Ryan M. Carey

Rapid Encoding and Perception of Novel Odors in the Rat

To gain insight into which parameters of neural activity are important in shaping the perception of odors, we combined a behavioral measure of odor perception with optical imaging of odor representations at the level of receptor neuron input to the rat olfactory bulb. Instead of the typical test of an animals ability to discriminate two familiar odorants by exhibiting an operant response, we used a spontaneously expressed response to a novel odorant—exploratory sniffing—as a measure of odor perception. This assay allowed us to measure the speed with which rats perform spontaneous odor discriminations. With this paradigm, rats discriminated and began responding to a novel odorant in as little as 140 ms. This time is comparable to that measured in earlier studies using operant behavioral readouts after extensive training. In a subset of these trials, we simultaneously imaged receptor neuron input to the dorsal olfactory bulb with near-millisecond temporal resolution as the animal sampled and then responded to the novel odorant. The imaging data revealed that the bulk of the discrimination time can be attributed to the peripheral events underlying odorant detection: receptor input arrives at the olfactory bulb 100–150 ms after inhalation begins, leaving only 50–100 ms for central processing and response initiation. In most trials, odor discrimination had occurred even before the initial barrage of receptor neuron firing had ceased and before spatial maps of activity across glomeruli had fully developed. These results suggest a coding strategy in which the earliest-activated glomeruli play a major role in the initial perception of odor quality, and place constraints on coding and processing schemes based on simple changes in spike rate.

Temporal structure of receptor neuron input to the olfactory bulb imaged in behaving rats.

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.

Effect of Sniffing on the Temporal Structure of Mitral/Tufted Cell Output from the Olfactory Bulb

Neural activity underlying odor representations in the mammalian olfactory system is strongly patterned by respiratory behavior. These dynamics are central to many models of olfactory information processing. We have found previously that sensory inputs to the olfactory bulb change both their magnitude and temporal structure as a function of sniff frequency. Here, we ask how sniff frequency affects responses of mitral/tufted (MT) cells—the principal olfactory bulb output neurons. We recorded from MT cells in anesthetized rats while reproducing sniffs recorded previously from awake animals and varying sniff frequency. The dynamics of a sniff-evoked response were consistent from sniff to sniff but varied across cells. Compared to the dynamics of receptor neuron activation by the same sniffs, the MT response was shorter and faster, reflecting a temporal sharpening of sensory inputs. Increasing sniff frequency led to moderate attenuation of MT response magnitude and significant changes in the temporal structure of the sniff-evoked MT cell response. Most MT cells responded with a shorter duration and shorter rise-time spike burst as sniff frequency increased, reflecting increased temporal sharpening of inputs by the olfactory bulb. These temporal changes were necessary and sufficient to maintain respiratory modulation in the MT cell population across the range of sniff frequencies expressed during behavior. These results suggest that the input–output relationship in the olfactory bulb varies dynamically as a function of sniff frequency and that one function of the postsynaptic network is to maintain robust temporal encoding of odor information across different odor sampling strategies.

Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment.

Low‐level Mechanisms for Processing Odor Information in the Behaving Animal

Sensory processing is typically thought to act on representations of sensory stimuli that are relatively fixed at low levels in the nervous system and become increasingly complex and subject to modulation at higher levels. Here we present recent findings from our laboratory demonstrating that, in the olfactory system, odor representations in the behaving animal can be transformed at low levels—as early as the primary sensory neurons themselves—via a variety of mechanisms. First, changes in odor sampling behavior, such as sniffing, can dramatically and rapidly alter primary odor representations by changing the strength and temporal structure of sensory input to the olfactory bulb, effectively shaping which features of the olfactory landscape are emphasized and likely altering how information is processed by the olfactory bulb network. Second, neural substrates exist for presynaptically modulating the strength of sensory input to the bulb as a function of behavioral state. The systems most likely to be involved in this modulation—cholinergic and serotonergic centrifugal inputs to the bulb—are linked to attention and arousal effects in other brain areas. Together, sniffing behavior and presynaptic inhibition have the potential to mediate, or at least contribute to, sensory processing phenomena, such as figure–ground separation, intensity invariance, and context‐dependent and attentional modulation of response properties. Thus, “high order” processing can occur even before sensory neurons transmit information to the brain.

Role of intraglomerular circuits in shaping temporally structured responses to naturalistic inhalation-driven sensory input to the olfactory bulb

Olfaction in mammals is a dynamic process driven by the inhalation of air through the nasal cavity. Inhalation determines the temporal structure of sensory neuron responses and shapes the neural dynamics underlying central olfactory processing. Inhalation-linked bursts of activity among olfactory bulb (OB) output neurons [mitral/tufted cells (MCs)] are temporally transformed relative to those of sensory neurons. We investigated how OB circuits shape inhalation-driven dynamics in MCs using a modeling approach that was highly constrained by experimental results. First, we constructed models of canonical OB circuits that included mono- and disynaptic feedforward excitation, recurrent inhibition and feedforward inhibition of the MC. We then used experimental data to drive inputs to the models and to tune parameters; inputs were derived from sensory neuron responses during natural odorant sampling (sniffing) in awake rats, and model output was compared with recordings of MC responses to odorants sampled with the same sniff waveforms. This approach allowed us to identify OB circuit features underlying the temporal transformation of sensory inputs into inhalation-linked patterns of MC spike output. We found that realistic input-output transformations can be achieved independently by multiple circuits, including feedforward inhibition with slow onset and decay kinetics and parallel feedforward MC excitation mediated by external tufted cells. We also found that recurrent and feedforward inhibition had differential impacts on MC firing rates and on inhalation-linked response dynamics. These results highlight the importance of investigating neural circuits in a naturalistic context and provide a framework for further explorations of signal processing by OB networks.

