered glucose uptake in WT neurons, suggesting that normal activity of Rab11 is needed for neuronal uptake of glucose. It is known that Rab11 activity is diminished in HD(140Q/140Q) neurons. Expression of dominant active Rab11 to enhance the activity of Rab11 normalized glucose uptake in HD(140Q/140Q) neurons. These results suggest that deficient activity of Rab11 is a novel mechanism for glucose hypometabolism in HD.     

Hyperglycemia downregulates total lipoprotein lipase activity in humans

To address the question whether an increase in insulinemia and/or glycemia affects the total activity of lipoprotein lipase (LPL) in circulation, the enzyme activity was measured after periods of hyperinsulinemia (HI), hyperglycemia (HG), and combined hyperinsulinemia and hyperglycemia (HIHG) induced by euglycemic hyperglycemic clamp, hyperglycemic clamp with the infusion of somatostatin to inhibit endogenous insulin secretion, and hyperglycemic clamp, respectively. The results obtained were compared to those after saline infusion (C). Twelve healthy normolipidemic and non-obese men with normal glucose tolerance were included in the study. At the end of each clamp study, LPL activity was determined first in vivo using an intravenous fat tolerance test and then in vitro in postheparin plasma. Whereas isolated HI had no effect on LPL activity in postheparin plasma, both HG and HIHG reduced LPL activity to 60 % and 56 % of that observed after saline infusion. Similarly, the k2 rate constant determined in intravenous fat tolerance test was reduced to 95 %, 84 %, and 54 % after periods of HI, HG, and HIHG, respectively. The activity of hepatic lipase, another lipase involved in lipoprotein metabolism, was not affected by hyperinsulinemia and/or hyperglycemia. In conclusion, our data suggest that hyperglycemia per se can downregulate the total LPL activity in circulation.     

Neurobiological studies of gamma-band bioelectrical activity in humans

The modem literature data were observed, which dedicated to the study of neurobiological studies of gamma-rhythm mechanisms, providing the cognitive functions in hymans: state of readiness and attention, providing of sensory indentification, perception and memorizations, decision-making, management of psychomotor response, emotional and semantic processing of an information. It was shown that synchronous gamma-activity is at integrative activity, which in deteriorated in pathology of thinking. Literature data were analysed concerning ot the changes of gamma-activity (spontaneous, evoked, provoked by photostimulation etc.) in a number of neuropsychiatric disorders: epilepsy, schizophrenia, Alzheimer's disease, attention deficit hyperactivity disorder, stroke etc. as compared with norm. The data observed testify to high significance of gamma-activity in the brain functioning.     

Antioxidant activity of soya hypocotyl tea in humans

Antioxidative activity of isoflavones has not been shown in humans. Newly-developed isoflavone-rich soya hypocotyl tea contains about 12 mg isoflavones per liter. 15 tea drinkers and 23 control young female students were randomly selected from volunteers, and underwent physical examination, blood chemistry and urinary analysis before and after one month of tea drinking. A three-day dietary record was taken before each physical examination. The tea drinkers showed a lower level of phosphatidylcholine hydroperoxide (PCOOH) and phosphatidyl-ethanolamine hydroperoxide (PEOOH) in the red blood cells and a significant reduction of 8-hydroxydeoxyguanine (8ohdG) in the urine compared to the controls.     

Decoding mental states from brain activity in humans

Recent advances in human neuroimaging have shown that it is possible to accurately decode a person's conscious experience based only on non-invasive measurements of their brain activity. Such 'brain reading' has mostly been studied in the domain of visual perception, where it helps reveal the way in which individual experiences are encoded in the human brain. The same approach can also be extended to other types of mental state, such as covert attitudes and lie detection. Such applications raise important ethical issues concerning the privacy of personal thought.