Building a bird brain: Sculpting neural circuits for a learned behavior

Development in animals is frequently characterized by periods of heightened capacity for both neural and behavioral change. So-called sensitive periods of development are windows of opportunity in which brain and behavior are most susceptible to modification. Understanding what factors regulate sensitive periods constitutes one of the main goals of developmental neuroscience. Why is the ability to learn complex behavioral patterns often restricted to sensitive periods of development? Songbirds provide a model system for unraveling the mysteries of neural mechanisms of learning during development. Like many songbirds, zebra finches (Taeniopygia guttata) learn a specific vocal pattern during a restricted period early in life. Young birds must hear songs produced by members of their species; this auditory experience is thought to engender specific changes in the brain to guide the process of vocal learning. Many studies of the songbird system have focused on examining relationships between brain development and learning. One goal of this work is to elucidate mechanisms that regulate basic processes of neural development, and in so doing to shed light on factors governing the emergence of a complex learned behavior.     

Moral intuition: Its neural substrates and normative significance

Philosophers use the phrase "moral intuition" to describe the appearance in consciousness of moral judgments or assessments without any awareness of having gone through a conscious reasoning process that produces this assessment. This paper investigates the neural substrates of moral intuition. We propose that moral intuitions are part of a larger set of social intuitions that guide us through complex, highly uncertain and rapidly changing social interactions. Such intuitions are shaped by learning. The neural substrates for moral intuition include fronto-insular, cingulate, and orbito-frontal cortices and associated subcortical structure such as the septum, basil ganglia and amygdala. Understanding the role of these structures undercuts many philosophical doctrines concerning the status of moral intuitions, but vindicates the claim that they can sometimes play a legitimate role in moral decision-making.     

Well-being and affective style: neural substrates and biobehavioural correlates

One of the most salient features of emotion is the pronounced variability among individuals in their reactions to emotional incentives and in their dispositional mood. Collectively, these individual differences have been described as affective style. Recent research has begun to dissect the constituents of affective style. The search for these components is guided by the neural systems that instantiate emotion and emotion regulation. In this article, this body of research and theory is applied specifically to positive affect and well-being. The central substrates and peripheral biological correlates of well-being are described. A resilient affective style is associated with high levels of left prefrontal activation, effective modulation of activation in the amygdala and fast recovery in response to negative and stressful events. In peripheral biology, these central patterns are associated with lower levels of basal cortisol and with higher levels of antibody titres to influenza vaccine. The article concludes with a consideration of whether these patterns of central and peripheral biology can be modified by training and shifted toward a more salubrious direction.     

The neural substrates of infant sleep in rats

Sleep is a poorly understood behavior that predominates during infancy but is studied almost exclusively in adults. One perceived impediment to investigations of sleep early in ontogeny is the absence of state-dependent neocortical activity. Nonetheless, in infant rats, sleep is reliably characterized by the presence of tonic (i.e., muscle atonia) and phasic (i.e., myoclonic twitching) components; the neural circuitry underlying these components, however, is unknown. Recently, we described a medullary inhibitory area (MIA) in week-old rats that is necessary but not sufficient for the normal expression of atonia. Here we report that the infant MIA receives projections from areas containing neurons that exhibit state-dependent activity. Specifically, neurons within these areas, including the subcoeruleus (SubLC), pontis oralis (PO), and dorsolateral pontine tegmentum (DLPT), exhibit discharge profiles that suggest causal roles in the modulation of muscle tone and the production of myoclonic twitches. Indeed, lesions in the SubLC and PO decreased the expression of muscle atonia without affecting twitching (resulting in “REM sleep without atonia”), whereas lesions of the DLPT increased the expression of atonia while decreasing the amount of twitching. Thus, the neural substrates of infant sleep are strikingly similar to those of adults, a surprising finding in light of theories that discount the contribution of supraspinal neural elements to sleep before the onset of state-dependent neocortical activity.     

Functional dissection of the neural substrates for sexual behaviors in Drosophila melanogaster

The male-specific Fruitless proteins (FruM) act to establish the potential for male courtship behavior in Drosophila melanogaster and are expressed in small groups of neurons throughout the nervous system. We screened ～1000 GAL4 lines, using assays for general courtship, male-male interactions, and male fertility to determine the phenotypes resulting from the GAL4-driven inhibition of FruM expression in subsets of these neurons. A battery of secondary assays showed that the phenotypic classes of GAL4 lines could be divided into subgroups on the basis of additional neurobiological and behavioral criteria. For example, in some lines, restoration of FruM expression in cholinergic neurons restores fertility or reduces male-male courtship. Persistent chains of males courting each other in some lines results from males courting both sexes indiscriminately, whereas in other lines this phenotype results from apparent habituation deficits. Inhibition of ectopic FruM expression in females, in populations of neurons where FruM is necessary for male fertility, can rescue female infertility. To identify the neurons responsible for some of the observed behavioral alterations, we determined the overlap between the identified GAL4 lines and endogenous FruM expression in lines with fertility defects. The GAL4 lines causing fertility defects generally had widespread overlap with FruM expression in many regions of the nervous system, suggesting likely redundant FruM-expressing neuronal pathways capable of conferring male fertility. From associations between the screened behaviors, we propose a functional model for courtship initiation.     

