Myelination of peripheral nerves is controlled by PI4KB through regulation of Schwann cell Golgi function.

Better understanding myelination of peripheral nerves would benefit patients affected by peripheral neuropathies, including Charcot-Marie-Tooth disease. Little is known about the role the Golgi compartment plays in Schwann cell (SC) functions. Here, we studied the role of Golgi in myelination of peripheral nerves in mice through SC-specific genetic inactivation of phosphatidylinositol 4-kinase beta (PI4KB), a Golgi-associated lipid kinase. Sciatic nerves of such mice showed thinner myelin of large diameter axons and gross aberrations in myelin organization affecting the nodes of Ranvier, the Schmidt-Lanterman incisures, and Cajal bands. Nonmyelinating SCs showed a striking inability to engulf small diameter nerve fibers. SCs of mutant mice showed a distorted Golgi morphology and disappearance of OSBP at the cis-Golgi compartment, together with a complete loss of GOLPH3 from the entire Golgi. Accordingly, the cholesterol and sphingomyelin contents of sciatic nerves were greatly reduced and so was the number of caveolae observed in SCs. Although the conduction velocity of sciatic nerves of mutant mice showed an 80% decrease, the mice displayed only subtle impairment in their motor functions. Our analysis revealed that Golgi functions supported by PI4KB are critically important for proper myelination through control of lipid metabolism, protein glycosylation, and organization of microvilli in the nodes of Ranvier of peripheral nerves.

Trade-off between information format and capacity in the olfactory system.

As information about the sensory environment passes between layers within the nervous system, the format of the information often changes. To examine how information format affects the capacity of neurons to represent stimuli, we measured the rate of information transmission in olfactory neurons in intact, awake locusts (Schistocerca americana) while pharmacologically manipulating patterns of correlated neuronal activity. Blocking the periodic inhibition underlying odor-elicited neural oscillatory synchronization increased information transmission rates. This suggests oscillatory synchrony, which serves other information processing roles, comes at a cost to the speed with which neurons can transmit information. Our results provide an example of a trade-off between benefits and costs in neural information processing.

Control of moth flight posture is mediated by wing mechanosensory feedback.

Flying insects rapidly stabilize after perturbations using both visual and mechanosensory inputs for active control. Insect halteres are mechanosensory organs that encode inertial forces to aid rapid course correction during flight but serve no aerodynamic role and are specific to two orders of insects (Diptera and Strepsiptera). Aside from the literature on halteres and recent work on the antennae of the hawkmoth Manduca sexta, it is unclear how other flying insects use mechanosensory information to control body dynamics. The mechanosensory structures found on the halteres, campaniform sensilla, are also present on wings, suggesting that the wings can encode information about flight dynamics. We show that the neurons innervating these sensilla on the forewings of M. sexta exhibit spike-timing precision comparable to that seen in previous reports of campaniform sensilla, including haltere neurons. In addition, by attaching magnets to the wings of moths and subjecting these animals to a simulated pitch stimulus via a rotating magnetic field during tethered flight, we elicited the same vertical abdominal flexion reflex these animals exhibit in response to visual or inertial pitch stimuli. Our results indicate that, in addition to their role as actuators during locomotion, insect wings serve as sensors that initiate reflexes that control body dynamics.

Olfactory system structure and function in newly hatched and adult locusts.

An important question in neuroscience is how sensory systems change as animals grow and interact with the environment. Exploring sensory systems in animals as they develop can reveal how networks of neurons process information as the neurons themselves grow and the needs of the animal change. Here we compared the structure and function of peripheral parts of the olfactory pathway in newly hatched and adult locusts. We found that populations of olfactory sensory neurons (OSNs) in hatchlings and adults responded with similar tunings to a panel of odors. The morphologies of local neurons (LNs) and projection neurons (PNs) in the antennal lobes (ALs) were very similar in both age groups, though they were smaller in hatchlings, they were proportional to overall brain size. The odor evoked responses of LNs and PNs were also very similar in both age groups, characterized by complex patterns of activity including oscillatory synchronization. Notably, in hatchlings, spontaneous and odor-evoked firing rates of PNs were lower, and LFP oscillations were lower in frequency, than in the adult. Hatchlings have smaller antennae with fewer OSNs; removing antennal segments from adults also reduced LFP oscillation frequency. Thus, consistent with earlier computational models, the developmental increase in frequency is due to increasing intensity of input to the oscillation circuitry. Overall, our results show that locusts hatch with a fully formed olfactory system that structurally and functionally matches that of the adult, despite its small size and lack of prior experience with olfactory stimuli.

