Regulation of glutamate synapses by nicotinic acetylcholine receptors in auditory cortex

Acetylcholine plays an important role in regulating the processing of sensory stimuli, and understanding its specific cellular actions is critical to understanding how sensory cortex develops and functions in different behavioral states. Here we review recent work on the cellular effects of nicotinic receptor activation in auditory cortex and describe how these actions could affect systems-level auditory function. In particular, we describe a novel function of nicotinic acetylcholine receptors to regulate glutamate synapses containing N-methyl-D-aspartate receptors during early postnatal development. The transient regulation of developing glutamate synapses also defines a window of vulnerability during which exposure to exogenous nicotine disrupts synapse development. Thus, it appears that nicotinic regulation of glutamate synapses is a critical feature of auditory cortex development.     

Nicotinic modulation of tone-evoked responses in auditory cortex reflects the strength of prior auditory learning

Nicotinic acetylcholine receptors (nAChRs) contribute to sensory-cognitive function, as demonstrated by evidence that nAChR activation enhances, and nAChR blockade impairs, neural processing of sensory stimuli and sensory-cognitive behavior. To better understand the relationship between nAChR function and behavior, here we compare the strength of nAChR-mediated physiology in individual animals to their prior auditory behavioral performance. Adult rats were trained on an auditory-cued, active avoidance task over 4 days and classified as “good,” “intermediate” or “poor” performers based on their initial rate of learning and eventual level of performance. Animals were then anesthetized, and tone-evoked local field potentials (LFPs) recorded in layer 4 of auditory cortex (ACx) before and after a test dose of nicotine (0.7 mg/kg, s.c.) or saline. In “good” performers, nicotine enhanced LFP amplitude and decreased response threshold to characteristic frequency (CF) stimuli, yet had opposite effects (decreased amplitude, increased threshold) on responses to spectrally distant stimuli; i.e., cortical receptive fields became more selective for CF stimuli. In contrast, nicotine had little effect on LFP amplitude in “intermediate” or “poor” performing animals. Nicotine did, however, reduce LFP onset latency in all three groups, indicating that all received an effective dose of the drug. Our findings suggest that nicotinic regulation of cortical receptive fields may be a distinguishing feature of the best-performing animals, and may facilitate sensory-related learning by enhancing receptive field selectivity.     

Relationship between nicotinic receptors and cognitive function in early Alzheimer's disease: a 2-[18F]fluoro-A-85380 PET study

Neuronal nicotinic acetylcholine receptors (nAChRs) are critical for higher order cognitive processes. Post-mortem studies suggest reductions in nAChRs (particularly the alpha(4)beta(2) subtype) with ageing and in Alzheimer's disease (AD). This study aimed to; (1) quantify nAChR distribution in vivo with 2-[18F]fluoro-A-85380 (2-FA) in 15 early AD patients compared to 14 age-matched, healthy controls (HC) and (2) correlate nAChR distribution with cognitive performance in both groups. All participants were non-smokers and underwent cognitive testing along with a dynamic PET scan after injection of 200 MBq of 2-FA. Brain regional 2-FA binding was assessed through a simplified estimation of Distribution Volume (DV(S)). The AD group differed significantly from HC on all cognitive measures employed, with impairments on measures of attention, working memory, language, executive function, visuospatial ability, verbal learning and verbal memory (p<.05). Contrary to post-mortem data this study found no evidence of in vivo nAChR loss in early AD despite significant cognitive impairment. Furthermore, no correlation between nAChR and cognitive performance was found for either group. The findings of the current study suggest preservation of nAChRs early in AD supporting previous studies. It is possible that while the clinical 2-FA PET method described here may be insensitive in detecting changes in early AD, such changes may be detected in more advanced stages of the illness.     

Conscious thought as simulation of behaviour and perception

A 'simulation' theory of cognitive function can be based on three assumptions about brain function. First, behaviour can be simulated by activating motor structures, as during an overt action but suppressing its execution. Second, perception can be simulated by internal activation of sensory cortex, as during normal perception of external stimuli. Third, both overt and covert actions can elicit perceptual simulation of their normal consequences. A large body of evidence supports these assumptions. It is argued that the simulation approach can explain the relations between motor, sensory and cognitive functions and the appearance of an inner world.     

