Phasic dopamine reinforces distinct striatal stimulus encoding in the olfactory tubercle driving dopaminergic reward prediction.

The learning of stimulus-outcome associations allows for predictions about the environment. Ventral striatum and dopaminergic midbrain neurons form a larger network for generating reward prediction signals from sensory cues. Yet, the network plasticity mechanisms to generate predictive signals in these distributed circuits have not been entirely clarified. Also, direct evidence of the underlying interregional assembly formation and information transfer is still missing. Here we show that phasic dopamine is sufficient to reinforce the distinctness of stimulus representations in the ventral striatum even in the absence of reward. Upon such reinforcement, striatal stimulus encoding gives rise to interregional assemblies that drive dopaminergic neurons during stimulus-outcome learning. These assemblies dynamically encode the predicted reward value of conditioned stimuli. Together, our data reveal that ventral striatal and midbrain reward networks form a reinforcing loop to generate reward prediction coding.

Discovering Precise Temporal Patterns in Large-Scale Neural Recordings through Robust and Interpretable Time Warping.

Though the temporal precision of neural computation has been studied intensively, a data-driven determination of this precision remains a fundamental challenge. Reproducible spike patterns may be obscured on single trials by uncontrolled temporal variability in behavior and cognition and may not be time locked to measurable signatures in behavior or local field potentials (LFP). To overcome these challenges, we describe a general-purpose time warping framework that reveals precise spike-time patterns in an unsupervised manner, even when these patterns are decoupled from behavior or are temporally stretched across single trials. We demonstrate this method across diverse systems: cued reaching in nonhuman primates, motor sequence production in rats, and olfaction in mice. This approach flexibly uncovers diverse dynamical firing patterns, including pulsatile responses to behavioral events, LFP-aligned oscillatory spiking, and even unanticipated patterns, such as 7 Hz oscillations in rat motor cortex that are not time locked to measured behaviors or LFP.

Odor Concentration Change Coding in the Olfactory Bulb.

Dynamical changes in the environment strongly impact our perception. Likewise, sensory systems preferentially represent stimulus changes, enhancing temporal contrast. In olfaction, odor concentration changes across consecutive inhalations (ΔCt ) can guide odor source localization, yet the neural representation of ΔCt has not been studied in vertebrates. We have found that, in the mouse olfactory bulb, a subset of mitral/tufted (M/T) cells represents ΔCt , enhancing the contrast between different concentrations. These concentration change responses are direction selective: they respond either to increments or decrements of concentration, reminiscent of ON and OFF selectivity in the retina. This contrast enhancement scales with the magnitude, but not the duration of the concentration step. Further, ΔCt can be read out from the total spike count per sniff, unlike odor identity and intensity, which are represented by fast temporal spike patterns. Our results demonstrate that a subset of M/T cells represents ΔCt , providing a signal that may instruct navigational decisions in downstream olfactory circuits.

Sniff Invariant Odor Coding.

Sampling regulates stimulus intensity and temporal dynamics at the sense organ. Despite variations in sampling behavior, animals must make veridical perceptual judgments about external stimuli. In olfaction, odor sampling varies with respiration, which influences neural responses at the olfactory periphery. Nevertheless, rats were able to perform fine odor intensity judgments despite variations in sniff kinetics. To identify the features of neural activity supporting stable intensity perception, in awake mice we measured responses of mitral/tufted (MT) cells to different odors and concentrations across a range of sniff frequencies. Amplitude and latency of the MT cells' responses vary with sniff duration. A fluid dynamics (FD) model based on odor concentration kinetics in the intranasal cavity can account for this variability. Eliminating sniff waveform dependence of MT cell responses using the FD model allows for significantly better decoding of concentration. This suggests potential schemes for sniff waveform invariant odor concentration coding.

Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing.

Oxytocin promotes social interactions and recognition of conspecifics that rely on olfaction in most species. The circuit mechanisms through which oxytocin modifies olfactory processing are incompletely understood. Here, we observed that optogenetically induced oxytocin release enhanced olfactory exploration and same-sex recognition of adult rats. Consistent with oxytocin's function in the anterior olfactory cortex, particularly in social cue processing, region-selective receptor deletion impaired social recognition but left odor discrimination and recognition intact outside a social context. Oxytocin transiently increased the drive of the anterior olfactory cortex projecting to olfactory bulb interneurons. Cortical top-down recruitment of interneurons dynamically enhanced the inhibitory input to olfactory bulb projection neurons and increased the signal-to-noise of their output. In summary, oxytocin generates states for optimized information extraction in an early cortical top-down network that is required for social interactions with potential implications for sensory processing deficits in autism spectrum disorders.

Neural Coding of Perceived Odor Intensity.

Stimulus intensity is a fundamental perceptual feature in all sensory systems. In olfaction, perceived odor intensity depends on at least two variables: odor concentration; and duration of the odor exposure or adaptation. To examine how neural activity at early stages of the olfactory system represents features relevant to intensity perception, we studied the responses of mitral/tufted cells (MTCs) while manipulating odor concentration and exposure duration. Temporal profiles of MTC responses to odors changed both as a function of concentration and with adaptation. However, despite the complexity of these responses, adaptation and concentration dependencies behaved similarly. These similarities were visualized by principal component analysis of average population responses and were quantified by discriminant analysis in a trial-by-trial manner. The qualitative functional dependencies of neuronal responses paralleled psychophysics results in humans. We suggest that temporal patterns of MTC responses in the olfactory bulb contribute to an internal perceptual variable: odor intensity.

