A Model of Stimulus-Specific Neural Assemblies in the Insect Antennal Lobe

It has been proposed that synchronized neural assemblies in the antennal lobe of insects encode the identity of olfactory stimuli. In response to an odor, some projection neurons exhibit synchronous firing, phase-locked to the oscillations of the field potential, whereas others do not. Experimental data indicate that neural synchronization and field oscillations are induced by fast GABAA-type inhibition, but it remains unclear how desynchronization occurs. We hypothesize that slow inhibition plays a key role in desynchronizing projection neurons. Because synaptic noise is believed to be the dominant factor that limits neuronal reliability, we consider a computational model of the antennal lobe in which a population of oscillatory neurons interact through unreliable GABAA and GABAB inhibitory synapses. From theoretical analysis and extensive computer simulations, we show that transmission failures at slow GABAB synapses make the neural response unpredictable. Depending on the balance between GABAA and GABAB inputs, particular neurons may either synchronize or desynchronize. These findings suggest a wiring scheme that triggers stimulus-specific synchronized assemblies. Inhibitory connections are set by Hebbian learning and selectively activated by stimulus patterns to form a spiking associative memory whose storage capacity is comparable to that of classical binary-coded models. We conclude that fast inhibition acts in concert with slow inhibition to reformat the glomerular input into odor-specific synchronized neural assemblies

Modelling the signal delivered by a population of first-order neurons in a moth olfactory system

A statistical model of the population of first-order olfactory receptor neurons (ORNs) is proposed and analysed. It describes the relationship between stimulus intensity (odour concentration) and coding variables such as rate and latency of the population of several thousand sex-pheromone sensitive ORNs in male moths. Although these neurons likely express the same olfactory receptor, they exhibit, at any concentration, a relatively large heterogeneity of responses in both peak firing frequency and latency of the first action potential fired after stimulus onset. The stochastic model is defined by a multivariate distribution of six model parameters that describe the dependence of the peak firing rate and the latency on the stimulus dose. These six parameters and their mutual linear correlations were estimated from experiments in single ORNs and included in the multidimensional model distribution. The model is utilized to reconstruct the peak firing rate and latency of the message sent to the brain by the whole ORN population at different stimulus intensities and to establish their main qualitative and quantitative properties. Finally, these properties are shown to be in agreement with those found previously in a vertebrate ORN population

Opposite role of slow and fast GABAergic inhibition in synchronization and spike timing precision

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Gain control network conditions in early sensory coding

Gain control is essential for the proper function of any sensory system. However, the precise mechanisms for achieving effective gain control in the brain are unknown. Based on our understanding of the existence and strength of connections in the insect olfactory system, we analyze the conditions that lead to controlled gain in a randomly connected network of excitatory and inhibitory neurons. We consider two scenarios for the variation of input into the system. In the first case, the intensity of the sensory input controls the input currents to a fixed proportion of neurons of the excitatory and inhibitory populations. In the second case, increasing intensity of the sensory stimulus will both, recruit an increasing number of neurons that receive input and change the input current that they receive. Using a mean field approximation for the network activity we derive relationships between the parameters of the network that ensure that the overall level of activity of the excitatory population remains unchanged for increasing intensity of the external stimulation. We find that, first, the main parameters that regulate network gain are the probabilities of connections from the inhibitory population to the excitatory population and of the connections within the inhibitory population. Second, we show that strict gain control is not achievable in a random network in the second case, when the input recruits an increasing number of neurons. Finally, we confirm that the gain control conditions derived from the mean field approximation are valid in simulations of firing rate models and Hodgkin-Huxley conductance based models