Cortical electrophysiological network dynamics of feedback learning

Understanding the neurophysiological mechanisms of learning is important for both fundamental and clinical neuroscience. We present a neurophysiologically inspired framework for understanding cortical mechanisms of feedback-guided learning. This framework is based on dynamic changes in systems-level oscillatory synchronization, reflecting changes in synaptic plasticity between stimulus-processing and motor areas that are modulated in a top-down fashion by different areas of the prefrontal cortex. We make new and testable predictions for how large-scale cortical networks support learning from feedback. Testing these predictions may provide new insights into the basic mechanisms underlying learning and how these mechanisms may be impaired in clinical disorders in which feedback learning is compromised.     

α7 Nicotinic Receptor Subunits Are Not Necessary for Hippocampal-Dependent Learning or Sensorimotor Gating: A Behavioral Characterization of Acra7-Deficient Mice

The α7 nicotinic acetylcholine receptor (nAChR) subunit is abundantly expressed in the hippocampus and contributes to hippocampal cholinergic synaptic transmission suggesting that it may contribute to learning and memory. There is also evidence for an association between levels of α7 nAChR and in sensorimotor gating impairments. To examine the role of α7 nAChRs in learning and memory and sensorimotor gating, Acra7 homozygous mutant mice and their wild-type littermates were tested in a Pavlovian conditioned fear test, for spatial learning in the Morris water task, and in the prepulse inhibition paradigm. Exploratory activity, motor coordination, and startle habituation were also evaluated. Acra7 mutant mice displayed the same levels of contextual and auditory-cue condition fear as wild-type mice. Similarly, there were no differences in spatial learning performance between mutant and wild-type mice. Finally, Acra7 mutant and wild-type mice displayed similar levels of prepulse inhibition. Other behavioral responses in Acra7 mutant mice were also normal, except for an anxiety-related behavior in the open-field test. The results of this study show that the absence of α7 nAChRs has little impact on normal, base-line behavioral responses. Future studies will examine the contribution of α7 nAChR to the enhancement of learning and sensorimotor gating following nicotine treatments.     

Multiple serotonergic mechanisms contributing to sensitization in aplysia: evidence of diverse serotonin receptor subtypes

The neurotransmitter serotonin (5-HT) plays an important role in memory encoding in Aplysia. Early evidence showed that during sensitization, 5-HT activates a cyclic AMP-protein kinase A (cAMP-PKA)-dependent pathway within specific sensory neurons (SNs), which increases their excitability and facilitates synaptic transmission onto their follower motor neurons (MNs). However, recent data suggest that serotonergic modulation during sensitization is more complex and diverse. The neuronal circuits mediating defensive reflexes contain a number of interneurons that respond to 5-HT in ways opposite to those of the SNs, showing a decrease in excitability and/or synaptic depression. Moreover, in addition to acting through a cAMP-PKA pathway within SNs, 5-HT is also capable of activating a variety of other protein kinases such as protein kinase C, extracellular signal-regulated kinases, and tyrosine kinases. This diversity of 5-HT responses during sensitization suggests the presence of multiple 5-HT receptor subtypes within the Aplysia central nervous system. Four 5-HT receptors have been cloned and characterized to date. Although several others probably remain to be characterized in molecular terms, especially the Gs-coupled 5-HT receptor capable of activating cAMP-PKA pathways, the multiplicity of serotonergic mechanisms recruited into action during learning in Aplysia can now be addressed from a molecular point of view.     

