Neural Circuit Dynamics for Sensory Detection.

We consider the question of how sensory networks enable the detection of sensory stimuli in a combinatorial coding space. We are specifically interested in the olfactory system, wherein recent experimental studies have reported the existence of rich, enigmatic response patterns associated with stimulus onset and offset. This study aims to identify the functional relevance of such response patterns (i.e., what benefits does such neural activity provide in the context of detecting stimuli in a natural environment). We study this problem through the lens of normative, optimization-based modeling. Here, we define the notion of a low-dimensional latent representation of stimulus identity, which is generated through action of the sensory network. The objective of our optimization framework is to ensure high-fidelity tracking of a nominal representation in this latent space in an energy-efficient manner. It turns out that the optimal motifs emerging from this framework possess morphologic similarity with prototypical onset and offset responses observed in vivo in locusts (Schistocerca americana) of either sex. Furthermore, this objective can be exactly achieved by a network with reciprocal excitatory-inhibitory competitive dynamics, similar to interactions between projection neurons and local neurons in the early olfactory system of insects. The derived model also makes several predictions regarding maintenance of robust latent representations in the presence of confounding background information and trade-offs between the energy of sensory activity and resultant behavioral measures such as speed and accuracy of stimulus detection.SIGNIFICANCE STATEMENT A key area of study in olfactory coding involves understanding the transformation from high-dimensional sensory stimulus to low-dimensional decoded representation. Here, we examine not only the dimensionality reduction of this mapping but also its temporal dynamics, with specific focus on stimuli that are temporally continuous. Through optimization-based synthesis, we examine how sensory networks can track representations without prior assumption of discrete trial structure. We show that such tracking can be achieved by canonical network architectures and dynamics, and that the resulting responses resemble observations from neurons in the insect olfactory system. Thus, our results provide hypotheses regarding the functional role of olfactory circuit activity at both single neuronal and population scales.

Differential effects of adaptation on odor discrimination.

Adaptation of neural responses is ubiquitous in sensory systems and can potentially facilitate many important computational functions. Here we examined this issue with a well-constrained computational model of the early olfactory circuits. In the insect olfactory system, the responses of olfactory receptor neurons (ORNs) on the antennae adapt over time. We found that strong adaptation of sensory input is important for rapidly detecting a fresher stimulus encountered in the presence of other background cues and for faithfully representing its identity. However, when the overlapping odorants were chemically similar, we found that adaptation could alter the representation of these odorants to emphasize only distinguishing features. This work demonstrates novel roles for peripheral neurons during olfactory processing in complex environments. NEW & NOTEWORTHY Olfactory systems face the problem of distinguishing salient information from a complex olfactory environment. The neural representations of specific odor sources should be consistent regardless of the background. How are olfactory representations robust to varying environmental interference? We show that in locusts the extraction of salient information begins in the periphery. Olfactory receptor neurons adapt in response to odorants. Adaptation can provide a computational mechanism allowing novel odorant components to be highlighted during complex stimuli.

Bioinspired Polarization Imaging Sensors: From Circuits and Optics to Signal Processing Algorithms and Biomedical Applications: Analysis at the focal plane emulates nature's method in sensors to image and diagnose with polarized light.

In this paper, we present recent work on bioinspired polarization imaging sensors and their applications in biomedicine. In particular, we focus on three different aspects of these sensors. First, we describe the electro-optical challenges in realizing a bioinspired polarization imager, and in particular, we provide a detailed description of a recent low-power complementary metal-oxide-semiconductor (CMOS) polarization imager. Second, we focus on signal processing algorithms tailored for this new class of bioinspired polarization imaging sensors, such as calibration and interpolation. Third, the emergence of these sensors has enabled rapid progress in characterizing polarization signals and environmental parameters in nature, as well as several biomedical areas, such as label-free optical neural recording, dynamic tissue strength analysis, and early diagnosis of flat cancerous lesions in a murine colorectal tumor model. We highlight results obtained from these three areas and discuss future applications for these sensors.

Precision detection of select human lung cancer biomarkers and cell lines using honeybee olfactory neural circuitry as a novel gas sensor.