Mechanisms and Function of Neural Synchronization in an Insect Olfactory System

One of the fundamental questions in modem integrative neurobiology relates to the encoding of sensory information by populations of neurons, and to the significance of this activity for perception, learning, memory and behavior. Synchronization of activity across a population of neurons has been observed many times over, but has never been demonstrated to be a necessary component of this coding process. Neural synchronization has been found in many brain areas in animals across several phyla, from molluscs to mammals. Studies in mammals have correlated the degree of neural synchronization with specific behavioral or cognitive states, such as sensorimotor tasks, segmentation and binocular rivalry suggesting a functional link. In the locust olfactory system, oscillatory synchronization is a prominent feature of the odor-evoked neural activity. Stimulation of the antenna by odors evokes synchronized firing in dynamic and odor-specific ensembles of the projection neurons of the antennal lobe, the principal neurons of the first-order olfactory relay in insects. The coherent activity of these projection neurons underlies an odor-evoked oscillatory field potential which can be recorded in the mushroom body, the second-order olfactory relay to which they project. In this dissertation, we investigated two important questions raised by these findings: how are such stimulus-evoked synchronous ensembles generated, and what is their functional significance? To address these questions, we performed electrophysiological experiments and recorded odor responses from neurons of the antennal lobes and mushroom bodies of locusts, in vivo and using natural odor stimulation in an unanesthetized, semi-intact preparation. We demonstrated the critical mechanism involved in neural synchronization of the antennal lobe neurons. The synchronization of the projection neurons relies critically on fast GABA (γ-aminobutyric acid) -mediated inhibition from the local interneurons. Projection neuron synchronization could be selectively blocked by local injection of the GABA receptor antagonist, picrotoxin. Picrotoxin spared the odor-specific, slow modulation of individual projection neuron responses, but desynchronized the firing of the odor-activated projection neuron assemblies. The oscillatory activity of the local intemeurons was also blocked by picrotoxin, which indicates that such activity depends on network synaptic dynamics. We also showed that the mushroom body networks are capable of generating oscillatory behavior of a similar frequency as that of its projection neuron inputs, and that they may thus be "tuned" to accept synchronized, oscillatory inputs of that frequency range. Our understanding of this mechanism, in tum, made possible the functional investigation of neural synchronization by selective disruption of projection neuron synchronization. We studied a population of neurons downstream from the antennal lobe projection neurons, the extrinsic neurons of the β-lobe of the mushroom body (βLNs). These βLNs were chosen for investigation because they were found to be odor-responsive and because their position in the olfactory pathway makes them a suitable "read-out" of population activity in the antennal lobe. We characterized βLN odor responses before and after selective disruption of the synchronization of the projection neuron ensembles with local picrotoxin injection into the antennal lobe. We showed that the tuning of these βLN responses was altered by PN desynchronization by changing existing responses and inducing new responses. This alteration in tuning resulted in a significant loss of odor specificity in individual βLN responses, an effect that never occurred in the responses of individual, desynchronized projection neurons. We thus propose that neural synchronization is indeed important for information processing in the brain: it serves, at least in part, as a temporal substrate for the transmission of information that is contained across co-activated neurons (relational code) early in the pathway.</p

The recruitment and function of inhibitory interneurons in olfactory bulb processing

Inhibitory interneurons are the “shush”-ers of the brain—their output causes a reduction in the output of other neurons. Inhibitory interactions play a critical role in the olfactory bulb, where they shape olfactory representations that guide behavior. However, the mechanisms by which interneuron activation improves olfactory function remain debated. In particular, the relative importance neural activity over short periods of time (~tens of milliseconds) versus long periods of time (hundreds to thousands of milliseconds) has provoked significant debate. Granule cells are inhibitory interneurons in the olfactory bulb that can respond and influence olfactory bulb activity across a wide range of timescales. The first part of this dissertation investigates the physiological mechanisms driving the timing of granule cell recruitment. We found that the specific timing of recruitment depends on the timing of synaptic excitation delivered from tufted cells. Tufted cells (unlike the more commonly studied mitral cells) are able to fire at long latencies due to intrinsic membrane properties that allow them to integrate weak inputs slowly while responding rapidly to strong inputs. Computational modeling revealed that the long-latency inhibition generated by this mechanism can improve performance on stimulus discrimination tasks. The second portion of this dissertation focuses on the downstream effects of granule cell recruitment. Highly correlated spiking can be advantageous for propagating information. However, these same correlations limit encoding by introducing redundancy. We investigated how granule cell recruitment altered correlations between mitral cell pairs across timescales. We found that granule cell recruitment increased fast timescale correlations (i.e. synchronous spiking) while simultaneously decreasing slow timescale correlations (i.e. firing rate similarity). Using computational modeling, we show that timescale-dependent correlation changes are functionally advantageous because they can circumvent the tradeoff between propagation and encoding. Taken together, these studies extend our understanding of olfactory bulb physiology by providing a mechanistic description of how inhibitory circuits shape activity across timescales. Our results indicate that granule cell recruitment requires dynamic and stimulus-dependent interactions between mitral, tufted, and granule cells, and that the inhibition recruited by this mechanism works at multiple timescales to effectively encode and propagate stimulus information

Neural Circuit Analyses of the Olfactory System in Drosophila: Input to Output: A Dissertation

This thesis focuses on several aspects of olfactory processing in Drosophila. In chapter I and II, I will discuss how odorants are encoded in the brain. In both insects and mammals, olfactory receptor neurons (ORNs) expressing the same odorant receptor gene converge onto the same glomerulus. This topographical organization segregates incoming odor information into combinatorial maps. One prominent theory suggests that insects and mammals discriminate odors based on these distinct combinatorial spatial codes. I tested the combinatorial coding hypothesis by engineering flies that have only one class of functional ORNs and therefore cannot support combinatorial maps. These files can be taught to discriminate between two odorants that activate the single functional class of ORN and identify an odorant across a range of concentrations, demonstrating that a combinatorial code is not required to support learned odor discrimination. In addition, these data suggest that odorant identity can be encoded as temporal patterns of ORN activity. Behaviors are influenced by motivational states of the animal. Chapter III of this thesis focuses on understanding how motivational states control behavior. Appetitive memory in Drosophilaprovides an excellent system for such studies because the motivational state of hunger promotes reliance on learned appetitive cues whereas satiety suppresses it. We found that activation of neuropeptide F (dNPF) neurons in fed flies releases appetitive memory performance from satiety-mediated suppression. Through a GAL4 screen, we identified six dopaminergic neurons that are a substrate for dNPF regulation. In satiated flies, these neurons inhibit mushroom body output, thereby suppressing appetitive memory performance. Hunger promotes dNPF release, which blocks the inhibitory dopaminergic neurons. The motivational drive of hunger thus affects behavior through a hierarchical inhibitory control mechanism: satiety inhibits memory performance through a subset of dopaminergic neurons, and hunger promotes appetitive memory retrieval via dNPF-mediated disinhibition of these neurons. The aforementioned studies utilize sophisticated genetic tools for Drosophila. In chapter IV, I will talk about two new genetic tools. We developed a new technique to restrict gene expression to different subsets of mushroom body neurons with unprecedented precision. We also adapted the light-activated adenylyl cyclase (PAC) from Euglena gracilis as a light-inducable cAMP system for Drosophila. This system can be used to induce cAMP synthesis in targeted neurons in live, behaving preparations

