ACTIVITY-DEPENDENT LATERAL INHIBITION IN THE MOUSE OLFACTORY BULB

Lateral inhibition is a circuit motif found throughout the nervous system that often generates contrast enhancement and center-surround receptive fields. While widespread lateral inhibition of mitral cells (the principal output neurons of the bulb) is mediated by granule cells (inhibitory interneurons), due to the distributed representation of odorant-evoked activity it is currently unclear how this inhibition is specified or what functions it mediates. Given the reciprocal nature of the connection between mitral and granule cells, mitral cells that are the targets of lateral inhibition (postsynaptic) are able to modulate the activity of the granule cells mediating this lateral inhibition. This led us to hypothesize that lateral inhibition could be modulated by the activity of both pre- as well as postsynaptic mitral cells. I first characterize the lateral interactions between mitral cells and show that the effectiveness of lateral inhibition between them is dependent on the activity of the postsynaptic neuron such that lateral inhibition is only able to reduce the firing rate within a specific range of postsynaptic firing rates. I call this activity-dependent lateral inhibition. I then investigated this novel form of inhibition further and provide evidence indicating that it results from cooperative activation of the inhibitory granule cells.I investigated the mechanism and functional implications of these physiological results further using computational techniques. First, I show that integration of activity between pre- and postsynaptic mitral cells within a granule cell is sufficient to result in activity-dependent inhibition. I then used this model to show that activity-dependent inhibition is able to enhance the contrast and decorrelate initially similar input patterns to the network in a spatially independent manner. These results provide evidence for a novel form of neuronal interaction dependent on the activity of neurons within the network which could have important functional implications in olfaction as well as other brain areas

Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb

The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb -- the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells -- are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures

Interoceptive Anxiety and Body Representation in Anorexia Nervosa

Individuals with anorexia nervosa (AN) typically display anxious traits prior to the onset of food avoidance and weight loss that characterize the disorder. Meal associated anxiety is an especially common clinical feature in these patients, and heightened sensitivity to sympathetically mediated interoceptive sensations has also been observed. However, it remains unclear how heightened interoceptive sensitivity relates to experiences of anxiety before and after meals. To investigate this relationship, we experimentally induced anxiety and panic symptoms with isoproterenol, a peripheral sympathetic agonist similar to adrenaline, across several different conditions: during panic provocation, during anticipation of a 1,000 Calorie meal, and after meal consumption. Fifteen AN and 15 age- and sex-matched healthy comparisons received bolus infusions of isoproterenol and saline in a double-blinded, randomized design. Participants rated anxiety symptoms after each infusion, completed panic rating scales, and traced the location of perceived palpitations on a manikin to index interoceptive “body map” representation. The AN group reported significantly elevated anxiety relative to healthy comparisons during infusions before and after the meal, but surprisingly, not during panic provocation. These symptoms were accompanied by geographical differences in patterns of perceived heartbeat sensations across each condition. In particular, the AN group localized heartbeat sensations disproportionately to the chest during meal related saline infusions, when no cardiorespiratory modulation actually occurred. The AN group also showed a trend toward higher panic attack rates during the meal anticipation period. Correcting for anxiety levels reported during saline infusions abolished group differences in anxiety change across all conditions, suggesting a significant contribution of anxious traits in AN. The observation of meal related “visceral illusions” provides further evidence that AN is associated with abnormal interoceptive representation of the heartbeat and suggests that meal consumption, particularly when anticipated, preferentially alters the processing of interoception related signals in AN

Framework for primary care organizations: the importance of a structural domain

Purpose. Conceptual frameworks for primary care have evolved over the last 40 years, yet little attention has been paid to the environmental, structural and organizational factors that facilitate or moderate service delivery. Since primary care is now of more interest to policy makers, it is important that they have a comprehensive and balanced conceptual framework to facilitate their understanding and appreciation. We present a conceptual framework for primary care originally developed to guide the measurement of the performance of primary care organizations within the context of a large mixed-method evaluation of four types of models of primary care in Ontario, Canada. Methods. The framework was developed following an iterative process that combined expert consultation and group meet-ings with a narrative review of existing frameworks, as well as trends in health management and organizational theory. Results. Our conceptual framework for primary care has two domains: structural and performance. The structural domain describes the health care system, practice context and organization of the practice in which any primary care organization operates. The performance domain includes features of health care service delivery and technical quality of clinical care. Conclusion. As primary care evolves through demonstration projects and reformed delivery models, it is important to evalu-ate its structural and organizational features as these are likely to have a significant impact on performance

