Abstract Top Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the past decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of an active dendritic tree is a highly non-linear function of its afferent rate, attaining extremely large dynamic ranges (above 50 dB). Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease in dynamic range. Author Summary Top Most neurons present cellular tree-like extensions known as dendrites, which receive input signals from synapses with other cells. Some neurons have very large and impressive dendritic arbors. What is the function of such elaborate and costly structures? The functional role of dendrites is not obvious because, if dendrites were an electrical passive medium, then signals from their periphery could not influence the neuron output activity. Dendrites, however, are not passive, but rather active media that amplify and support pulses (dendritic spikes). These voltage pulses do not simply add but can also annihilate each other when they collide. To understand the net effect of the complex interactions among dendritic spikes under massive synaptic input, here we examine a computational model of excitable dendritic trees. We show that, in contrast to passive trees, they have a very large dynamic range, which implies a greater capacity of the neuron to distinguish among the widely different intensities of input which it receives. Our results provide an explanation to the concentration invariance property observed in olfactory processing, due to the very similar response to different inputs. In addition, our modeling approach also suggests a microscopic neural basis for the century old psychophysical laws.

The mammalian olfactory bulb receives multiple modulatory inputs, including a cholinergic input from the basal forebrain. Understanding the functional roles played by the cholinergic input requires an understanding of the cellular mechanisms it modulates. In an in vitro olfactory bulb slice preparation we demonstrate cholinergic muscarinic modulation of glutamate release onto granule cells that results in -aminobutyric acid (GABA) release onto mitral/tufted cells. We demonstrate that the broad-spectrum cholinergic agonist carbachol triggers glutamate release from mitral/tufted cells that activates both AMPA and NMDA receptors on granule cells. Activation of the granule cell glutamate receptors leads to calcium influx through voltage-gated calcium channels, resulting in spike-independent, asynchronous GABA release at reciprocal dendrodendritic synapses that granule cells form with mitral/tufted cells. This cholinergic modulation of glutamate release persists through much of postnatal bulbar development, suggesting a functional role for cholinergic inputs from the basal forebrain in bulbar processing of olfactory inputs and possibly in postnatal development of the olfactory bulb.

Olfactory nerve axons terminate in olfactory bulb glomeruli forming excitatory synapses onto the dendrites of mitral/tufted (M/T) and juxtaglomerular cells, including external tufted (ET) and periglomerular (PG) cells. PG cells are heterogeneous in neurochemical expression and synaptic organization. We used a line of mice expressing green fluorescent protein under the control of the glutamic acid decarboxylase 65-kDa gene (GAD65+) promoter to characterize a neurochemically identified subpopulation of PG cells by whole cell recording and subsequent morphological reconstruction. GAD65+ GABAergic PG cells form two functionally distinct populations: 33% are driven by monosynaptic olfactory nerve (ON) input (ON-driven PG cells), the remaining 67% receive their strongest drive from an ONETPG circuit with no or weak monosynaptic ON input (ET-driven PG cells). In response to ON stimulation, ON-driven PG cells exhibit paired-pulse depression (PPD), which is partially reversed by GABAB receptor antagonists. The ONETPG circuit exhibits phasic GABAB-R-independent PPD. ON input to both circuits is under tonic GABAB-R-dependent inhibition. We hypothesize that this tonic GABABR-dependent presynaptic inhibition of olfactory nerve terminals is due to autonomous bursting of ET cells in the ONETPG circuit, which drives tonic spontaneous GABA release from ET-driven PG cells. Both circuits likely produce tonic and phasic postsynaptic inhibition of other intraglomerular targets. Thus olfactory bulb glomeruli contain at least two functionally distinct GABAergic circuits that may play different roles in olfactory coding.