Ecological hazard/risk assessment: lessons learned and new directions

A series of workshops held in the 1970s and 1980s, beginning at the University of Michigan Biological Station near Pellston, Michigan (and thus called the Pellston Series), focused on identifying the basic tenets of ecological hazard/risk assessment. The purpose of this discussion, produced roughly two decades after the first Pellston workshop, is to examine the impacts of this series on the development of the ecological hazard/risk assessment process, to explore some barriers hindering the development of this process, and suggest some new directions and challenges yet unaddressed by any of the workshop series. Probably the most important factor identified since the series of workshops began is persuasive circumstantial evidence that the learning process proceeds at different rates for individuals and institutions both in the government and private sectors, including academe. Evidence presently available suggests that individuals are frequently two or three decades ahead of institutions, and some individuals have already rejected paradigms generally accepted by the profession and are developing new ones. The major contribution of the workshops to the profession was connecting toxicity with environmental fate and transformation of chemicals and thus, bioavailability. Astonishingly, before the first Pellston workshop, this now-obvious connection did not play a dominant role in the peer-reviewed professional literature or in government documents, although the indefatigable investigator could find some minor indications that some professionals were aware of the importance of these relationships. Major suggestions for new directions and challenges focus on: (1) an emphasis on ecosystem health or condition rather than on mere absence of deleterious effects; (2) entering the information age requires that the type of information discussed here be integrated with and related to the broader array of other types of information used in making decisions at the societal or system level — failure to do so will mean that hazard/risk information will have little or no impact; (3) restoration ecology must emerge as a field of considerable importance because inevitably some estimates of hazard/risk will be inaccurate and damage will be done to ecosystems, which must then be repaired; (4) for all of this to function, environmental literacy must be markedly improved over its present level.     

A mathematical model for selective differentiation of neural progenitor cells on micropatterned polymer substrates

The biological hypothesis that the astrocyte-secreted cytokine, interleukin-6 (IL6), stimulates differentiation of adult rat hippocampal progenitor cells (AHPCs) is considered from a mathematical perspective. The proposed mathematical model includes two different mechanisms for stimulation and is based on mass-action kinetics. Both biological mechanisms involve sequential binding, with one pathway solely utilizing surface receptors while the other pathway also involves soluble receptors. Choosing biologically-reasonable values for parameters, simulations of the mathematical model show good agreement with experimental results. A global sensitivity analysis is also conducted to determine both the most influential and non-influential parameters on cellular differentiation, providing additional insights into the biological mechanisms.     

Sleep modulates the neural substrates of both spatial and contextual memory consolidation

It is known that sleep reshapes the neural representations that subtend the memories acquired while navigating in a virtual environment. However, navigation is not process-pure, as manifold learning components contribute to performance, notably the spatial and contextual memory constituents. In this context, it remains unclear whether post-training sleep globally promotes consolidation of all of the memory components embedded in virtual navigation, or rather favors the development of specific representations. Here, we investigated the effect of post-training sleep on the neural substrates of the consolidation of spatial and contextual memories acquired while navigating in a complex 3D, naturalistic virtual town. Using fMRI, we mapped regional cerebral activity during various tasks designed to tap either the spatial or the contextual memory component, or both, 72 h after encoding with or without sleep deprivation during the first post-training night. Behavioral performance was not dependent upon post-training sleep deprivation, neither in a natural setting that engages both spatial and contextual memory processes nor when looking more specifically at each of these memory representations. At the neuronal level however, analyses that focused on contextual memory revealed distinct correlations between performance and neuronal activity in frontal areas associated with recollection processes after post-training sleep, and in the parahippocampal gyrus associated with familiarity processes in sleep-deprived participants. Likewise, efficient spatial memory was associated with posterior cortical activity after sleep whereas it correlated with parahippocampal/medial temporal activity after sleep deprivation. Finally, variations in place-finding efficiency in a natural setting encompassing spatial and contextual elements were associated with caudate activity after post-training sleep, suggesting the automation of navigation. These data indicate that post-training sleep modulates the neural substrates of the consolidation of both the spatial and contextual memories acquired during virtual navigation.     

Control of neural stem cell survival by electroactive polymer substrates

Stem cell function is regulated by intrinsic as well as microenvironmental factors, including chemical and mechanical signals. Conducting polymer-based cell culture substrates provide a powerful tool to control both chemical and physical stimuli sensed by stem cells. Here we show that polypyrrole (PPy), a commonly used conducting polymer, can be tailored to modulate survival and maintenance of rat fetal neural stem cells (NSCs). NSCs cultured on PPy substrates containing different counter ions, dodecylbenzenesulfonate (DBS), tosylate (TsO), perchlorate (ClO(4)) and chloride (Cl), showed a distinct correlation between PPy counter ion and cell viability. Specifically, NSC viability was high on PPy(DBS) but low on PPy containing TsO, ClO(4) and Cl. On PPy(DBS), NSC proliferation and differentiation was comparable to standard NSC culture on tissue culture polystyrene. Electrical reduction of PPy(DBS) created a switch for neural stem cell viability, with widespread cell death upon polymer reduction. Coating the PPy(DBS) films with a gel layer composed of a basement membrane matrix efficiently prevented loss of cell viability upon polymer reduction. Here we have defined conditions for the biocompatibility of PPy substrates with NSC culture, critical for the development of devices based on conducting polymers interfacing with NSCs.     

