Further Evidence for an Intrinsic Neuraminidase in CNS Myelin

An intrinsic neuraminidase activity in rat brain CNS myelin has been demonstrated and compared with the neuraminidase activity in rat brain microsomes. With use of ganglioside GM3 as a substrate, the myelin-associated neuraminidase exhibited a shallow pH curve with an optimum at pH 4.8 whereas the microsomal activity had a marked optimum at pH 4-4.3. Neuraminidase activity in both fractions was optimized in 0.3% Triton CF-54 but activation was much greater in the microsomes. When the neuraminidase activities were examined at 60 degrees C, the myelin neuraminidase activity was more than sevenfold of that observed at 37 degrees C and was linear for at least 2 h; the microsomal activity increased only fivefold initially and exhibited a continual loss in activity. Addition of excess microsomes to the total homogenate prior to myelin isolation resulted in no change in myelin neuraminidase activity. When the two membrane fractions were examined at equivalent protein concentrations in the presence of additional cations or EDTA (1 mM), similar but not identical effects on neuraminidase activity were seen. The microsomal neuraminidase was considerably more susceptible to inhibition by divalent copper ion. Activity in both fractions was markedly inhibited by Hg2+ and Ag+ whereas EDTA had no effect on either activity. The myelin-associated neuraminidase activity was the highest in cerebral hemispheres, followed by brainstem, cerebellum, and spinal cord and was extremely low in sciatic nerve. In fact, the myelin neuraminidase activity was higher than the microsomal enzyme activity in the cerebral hemispheres.(ABSTRACT TRUNCATED AT 250 WORDS)     

Focus: Addiction: Behavioral Economics of Self-Control Failure

The main idea in this article is that addiction is a consequence of falling victim to decision failures that lead to preference for the addictive behaviors. Addiction is viewed as valuation disease, where the nervous system overvalues cues associated with drugs or drug-taking. Thus, addiction can be viewed as a diminished capacity to choose. Addicted individuals assign lower values to delayed rewards than to immediate ones. The preference for immediate gratification leads to self-control problems. This article highlights a number of motivational forces that can generate self-control failure.     

A Conserved Behavioral State Barrier Impedes Transitions between Anesthetic-Induced Unconsciousness and Wakefulness: Evidence for Neural Inertia

One major unanswered question in neuroscience is how the brain transitions between conscious and unconscious states. General anesthetics offer a controllable means to study these transitions. Induction of anesthesia is commonly attributed to drug-induced global modulation of neuronal function, while emergence from anesthesia has been thought to occur passively, paralleling elimination of the anesthetic from its sites in the central nervous system (CNS). If this were true, then CNS anesthetic concentrations on induction and emergence would be indistinguishable. By generating anesthetic dose-response data in both insects and mammals, we demonstrate that the forward and reverse paths through which anesthetic-induced unconsciousness arises and dissipates are not identical. Instead they exhibit hysteresis that is not fully explained by pharmacokinetics as previously thought. Single gene mutations that affect sleep-wake states are shown to collapse or widen anesthetic hysteresis without obvious confounding effects on volatile anesthetic uptake, distribution, or metabolism. We propose a fundamental and biologically conserved concept of neural inertia, a tendency of the CNS to resist behavioral state transitions between conscious and unconscious states. We demonstrate that such a barrier separates wakeful and anesthetized states for multiple anesthetics in both flies and mice, and argue that it contributes to the hysteresis observed when the brain transitions between conscious and unconscious states.     