Human breath contains biomarkers (odorants) that can be targeted for early disease detection. It is well known that honeybees have a keen sense of smell and can detect a wide variety of odors at low concentrations. Here, we employ honeybee olfactory neuronal circuitry to classify human lung cancer volatile biomarkers at different concentrations and their mixtures at concentration ranges relevant to biomarkers in human breath from parts-per-billion to parts-per-trillion. We also validated this brain-based sensing technology by detecting human non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines using the 'smell' of the cell cultures. Different lung cancer biomarkers evoked distinct spiking response dynamics in the honeybee antennal lobe neurons indicating that those neurons encoded biomarker-specific information. By investigating lung cancer biomarker-evoked population neuronal responses from the honeybee antennal lobe, we classified individual human lung cancer biomarkers successfully (88% success rate). When we mixed six lung cancer biomarkers at different concentrations to create 'synthetic lung cancer' vs. 'synthetic healthy' human breath, honeybee population neuronal responses were able to classify those complex breath mixtures reliably with exceedingly high accuracy (93-100% success rate with a leave-one-trial-out classification method). Finally, we employed this sensor to detect human NSCLC and SCLC cell lines and we demonstrated that honeybee brain olfactory neurons could distinguish between lung cancer vs. healthy cell lines and could differentiate between different NSCLC and SCLC cell lines successfully (82% classification success rate). These results indicate that the honeybee olfactory system can be used as a sensitive biological gas sensor to detect human lung cancer.

Harnessing insect olfactory neural circuits for detecting and discriminating human cancers.

There is overwhelming evidence that presence of cancer alters cellular metabolic processes, and these changes are manifested in emitted volatile organic compound (VOC) compositions of cancer cells. Here, we take a novel forward engineering approach by developing an insect olfactory neural circuit-based VOC sensor for cancer detection. We obtained oral cancer cell culture VOC-evoked extracellular neural responses from in vivo insect (locust) antennal lobe neurons. We employed biological neural computations of the antennal lobe circuitry for generating spatiotemporal neuronal response templates corresponding to each cell culture VOC mixture, and employed these neuronal templates to distinguish oral cancer cell lines (SAS, Ca9-22, and HSC-3) vs. a non-cancer cell line (HaCaT). Our results demonstrate that three different human oral cancers can be robustly distinguished from each other and from a non-cancer oral cell line. By using high-dimensional population neuronal response analysis and leave-one-trial-out methodology, our approach yielded high classification success for each cell line tested. Our analyses achieved 76-100% success in identifying cell lines by using the population neural response (n = 194) collected for the entire duration of the cell culture study. We also demonstrate this cancer detection technique can distinguish between different types of oral cancers and non-cancer at different time-matched points of growth. This brain-based cancer detection approach is fast as it can differentiate between VOC mixtures within 250 ms of stimulus onset. Our brain-based cancer detection system comprises a novel VOC sensing methodology that incorporates entire biological chemosensory arrays, biological signal transduction, and neuronal computations in a form of a forward-engineered technology for cancer VOC detection.

Response properties of visual neurons in the turtle nucleus isthmi.

The optic tectum holds a central position in the tectofugal pathway of non-mammalian species and is reciprocally connected with the nucleus isthmi. Here, we recorded from individual nucleus isthmi pars parvocellularis (Ipc) neurons in the turtle eye-attached whole-brain preparation in response to a range of computer-generated visual stimuli. Ipc neurons responded to a variety of moving or flashing stimuli as long as those stimuli were small. When mapped with a moving spot, the excitatory receptive field was of circular Gaussian shape with an average half-width of less than 3°. We found no evidence for directional sensitivity. For moving spots of varying sizes, the measured Ipc response-size profile was reproduced by the linear Difference-of-Gaussian model, which is consistent with the superposition of a narrow excitatory center and an inhibitory surround. Intracellular Ipc recordings revealed a strong inhibitory connection from the nucleus isthmi pars magnocellularis (Imc), which has the anatomical feature to provide a broad inhibitory projection. The recorded Ipc response properties, together with the modulatory role of the Ipc in tectal visual processing, suggest that the columns of Ipc axon terminals in turtle optic tectum bias tectal visual responses to small dark changing features in visual scenes.

Dynamic contrast enhancement and flexible odor codes.

Sensory stimuli evoke spiking activities patterned across neurons and time that are hypothesized to encode information about their identity. Since the same stimulus can be encountered in a multitude of ways, how stable or flexible are these stimulus-evoked responses? Here we examine this issue in the locust olfactory system. In the antennal lobe, we find that both spatial and temporal features of odor-evoked responses vary in a stimulus-history dependent manner. The response variations are not random, but allow the antennal lobe circuit to enhance the uniqueness of the current stimulus. Nevertheless, information about the odorant identity is conf ounded due to this contrast enhancement computation. Notably, predictions from a linear logical classifier (OR-of-ANDs) that can decode information distributed in flexible subsets of neurons match results from behavioral experiments. In sum, our results suggest that a trade-off between stability and flexibility in sensory coding can be achieved using a simple computational logic.

Non-invasive aerosol delivery and transport of gold nanoparticles to the brain.

