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

Pharmacological analysis of ionotropic glutamate and GABA recptor function in neuronal circuits of the zebrafish olfactory bulb

In the olfactory bulb and other brain areas, basic cellular and synaptic properties of individual neurons have been studied extensively in reduced preparations. Nevertheless, it is still poorly understood how intactions between multiple neurons shape spatio-temporal activity patterns and give rise to the computational properties of the the intact circuit. In this thesis, I used pharmacological manipulations of excitatory and inhibitory neurotransmitter receptors to examine the synaptic interactions underlying spontaneous and odor-evoked activity patterns in the intact olfactory bulb of zebrafish. Electrophysiological and one- and two-photon calcium imaging methods were used to record activity from the principal neurons of the OB (mitral cells, MCs), their sensory input, and local interneurons. The combined blockade of AMPA/kainate and NMDA receptors abolished odor-evoked excitation of MCs, indicating that sensory input to the OB is mediated by ionotropic glutamate receptors. Surprisingly, however, the blockade of AMPA/Kainiate receptors alone increased the mean response of MCs and decreased the mean response of interneurons (INs), and the blockade of NMDA receptors caused little or no change in the mean responses of MCs and INs. In addition, antagonists of both glutamate receptor types had diverse effects on the magnitude and time course of individual MC and IN responses and, thus, changed spatio-temporal activity patterns across neuronal populations. The blockade of GABA(A) receptors increased spontaneous and odor evoked firing rates of mitral cells and often induced rhythmic bursting. Moreover, the blockade of, GABA(A) or AMPA/kainate receptors abolished fast oscillatory activity in the local field potential. Blockade of GABA(B) receptors reduced calcium influx in afferent sensory axons and modulated response time courses of mitral cells. These results indicate that (1) IN activity during an odor response depends mainly on AMPA/Kainiate receptor input, (2) interactions between MCs and INs regulate the total OB output activity, (3) AMPA/Kainiate receptors and GABA(A) receptors underly the synchronization of odor-dependent neuronal ensembles and (4) odor-specific patterns of OB output activity are shaped by circuits containing iGlu receptors and GABA receptors. These results provide insights into the mechanisms underlying the processing of odor-encoding activity patterns in the OB.Im olfaktorischen Bulbus (OB) und anderen Hirnarealen wurden grundlegende zelluläre und synaptische Eigenschaften der Einzelneurone ausführlich in reduzierten Präparaten studiert. Trotzdem ist kaum bekannt, wie die Interaktionen mehrerer Nervenzellen untereinander räumlich-zeitlich strukturierte Aktivitätsmuster formen und dadurch die rechnerischen Eigenschaften der intakten Schaltkreise entstehen. In dieser Arbeit nutzte ich pharmakologische Manipulationen der erregenden und hemmenden Neurotransmitter-Rezeptoren, um die synaptischen Interaktionen zu untersuchen, die spontanen und geruchsinduzierten Aktivitätsmustern im intakten OB des Zebrafisch zugrunde liegen. Methoden der Elektrophysiology sowie der konventionellen und Zwei-Photonen-Mikroskopie wurden genutzt, um Aktivität von Ausgangsneuronen des OB (Mitralzellen, MCs), ihrem sensorischen Eingang, und Interneuronen (INs) zu messen. Die gleichzeitige Blockierung von AMPA/Kainate- und NMDA-Rezeptoren verhinderte die geruchsinduzierte Erregung von MCs, was darauf hinweist, dass der sensorische Eingang des OB durch ionotrope Glutamatrezeptoren vermittelt wird. Die Blockierung von AMPA/Kainate Rezeptoren allein jedoch erhöhte überraschender Weise im Mittel die Antwort von MCs und reduzierte im Mittel die Antwort von INs. Die Blockierung von NMDA Rezeptoren allein lösten im Mittel geringe oder keine Veränderung der Antworten von MCs and INs aus. Außerdem hatten die Antagonisten für beide Glutamatrezeptoren unterschiedliche Einflüsse auf Größe und Zeitverlauf individueller MC- und IN- Antworten und veränderten daher das räumlich-zeitliche Aktivitätsmuster innerhalb der Nervenzellpopulation. Die Blockierung von GABA(A)-Rezeptoren erhöhte spontane und geruchsinduzierte Feuerraten in MCs und induzierten oft rhythmische, stoßweise Aktivität. Die Blockierung von GABA(A)- und AMPA/Kainate-Rezeptoren hob überdies geruchsinduzierte Oszillationen im Feldpotenzial auf. Die Blockierung von GABA(B)-Rezeptoren verringerte den Kalziumeinstrom in die Endigungen afferenter sensorischer Axone und modulierte den Zeitverlauf von MC-Antworten. Die Ergebnisse zeigen, dass (1) die Aktivität der Interneurone während der Geruchsantwort hauptsächlich von AMPA/Kainate-Rezeptoren abhängt, (2) die Interaktionen zwischen Mitralzellen und Interneuronen die Gesamtaktivität des Ausgangssingnales des olfaktorischen Bulbus regulieren, (3) AMPA/Kainate-Rezeptoren und GABA(A)-Rezeptoren der Synchronisation geruchsabhängiger Gruppen von Nervenzellen zugrunde liegen und (4) geruchsspezifische Muster im Ausgangssignal des olfaktorischen Bulbus durch Schaltkreise geformt werden, die iGlu Rezeptoren und GABA Rezeptoren enthalten. Diese Ergebnisse ermöglichen Einblick in die Mechanismen die der Verarbeitung geruchskodierender Aktivitätsmuster im olfaktorischen Bulbus unterliegen