盲人的跨感觉通道重组

失去视觉的盲人往往伴随着行为代偿,如听觉和触觉能力的提高。脑成像等认知神经科学研究发现,盲人行为代偿的神经机制之一是大脑皮层的跨感觉通道重组,即盲人的视皮层并没有因为视觉剥夺而失去作用,而是广泛地参与了其他感知觉任务。原本暂时的神经联结由于受到新的感觉信息传入方式的持续激活而固化,从而形成新的神经回路,可能是此类跨通道重组的神经基础。     

Occupational therapy using a sensory integrative approach for children with developmental disabilities

This article provides an introduction and overview of sensory integration theory as it is used in occupational therapy practice for children with developmental disabilities. This review of the theoretical tenets of the theory, its historical foundations, and early research provides the reader with a basis for exploring current uses and applications. The key principles of the sensory integrative approach, including concepts such as "the just right challenge" and "the adaptive response" as conceptualized by A. Jean Ayres, the theory's founder, are presented to familiarize the reader with the approach. The state of research in this area is presented, including studies underway to further delineate the subtypes of sensory integrative dysfunction, the neurobiological mechanisms of poor sensory processing, advances in theory development, and the development of a fidelity measure for use in intervention studies. Finally, this article reviews the current state of the evidence to support this approach and suggests that consensual knowledge and empirical research are needed to further elucidate the theory and its utility for a variety of children with developmental disabilities. This is especially critical given the public pressure by parents of children with autism and other developmental disabilities to obtain services and who have anecdotally noted the utility of sensory integration therapy for helping their children function more independently. Key limiting factors to research include lack of funding, paucity of doctorate trained clinicians and researchers in occupational therapy, and the inherent heterogeneity of the population of children affected by sensory integrative dysfunction. A call to action for occupational therapy researchers, funding agencies, and other professions is made to support ongoing efforts and to develop initiatives that will lead to better diagnoses and effective intervention for sensory integrative dysfunction, which will improve the lives of children and their families.     

Beta2 subunit containing acetylcholine receptors mediate nicotine withdrawal deficits in the acquisition of contextual fear conditioning

Acute nicotine enhances contextual fear conditioning, whereas withdrawal from chronic nicotine produces impairments. However, the nicotinic acetylcholine receptors (nAChR) that are involved in nicotine withdrawal deficits in contextual fear conditioning are unknown. The present study used genetic and pharmacological techniques to investigate the nAChR subtype(s) involved in the effects of nicotine withdrawal on contextual fear conditioning. beta2 or alpha 7 nAChR subunit knockout (KO) and corresponding wild-type (WT) mice were withdrawn from 12 days of chronic nicotine treatment (6.3mg/kg/day), and trained with 2 conditioned stimulus (CS; 85 dB white noise)--unconditioned stimulus (US; 0.57 mA footshock) pairings on day 13. On day 14, mice were tested for contextual and cued freezing. beta2 KO mice did not show nicotine withdrawal-related deficits in contextual fear conditioning, in contrast to WT mice and alpha 7 KO mice. A follow-up study investigated if nicotine withdrawal disrupts acquisition or recall of contextual fear conditioning. The high affinity nAChR antagonist dihydro-beta-erythroidine (DH beta E; 3mg/kg) was administered prior to training or testing to precipitate withdrawal in chronic nicotine-treated C57BL/6 mice. Deficits in contextual fear conditioning were observed in chronic nicotine-treated mice when DH beta E was administered prior to training, but not when administered at testing. These results indicate that beta2-containing nAChRs, such as the alpha 4 beta 2 receptor, mediate nicotine withdrawal deficits in contextual fear conditioning. In addition, nicotine withdrawal selectively affects acquisition but not recall or expression of the learned response.     

Within-person relationships between mood and creativity

State mood has been proposed as a facilitator of creative behavior. Whereas positive mood compared to neutral mood generally facilitates creative performance, mood effects are weaker and less consistent when positive mood is compared to negative mood. These inconsistent results may be due to focusing only on mood valence, while neglecting or confounding mood activation. The current study is based on the dual-pathway model, which describes separate roles for mood valence and mood activation in facilitating creativity. We used experience sampling methodology to investigate the concurrent and lagged effects of mood valence and activation on creative process engagement (CPE) within-person over time among individuals working on a long-term project requiring creativity. We also investigated the moderating effects of individual differences in goal orientation and supervisory support on within-person mood-creativity relationships. As expected, we found that activating positive and activating negative moods were positively associated with concurrent CPE, whereas deactivating moods of both valences were negatively related to CPE. Activating negative mood had a significant lagged effect on CPE, whereas activating positive mood did not. We also found that activating positive mood was more strongly related to concurrent CPE among individuals with high rather than low learning goal orientation. Further, activating positive mood interacted with prove goal orientation and supervisory support for creativity, such that activating positive mood had the strongest association with CPE when both prove goal orientation and supervisory support were high.     