Olfactory receptor neurons generate multiple response motifs, increasing coding space dimensionality.

Odorants binding to olfactory receptor neurons (ORNs) trigger bursts of action potentials, providing the brain with its only experience of the olfactory environment. Our recordings made in vivo from locust ORNs showed that odor-elicited firing patterns comprise four distinct response motifs, each defined by a reliable temporal profile. Different odorants could elicit different response motifs from a given ORN, a property we term motif switching. Further, each motif undergoes its own form of sensory adaptation when activated by repeated plume-like odor pulses. A computational model constrained by our recordings revealed that organizing responses into multiple motifs provides substantial benefits for classifying odors and processing complex odor plumes: each motif contributes uniquely to encode the plume's composition and structure. Multiple motifs and motif switching further improve odor classification by expanding coding dimensionality. Our model demonstrated that these response features could provide benefits for olfactory navigation, including determining the distance to an odor source.

Temporal encoding in a nervous system.

We examined the extent to which temporal encoding may be implemented by single neurons in the cercal sensory system of the house cricket Acheta domesticus. We found that these neurons exhibit a greater-than-expected coding capacity, due in part to an increased precision in brief patterns of action potentials. We developed linear and non-linear models for decoding the activity of these neurons. We found that the stimuli associated with short-interval patterns of spikes (ISIs of 8 ms or less) could be predicted better by second-order models as compared to linear models. Finally, we characterized the difference between these linear and second-order models in a low-dimensional subspace, and showed that modification of the linear models along only a few dimensions improved their predictive power to parity with the second order models. Together these results show that single neurons are capable of using temporal patterns of spikes as fundamental symbols in their neural code, and that they communicate specific stimulus distributions to subsequent neural structures.

Insect neuroscience: Filling the knowledge gap on gap junctions.

Gap junctions, too small to spot in images used to create connectome maps, play outsized roles in shaping neural activity. A recent study reveals a surprising new gap junction function: they can stabilize a neuron's membrane potential against unwanted oscillations.

Characterizing the fine structure of a neural sensory code through information distortion.

We present an application of the information distortion approach to neural coding. The approach allows the discovery of neural symbols and the corresponding stimulus space of a neuron or neural ensemble simultaneously and quantitatively, making few assumptions about the nature of either code or relevant features. The neural codebook is derived by quantitizing sensory stimuli and neural responses into small reproduction sets, and optimizing the quantization to minimize the information distortion function. The application of this approach to the analysis of coding in sensory interneurons involved a further restriction of the space of allowed quantitizers to a smaller family of parametric distributions. We show that, for some cells in this system, a significant amount of information is encoded in patterns of spikes that would not be discovered through analyses based on linear stimulus-response measures.

Feedback inhibition and its control in an insect olfactory circuit.

Inhibitory neurons play critical roles in regulating and shaping olfactory responses in vertebrates and invertebrates. In insects, these roles are performed by relatively few neurons, which can be interrogated efficiently, revealing fundamental principles of olfactory coding. Here, with electrophysiological recordings from the locust and a large-scale biophysical model, we analyzed the properties and functions of GGN, a unique giant GABAergic neuron that plays a central role in structuring olfactory codes in the locust mushroom body. Our simulations suggest that depolarizing GGN at its input branch can globally inhibit KCs several hundred microns away. Our in vivorecordings show that GGN responds to odors with complex temporal patterns of depolarization and hyperpolarization that can vary with odors and across animals, leading our model to predict the existence of a yet-undiscovered olfactory pathway. Our analysis reveals basic new features of GGN and the olfactory network surrounding it.

Annealing and the Normalized N-Cut.

We describe an annealing procedure that computes the normalized N-cut of a weighted graph G. The first phase transition computes the solution of the approximate normalized 2-cut problem, while the low temperature solution computes the normalized N-cut. The intermediate solutions provide a sequence of refinements of the 2-cut that can be used to split the data to K clusters with 2

Schwann-Cell-Specific Deletion of Phosphatidylinositol 4-Kinase Alpha Causes Aberrant Myelination.