第933回千葉医学会例会・第1内科教室同門会例会

Prominent theories emphasize key roles for the insular cortex in the central representation of interoceptive sensations, but how this brain region responds dynamically to changes in interoceptive state remains incompletely understood. Here, we systematically modulated cardiorespiratory sensations in humans using bolus infusions of isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline. To identify central neural processes underlying these parametrically modulated interoceptive states, we used pharmacological functional magnetic resonance imaging (phMRI) to simultaneously measure blood-oxygenation-level dependent (BOLD) and arterial spin labelling (ASL) signals in healthy participants. Isoproterenol infusions induced dose-dependent increases in heart rate and cardiorespiratory interoception, with all participants endorsing increased sensations at the highest dose. These reports were accompanied by increased BOLD and ASL activation of the right insular cortex at the highest dose. Different responses across insula subregions were also observed. During anticipation, insula activation increased in more anterior regions. During stimulation, activation increased in the mid-dorsal and posterior insula on the right, but decreased in the same regions on the left. This study demonstrates the feasibility of phMRI for assessing brain activation during adrenergic interoceptive stimulation, and provides further evidence supporting a dynamic role for the insula in representing changes in cardiorespiratory states.This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’

Profound Context-Dependent Plasticity of Mitral Cell Responses in Olfactory Bulb

On the basis of its primary circuit it has been postulated that the olfactory bulb (OB) is analogous to the retina in mammals. In retina, repeated exposure to the same visual stimulus results in a neural representation that remains relatively stable over time, even as the meaning of that stimulus to the animal changes. Stability of stimulus representation at early stages of processing allows for unbiased interpretation of incoming stimuli by higher order cortical centers. The alternative is that early stimulus representation is shaped by previously derived meaning, which could allow more efficient sampling of odor space providing a simplified yet biased interpretation of incoming stimuli. This study helps place the olfactory system on this continuum of subjective versus objective early sensory representation. Here we show that odor responses of the output cells of the OB, mitral cells, change transiently during a go–no-go odor discrimination task. The response changes occur in a manner that increases the ability of the circuit to convey information necessary to discriminate among closely related odors. Remarkably, a switch between which of the two odors is rewarded causes mitral cells to switch the polarity of their divergent responses. Taken together these results redefine the function of the OB as a transiently modifiable (active) filter, shaping early odor representations in behaviorally meaningful ways

Regulation of Spike Timing-Dependent Plasticity of Olfactory Inputs in Mitral Cells in the Rat Olfactory Bulb

The recent history of activity input onto granule cells (GCs) in the main olfactory bulb can affect the strength of lateral inhibition, which functions to generate contrast enhancement. However, at the plasticity level, it is unknown whether and how the prior modification of lateral inhibition modulates the subsequent induction of long-lasting changes of the excitatory olfactory nerve (ON) inputs to mitral cells (MCs). Here we found that the repetitive stimulation of two distinct excitatory inputs to the GCs induced a persistent modification of lateral inhibition in MCs in opposing directions. This bidirectional modification of inhibitory inputs differentially regulated the subsequent synaptic plasticity of the excitatory ON inputs to the MCs, which was induced by the repetitive pairing of excitatory postsynaptic potentials (EPSPs) with postsynaptic bursts. The regulation of spike timing-dependent plasticity (STDP) was achieved by the regulation of the inter-spike-interval (ISI) of the postsynaptic bursts. This novel form of inhibition-dependent regulation of plasticity may contribute to the encoding or processing of olfactory information in the olfactory bulb