Learning in a simple motor system

Motor learning is a very basic, essential form of learning that appears to share common mechanisms across different motor systems. We evaluate and compare a few conceptual models for learning in a relatively simple neural system, the vestibulo-ocular reflex (VOR) of vertebrates. We also compare the different animal models that have been used to study the VOR. In the VOR, a sensory signal from the semicircular canals is transformed into a motor signal that moves the eyes. The VOR can modify the transformation under the guidance of vision. The changes are persistent and share some characteristics with other types of associative learning. The cerebellar cortex is directly linked to the VOR reflex circuitry in a partnership that is present in all vertebrates, and which is necessary for motor learning. Early theories of Marr, Albus, and Ito, in which motor memories are stored solely in the cerebellar cortex, have not explained the bulk of the experimental data. Many studies appear to indicate a site of learning in the vestibular nuclei, and the most successful models have incorporated long-term memory storage in both the cerebellar cortex and the brainstem. Plausible cellular mechanisms for learning have been identified in both structures. We propose that short-term motor memory is initially stored in the cerebellar cortex, and that during consolidation of the motor memory the locus of storage shifts to include a brainstem site. We present experimental results that support our hypothesis.     

Stimulus-Specific Delay Activity in Human Primary Visual Cortex

ABSTRACT— Working memory (WM) involves maintaining information in an on-line state. One emerging view is that information in WM is maintained via sensory recruitment , such that information is stored via sustained activity in the sensory areas that encode the to-be-remembered information. Using functional magnetic resonance imaging, we observed that key sensory regions such as primary visual cortex (V1) showed little evidence of sustained increases in mean activation during a WM delay period, though such amplitude increases have typically been used to determine whether a region is involved in on-line maintenance. However, a multivoxel pattern analysis of delay-period activity revealed a sustained pattern of activation in V1 that represented only the intentionally stored feature of a multifeature object. Moreover, the pattern of delay activity was qualitatively similar to that observed during the discrimination of sensory stimuli, suggesting that WM representations in V1 are reasonable "copies" of those evoked during pure sensory processing.     

Congenital prosopagnosia: face-blind from birth

Congenital prosopagnosia refers to the deficit in face processing that is apparent from early childhood in the absence of any underlying neurological basis and in the presence of intact sensory and intellectual function. Several such cases have been described recently and elucidating the mechanisms giving rise to this impairment should aid our understanding of the psychological and neural mechanisms mediating face processing. Fundamental questions include: What is the nature and extent of the face-processing deficit in congenital prosopagnosia? Is the deficit related to a more general perceptual deficit such as the failure to process configural information? Are any neural alterations detectable using fMRI, ERP or structural analyses of the anatomy of the ventral visual cortex? We discuss these issues in relation to the existing literature and suggest directions for future research.     

A general mechanism for decision-making in the human brain?

A new fMRI study by Heekeren and colleagues suggests that left dorsolateral prefrontal cortex (DLPFC) contains a region that integrates sensory evidence supporting perceptual decisions. DLPFC meets two criteria posited by Heekeren et al. for such a region: (1) its activity is correlated in time with the output of sensory areas of the visual cortex measured simultaneously, and (2) as expected of an integrator, its activity is greater on trials for which the sensory evidence is substantial than on trials for which the sensory evidence is weak. Complementary experiments in humans and monkeys now offer a realistic hope of elucidating decision-making networks in the primate brain.     