Juvenile hormone drives the maturation of spontaneous mushroom body neural activity and learned behavior

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A learned neural network that simulates properties of the neuronal population vector

This paper considers steady-state and timedependent characteristics of the response of the hidden-layer neurons in a dynamic model for the neural network trained through supervised learning to perform transformation of input signals into output signals. This transformation is set up so as to correspond to variation in the directions of two-dimensional vectors and is treated as creation by the network of a movement direction in response to a stimulus direction. The input vector is encoded in the state of the input layer at the initial instant of time, and the output vector in the state of the output layer at great values of time. After the network has been trained on examples of the input-output relation, the hidden neurons turn out to be broadly tuned to direction. The corresponding dependence for their activity is approximated with a smooth function, whose maximum allows some preferred direction to be attributed to each neuron. If each hidden neuron is assigned a vector pointing in its preferred direction, then any arbitrarily chosen direction can be characterized by an imaginary neuronal population vector (Georgopoulos et al. 1986) defined as the sum of the vectors of preferred direction for the neurons, with the weights equal to their activities for the chosen direction. It is demonstrated that, although hidden neurons are broadly tuned to direction, the population vector points in a direction congruent with that of the input vector at the initial moment of time and accurately predicts the direction of the output vector at great values of time. In between, the population vector turns continuously from the one direction towards the other. The dynamic and stationary properties of the population vector of the hidden-layer neurons, as obtained within the framework of the model in question, show a close similarity to the experimentally observed (Georgopoulos et al. 1986; Georgopoulos et al. 1989) behaviour of the population vector constructed in the same manner on the ensemble of motor cortex neurons sensitive to a certain type of movement.     

药物成瘾中不同环境线索诱发觅药行为的机制

接触药物相关环境线索可激发成瘾者对药物的渴求感及复吸行为。实验动物研究中药物相关环境线索分为三类:伴药线索、辨别线索和情境线索。在长期停药及用药行为消退后三种环境线索均能诱发觅药行为恢复,而行为机制各具特点:伴药线索条件性强化觅药行为,辨别线索直接激发觅药行为发生,情境线索设定场景诱发觅药行为恢复。三种线索行为效应的神经基础局部相同而又各具特点,其机制的研究有助于对成瘾药物复吸机制的理解及临床戒毒治疗。     

Early induction of neural crest cells: lessons learned from frog,fish and chick

The identification of genes in Xenopus, chick and zebrafish expressed early in prospective neural crest (NC) cells has challenged the previous view that the NC is induced during the closure of the neural tube. We compare here the early inductive molecular mechanisms in different organisms and, despite observed differences, propose a general common model for NC induction.     

Culture-sensitive neural substrates of human cognition: a transcultural neuroimaging approach

Our brains and minds are shaped by our experiences, which mainly occur in the context of the culture in which we develop and live. Although psychologists have provided abundant evidence for diversity of human cognition and behaviour across cultures, the question of whether the neural correlates of human cognition are also culture-dependent is often not considered by neuroscientists. However, recent transcultural neuroimaging studies have demonstrated that one's cultural background can influence the neural activity that underlies both high- and low-level cognitive functions. The findings provide a novel approach by which to distinguish culture-sensitive from culture-invariant neural mechanisms of human cognition.     

Differentiable, multi-dimensional, knowledge-based energy terms for torsion angle probabilities and propensities

Rotatable torsion angles are the major degrees of freedom in proteins. Adjacent angles are highly correlated and energy terms that rely on these correlations are intensively used in molecular modeling. However, the utility of torsion based terms is not yet fully exploited. Many of these terms do not capture the full scale of the correlations. Other terms, which rely on lookup tables, cannot be used in the context of force-driven algorithms because they are not fully differentiable. This study aims to extend the usability of torsion terms by presenting a set of high-dimensional and fully-differentiable energy terms that are derived from high-resolution structures. The set includes terms that describe backbone conformational probabilities and propensities, side-chain rotamer probabilities, and an elaborate term that couples all the torsion angles within the same residue. The terms are constructed by cubic spline interpolation with periodic boundary conditions that enable full differentiability and high computational efficiency. We show that the spline implementation does not compromise the accuracy of the original database statistics. We further show that the side-chain relevant terms are compatible with established rotamer probabilities. Despite their very local characteristics, the new terms are often able to identify native and native-like structures within decoy sets. Finally, force-based minimization of NMR structures with the new terms improves their torsion angle statistics with minor structural distortion (0.5 A RMSD on average). The new terms are freely available in the MESHI molecular modeling package. The spline coefficients are also available as a documented MATLAB file.