Les spiking neurons : une leçon de la biologie pour le codage et le traitement des données

Des modèles fins du fonctionnement neuronal, les neurones impulsionnels ou spiking neurons, donnent lieu à la définition de modèles de calcul originaux permettant tout aussi bien l'étude de propriétés importantes du fonctionnement cérébral que la réalisation de traitements de données performants. Nous décrivons ici les principales caractéristiques de ces modèles impulsionnels et proposons un panorama de leurs cadres d'utilisation dans des perspectives biologiques et informatiques

Molecular and Behavioral Analysis of \u3cem\u3eDrosophila\u3c/em\u3e Circadian Photoreception and Circadian Thermoreception: A Dissertation

Circadian clocks are biological timekeepers that help maintain an organism’s behavior and physiological state optimally timed to the Earth’s day/night cycle. To do this, these internal pacemakers must accurately keep track of time. Equally importantly, they must be able to adjust their oscillations in response to external time cues to remain properly synchronized with the environment, and correctly anticipate environmental changes. When the internal clock is offset from its surrounding day/night cycle, clinically relevant disruptions develop, ranging from inconveniences such as jet-lag to more severe problems such as sleep disorders or mood disorders. In this work, I have used the fruit fly, Drosophila melanogaster, as a model organism to investigate how light and temperature can synchronize circadian systems. My initial studies centered on an intracellular photoreceptor, CRYPTOCHROME (CRY). CRY is a blue light photoreceptor previously identified as a major component of the primary light-input pathway into the Drosophila circadian clock. We used molecular techniques to show that after light-activation, CRY binds to the key circadian molecule TIMELESS (TIM). This interaction irreversibly targets TIM, but not CRY, for degradation. Further studies characterizing a newly isolated cry mutant, crym, showed that the carboxyl-terminus of CRY is not necessary for CRY’s ability to impart photic information to the molecular clock. Instead, the C-terminus appears to be necessary for normal CRY stability and protein-protein interactions. Thus, we conclude that in contrast to previous reports on CRYs of other species, where the C-terminal domain was required for transduction of photic information, the C-terminus of DrosophilaCRY has a purely modulatory function. During the second part of my dissertation work, I focused my studies on circadian thermoreception. While the effects of light in synchronization of the Drosophilaclock to environmental cycles have been extensively characterized, significantly less is known about temperature input pathways into the circadian pacemaker. I have used two approaches to look at how temperature affects the circadian system. First, I conducted a series of behavioral analyses looking at how locomotor rhythms can be phase-shifted in response to temperature cycles. By examining the behavior of genetically ablated flies, we determined that the well-characterized neurons controlling morning and evening surges of activity during light/dark cycles are also implicated in morning and evening behaviors under temperature cycles. However, we also find evidence of cells that contribute to modulating afternoon and evening behavior specifically under temperature cycles. These data contribute to a growing number of studies in the field suggesting that pacemaker cells may play different roles under various environmental conditions. Additionally, we provide data showing that intercellular communication plays an important role in regulating circadian response to temperature cycles. When the morning oscillator is absent or attenuated, the evening cells respond abnormally quickly to temperature cycles. My work thus provides information on the roles of different cell groups during temperature cycles, and suggests that beyond simply synchronizing individual oscillating cells, intercellular network activity may also have a role in modulating proper response to environmental time cues. Finally, I present some preliminary work looking at effects of temperature on known circadian molecules. Using a combination of in vivo and cell culture techniques, I have found that TIM protein levels decrease at higher temperatures. My cell culture data suggest that this is a proteasome-independent degradation event. As TIM is also a key molecule in the light-input pathway, the stability of TIM proteins may be a key point of integration for light and temperature input pathways. While additional research needs to be conducted to confirm these effects in vivoin wild-type flies, these preliminary results identify a possible avenue for further study. Taken together, my work has contributed new data on both molecular and neuronal substrates involved in processing light and temperature inputs into the Drosophila circadian clock