Unawareness of visual and sensorimotor defects: A hypothesis

A theory is proposed to account for unawareness of blindness, hemianopsia, and hemiplegia, and for phantom limb after amputation. It is assumed that interruption of a sensory pathway at any level--from peripheral nerve to primary sensory cortex--is not associated with any immediate sensory experience that uniquely specifies the defect. Instead the sensory loss must be discovered by a process of self-observation and inference. Discovery is easy for defects that create major functional disability, such as total blindness. Hence unawareness of total blindness occurs only in association with severe intellectual impairment, precluding the required self-observation and inference. In contrast, hemianopsia is difficult to discover because several mechanisms automatically compensate the defect effectively. Thus unawareness of hemianopsia is common, even in intellectually normal individuals. Insensate fields are often the source of suggested (false) percepts, because no information from such a field specifies the absence of a sensory stimulus. The most powerful source of suggestion is sensory activity in uninvolved portions of the affected sensory field. Thus hemianopsics may perceive complete geometric forms when only incomplete forms are shown and the missing portion falls in the hemianopsic fields. Such perceptual completion also occurs in hemianesthetic hemiplegics, creating the illusion that there are normally functioning limbs on the affected side. This perceptual completion increases the difficulty of discovery of hemianesthetic hemiplegia, but the disability is still sufficiently obvious that some additional cognitive impairment is invariably present in patients with lasting unawareness of hemiplegia. Phantom limb after amputation is the product of perceptual completion without associated cognitive impairment. The patient with phantom limb is thus aware of the illusory quality of his phantom. Some insight into the neural basis of perceptual completion and of unawareness of sensory loss may derive from considering sensory systems and associative cortex as parallel-distributed processing mechanisms.     

The Senses as Signalling Systems

A central goal of the philosophy of perception is to uncover the nature of sensory capacities. Ideally, we would like an account that specifies what conditions need to be met in order for an organism to count as having the capacity to sense or perceive its environment. And, on the assumption that sensory states are the kinds of things that can be accurate or inaccurate, a further goal of the philosophy of perception is to identify the accuracy conditions for sensory states. In this paper I recommend a novel approach to these core issues, one that draws heavily on game-theoretic treatments of signalling in nature. A benefit of the approach is that it helps us to understand why biologists attribute sensory powers to such a diverse range of organisms, including plants, fungi, and algae.     

Endogenous BDNF is required for long-term memory formation in the rat parietal cortex

Information storage in the brain is a temporally graded process involving different memory phases as well as different structures in the mammalian brain. Cortical plasticity seems to be essential to store stable long-term memories, although little information is available at the moment regarding molecular and cellular events supporting memory consolidation in the neocortex. Brain-derived neurotrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in hippocampal and cortical neurons. We have recently demonstrated that endogenous BDNF in the hippocampus is involved in memory formation. Here we examined the role of BDNF in the parietal cortex (PCx) in short-term (STM) and long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the PCx impaired both STM and LTM retention scores and decreased the phosphorylation state of cAMP response element-binding protein (CREB). In contrast, intracortical administration of recombinant human BDNF facilitated LTM and increased CREB activation. Moreover, inhibitory avoidance training is associated with a rapid and transient increase in phospho-CREB/total CREB ratio in the PCx. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of inhibitory avoidance learning, possibly involving CREB activation-dependent mechanisms. The present data support the idea that early sensory areas constitute important components of the networks subserving memory formation and that information processing in neocortex plays an important role in memory formation.     

大脑视知觉调控的神经机制

大脑的知觉加工并非单纯由外部刺激驱动,而是存在自上而下的知觉调控。尽管这一现象被大量实验研究证实,但其神经机制仍然是认知神经科学研究的重要问题。本研究系统介绍了知觉调控的神经基础、实现形式、研究范式,及其理论模型,分析指出了当前研究面临的主要问题,并对未来的研究进行了展望,以期促进该问题研究的进一步开展。     

Identifying emergent leaders in psychotherapy groups

This paper is the second in the series on group development and emergent leadership. It describes the design of a sociometric instrument which will be used for the identification of the four emerging leaders from the perspective of the group participants themselves. These four leaders, Task, Emotional, Scapegoat and Defiant, perform ongoing maintenance functions in the group and take up the critical function of spokesmen in the group's dialectical processing of phase-specific, group level issues. The goal here is to design an instrument which would allow both clinician and researcher to identify these critical persons early in a group's life.Ariadne P. Back is in private practice in Chicago, Illinois.