Targeted delivery of nanoscale carriers containing packaged payloads to the central nervous system has potential use in many diagnostic and therapeutic applications. Moreover, understanding of the bio-interactions of the engineered nanoparticles used for tissue-specific delivery by non-invasive delivery approaches are also of paramount interest. Here, we have examined this issue systematically in a relatively simple invertebrate model using insects. We synthesized 5 nm, positively charged gold nanoparticles (AuNPs) and targeted their delivery using the electrospray aerosol generator. Our results revealed that after the exposure of synthesized aerosol to the insect antenna, AuNPs reached the brain within an hour. Nanoparticle accumulation in the brain increased linearly with the exposure time. Notably, electrophysiological recordings from neurons in the insect brain several hours after exposure did not show any significant alterations in their spontaneous and odor-evoked spiking properties. Taken together, our findings reveal that aerosolized delivery of nanoparticles can be an effective non-invasive approach for delivering nanoparticles to the brain, and also presents an approach to monitor the short-term nano-biointeractions.

Engaging and disengaging recurrent inhibition coincides with sensing and unsensing of a sensory stimulus.

Even simple sensory stimuli evoke neural responses that are dynamic and complex. Are the temporally patterned neural activities important for controlling the behavioral output? Here, we investigated this issue. Our results reveal that in the insect antennal lobe, due to circuit interactions, distinct neural ensembles are activated during and immediately following the termination of every odorant. Such non-overlapping response patterns are not observed even when the stimulus intensity or identities were changed. In addition, we find that ON and OFF ensemble neural activities differ in their ability to recruit recurrent inhibition, entrain field-potential oscillations and more importantly in their relevance to behaviour (initiate versus reset conditioned responses). Notably, we find that a strikingly similar strategy is also used for encoding sound onsets and offsets in the marmoset auditory cortex. In sum, our results suggest a general approach where recurrent inhibition is associated with stimulus 'recognition' and 'derecognition'.

Behavioural correlates of combinatorial versus temporal features of odour codes.

Most sensory stimuli evoke spiking responses that are distributed across neurons and are temporally structured. Whether the temporal structure of ensemble activity is modulated to facilitate different neural computations is not known. Here, we investigated this issue in the insect olfactory system. We found that an odourant can generate synchronous or asynchronous spiking activity across a neural ensemble in the antennal lobe circuit depending on its relative novelty with respect to a preceding stimulus. Regardless of variations in temporal spiking patterns, the activated combinations of neurons robustly represented stimulus identity. Consistent with this interpretation, locusts reliably recognized both solitary and sequential introductions of trained odourants in a quantitative behavioural assay. However, predictable behavioural responses across locusts were observed only to novel stimuli that evoked synchronized spiking patterns across neural ensembles. Hence, our results indicate that the combinatorial ensemble response encodes for stimulus identity, whereas the temporal structure of the ensemble response selectively emphasizes novel stimuli.

Multi-unit recording methods to characterize neural activity in the locust (Schistocerca americana) olfactory circuits.

Detection and interpretation of olfactory cues are critical for the survival of many organisms. Remarkably, species across phyla have strikingly similar olfactory systems suggesting that the biological approach to chemical sensing has been optimized over evolutionary time. In the insect olfactory system, odorants are transduced by olfactory receptor neurons (ORN) in the antenna, which convert chemical stimuli into trains of action potentials. Sensory input from the ORNs is then relayed to the antennal lobe (AL; a structure analogous to the vertebrate olfactory bulb). In the AL, neural representations for odors take the form of spatiotemporal firing patterns distributed across ensembles of principal neurons (PNs; also referred to as projection neurons). The AL output is subsequently processed by Kenyon cells (KCs) in the downstream mushroom body (MB), a structure associated with olfactory memory and learning. Here, we present electrophysiological recording techniques to monitor odor-evoked neural responses in these olfactory circuits. First, we present a single sensillum recording method to study odor-evoked responses at the level of populations of ORNs. We discuss the use of saline filled sharpened glass pipettes as electrodes to extracellularly monitor ORN responses. Next, we present a method to extracellularly monitor PN responses using a commercial 16-channel electrode. A similar approach using a custom-made 8-channel twisted wire tetrode is demonstrated for Kenyon cell recordings. We provide details of our experimental setup and present representative recording traces for each of these techniques.

A spatiotemporal coding mechanism for background-invariant odor recognition.

Sensory stimuli evoke neural activity that evolves over time. What features of these spatiotemporal responses allow the robust encoding of stimulus identity in a multistimulus environment? Here we examined this issue in the locust (Schistocerca americana) olfactory system. We found that sensory responses evoked by an odorant (foreground) varied when presented atop or after an ongoing stimulus (background). These inconsistent sensory inputs triggered dynamic reorganization of ensemble activity in the downstream antennal lobe. As a result, partial pattern matches between neural representations encoding the same foreground stimulus across conditions were achieved. The degree and segments of response overlaps varied; however, any overlap observed was sufficient to drive background-independent responses in the downstream neural population. Notably, recognition performance of locusts in behavioral assays correlated well with our physiological findings. Hence, our results reveal how background-independent recognition of odors can be achieved using spatiotemporal patterns of neural activity.