Amplification of asynchronous inhibition-mediated synchronization by feedback in recurrent networks

Synchronization of 30-80 Hz oscillatory activity of the principle neurons in the olfactory bulb (mitral cells) is believed to be important for odor discrimination. Previous theoretical studies of these fast rhythms in other brain areas have proposed that principle neuron synchrony can be mediated by short-latency, rapidly decaying inhibition. This phasic inhibition provides a narrow time window for the principle neurons to fire, thus promoting synchrony. However, in the olfactory bulb, the inhibitory granule cells produce long lasting, small amplitude, asynchronous and aperiodic inhibitory input and thus the narrow time window that is required to synchronize spiking does not exist. Instead, it has been suggested that correlated output of the granule cells could serve to synchronize uncoupled mitral cells through a mechanism called "stochastic synchronization", wherein the synchronization arises through correlation of inputs to two neural oscillators. Almost all work on synchrony due to correlations presumes that the correlation is imposed and fixed. Building on theory and experiments that we and others have developed, we show that increased synchrony in the mitral cells could produce an increase in granule cell activity for those granule cells that share a synchronous group of mitral cells. Common granule cell input increases the input correlation to the mitral cells and hence their synchrony by providing a positive feedback loop in correlation. Thus we demonstrate the emergence and temporal evolution of input correlation in recurrent networks with feedback. We explore several theoretical models of this idea, ranging from spiking models to an analytically tractable model. © 2010 Marella, Ermentrout

Effects of short-term plasticity in UP-DOWN cortical dynamics

Neuronal dynamics are strongly influenced by short-term plasticity (STP), that is, changes in synaptic efficacy that occur on a short (from milliseconds to seconds) time scale. Depending on the brain areas considered, STP can be dominated by short-term depression (STD), short-term facilitation (STF), or both mechanisms can coexist simultaneously. These two plasticity mechanisms modulate particular patterns of electrophysiological activity characterized by alternating UP and DOWN states. In this work, we develop a network model made up of excitatory and inhibitory multi-compartment neurons endowed with both mechanisms (STD and STF), spatially arranged to emulate the connectivity circuitry observed experimentally in the visual cortex. Our results reveal that both depression and facilitation can be involved in the switching process between different activity patterns, from an alternation of UP and DOWN states (for relatively low levels of depression and high levels of facilitation) to an asynchronous firing regime (for relatively high levels of depression and low levels of facilitation). For STD and STF, we identify the critical levels of depression and facilitation that push the network into the different regimes. Furthermore, we also find that these critical levels separate different growth rates of the mean synaptic conductances of the whole network with respect to the depression levels. This latter data is paramount to understanding how excitation and inhibition are organized to generate different brain activity regimes. Finally, after observing the changes in the trajectories of excitatory and inhibitory instantaneous firing rates near these critical boundaries, we identify dynamic patterns that shed light on the type of bifurcations that should arise in a rate model for this complex network"AG has been funded by Catalan Research Agency (AGAUR) grant 2017-SGR-1049, by the Spanish Ministerio de Ciencia e Innovación grant PID2021-122954-I00 and by the Spanish State Research Agency through the Severo Ochoa and María de Maeztu Program for Centers and Units of Excellence in R&D (CEX2020-001084-M)."Peer ReviewedPostprint (published version

Circuit-level Mechanisms of EtOH-dependent dopamine release.

Alcoholism is the third leading cause of preventable mortality in the world. In the last decades a large body of experimental data has paved the way to a clearer knowledge of the specific molecular targets through which ethanol (EtOH) acts on brain circuits. Yet how these multiple mechanisms play together to result in a dysregulated dopamine (DA) release under alcohol influence remains unclear. In this manuscript, we delineate potential circuit-level mechanisms responsible for EtOH-dependent increase and dysregulation of DA release from the ventral tegmental area (VTA) into nucleus accumbens (Nac). For this purpose, we build a circuit model of the VTA composed of DA and GABAergic neurons, that integrate external Glutamatergic (Glu) inputs to result in DA release. In particular, we reproduced a non-monotonic dose dependence of DA neurons firing activity on EtOH: an increase in firing at small to intermediate doses and a drop below baseline (alcohol-free) levels at high EtOH concentrations. Our simulations predict that a certain level of synchrony is necessary for the firing rate increase produced by EtOH. Moreover, EtOH effect on the DA neuron firing rate and, consequently, DA release can reverse depending on the average activity level of the Glu afferents to VTA. Further, we propose a mechanism for emergence of transient (phasic) DA peaks and the increase in their frequency in EtOH. Phasic DA transients result from DA neuron population bursts, and these bursts are enhanced in EtOH. These results suggest the role of synchrony and average activity level of Glu afferents to VTA in shaping the phasic and tonic DA release under the acute influence of EtOH and in normal conditions