Active membrane remodeling during myelination relies on phospholipid synthesis and membrane polarization, both of which are known to depend on inositol phospholipids. Here, we show that sciatic nerves of mice lacking phosphatidylinositol 4-kinase alpha (PI4KA) in Schwann cells (SCs) show substantially reduced myelin thickness with grave consequences on nerve conductivity and motor functions. Surprisingly, prolonged inhibition of PI4KA in immortalized mouse SCs failed to decrease plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) levels or PI 3-kinase (PI3K) activation, in spite of large reductions in plasma membrane PI4P levels. Instead, it caused rearrangements of the actin cytoskeleton, which was also observed in sciatic nerves of knockout animals. PI4KA inactivation disproportionally reduced phosphatidylserine, phosphatidylethanolamine, and sphingomyelin content in mutant nerves, with similar changes observed in SCs treated with a PI4KA inhibitor. These studies define a role for PI4KA in myelin formation primarily affecting metabolism of key phospholipids and the actin cytoskeleton.

Dejittered spike-conditioned stimulus waveforms yield improved estimates of neuronal feature selectivity and spike-timing precision of sensory interneurons.

What is the meaning associated with a single action potential in a neural spike train? The answer depends on the way the question is formulated. One general approach toward formulating this question involves estimating the average stimulus waveform preceding spikes in a spike train. Many different algorithms have been used to obtain such estimates, ranging from spike-triggered averaging of stimuli to correlation-based extraction of "stimulus-reconstruction" kernels or spatiotemporal receptive fields. We demonstrate that all of these approaches miscalculate the stimulus feature selectivity of a neuron. Their errors arise from the manner in which the stimulus waveforms are aligned to one another during the calculations. Specifically, the waveform segments are locked to the precise time of spike occurrence, ignoring the intrinsic "jitter" in the stimulus-to-spike latency. We present an algorithm that takes this jitter into account. "Dejittered" estimates of the feature selectivity of a neuron are more accurate (i.e., provide a better estimate of the mean waveform eliciting a spike) and more precise (i.e., have smaller variance around that waveform) than estimates obtained using standard techniques. Moreover, this approach yields an explicit measure of spike-timing precision. We applied this technique to study feature selectivity and spike-timing precision in two types of sensory interneurons in the cricket cercal system. The dejittered estimates of the mean stimulus waveforms preceding spikes were up to three times larger than estimates based on the standard techniques used in previous studies and had power that extended into higher-frequency ranges. Spike timing precision was approximately 5 ms.

Neural Encoding of Odors during Active Sampling and in Turbulent Plumes.

Sensory inputs are often fluctuating and intermittent, yet animals reliably utilize them to direct behavior. Here we ask how natural stimulus fluctuations influence the dynamic neural encoding of odors. Using the locust olfactory system, we isolated two main causes of odor intermittency: chaotic odor plumes and active sampling behaviors. Despite their irregularity, chaotic odor plumes still drove dynamic neural response features including the synchronization, temporal patterning, and short-term plasticity of spiking in projection neurons, enabling classifier-based stimulus identification and activating downstream decoders (Kenyon cells). Locusts can also impose odor intermittency through active sampling movements with their unrestrained antennae. Odors triggered immediate, spatially targeted antennal scanning that, paradoxically, weakened individual neural responses. However, these frequent but weaker responses were highly informative about stimulus location. Thus, not only are odor-elicited dynamic neural responses compatible with natural stimulus fluctuations and important for stimulus identification, but locusts actively increase intermittency, possibly to improve stimulus localization.

Olfactory coding: tagging and tuning odor-activated synapses for memory.

A recent study in the locust olfactory system shows how neuromodulators can alter the rules of synaptic plasticity to form associative memories through the use of 'tagged' synapses.

Information transmission in cercal giant interneurons is unaffected by axonal conduction noise.

What are the fundamental constraints on the precision and accuracy with which nervous systems can process information? One constraint must reflect the intrinsic "noisiness" of the mechanisms that transmit information between nerve cells. Most neurons transmit information through the probabilistic generation and propagation of spikes along axons, and recent modeling studies suggest that noise from spike propagation might pose a significant constraint on the rate at which information could be transmitted between neurons. However, the magnitude and functional significance of this noise source in actual cells remains poorly understood. We measured variability in conduction time along the axons of identified neurons in the cercal sensory system of the cricket Acheta domesticus, and used information theory to calculate the effects of this variability on sensory coding. We found that the variability in spike propagation speed is not large enough to constrain the accuracy of neural encoding in this system.

Insect-machine interface: a carbon nanotube-enhanced flexible neural probe.