Computational modeling of the external tufted cell of the mammalian olfactory bulb

We explore the model’s parameter space using detailed parameter sweeps and Latin hypercube sampling, demarcating regions of bursting, tonic, and excitable behavior. To study the sensitivity of various functional characteristics to changes in parameter values, we employ specialized smooth optimization methods for bursting neural models [8]. We find that the half-activation voltages for ICaT and INaP are most critical for control of interburst period and duty cycle. We also investigate the phase response properties of the ET cell model and its responses to periodic input.

Effects of synaptic and intrinsic parameters in shaping dynamic responses to olfactory input: a combined computational-experimental study of two glomerular microcircuits

Initial synaptic processing of odors occurs in the mammalian olfactory bulb (OB): temporally dynamic odorant-evoked inputs are first processed at the olfactory receptor neuron (ORN) level, and similarly dynamic, patterned output is transmitted from the mitral cell (MC) layer to olfactory cortex. Prior work has shown that bursts of odor-evoked ORN activity exhibit odor-specific and glomerulus-specific durations, rise times, latencies, and amplitudes [1]. Similarly diverse patterning is seen in MC activity, which is temporally organized around the respiratory cycle and changes qualitatively during odor sampling. The temporal spread of sensory input following a single inhalation (~100-300 ms) is comparable to the range of discrimination times for different olfactory tasks [2,3], consistent with these dynamics being important in shaping odor perception. Situated between the ORN input and MC output layers, the neuronal circuitry of the glomerular layer acts to consolidate and modulate OB output. Thousands of juxtaglomerular neurons from three distinct classes form the neuronal network within a glomerulus; several synaptic and gap junctional microcircuits have been identified in the intraglomerular network [4]. What transformation(s) of ORN input into MC output might the intraglomerular circuitry perform? We investigate temporal dynamics in computational models of two intraglomerular microcircuits: the classical ORN-MC circuit and a variant circuit that incorporates between the ORN and MC an external tufted (ET) cell capable of endogenous bursting [5]. These neurons are represented with single-compartment, Hodgkin-Huxley-style models [6,7]. Circuit inputs are calcium signals recorded from the presynaptic terminals of ORNs of head-fixed rats exposed to odorants using a ‘sniff playback’ mechanism [8,9]. These calcium signals are converted to excitatory synaptic inputs with temporal signatures closely matching that of inputs to the real neurons. The response dynamics of the circuits’ MC output are strongly shaped by the input signal. We explore how the circuits’ dynamics vary for different odorants, synaptic strengths, and degrees of synaptic adaptation, and we compare the two circuits’ dynamics as parameters controlling intrinsic properties of the ET and MC cells are varied.

A combined computational-experimental study of dynamic responses to olfactory input in a glomerular circuit

Odorant-evoked input to and output from the mammalian olfactory bulb (OB) is temporally dynamic. Olfactory receptor neuron (ORN) inputs are tightly coupled to the respiratory cycle, and inhalation-evoked input bursts occur with durations, rise times, latencies, and strengths (amplitudes) that vary across glomeruli (for the same odorant) and also in individual glomeruli for different odorants [1]. The temporal spread of sensory input following a single inhalation (~100-300 ms) is comparable to the range of discrimination times for different olfactory tasks [2,3], consistent with these dynamics being important in shaping odor perception. Similarly diverse temporal patterns of activity occur at the level of output from the OB, among mitral cells (MCs), whose firing patterns express strong temporal structure organized around the respiratory cycle and modulated by odorant presentation; significant odor information is carried in these temporal patterns across the MC population. We investigate these temporal dynamics using a computational model of the ORN-MC circuit that uses a single-compartment, Hodgkin-Huxley-style MC model [4]. The input to the model MC is taken from recordings of odorant-evoked calcium influx into the presynaptic terminals of ORNs of awake, head-fixed rats engaged in an olfactory discrimination task [1,5]. This calcium signal is converted to an excitatory synaptic input for the model MC having a temporal signature that presumably closely reproduces that of the signal received by real MCs. The response dynamics of the MC model are strongly shaped by the input signal (Figure ​(Figure1).1). We explore how these dynamics vary for different odorants, synaptic strengths, and intrinsic MC parameters. We also investigate the response of a variant circuit that incorporates a mediating external tufted cell model between the ORN and MC [6]. Figure 1 Sniffing and odor-evoked ORN input (top) imaged from an awake rat; ORN input is used to drive a model MC (bottom). Each sniff-evoked burst of ORN input elicits a burst of action potentials in the model MC.