Neuropeptide Co-Release with Gaba May Explain Functional Non-Monotonic Uncertainty Responses in Dopamine Neurons

Co-release of the inhibitory neurotransmitter GABA and the neuropeptide substance-P (SP) from single axons is a conspicuous feature of the basal ganglia, yet its computational role, if any, has not been resolved. In a new learning model, co-release of GABA and SP from axons of striatal projection neurons emerges as a highly efficient way to compute the uncertainty responses that are exhibited by dopamine (DA) neurons when animals adapt to probabilistic contingencies between rewards and the stimuli that predict their delivery. Such uncertainty-related dopamine release appears to be an adaptive phenotype, because it promotes behavioral switching at opportune times. Understanding the computational linkages between SP and DA in the basal ganglia is important, because Huntington's disease is characterized by massive SP depletion, whereas Parkinson's disease is characterized by massive DA depletion.

A Local Circuit Model of Learned Straitial and Dopamine Cell Responses under Probabilistic Schedules of Reward

Before choosing, it helps to know both the expected value signaled by a predictive cue and the associated uncertainty that the reward will be forthcoming. Recently, Fiorillo et al. (2003) found the dopamine (DA) neurons of the SNc exhibit sustained responses related to the uncertainty that a cure will be followed by reward, in addition to phasic responses related to reward prediction errors (RPEs). This suggests that cue-dependent anticipations of the timing, magnitude, and uncertainty of rewards are learned and reflected in components of the DA signals broadcast by SNc neurons. What is the minimal local circuit model that can explain such multifaceted reward-related learning? A new computational model shows how learned uncertainty responses emerge robustly on single trial along with phasic RPE responses, such that both types of DA responses exhibit the empirically observed dependence on conditional probability, expected value of reward, and time since onset of the reward-predicting cue. The model includes three major pathways for computing: immediate expected values of cures, timed predictions of reward magnitudes (and RPEs), and the uncertainty associated with these predictions. The first two model pathways refine those previously modeled by Brown et al. (1999). A third, newly modeled, pathway is formed by medium spiny projection neurons (MSPNs) of the matrix compartment of the striatum, whose axons co-release GABA and a neuropeptide, substance P, both at synapses with GABAergic neurons in the SNr and with the dendrites (in SNr) of DA neurons whose somas are in ventral SNc. Co-release enables efficient computation of sustained DA uncertainty responses that are a non-monotonic function of the conditonal probability that a reward will follow the cue. The new model's incorporation of a striatal microcircuit allowed it to reveals that variability in striatal cholinergic transmission can explain observed difference, between monkeys, in the amplitutude of the non-monotonic uncertainty function. Involvement of matriceal MSPNs and striatal cholinergic transmission implpies a relation between uncertainty in the cue-reward contigency and action-selection functions of the basal ganglia. The model synthesizes anatomical, electrophysiological and behavioral data regarding the midbrain DA system in a novel way, by relating the ability to compute uncertainty, in parallel with other aspects of reward contingencies, to the unique distribution of SP inputs in ventral SN.

Dopaminergic and Non-Dopaminergic Value Systems in Conditioning and Outcome-Specific Revaluation

Animals are motivated to choose environmental options that can best satisfy current needs. To explain such choices, this paper introduces the MOTIVATOR (Matching Objects To Internal Values Triggers Option Revaluations) neural model. MOTIVATOR describes cognitiveemotional interactions between higher-order sensory cortices and an evaluative neuraxis composed of the hypothalamus, amygdala, and orbitofrontal cortex. Given a conditioned stimulus (CS), the model amygdala and lateral hypothalamus interact to calculate the expected current value of the subjective outcome that the CS predicts, constrained by the current state of deprivation or satiation. The amygdala relays the expected value information to orbitofrontal cells that receive inputs from anterior inferotemporal cells, and medial orbitofrontal cells that receive inputs from rhinal cortex. The activations of these orbitofrontal cells code the subjective values of objects. These values guide behavioral choices. The model basal ganglia detect errors in CS-specific predictions of the value and timing of rewards. Excitatory inputs from the pedunculopontine nucleus interact with timed inhibitory inputs from model striosomes in the ventral striatum to regulate dopamine burst and dip responses from cells in the substantia nigra pars compacta and ventral tegmental area. Learning in cortical and striatal regions is strongly modulated by dopamine. The model is used to address tasks that examine food-specific satiety, Pavlovian conditioning, reinforcer devaluation, and simultaneous visual discrimination. Model simulations successfully reproduce discharge dynamics of known cell types, including signals that predict saccadic reaction times and CS-dependent changes in systolic blood pressure.

