A biophysical and statistical modeling paradigm for connecting neural physiology and function.

To understand single neuron computation, it is necessary to know how specific physiological parameters affect neural spiking patterns that emerge in response to specific stimuli. Here we present a computational pipeline combining biophysical and statistical models that provides a link between variation in functional ion channel expression and changes in single neuron stimulus encoding. More specifically, we create a mapping from biophysical model parameters to stimulus encoding statistical model parameters. Biophysical models provide mechanistic insight, whereas statistical models can identify associations between spiking patterns and the stimuli they encode. We used public biophysical models of two morphologically and functionally distinct projection neuron cell types: mitral cells (MCs) of the main olfactory bulb, and layer V cortical pyramidal cells (PCs). We first simulated sequences of action potentials according to certain stimuli while scaling individual ion channel conductances. We then fitted point process generalized linear models (PP-GLMs), and we constructed a mapping between the parameters in the two types of models. This framework lets us detect effects on stimulus encoding of changing an ion channel conductance. The computational pipeline combines models across scales and can be applied as a screen of channels, in any cell type of interest, to identify ways that channel properties influence single neuron computation.

Mouse Navigation Strategies for Odor Source Localization.

Navigating an odor landscape is a critical behavior for the survival of many species, including mice. An ethologically relevant mouse behavior is locating food using information about odor concentration. To approximate this behavior, we used an open field odor-based spot-finding task indoors with little wind, examining navigation strategies as mice search for and approach an odor source. After mice were trained to navigate to odor sources paired with food reward, we observed behavioral changes consistent with localization 10-45 cm away from the source. These behaviors included orientation toward the source, decreased velocity, and increased exploration time. We also found that the amplitude of 'casting,' which we define as lateral back and forth movement of the nose, increased with proximity to the source. Based on these observations, we created a concentration-sensitive agent-based model to simulate mouse behavior. This model provided evidence for a binaral-sniffing strategy (inter-nostril comparison of concentration in a single sniff) and a serial-sniffing strategy (sampling concentration, moving in space, and then sampling again). Serial-sniffing may be accomplished at farther distances by moving the body and at closer distances by moving the head (casting). Together, these results elucidate components of behavioral strategies for odor-based navigation.

Decreased amplitude and reliability of odor-evoked responses in two mouse models of autism.

Sensory processing deficits are increasingly recognized as core symptoms of autism spectrum disorders (ASDs). However the molecular and circuit mechanisms that lead to sensory deficits are unknown. We show that two molecularly disparate mouse models of autism display similar deficits in sensory-evoked responses in the mouse olfactory system. We find that both Cntnap2- and Shank3-deficient mice of both sexes exhibit reduced response amplitude and trial-to-trial reliability during repeated odor presentation. Mechanistically, we show that both mouse models have weaker and fewer synapses between olfactory sensory nerve (OSN) terminals and olfactory bulb tufted cells and weaker synapses between OSN terminals and inhibitory periglomerular cells. Consequently, deficits in sensory processing provide an excellent candidate phenotype for analysis in ASDs.NEW & NOTEWORTHY The genetics of autism spectrum disorder (ASD) are complex. How the many risk genes generate the similar sets of symptoms that define the disorder is unknown. In particular, little is understood about the functional consequences of these genetic alterations. Sensory processing deficits are important aspects of the ASD diagnosis and may be due to unreliable neural circuits. We show that two mouse models of autism, Cntnap2- and Shank3-deficient mice, display reduced odor-evoked response amplitudes and reliability. These data suggest that altered sensory-evoked responses may constitute a circuit phenotype in ASDs.

Differences in Glomerular-Layer-Mediated Feedforward Inhibition onto Mitral and Tufted Cells Lead to Distinct Modes of Intensity Coding.

Understanding how each of the many interneuron subtypes affects brain network activity is critical. In the mouse olfactory system, mitral cells (MCs) and tufted cells (TCs) comprise parallel pathways of olfactory bulb output that are thought to play distinct functional roles in odor coding. Here, in acute mouse olfactory bulb slices, we test how the two major classes of olfactory bulb interneurons differentially contribute to differences in MC versus TC response properties. We show that, whereas TCs respond to olfactory sensory neuron (OSN) stimulation with short latencies regardless of stimulation intensity, MC latencies correlate negatively with stimulation intensity. These differences between MCs and TCs are caused in part by weaker excitatory and stronger inhibitory currents onto MCs than onto TCs. These differences in inhibition between MCs and TCs are most pronounced during the first 150 ms after stimulation and are mediated by glomerular layer circuits. Therefore, blocking inhibition originating in the glomerular layer, but not granule-cell-mediated inhibition, reduces MC spike latency at weak stimulation intensities and distinct temporal patterns of odor-evoked responses in MCs and TCs emerge in part due to differences in glomerular-layer-mediated inhibition.SIGNIFICANCE STATEMENT Olfactory bulb mitral and tufted cells display different odor-evoked responses and are thought to form parallel channels of olfactory bulb output. Therefore, determining the circuit-level causes that drive these differences is vital. Here, we find that longer-latency responses in mitral cells, compared with tufted cells, are due to weaker excitation and stronger glomerular-layer-mediated inhibition.