A network that performs brute-force conversion of a temporal sequence to a spatial pattern: relevance to odor recognition.

A classic problem in neuroscience is how temporal sequences (TSs) can be recognized. This problem is exemplified in the olfactory system, where an odor is defined by the TS of olfactory bulb (OB) output that occurs during a sniff. This sequence is discrete because the output is subdivided by gamma frequency oscillations. Here we propose a new class of "brute-force" solutions to recognition of discrete sequences. We demonstrate a network architecture in which there are a small number of modules, each of which provides a persistent snapshot of what occurs in a different gamma cycle. The collection of these snapshots forms a spatial pattern (SP) that can be recognized by standard attractor-based network mechanisms. We will discuss the implications of this strategy for recognizing odor-specific sequences generated by the OB.

Perception of sniff phase in mouse olfaction.

Olfactory systems encode odours by which neurons respond and by when they respond. In mammals, every sniff evokes a precise, odour-specific sequence of activity across olfactory neurons. Likewise, in a variety of neural systems, ranging from sensory periphery to cognitive centres, neuronal activity is timed relative to sampling behaviour and/or internally generated oscillations. As in these neural systems, relative timing of activity may represent information in the olfactory system. However, there is no evidence that mammalian olfactory systems read such cues. To test whether mice perceive the timing of olfactory activation relative to the sniff cycle ('sniff phase'), we used optogenetics in gene-targeted mice to generate spatially constant, temporally controllable olfactory input. Here we show that mice can behaviourally report the sniff phase of optogenetically driven activation of olfactory sensory neurons. Furthermore, mice can discriminate between light-evoked inputs that are shifted in the sniff cycle by as little as 10 milliseconds, which is similar to the temporal precision of olfactory bulb odour responses. Electrophysiological recordings in the olfactory bulb of awake mice show that individual cells encode the timing of photoactivation in relation to the sniff in both the timing and the amplitude of their responses. Our work provides evidence that the mammalian olfactory system can read temporal patterns, and suggests that timing of activity relative to sampling behaviour is a potent cue that may enable accurate olfactory percepts to form quickly.

Precise olfactory responses tile the sniff cycle.

In terrestrial vertebrates, sniffing controls odorant access to receptors, and therefore sets the timescale of olfactory stimuli. We found that odorants evoked precisely sniff-locked activity in mitral/tufted cells in the olfactory bulb of awake mouse. The trial-to-trial response jitter averaged 12 ms, a precision comparable to other sensory systems. Individual cells expressed odor-specific temporal patterns of activity and, across the population, onset times tiled the duration of the sniff cycle. Responses were more tightly time-locked to the sniff phase than to the time after inhalation onset. The spikes of single neurons carried sufficient information to discriminate odors. In addition, precise locking to sniff phase may facilitate ensemble coding by making synchrony relationships across neurons robust to variation in sniff rate. The temporal specificity of mitral/tufted cell output provides a potentially rich source of information for downstream olfactory areas.

Internal dynamics of superhelical DNA.

We present the first data on the temporal kinetics of monomer mean square displacements in DNA circles with defined degrees of superhelicity. The segmental dynamics of specifically labeled DNA plasmids with superhelical densities between 0 and -0.016 was assessed by fluorescence correlation spectroscopy. Introduction of superhelicity leads to progressively faster dynamics in the long time regime corresponding to the coil diffusion as observed previously by Langowski et al. [Biopolymers 34, 639 (1994)10.1002/bip.360340506], but also in the short time range corresponding to the segmental motion within the DNA coil.

Fluorescence correlation spectroscopy analysis of segmental dynamics in actin filaments.

We adapt fluorescence correlation spectroscopy (FCS) formalism to the studies of the dynamics of semiflexible polymers and derive expressions relating FCS correlation function to the longitudinal and transverse mean-square displacements of polymer segments. The obtained relations do not depend on any specific model of polymer dynamics. We use the derived expressions to measure the dynamics of actin filaments in two experimental situations: filaments labeled at distinct positions and homogeneously labeled filaments. Both approaches give consistent results and allow to measure the temporal dependence of the segmental mean-square displacement over almost five decades in time, from approximately 40 micros to approximately 2 s. These noninvasive measurements allow for a detailed quantitative comparison of the experimental data to the current theories of semiflexible polymer dynamics. Good quantitative agreement is found between the experimental results and theories explicitly accounting for the hydrodynamic interactions between polymer segments.

Monomer dynamics in double- and single-stranded DNA polymers.

We present the first measurements of the kinetics of random motion of individual monomers within large polymer coils. We use double- and single-stranded DNA (dsDNA and ssDNA) as models of semiflexible and flexible polymers, respectively. Fluorescence fluctuations of DNA fragments labeled specifically at a single position reveal the time dependence of the DNA monomer's mean-square displacement . The monomer motions within dsDNA and ssDNA coils are characterized by two qualitatively different kinetic regimes: close to proportional to t(2/3) for ssDNA and proportional to sqrt[t] for dsDNA. While the kinetic behavior of ssDNA is consistent with the generally accepted Zimm theory of polymer dynamics, the kinetic behavior of dsDNA monomers is in good agreement with the Rouse model.