The Decision to Engage Cognitive Control Is Driven by Expected Reward-Value: Neural and Behavioral Evidence

Cognitive control is a fundamental skill reflecting the active use of task-rules to guide behavior and suppress inappropriate automatic responses. Prior work has traditionally used paradigms in which subjects are told when to engage cognitive control. Thus, surprisingly little is known about the factors that influence individuals'' initial decision of whether or not to act in a reflective, rule-based manner. To examine this, we took three classic cognitive control tasks (Stroop, Wisconsin Card Sorting Task, Go/No-Go task) and created novel ‘free-choice’ versions in which human subjects were free to select an automatic, pre-potent action, or an action requiring rule-based cognitive control, and earned varying amounts of money based on their choices. Our findings demonstrated that subjects'' decision to engage cognitive control was driven by an explicit representation of monetary rewards expected to be obtained from rule-use. Subjects rarely engaged cognitive control when the expected outcome was of equal or lesser value as compared to the value of the automatic response, but frequently engaged cognitive control when it was expected to yield a larger monetary outcome. Additionally, we exploited fMRI-adaptation to show that the lateral prefrontal cortex (LPFC) represents associations between rules and expected reward outcomes. Together, these findings suggest that individuals are more likely to act in a reflective, rule-based manner when they expect that it will result in a desired outcome. Thus, choosing to exert cognitive control is not simply a matter of reason and willpower, but rather, conforms to standard mechanisms of value-based decision making. Finally, in contrast to current models of LPFC function, our results suggest that the LPFC plays a direct role in representing motivational incentives.     

Intrinsic Behavioral and Physiological Differences Among Laboratory Populations of Prairie Deermice

The emphasis of this presentation is that social behavior isbasically involved in the curtailment of growth of laboratorypopulations of prairie deermice through inhibiting influenceson the reproductive development and function of population animals.Reproductive inhibition is not directly related to the numbersof animals present per se since physiological characteristicsare similar between animals from populations differing widelyin density under identical conditions of the physical environment.Thus, density should be interpreted relative to social or otherbehavioral factors and we should think of animals in a populationin a qualitative as well as a quantitative sense. Populationgrowth is controlled either by cessation of reproduction orby mortality of young and while 95% of the young remain reproductivelyimmature and fail to reproduce, the weights and characteristicsof their reproductive organs differ dependent upon the mechanismby which population growth is curtailed. Mechanisms of growthcurtailment thus develop intrinsically to each population andinvolve communication through one or more of the senses of touch,smell, sight, hearing or taste. My data suggest that tactilecues from population animals (not necessarily overt aggression)may be of major importance in producing the reproductive retardationobserved although chemosignals or other stimuli such as visualor auditory cues may act to slow reproductive recovery of inhibitedanimals. Data presented support the contention of a behavioral-physiologicalrelationship distinct for each population.     

Direct Behavioral and Neurophysiological Evidence for Retronasal Olfaction in Mice

The neuroscience of flavor perception is hence becoming increasingly important to understand food flavor perception that guides food selection, ingestion and appreciation. We recently provided evidence that rats can use the retronasal mode of olfaction, an essential element of human flavor perception. We showed that in rats, like humans, odors can acquire a taste. We and others also defined how the input of the olfactory bulb (OB) -not functionally imageable in humans- codes retronasal smell in anesthetized rat. The powerful awake transgenic mouse, however, would be a valuable additional model in the study of flavor neuroscience. We used a go/no-go behavioral task to test the mouse''s ability to detect and discriminate the retronasal odor amyl acetate. In this paradigm a tasteless aqueous odor solution was licked by water-restricted head-fixed mice from a lick spout. Orthonasal contamination was avoided. The retronasal odor was successfully discriminated by mice against pure distilled water in a concentration-dependent manner. Bulbectomy removed the mice''s ability to discriminate the retronasal odor but not tastants. The OB showed robust optical calcium responses to retronasal odorants in these awake mice. These results suggest that mice, like rats, are capable of smelling retronasally. This direct neuro-behavioral evidence establishes the mouse as a useful additional animal model for flavor research.     