We developed microfabricated flexible neural probes (FNPs) to provide a bi-directional electrical link to the moth Manduca sexta. These FNPs can deliver electrical stimuli to, and capture neural activity from, the insect's central nervous system. They are comprised of two layers of polyimide with gold sandwiched in between in a split-ring geometry that incorporates the bi-cylindrical anatomical structure of the insect's ventral nerve cord. The FNPs provide consistent left and right abdominal stimulation both across animals and within an individual animal. The features of the stimulation (direction, threshold charge) are aligned with anatomical features of the moth. We also have used these FNPs to record neuronal activity in the ventral nerve cord of the moth. Finally, by integrating carbon nanotube (CNT)-Au nanocomposites into the FNPs we have reduced the interfacial impedance between the probe and the neural tissue, thus reducing the magnitude of stimulation voltage. This in turn allows use of the FNPs with a wireless stimulator, enabling stimulation and flight biasing of freely flying moths. Together, these FNPs present a potent new platform for manipulating and measuring the neural circuitry of insects, and for other nerves in humans and other animals with similar dimensions as the ventral nerve cord of the moth.

Flexible split-ring electrode for insect flight biasing using multisite neural stimulation.

We describe a flexible multisite microelectrode for insect flight biasing using neural stimulation. The electrode is made of two layers of polyimide (PI) with gold sandwiched in between in a split-ring geometry. The split-ring design in conjunction with the flexibility of the PI allows for a simple insertion process and provides good attachment between the electrode and ventral nerve cord of the insect. Stimulation sites are located at the ends of protruding tips that are circularly distributed inside the split-ring structure. These protruding tips penetrate into the connective tissue surrounding the nerve cord. We have been able to insert the electrode into pupae of the giant sphinx moth Manduca sexta as early as seven days before the adult moth emerges, and we are able to use the multisite electrode to deliver electrical stimuli that evoke multidirectional, graded abdominal motions in both pupae and adult moths. Finally, in loosely tethered flight, we have used stimulation through the flexible microelectrodes to alter the abdominal angle, thus causing the flying moth to deviate to the left or right of its intended path.

Computational mechanisms of mechanosensory processing in the cricket.

Crickets and many other orthopteran insects face the challenge of gathering sensory information from the environment from a set of multi-modal sensory organs and transforming these stimuli into patterns of neural activity that can encode behaviorally relevant stimuli. The cercal mechanosensory system transduces low frequency air movements near the animal's body and is involved in many behaviors including escape from predators, orientation with respect to gravity, flight steering, aggression and mating behaviors. Three populations of neurons are sensitive to both the direction and dynamics of air currents: an array of mechanoreceptor-coupled sensory neurons, identified local interneurons and identified projection interneurons. The sensory neurons form a functional map of air current direction within the central nervous system that represents the direction of air currents as three-dimensional spatio-temporal activity patterns. These dynamic activity patterns provide excitatory input to interneurons whose sensitivity and spiking output depend on the location of the neuronal arbors within the sensory map and the biophysical and electronic properties of the cell structure. Sets of bilaterally symmetric interneurons can encode the direction of an air current stimulus by their ensemble activity patterns, functioning much like a Cartesian coordinate system. These interneurons are capable of responding to specific dynamic stimuli with precise temporal patterns of action potentials that may encode these stimuli using temporal encoding schemes. Thus, a relatively simple mechanosensory system employs a variety of complex computational mechanisms to provide the animal with relevant information about its environment.

Analysis of neural coding through quantization with an information-based distortion measure.

We discuss an analytical approach through which the neural symbols and corresponding stimulus space of a neuron or neural ensemble can be discovered simultaneously and quantitatively, making few assumptions about the nature of the code or relevant features. The basis for this approach is to conceptualize a neural coding scheme as a collection of stimulus-response classes akin to a dictionary or 'codebook', with each class corresponding to a spike pattern 'codeword' and its corresponding stimulus feature in the codebook. The neural codebook is derived by quantizing the neural responses into a small reproduction set, and optimizing the quantization to minimize an information-based distortion function. We apply this approach to the analysis of coding in sensory interneurons of a simple invertebrate sensory system. For a simple sensory characteristic (tuning curve), we demonstrate a case for which the classical definition of tuning does not describe adequately the performance of the cell studied. Considering a more involved sensory operation (sensory discrimination), we also show that, for some cells in this system, a significant amount of information is encoded in patterns of spikes that would not be discovered through analyses based on linear stimulus-response measures.