Brain Learning and Recognition: The Large and the Small of It in Inferotemporal Cortex

Anterior inferotemporal cortex (ITa) plays a key role in visual object recognition. Recognition is tolerant to object position, size, and view changes, yet recent neurophysiological data show ITa cells with high object selectivity often have low position tolerance, and vice versa. A neural model learns to simulate both this tradeoff and ITa responses to image morphs using large-scale and small-scale IT cells whose population properties may support invariant recognition.

Statistical Properties of Single and Competing Non-Linear Fast-Slow Oscillators in Noise

Statistical properties offast-slow Ellias-Grossberg oscillators are studied in response to deterministic and noisy inputs. Oscillatory responses remain stable in noise due to the slow inhibitory variable, which establishes an adaptation level that centers the oscillatory responses of the fast excitatory variable to deterministic and noisy inputs. Competitive interactions between oscillators improve the stability in noise. Although individual oscillation amplitudes decrease with input amplitude, the average to'tal activity increases with input amplitude, thereby suggesting that oscillator output is evaluated by a slow process at downstream network sites.

Simulating Effects of Learning and Lesions with a Model of Intrinsic and Synaptically Gated Responses of Striatal Cholinergic Interneurons

The giant cholinergic interneurons of the striatum are tonically active neurons (TANs) that respond with characteristic pauses to novel events and to appetitive and aversive conditioned stimuli. Fluctuations in acetylcholine release by TANs modulate performance- and learning-related dynamics in the striatum. Whereas tonic activity emerges from intrinsic properties of these neurons, glutamatergic inputs from thalamic centromedian-parafascicular nuclei, and dopaminergic inputs from midbrain, are required for the generation of pause responses. No prior computational models encompass both intrinsic and synaptically-gated dynamics. We present a mathematical model that robustly accounts for behavior-related electrophysiological properties of TANs in terms of their intrinsic physiological properties and known afferents. In the model, balanced intrinsic hyperpolarizing and depolarizing currents engender tonic firing, and glutamatergic inputs from thalamus (and cortex) both directly excite and indirectly inhibit TANs. If the latter inhibition, presumably mediated by GABAergic interneurons, exceeds a threshold, its effect is amplified by a KIR current to generate a prolonged pause. In the model, the intrinsic mechanisms and external inputs are both modulated by learning-dependent dopamine (DA) signals and our simulations revealed that many learning-dependent behaviors of TANs are explicable without recourse to learning-dependent changes in synapses onto TANs. The "teaching signal" that modulates reinforcement learning at cortico-striatal synapses may be a sequence composed of an adaptively scaled DA burst, a brief ACh burst, and a scaled ACh pause. Such an interpretation is consistent with recent data on cholinergic control of LTD of cortical synapses onto striatal spiny projection neurons.

Fuzzy ART: An Adaptive Resonance Algorithm for Rapid, Stable Classification of Analog Patterns

The Fuzzy ART system introduced herein incorporates computations from fuzzy set theory into ART 1. For example, the intersection (n) operator used in ART 1 learning is replaced by the MIN operator (A) of fuzzy set theory. Fuzzy ART reduces to ART 1 in response to binary input vectors, but can also learn stable categories in response to analog input vectors. In particular, the MIN operator reduces to the intersection operator in the binary case. Learning is stable because all adaptive weights can only decrease in time. A preprocessing step, called complement coding, uses on-cell and off-cell responses to prevent category proliferation. Complement coding normalizes input vectors while preserving the amplitudes of individual feature activations.

Synchronized Oscillations During Cooperative Feature Lining in a Cortical Model of Visual Perception

A neural network model of synchronized oscillations in visual cortex is presented to account for recent neurophysiological findings that such synchronization may reflect global properties of the stimulus. In these experiments, synchronization of oscillatory firing responses to moving bar stimuli occurred not only for nearby neurons, but also occurred between neurons separated by several cortical columns (several mm of cortex) when these neurons shared some receptive field preferences specific to the stimuli. These results were obtained for single bar stimuli and also across two disconnected, but colinear, bars moving in the same direction. Our model and computer simulations obtain these synchrony results across both single and double bar stimuli using different, but formally related, models of preattentive visual boundary segmentation and attentive visual object recognition, as well as nearest-neighbor and randomly coupled models.