Postnatal Odor Exposure Increases the Strength of Interglomerular Lateral Inhibition onto Olfactory Bulb Tufted Cells.

Lateral inhibition between pairs of olfactory bulb (OB) mitral cells (MCs) and tufted cells (TCs) is linked to a variety of computations including gain control, decorrelation, and gamma-frequency synchronization. Differential effects of lateral inhibition onto MCs and TCs via distinct lateral inhibitory circuits are one of several recently described circuit-level differences between MCs and TCs that allow each to encode separate olfactory features in parallel. Here, using acute OB slices from mice, we tested whether lateral inhibition is affected by prior odor exposure and if these effects differ between MCs and TCs. We found that early postnatal odor exposure to the M72 glomerulus ligand acetophenone increased the strength of interglomerular lateral inhibition onto TCs, but not MCs, when the M72 glomerulus was stimulated. These increases were specific to exposure to M72 ligands because exposure to hexanal did not increase the strength of M72-mediated lateral inhibition. Therefore, early life experiences may be an important factor shaping TC odor responses. SIGNIFICANCE STATEMENT: Responses of olfactory (OB) bulb mitral cells (MCs) and tufted cells (TCs) are known to depend on prior odor exposure, yet the specific circuit mechanisms underlying these experience-dependent changes are unknown. Here, we show that odor exposure alters one particular circuit element, interglomerular lateral inhibition, which is known to be critical for a variety of OB computations. Early postnatal odor exposure to acetophenone, a ligand of M72 olfactory sensory neurons, increases the strength of M72-mediated lateral inhibition onto TCs, but not MCs, that project to nearby glomeruli. These findings add to a growing list of differences between MCs and TCs suggesting that that these two cell types play distinct roles in odor coding.

Distinct lateral inhibitory circuits drive parallel processing of sensory information in the mammalian olfactory bulb.

Splitting sensory information into parallel pathways is a common strategy in sensory systems. Yet, how circuits in these parallel pathways are composed to maintain or even enhance the encoding of specific stimulus features is poorly understood. Here, we have investigated the parallel pathways formed by mitral and tufted cells of the olfactory system in mice and characterized the emergence of feature selectivity in these cell types via distinct lateral inhibitory circuits. We find differences in activity-dependent lateral inhibition between mitral and tufted cells that likely reflect newly described differences in the activation of deep and superficial granule cells. Simulations show that these circuit-level differences allow mitral and tufted cells to best discriminate odors in separate concentration ranges, indicating that segregating information about different ranges of stimulus intensity may be an important function of these parallel sensory pathways.

Morphological analysis of activity-reduced adult-born neurons in the mouse olfactory bulb.

Adult-born neurons (ABNs) are added to the olfactory bulb (OB) throughout life in rodents. While many factors have been identified as regulating the survival and integration of ABNs into existing circuitry, the understanding of how these factors affect ABN morphology and connectivity is limited. Here we compare how cell intrinsic [small interfering RNA (siRNA) knock-down of voltage gated sodium channels Na(V)1.1-1.3] and circuit level (naris occlusion) reductions in activity affect ABN morphology during integration into the OB. We found that both manipulations reduce the number of dendritic spines (and thus likely the number of reciprocal synaptic connections) formed with the surrounding circuitry and inhibited dendritic ramification of ABNs. Further, we identified regions of ABN apical dendrites where the largest and most significant decreases occur following siRNA knock-down or naris occlusion. In siRNA knock-down cells, reduction of spines is observed in proximal regions of the apical dendrite. This suggests that distal regions of the dendrite may remain active independent of Na(V)1.1-1.3 channel expression, perhaps facilitated by activation of T-type calcium channels and NMDA receptors. By contrast, circuit level reduction of activity by naris occlusion resulted in a global depression of spine number. Together, these results indicate that ABNs retain the ability to develop their typical overall morphological features regardless of experienced activity, and activity modulates the number and location of formed connections.

Dendritic processing within olfactory bulb circuits.

Odors elicit a well-organized pattern of activation in glomeruli across the surface of the olfactory bulb. However, the mechanisms by which this map is transformed into an odor code by the bulb circuitry remain unclear. Recent physiological studies in bulb slices have identified several synaptic processes that could be involved in sharpening odorant signals. Mitral cells within a single odorant receptor-specific network can be synchronized by dendrodendritic excitatory interactions in a glomerulus, whereas mitral cells in different networks engage in long-lasting lateral inhibition mediated by dendrodendritic synapses with interneurons. The emerging picture is one in which groups of mitral cells use a unique set of mechanisms to accomplish computational functions similar to those performed by analogous modular structures in other sensory systems.