Connectivity and dynamics in the olfactory bulb

Dendrodendritic interactions between excitatory mitral cells and inhibitory granule cells in the olfactory bulb create a dense interaction network, reorganizing sensory representations of odors and, consequently, perception. Large-scale computational models are needed for revealing how the collective behavior of this network emerges from its global architecture. We propose an approach where we summarize anatomical information through dendritic geometry and density distributions which we use to calculate the probability of synapse between mitral and granule cells, while capturing activity patterns of each cell type in the neural dynamical systems theory of Izhikevich. In this way, we generate an efficient, anatomically and physiologically realistic large-scale model of the olfactory bulb network. Our model reproduces known connectivity between sister vs. non-sister mitral cells; measured patterns of lateral inhibition; and theta, beta, and gamma oscillations. It in turn predicts testable relations between network structure, lateral inhibition, and odor pattern decorrelation; between the density of granule cell activity and LFP oscillation frequency; how cortical feedback to granule cells affects mitral cell activity; and how cortical feedback to mitral cells is modulated by the network embedding. Additionally, the methodology we describe here provides a tractable tool for other researchers.

Short-Term Plasticity in Cortical GABAergic Synapses on Olfactory Bulb Granule Cells Is Modulated by Endocannabinoids

Olfactory bulb and higher processing areas are synaptically interconnected, providing rapid regulation of olfactory bulb circuit dynamics and sensory processing. Short-term plasticity changes at any of these synapses could modulate sensory processing and potentially short-term sensory memory. A key olfactory bulb circuit for mediating cortical feedback modulation is granule cells, which are targeted by multiple cortical regions including both glutamatergic excitatory inputs and GABAergic inhibitory inputs. There is robust endocannabinoid modulation of excitatory inputs to granule cells and here we explored whether there was also endocannabinoid modulation of the inhibitory cortical inputs to granule cells. We expressed light-gated cation channel channelrhodopsin-2 (ChR2) in GABAergic neurons in the horizontal limb of the diagonal band of Broca (HDB) and their projections to granule cells in olfactory bulb. Selective optical activation of ChR2 positive axons/terminals generated strong, frequency-dependent short-term depression of GABAA-mediated-IPSC in granule cells. As cannabinoid type 1 (CB1) receptor is heavily expressed in olfactory bulb granule cell layer (GCL) and there is endogenous endocannabinoid release in GCL, we investigated whether activation of CB1 receptor modulated the HDB IPSC and short-term depression at the HDB→granule cell synapse. Activation of the CB1 receptor by the exogenous agonist Win 55,212-2 significantly decreased the peak amplitude of individual IPSC and decreased short-term depression, while blockade of the CB1 receptor by AM 251 slightly increased individual IPSCs and increased short-term depression. Thus, we conclude that there is tonic endocannabinoid activation of the GABAergic projections of the HDB to granule cells, similar to the modulation observed with glutamatergic projections to granule cells. Modulation of inhibitory synaptic currents and frequency-dependent short-term depression could regulate the precise balance of cortical feedback excitation and inhibition of granule cells leading to changes in granule cell mediated inhibition of olfactory bulb output to higher processing areas.

A non-canonical feedforward pathway for computing odor identity

Sensory systems rely on statistical regularities in the experienced inputs to either group disparate stimuli, or parse them into separate categories1,2. While considerable progress has been made in understanding invariant object recognition in the visual system3–5, how this is implemented by olfactory neural circuits remains an open question6–10. The current leading model states that odor identity is primarily computed in the piriform cortex, drawing from mitral cell (MC) input6–9,11. Surprisingly, the role of tufted cells (TC)12–16, the other principal cell-type of the olfactory bulb (OB) in decoding odor identity, and their dependence on cortical feedback, has been overlooked. Tufted cells preferentially project to the anterior olfactory nucleus (AON) and olfactory striatum, while mitral cells strongly innervate the piriform cortex (PC). Here we show that classifiers based on the population activity of tufted cells successfully decode both odor identity and intensity across a large concentration range. In these computations, tufted cells substantially outperform mitral cells, and are largely unaffected by silencing of cortical feedback. Further, cortical feedback from AON controls preferentially the gain of tufted cell odor representations, while PC feedback specifically restructures mitral cell responses, matching biases in feedforward connectivity. Leveraging cell-type specific analyses, we identify a non-canonical feedforward pathway for odor recognition and discrimination mediated by the tufted cells, and propose that OB target areas, other than the piriform cortex, such as AON and olfactory striatum, are well-positioned to compute odor identity.

Corticothalamic feedback sculpts visual spatial integration in mouse thalamus

ABSTRACTEn route from retina to cortex, visual information travels through the dorsolateral geniculate nucleus of the thalamus (dLGN), where extensive cortico-thalamic (CT) feedback has been suggested to modulate spatial processing. How this modulation arises from direct excitatory and indirect inhibitory CT feedback components remains enigmatic. We show that in awake mice topographically organized cortical feedback modulates spatial integration in dLGN by sharpening receptive fields (RFs) and increasing surround suppression. Guided by a network model revealing wide-scale inhibitory CT feedback necessary to reproduce these effects, we targeted the visual sector of the thalamic reticular nucleus (visTRN) for recordings. We found that visTRN neurons have large receptive fields, show little surround suppression, and have strong feedback-dependent responses to large stimuli, making them an ideal candidate for mediating feedback-enhanced surround suppression in dLGN. We conclude that cortical feedback sculpts spatial integration in dLGN, likely via recruitment of neurons in visTRN.

Distinct organization of two cortico-cortical feedback pathways

Neocortical feedback is critical for processes like attention, prediction, and learning. A mechanistic understanding of its function requires deciphering its cell-type wiring logic. Recent studies revealed a disinhibitory circuit between motor and sensory areas in mice, where feedback preferentially targets vasointestinal peptide-expressing interneurons, in addition to pyramidal cells. It is unknown whether this circuit motif is a general cortico-cortical feedback organizing principle. Combining multiple simultaneous whole-cell recordings with optogenetics we found that in contrast to this wiring rule, feedback between the hierarchically organized visual areas (lateral-medial to V1) preferentially activated somatostatin-expressing interneurons. Functionally, both feedback circuits temporally sharpened feed-forward excitation by eliciting a transient increase followed by a prolonged decrease in pyramidal firing rate under sustained feed-forward input. However, under feed-forward transient input, the motor-sensory feedback facilitated pyramidal cell bursting while visual feedback increased spike time precision. Our findings argue for multiple feedback motifs implementing different dynamic non-linear operations.