Electrophysiological Evidence for Intrinsic Pacemaker Currents in Crayfish Parasol Cells

I used sharp intracellular electrodes to record from parasol cells in the semi-isolated crayfish brain to investigate pacemaker currents. Evidence for the presence of the hyperpolarization-activated inward rectifier potassium current was obtained in about half of the parasol cells examined, where strong, prolonged hyperpolarizing currents generated a slowly-rising voltage sag, and a post-hyperpolarization rebound. The amplitudes of both the sag voltage and the depolarizing rebound were dependent upon the strength of the hyperpolarizing current. The voltage sag showed a definite threshold and was non-inactivating. The voltage sag and rebound depolarization evoked by hyperpolarization were blocked by the presence of 5–10 mM Cs²⁺ ions, 10 mM tetraethyl ammonium chloride, and 10 mM cobalt chloride in the bathing medium, but not by the drug ZD 7288. Cs⁺ ions in normal saline in some cells caused a slight increase in mean resting potential and a reduction in spontaneous burst frequency. Many of the neurons expressing the hyperpolarization-activated inward potassium current also provided evidence for the presence of the transient potassium current I_A, which was inferred from experimental observations of an increased latency of post-hyperpolarization response to a depolarizing step, compared to the response latency to the depolarization alone. The latency increase was reduced in the presence of 4-aminopyridine (4-AP), a specific blocker of I_A. The presence of 4-AP in normal saline also induced spontaneous bursting in parasol cells. It is conjectured that, under normal physiological conditions, these two potassium currents help to regulate burst generation in parasol cells, respectively, by helping to maintain the resting membrane potential near a threshold level for burst generation, and by regulating the rate of rise of membrane depolarizing events leading to burst generation. The presence of post-burst hyperpolarization may depend upon I_A channels in parasol cells.     

Perceived Cost and Intrinsic Motor Variability Modulate the Speed-Accuracy Trade-Off

Fitts’ Law describes the speed-accuracy trade-off of human movements, and it is an elegant strategy that compensates for random and uncontrollable noise in the motor system. The control strategy during targeted movements may also take into account the rewards or costs of any outcomes that may occur. The aim of this study was to test the hypothesis that movement time in Fitts’ Law emerges not only from the accuracy constraints of the task, but also depends on the perceived cost of error for missing the targets. Subjects were asked to touch targets on an iPad^® screen with different costs for missed targets. We manipulated the probability of error by comparing children with dystonia (who are characterized by increased intrinsic motor variability) to typically developing children. The results show a strong effect of the cost of error on the Fitts’ Law relationship characterized by an increase in movement time as cost increased. In addition, we observed a greater sensitivity to increased cost for children with dystonia, and this behavior appears to minimize the average cost. The findings support a proposed mathematical model that explains how movement time in a Fitts-like task is related to perceived risk.     

Neural Correlates of Task Cost for Stance Control with an Additional Motor Task: Phase-Locked Electroencephalogram Responses

With appropriate reallocation of central resources, the ability to maintain an erect posture is not necessarily degraded by a concurrent motor task. This study investigated the neural control of a particular postural-suprapostural procedure involving brain mechanisms to solve crosstalk between posture and motor subtasks. Participants completed a single posture task and a dual-task while concurrently conducting force-matching and maintaining a tilted stabilometer stance at a target angle. Stabilometer movements and event-related potentials (ERPs) were recorded. The added force-matching task increased the irregularity of postural response rather than the size of postural response prior to force-matching. In addition, the added force-matching task during stabilometer stance led to marked topographic ERP modulation, with greater P2 positivity in the frontal and sensorimotor-parietal areas of the N1-P2 transitional phase and in the sensorimotor-parietal area of the late P2 phase. The time-frequency distribution of the ERP primary principal component revealed that the dual-task condition manifested more pronounced delta (1–4 Hz) and beta (13–35 Hz) synchronizations but suppressed theta activity (4–8 Hz) before force-matching. The dual-task condition also manifested coherent fronto-parietal delta activity in the P2 period. In addition to a decrease in postural regularity, this study reveals spatio-temporal and temporal-spectral reorganizations of ERPs in the fronto-sensorimotor-parietal network due to the added suprapostural motor task. For a particular set of postural-suprapostural task, the behavior and neural data suggest a facilitatory role of autonomous postural response and central resource expansion with increasing interregional interactions for task-shift and planning the motor-suprapostural task.     

Behavioral Correlates of Primates Conservation Status: Intrinsic Vulnerability to Anthropogenic Threats

Behavioral traits are likely to influence species vulnerability to anthropogenic threats and in consequence, their risk of extinction. Several studies have addressed this question and have highlighted a correlation between reproductive strategies and different viability proxies, such as introduction success and local extinction risk. Yet, very few studies have investigated the effective impact of social behaviour, and evidence regarding global extinction risk remains scant. Here we examined the effects of three main behavioral factors: the group size, the social and reproductive system, and the strength of sexual selection on global extinction risk. Using Primates as biological model, we performed comparative analysis on 93 species. The conservation status as described by the IUCN Red List was considered as a proxy for extinction risk. In addition, we added previously identified intrinsic factors of vulnerability to extinction, and a measure of the strength of the human impact for each species, described by the human footprint. Our analysis highlighted a significant effect of two of the three studied behavioral traits, group size and social and reproductive system. Extinction risk is negatively correlated with mean group size, which may be due to an Allee effect resulting from the difficulties for solitary and monogamous species to find a partner at low densities. Our results also indicate that species with a flexible mating system are less vulnerable. Taking into account these behavioral variables is thus of high importance when establishing conservation plans, particularly when assessing species relative vulnerability.     

Behavioral and Neural Correlates of Executive Functioning in Musicians and Non-Musicians

Executive functions (EF) are cognitive capacities that allow for planned, controlled behavior and strongly correlate with academic abilities. Several extracurricular activities have been shown to improve EF, however, the relationship between musical training and EF remains unclear due to methodological limitations in previous studies. To explore this further, two experiments were performed; one with 30 adults with and without musical training and one with 27 musically trained and untrained children (matched for general cognitive abilities and socioeconomic variables) with a standardized EF battery. Furthermore, the neural correlates of EF skills in musically trained and untrained children were investigated using fMRI. Adult musicians compared to non-musicians showed enhanced performance on measures of cognitive flexibility, working memory, and verbal fluency. Musically trained children showed enhanced performance on measures of verbal fluency and processing speed, and significantly greater activation in pre-SMA/SMA and right VLPFC during rule representation and task-switching compared to musically untrained children. Overall, musicians show enhanced performance on several constructs of EF, and musically trained children further show heightened brain activation in traditional EF regions during task-switching. These results support the working hypothesis that musical training may promote the development and maintenance of certain EF skills, which could mediate the previously reported links between musical training and enhanced cognitive skills and academic achievement.     

Evidence for Intrinsic Differences in the Formation of Chromatin Domains in Drosophila Melanogaster

The results of an investigation into intrinsic differences in the formation of two different heterochromatic domains are presented. The study utilized two different position effect variegation mutants in Drosophila melanogaster for investigating the process of compacting different stretches of DNA into heterochromatin. Each stretch of DNA encodes for a gene that affects different aspects of bristle morphology. The expression of each gene is prevented when it is compacted into heterochromatin thus the genes serve as effective reporter systems to monitor the spread of heterochromatin. Both variegating mutants are scored in the same cell such that environmental and genetic background differences are unambiguously eliminated. Any differences observed in the repression of the two genes must therefore be the result of intrinsic differences in the heterochromatic compaction process for the two stretches of DNA. Studies of the effects different enhancers of variegation have upon the compaction of the two genes indicate each compaction event occurs independently of the other, and that different components are involved in the two processes. These results are discussed with regard to spreading heterochromatin and the role this process may play in regulating gene expression.     

Behavioral and Morphological Studies of Fetal Neural Transplants into SCN-Lesioned Rats