Membrane resonance enables stable and robust gamma oscillations

Neuronal mechanisms underlying beta/gamma oscillations (20-80 Hz) are not completely understood. Here, we show that in vivo beta/gamma oscillations in the cat visual cortex sometimes exhibit remarkably stable frequency even when inputs fluctuate dramatically. Enhanced frequency stability is associated with stronger oscillations measured in individual units and larger power in the local field potential. Simulations of neuronal circuitry demonstrate that membrane properties of inhibitory interneurons strongly determine the characteristics of emergent oscillations. Exploration of networks containing either integrator or resonator inhibitory interneurons revealed that: (i) Resonance, as opposed to integration, promotes robust oscillations with large power and stable frequency via a mechanism called RING (Resonance INduced Gamma); resonance favors synchronization by reducing phase delays between interneurons and imposes bounds on oscillation cycle duration; (ii) Stability of frequency and robustness of the oscillation also depend on the relative timing of excitatory and inhibitory volleys within the oscillation cycle; (iii) RING can reproduce characteristics of both Pyramidal INterneuron Gamma (PING) and INterneuron Gamma (ING), transcending such classifications; (iv) In RING, robust gamma oscillations are promoted by slow but are impaired by fast inputs. Results suggest that interneuronal membrane resonance can be an important ingredient for generation of robust gamma oscillations having stable frequency

On the role of parvalbumin interneurons in neuronal network activity in the prefrontal cortex

The prefrontal cortex (PFC) is an area important for executive functions, the initiation and temporal organization of goal-directed behavior, as well as social behaviors. Inhibitory interneurons expressing parvalbumin (PV) have a vital role in modulating PFC circuit plasticity and output, as inhibition by PV interneurons on excitatory pyramidal neurons regulates the excitability of the network. Thus, dysfunctions of prefrontal PV interneurons are implicated in the pathophysiology of a range of PFC-dependent neuropsychiatric disorders characterized by excitation and inhibition (E/I) imbalance and impaired gamma oscillations. In particular, the hypofunction of receptors important for neurotransmission and regulating cellular functions, such as the N-methyl-D-aspartate receptors (NMDARs) and the tyrosine receptor kinase B (trkB), has been implicated in PV dysfunction. Notably, this hypofunction is known to impair the normal development of PV interneurons. However, it can also affect adult brain activity. The effects of altered receptors on PV interneurons are multiple, from impaired morphological connectivity to disruption of intrinsic activity, but have not yet been fully characterized. Moreover, the effects of deficits of PV neuron-mediated inhibition on neuronal network activity are complex, involved with compensatory mechanisms, and not fully understood either. For instance, the E/I imbalance due to PV inhibition has been suggested to functionally disrupt the cortex, which can be observed through an abnormal increase in broadband gamma activity. But as the synchronous activity of cortical PV interneurons is necessary for the generation of cortical gamma oscillations, it is paradoxical that deficient PV inhibition is associated with increased broadband gamma power. This thesis aims to examine the role of PV interneurons in shaping neuronal network activity in the mouse PFC by investigating the microscopic to macroscopic functional effects of disrupting receptors necessary for the proper activity of PV interneurons. In paper I, we observed that the increase of broadband gamma power due to NMDAR hypofunction in PV neurons is associated with asynchronies of network activity, confirming that dysfunction of neuronal inhibition can cause desynchronization at multiple time scales (affecting entrainment of spikes by the LFP, as well as cross-frequency coupling and brain states fragmentation). In Paper II, we prompted and analyzed the rippling effect of PV dysfunction in the adult PFC by expressing a dominant-negative trkB receptor specifically in PV interneurons. Despite avoiding interfering with the development of the brain, we found pronounced morphological and functional alterations in the targeted PV interneurons. These changes were associated with unusual aggressive behavior coupled with gamma-band alterations and a decreased modulation of prefrontal excitatory neuronal populations by PV interneurons. Thus, the work presented in this thesis furthers our understanding of the role of PV function in PFC circuitry, particularly of two receptors that are central to the role of PV interneurons in coordinating local circuit activity. A better understanding of the potential mechanisms that could explain the neuronal changes seen in individuals with neuropsychiatric dysfunctions could lead to using gamma oscillations or BDNF-trkB levels as biomarkers in psychiatric disorders. It also presents possibilities for potential treatments designed around reestablishing E/I balance by modifying receptor levels in particular cell types

Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus

Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC– and AAC–pyramidal cell pairs, while an antagonist of CB1 cannabinoid receptors recovered the suppression in RSBC–pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC– and AAC–pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources