Thomas A. Cleland

Behavioral models of odor similarity.

Carbon chain length in several classes of straight-chain aliphatic odorants has been proposed as a model axis of similarity for olfactory research, on the basis of successes of studies in insect and vertebrate species. To assess the influence of task on measured perceptual similarities among odorants and to demonstrate that the systematic similarities observed within homologous odorant series are not task specific, the authors compare 3 different behavioral paradigms for rats (olfactory habituation, generalization, and discrimination). Although overall patterns of odorant similarity are consistent across all 3 of these paradigms, both quantitative measurements of perceptual similarity and comparability with 2-deoxyglucose imaging data from the olfactory bulb are dependent on the specific behavioral tasks used. Thus, behavioral indices of perceptual similarity are affected by task parameters such as learning and reward associations.

Non-topographical contrast enhancement in the olfactory bulb

BackgroundContrast enhancement within primary stimulus representations is a common feature of sensory systems that regulates the discrimination of similar stimuli. Whereas most sensory stimulus features can be mapped onto one or two dimensions of quality or location (e.g., frequency or retinotopy), the analogous similarities among odor stimuli are distributed high-dimensionally, necessarily yielding a chemotopically fragmented map upon the surface of the olfactory bulb. While olfactory contrast enhancement has been attributed to decremental lateral inhibitory processes among olfactory bulb projection neurons modeled after those in the retina, the two-dimensional topology of this mechanism is intrinsically incapable of mediating effective contrast enhancement on such fragmented maps. Consequently, current theories are unable to explain the existence of olfactory contrast enhancement.ResultsWe describe a novel neural circuit mechanism, non-topographical contrast enhancement (NTCE), which enables contrast enhancement among high-dimensional odor representations exhibiting unpredictable patterns of similarity. The NTCE algorithm relies solely on local intraglomerular computations and broad feedback inhibition, and is consistent with known properties of the olfactory bulb input layer. Unlike mechanisms based upon lateral projections, NTCE does not require a built-in foreknowledge of the similarities in molecular receptive ranges expressed by different olfactory bulb glomeruli, and is independent of the physical location of glomeruli within the olfactory bulb.ConclusionNon-topographical contrast enhancement demonstrates how intrinsically high-dimensional sensory data can be represented and processed within a physically two-dimensional neural cortex while retaining the capacity to represent stimulus similarity. In a biophysically constrained computational model of the olfactory bulb, NTCE successfully mediates contrast enhancement among odorant representations in the natural, high-dimensional similarity space defined by the olfactory receptor complement and underlies the concentration-independence of odor quality representations.

Variant Brain-Derived Neurotrophic Factor (Val66Met) Alters Adult Olfactory Bulb Neurogenesis and Spontaneous Olfactory Discrimination

Neurogenesis, the division, migration, and differentiation of new neurons, occurs throughout life. Brain derived neurotrophic factor (BDNF) has been identified as a potential signaling molecule regulating neurogenesis in the subventricular zone (SVZ), but its functional consequences in vivo have not been well defined. We report marked and unexpected deficits in survival but not proliferation of newly born cells of adult knock-in mice containing a variant form of BDNF [a valine (Val) to methionine (Met) substitution at position 66 in the prodomain of BDNF (Val66Met)], a genetic mutation shown to lead to a selective impairment in activity-dependent BDNF secretion. Utilizing knock-out mouse lines, we identified BDNF and tyrosine receptor kinase B (TrkB) as the critical molecules for the observed impairments in neurogenesis, with p75 knock-out mice showing no effect on cell proliferation or survival. We then localized the activated form of TrkB to a discrete population of cells, type A migrating neuroblasts, and demonstrate a decrease in TrkB phosphorylation in the SVZ of Val66Met mutant mice. With these findings, we identify TrkB signaling, potentially through activity dependent release of BDNF, as a critical step in the survival of migrating neuroblasts. Utilizing a behavioral task shown to be sensitive to disruptions in olfactory bulb neurogenesis, we identified specific impairments in spontaneous olfactory discrimination, but not general olfactory sensitivity or habituation to olfactory stimuli in BDNF mutant mice. Through these observations, we have identified novel links between genetic variant BDNF and adult neurogenesis in vivo, which may contribute to significant impairments in olfactory function.

Chronic in vivo imaging in the mouse spinal cord using an implanted chamber

Understanding and treatment of spinal cord pathology is limited in part by a lack of time-lapse in vivo imaging strategies at the cellular level. We developed a chronically implanted spinal chamber and surgical procedure suitable for time-lapse in vivo multiphoton microscopy of mouse spinal cord without the need for repeat surgical procedures. We routinely imaged mice repeatedly for more than 5 weeks postoperatively with up to ten separate imaging sessions and observed neither motor-function deficit nor neuropathology in the spinal cord as a result of chamber implantation. Using this chamber we quantified microglia and afferent axon dynamics after a laser-induced spinal cord lesion and observed massive microglia infiltration within 1 d along with a heterogeneous dieback of axon stumps. By enabling chronic imaging studies over timescales ranging from minutes to months, our method offers an ideal platform for understanding cellular dynamics in response to injury and therapeutic interventions.

The anatomical logic of smell

Olfactory receptor neurons (ORNs) expressing the same odorant receptor gene share ligand-receptor affinity profiles and converge onto common glomerular targets in the brain. The activation patterns of different ORN populations, evoked by differential binding of odorant molecular moieties, constitute the primary odor representation. However, odorants possess properties other than receptor-binding sites that can contribute to odorant discrimination. Among terrestrial vertebrates, odorant sorptiveness--volatility and water solubility--imposes physicochemical constraints on migration through the nose during inspiration. The non-uniform distributions of ORN populations along the inspiratory axis enable sorptiveness to modify odor representations by affecting the number of molecules reaching different receptors during a sniff. Animals can then modify and analyze odor representation further by the dynamic regulation of sniffing.

Cholinergic modulation of sensory representations in the olfactory bulb

We present a computational model of the mammalian olfactory bulb (OB) designed to investigate how cholinergic inputs modulate olfactory sensory representations. The model integrates experimental data derived from diverse physiological studies of cholinergic modulation of OB circuitry into a simulation of bulbar responses to realistic odorants. Experimentally-observed responses to a homologous series of odorants (unbranched aliphatic aldehydes) were simulated; realistic cholinergic inputs to the OB model served to increase the discriminability of the bulbar responses generated to very similar odorants. This simulation predicted, correctly, that missing cholinergic inputs to the OB would result in greater generalization between similar aliphatic aldehydes. Based on the assumption that the overlap between the neural representations of two sensory stimuli is predictive of their perceptual similarity, we tested this prediction in a behavioral experiments with rats. We show that, indeed, rats with selective lesions of cholinergic neurons that project to the OB and cortex discriminate less well between aliphatic aldehydes with similar carbon chain lengths than do rats that received sham lesions.

Early transformations in odor representation

Sensory representations are repeatedly transformed by neural computations that determine which of their attributes can be effectively processed at each stage. Whereas some early computations are common across multiple sensory systems, they can utilize dissimilar underlying mechanisms depending on the properties of each modality. Recent work in the olfactory bulb has substantially clarified the neural algorithms underlying early odor processing. The high-dimensionality of odor space strictly limits the utility of topographical representations, forcing similarity-dependent computations such as decorrelation to employ unusual neural algorithms. The distinct architectures and properties of the two prominent computational layers in the olfactory bulb suggest that the bulb is directly comparable not only to the retina but also to primary visual cortex.

How Spike Synchronization Among Olfactory Neurons Can Contribute to Sensory Discrimination

Recent studies in honeybees have demonstrated that, when odor-evoked action potentials in antennal lobe neurons are pharmacologically desynchronized, the bees are impaired in their ability to discriminate chemically similar odor stimuli. Using a reduced computational model of the honeybee antennal lobe, we show how changes in spike-synchronization properties alone, independent of changes in overall spike-discharge rate or differences in activity levels among responsive neurons, can produce changes in associative learning similar to those observed experimentally.

Noradrenergic neuromodulation in the olfactory bulb modulates odor habituation and spontaneous discrimination

Noradrenergic projections from the locus coeruleus (LC) project to the olfactory bulb (OB), a cortical structure implicated in odor learning and perceptual differentiation among similar odorants. The authors tested the role of OB noradrenaline (NA) in short-term olfactory memory using an animal model of LC degeneration coupled with intrabulbar infusions of NA. Specifically, the authors lesioned cortical noradrenergic fibers in mice with the noradrenergic neurotoxin N-Ethyl-N-(2-chloroethyl)-2-bromobenzylamine hydrochloride (DSP4) and measured the effects on an olfactory habituation/spontaneous discrimination task. DSP4-treated mice failed to habituate to repeated odor presentations, indicating that they could not remember odors over the 5-min intertrial interval. The authors then infused NA bilaterally into the OBs of both DSP4-treated and nonlesioned control animals at two concentrations (10(-3)M and 10(-5)M, 2 microl/side). In DSP4-treated animals, NA administration at either concentration restored normal habituation and spontaneous discrimination performance, indicating that noradrenergic neuromodulation mediates these aspects of perceptual learning and that its efficacy does not require activity-dependent local regulation of NA release. Functional OB learning mechanisms may be necessary for normal odor recognition and differentiation among physically similar odorants.

Olfactory bulb habituation to odor stimuli

Habituation is a simple form of memory, yet its neurobiological mechanisms are only beginning to be understood in mammals. In the olfactory system, the neural correlates of habituation at a fast experimental timescale involving very short intertrial intervals (tens of seconds) have been shown to depend on synaptic adaptation in olfactory cortex. In contrast, behavioral habituation to odorants on a longer timescale with intertrial intervals of several minutes depends on processes in the olfactory bulb, as demonstrated by pharmacological studies. We here show that behavioral habituation to odorants on this longer timescale has a neuronal activity correlate in the olfactory bulb. Spiking responses of mitral cells in the rat olfactory bulb adapt to, and recover from, repeated odorant stimulation with 5-min intertrial intervals with a time course similar to that of behavioral habituation. Moreover, both the behavioral and neuronal effects of odor habituation require functioning N-methyl-d-aspartic acid receptors in the olfactory bulb.