Synchronized Oscillations During Cooperative Feature Linking in a Cortical Model of Visual Perception

A neural network model of synchronized oscillator activity in visual cortex is presented in order to account for recent neurophysiological findings that such synchronization may reflect global properties of the stimulus. In these recent experiments, it was reported that synchronization of oscillatory firing responses to moving bar stimuli occurred not only for nearby neurons, but also occurred between neurons separated by several cortical columns (several mm of cortex) when these neurons shared some receptive field preferences specific to the stimuli. These results were obtained not only for single bar stimuli but also across two disconnected, but colinear, bars moving in the same direction. Our model and computer simulations obtain these synchrony results across both single and double bar stimuli. For the double bar case, synchronous oscillations are induced in the region between the bars, but no oscillations are induced in the regions beyond the stimuli. These results were achieved with cellular units that exhibit limit cycle oscillations for a robust range of input values, but which approach an equilibrium state when undriven. Single and double bar synchronization of these oscillators was achieved by different, but formally related, models of preattentive visual boundary segmentation and attentive visual object recognition, as well as nearest-neighbor and randomly coupled models. In preattentive visual segmentation, synchronous oscillations may reflect the binding of local feature detectors into a globally coherent grouping. In object recognition, synchronous oscillations may occur during an attentive resonant state that triggers new learning. These modelling results support earlier theoretical predictions of synchronous visual cortical oscillations and demonstrate the robustness of the mechanisms capable of generating synchrony.

A Neural Network of Adaptively Timed Reinforcement Learning and Hippocampal Dynamics

A neural model is described of how adaptively timed reinforcement learning occurs. The adaptive timing circuit is suggested to exist in the hippocampus, and to involve convergence of dentate granule cells on CA3 pyramidal cells, and NMDA receptors. This circuit forms part of a model neural system for the coordinated control of recognition learning, reinforcement learning, and motor learning, whose properties clarify how an animal can learn to acquire a delayed reward. Behavioral and neural data are summarized in support of each processing stage of the system. The relevant anatomical sites are in thalamus, neocortex, hippocampus, hypothalamus, amygdala, and cerebellum. Cerebellar influences on motor learning are distinguished from hippocampal influences on adaptive timing of reinforcement learning. The model simulates how damage to the hippocampal formation disrupts adaptive timing, eliminates attentional blocking, and causes symptoms of medial temporal amnesia. It suggests how normal acquisition of subcortical emotional conditioning can occur after cortical ablation, even though extinction of emotional conditioning is retarded by cortical ablation. The model simulates how increasing the duration of an unconditioned stimulus increases the amplitude of emotional conditioning, but does not change adaptive timing; and how an increase in the intensity of a conditioned stimulus "speeds up the clock", but an increase in the intensity of an unconditioned stimulus does not. Computer simulations of the model fit parametric conditioning data, including a Weber law property and an inverted U property. Both primary and secondary adaptively timed conditioning are simulated, as are data concerning conditioning using multiple interstimulus intervals (ISIs), gradually or abruptly changing ISis, partial reinforcement, and multiple stimuli that lead to time-averaging of responses. Neurobiologically testable predictions are made to facilitate further tests of the model.

A literary occupation: responses of German writers in service in occupied Europe

This thesis examines the literary output of German servicemen writers writing from the occupied territories of Europe in the period 1940-1944. Whereas literary-biographical studies and appraisals of the more significant individual writers have been written, and also a collective assessment of the Eastern front writers, this thesis addresses in addition the German literary responses in France and Greece, as being then theatres of particular cultural/ideological attention. Original papers of the writer Felix Hartlaub were consulted by the author at the Deutsches Literatur Archiv (DLA) at Marbach. Original imprints of the wartime works of the subject writers are referred to throughout, and citations are from these. As all the published works were written under conditions of wartime censorship and, even where unpublished, for fear of discovery written in oblique terms, the texts were here examined for subliminal authorial intention. The critical focus of the thesis is on literary quality: on aesthetic niveau, on applied literary form, and on integrity of authorial intention. The thesis sought to discover: (1) the extent of the literary output in book-length forms. (2) the auspices and conditions under which this literary output was produced. (3) the publication history and critical reception of the output. The thesis took into account, inter alia: (1) occupation policy as it pertained locally to the writers’ remit; (2) the ethical implications of this for the writers; (3) the writers’ literary stratagems for negotiating the constraints of censorship.

The student bullying of teachers in Irish second level schools: exploring the influence of historical low state intervention in education on the development of contemporary policy responses in Ireland

The student bullying of teachers (SBT) is a distinct and complex form of bullying with a multiplicity of diverse, changeable and intersecting causes which is experienced by and affects teachers in a variety of ways. SBT is both a national and an international phenomenon which is under-recognised in academic, societal and political spheres, resulting in limited conceptual understanding and awareness of the issue. This study explores teachers’ experiences of SBT behaviours in Irish second level schools as well as teachers’ perceptions regarding training, policies and supports in Ireland to address the issue. Specifically, the study seeks to explore the influence of historical low State intervention in education on contemporary policies and supports to deal with SBT in Ireland. A mixed methods approach involving a survey of 531 second level school teachers and 17 semi-structured interviews with teachers, Year Heads and representatives from teacher trade unions and school management bodies was employed to collect and analyse data. Findings indicate that SBT behaviours are prevalent in many forms in Irish second level schools. The hidden nature of the phenomenon has simultaneously contributed to and is reinforced by limited understanding of the issue as well as teachers’ reluctance to disclose their experiences. Findings reveal that teachers perceive the contemporary policies, training and support structures in Ireland to be inadequate in equipping them to effectively deal with SBT. State intervention in addressing SBT behaviours to date, has been limited, therefore many teachers are forced to respond to the issue based on their own initiatives and assumptions rather than from an informed critically reflective approach, supported by national guidelines and sufficient State investment. This has resulted in a piecemeal, un-coordinated and ad-hoc approach to SBT in Irish schools both in terms of teachers’ management of SBT behaviours and with respect to the supports extended to staff. The potential negative consequences of SBT behaviours on teachers’ wellbeing and professional performance and thus, on the education system itself, underlines the need for a strategic, evidence-based, resourced and integrated approach which includes, as a pivotal component, consultation with teachers, whose contribution to the process is crucial.

CD4+ CD25+ regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo.

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II-restricted interferon gamma-producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

Identification of major factors influencing ELISpot-based monitoring of cellular responses to antigens from Mycobacterium tuberculosis.

A number of different interferon-gamma ELISpot protocols are in use in laboratories studying antigen-specific immune responses. It is therefore unclear how results from different assays compare, and what factors most significantly influence assay outcome. One such difference is that some laboratories use a short in vitro stimulation period of cells before they are transferred to the ELISpot plate; this is commonly done in the case of frozen cells, in order to enhance assay sensitivity. Other differences that may be significant include antibody coating of plates, the use of media with or without serum, the serum source and the number of cells added to the wells. The aim of this paper was to identify which components of the different ELISpot protocols influenced assay sensitivity and inter-laboratory variation. Four laboratories provided protocols for quantifying numbers of interferon-gamma spot forming cells in human peripheral blood mononuclear cells stimulated with Mycobacterium tuberculosis derived antigens. The differences in the protocols were compared directly. We found that several sources of variation in assay protocols can be eliminated, for example by avoiding serum supplementation and using AIM-V serum free medium. In addition, the number of cells added to ELISpot wells should also be standardised. Importantly, delays in peripheral blood mononuclear cell processing before stimulation had a marked effect on the number of detectable spot forming cells; processing delay thus should be minimised as well as standardised. Finally, a pre-stimulation culture period improved the sensitivity of the assay, however this effect may be both antigen and donor dependent. In conclusion, small differences in ELISpot protocols in routine use can affect the results obtained and care should be given to conditions selected for use in a given study. A pre-stimulation step may improve the sensitivity of the assay, particularly when cells have been previously frozen.

A variant of SCID with specific immune responses and predominance of gamma delta T cells.

We describe here a patient with a clinical and molecular diagnosis of recombinase activating gene 1-deficient (RAG1-deficient) SCID, who produced specific antibodies despite minimal B cell numbers. Memory B cells were detected and antibodies were produced not only against some vaccines and infections, but also against autoantigens. The patient had severely reduced levels of oligoclonal T cells expressing the alphabeta TCR but surprisingly normal numbers of T cells expressing the gammadelta TCR. Analysis at a clonal level and TCR complementarity-determining region-3 spectratyping for gammadelta T cells revealed a diversified oligoclonal repertoire with predominance of cells expressing a gamma4-delta3 TCR. Several gammadelta T cell clones displayed reactivity against CMV-infected cells. These observations are compatible with 2 non-mutually exclusive explanations for the gammadelta T cell predominance: a developmental advantage and infection-triggered, antigen-driven peripheral expansion. The patient carried the homozygous hypomorphic R561H RAG1 mutation leading to reduced V(D)J recombination but lacked all clinical features characteristic of Omenn syndrome. This report describes a new phenotype of RAG deficiency and shows that the ability to form specific antibodies does not exclude the diagnosis of SCID.