We have studied the effects of fetal neuronal grafts on the temporal pattern of drinking behavior of suprachiasmatic nuclei (SCN)-lesioned adult rats. Additionally, in an independent set of animals, the immunohistochemical staining for vasopressin, vasoactive intestinal polypeptide, and neuropeptide Y and the retinal connections to the hypothalamus were studied. The behavioral experiments indicate that anterior hypothalamic transplants induced reorganization of the temporal pattern of drinking behavior when placed in the third ventricle of adult hosts bearing complete SCN lesions, but not when placed in a cavity in the occipital cortex. Such rhythmicity persists only when the animals were recorded under constant darkness but not under constant light, indicating that the restored rhythmicity was generated endogenously but that the oscillator was extremely sensitive to light. Fetal occipital cortex induced reorganization of the temporal pattern of previously arrhythmic hosts, but it disappeared when the animals were recorded under constant light or constant darkness. It is clear that this rhythmicity was exogenous. In contrast to the cortical transplants, the hypothalamic transplants showed a morphological organization similar to that found in the normal hypothalamus regardless of their placement in the host brain. From these observations it is concluded that development of neocortex is more affected by environmental factors than that of the hypothalamus. Both hypothalamic and cortical transplants induced sprouting of retinal fibers into the anterior hypothalamus and the grafted tissue. It is possible that such fibers could be the neuroanatomical substrate by which rhythmicity is induced by cortical tissue.     

Behavioral and Morphological Studies of Fetal Neural Transplants into SCN-Lesioned Rats

We have studied the effects of fetal neuronal grafts on the temporal pattern of drinking behavior of suprachiasmatic nuclei (SCN)-lesioned adult rats. Additionally, in an independent set of animals, the immunohistochemical staining for vasopressin, vasoactive intestinal polypeptide, and neuropeptide Y and the retinal connections to the hypothalamus were studied. The behavioral experiments indicate that anterior hypothalamic transplants induced reorganization of the temporal pattern of drinking behavior when placed in the third ventricle of adult hosts bearing complete SCN lesions, but not when placed in a cavity in the occipital cortex. Such rhythmicity persists only when the animals were recorded under constant darkness but not under constant light, indicating that the restored rhythmicity was generated endogenously but that the oscillator was extremely sensitive to light. Fetal occipital cortex induced reorganization of the temporal pattern of previously arrhythmic hosts, but it disappeared when the animals were recorded under constant light or constant darkness. It is clear that this rhythmicity was exogenous. In contrast to the cortical transplants, the hypothalamic transplants showed a morphological organization similar to that found in the normal hypothalamus regardless of their placement in the host brain. From these observations it is concluded that development of neocortex is more affected by environmental factors than that of the hypothalamus. Both hypothalamic and cortical transplants induced sprouting of retinal fibers into the anterior hypothalamus and the grafted tissue. It is possible that such fibers could be the neuroanatomical substrate by which rhythmicity is induced by cortical tissue.     

Identification of an Intrinsic Determinant Critical for Maspin Subcellular Localization and Function

Maspin, a multifaceted tumor suppressor, belongs to the serine protease inhibitor superfamily, but only inhibits serine protease-like enzymes such as histone deacetylase 1 (HDAC1). Maspin is specifically expressed in epithelial cells and it is differentially regulated during tumor progression. A new emerging consensus suggests that a shift in maspin subcellular localization from the nucleus to the cytoplasm stratifies with poor cancer prognosis. In the current study, we employed a rational mutagenesis approach and showed that maspin reactive center loop (RCL) and its neighboring sequence are critical for maspin stability. Further, when expressed in multiple tumor cell lines, single point mutation of Aspartate³⁴⁶ (D³⁴⁶) to Glutamate (E³⁴⁶), maspin^D346E, was predominantly nuclear, whereas wild type maspin (maspin^WT) was both cytoplasmic and nuclear. Evidence from cellular fractionation followed by immunological and proteomic protein identification, combined with the evidence from fluorescent imaging of endogenous proteins, fluorescent protein fusion constructs, as well as bimolecular fluorescence complementation (BiFC) showed that the increased nuclear enrichment of maspin^D346E was, at least in part, due to its increased affinity to HDAC1. Maspin^D346E was also more potent than maspin^WT as an HDAC inhibitor. Taken together, our evidence demonstrates that D³⁴⁶ is a critical cis-element in maspin sequence that determines the molecular context and subcellular localization of maspin. A mechanistic model derived from our evidence suggests a new window of opportunity for the development of maspin-based biologically competent HDAC inhibitors for cancer treatment.