Abstract Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (Golf), are expressed in the kidney. AC3 and Golf colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3−/− mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. Furthermore, at least one member of the renal repertoire of ORs is expressed in a MD cell line. Thus, key components of olfaction are expressed in the renal distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR. Keywords: adenylate cyclase 3 glomerular filtration rate Golf macula densa renin

Many mammals display brief bouts of high-frequency (4–10 Hz) sniffing when sampling odors. Given this, high-frequency sniffing is thought to play an important role in odor information processing. Here, we asked what role rapid sampling behavior plays in odor coding and odor discrimination by monitoring sniffing during performance of discrimination tasks under different paradigms and across different levels of difficulty and by imaging olfactory receptor neuron (ORN) input to the olfactory bulb (OB) during behavior. To eliminate confounds of locomotion and object approach, all experiments were performed in head-fixed rats. Rats showed individual differences in sniffing strategies that emerged during discrimination learning, with some rats showing brief bouts of rapid sniffing on odorant onset and others showing little or no change in sniff frequency. All rats performed with high accuracy, indicating that rapid sniffing is not necessary for odor discrimination. Sniffing strategies remained unchanged even when task difficulty was increased. In the imaging experiments, rapid sniff bouts did not alter the magnitude of odorant-evoked inputs compared with trials in which rapid sniffing was not expressed. Furthermore, rapid sniff bouts typically began before detectable activation of ORNs and ended immediately afterward. Thus rapid sniffing did not enable multiple samples of an odorant before decision-making. These results suggest that the major functional contribution of rapid sniffing to odor discrimination performance is to enable the animal to acquire the stimulus more quickly once it is available rather than to directly influence the low-level neural processes underlying odor perception.

The dynamics of sensory input to the nervous system play a critical role in shaping higher-level processing. In the olfactory system, the dynamics of input from olfactory receptor neurons (ORNs) are poorly characterized and depend on multiple factors, including respiration-driven airflow through the nasal cavity, odorant sorption kinetics, receptor–ligand interactions between odorant and receptor, and the electrophysiological properties of ORNs. Here, we provide a detailed characterization of the temporal organization of ORN input to the mammalian olfactory bulb (OB) during natural respiration, using calcium imaging to monitor ORN input to the OB in awake, head-fixed rats expressing odor-guided behaviors. We report several key findings. First, across a population of homotypic ORNs, each inhalation of odorant evokes a burst of action potentials having a rise time of about 80 ms and a duration of about 100 ms. This rise time indicates a relatively slow, progressive increase in ORN activation as odorant flows through the nasal cavity. Second, the dynamics of ORN input differ among glomeruli and for different odorants and concentrations, but remain reliable across successive inhalations. Third, inhalation alone (in the absence of odorant) evokes ORN input to a significant fraction of OB glomeruli. Finally, high-frequency sniffing of odorant strongly reduces the temporal coupling between ORN inputs and the respiratory cycle. These results suggest that the dynamics of sensory input to the olfactory system may play a role in coding odor information and that, in the awake animal, strategies for processing odor information may change as a function of sampling behavior.

The adult mammalian brain maintains a prominent stem cell niche in the subventricular zone supplying new neurons to the olfactory bulb. We examined the dynamics of synaptogenesis by imaging the formation and elimination of clusters of a postsynaptic marker (PSD95), genetically targeted to adult-born neurons. We imaged in vivo adult-born periglomerular neurons (PGNs) during two phases of development, immaturity and maturity. Immature PGNs showed high levels of PSD95 puncta dynamics during 12–72 h intervals. Mature PGNs were more stable compared with immature PGNs but still remained dynamic, suggesting that synaptogenesis persists long after these neurons integrated into the network. By combining intrinsic signal and two photon imaging we followed PSD95 puncta in sensory enriched glomeruli. Sensory input upregulated the development of adult-born PGNs only in enriched glomeruli. Our data provide evidence for an activity-based mechanism that enhances synaptogenesis of adult-born PGNs during their initial phases of development. Key words: adult-neurogenesis; synaptogenesis; olfactory bulb; in vivo imaging; periglomerular; sensory enrichment