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The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output. Nerve cells or neurons communicate with one another using electrical impulses and chemical messengers called neurotransmitters. Additional molecules known as neuromodulators regulate the communication process. In contrast to neurotransmitters, neuromodulators do not send messages directly from one neuron to the next. Instead they change the way that neurons respond to neurotransmitters. For example, the neuromodulator acetylcholine is most abundant in a region called the striatum. Located deep within the brain, the striatum contributes to learning and memory, motivation, and movement. Studies in rodents show that neurons within the striatum called cholinergic interneurons are almost continuously active. Each time these cells fire, they release acetylcholine. But whenever an animal experiences something unusual or important, the interneurons temporarily stop firing. Zucca et al. wanted to know whether these pauses in firing also act as a signal within the striatum. To find out, Zucca et al. inserted a light-sensitive ion channel into cholinergic interneurons in the mouse striatum. Activating the ion channels with a laser beam stopped the interneurons from firing. Zucca et al. showed that these pauses in firing reduced the activity of another group of neurons, the spiny projection neurons. These are the major output neurons of the striatum. They send messages from the striatum to other parts of the brain. The results thus suggest that cholinergic interneurons signal notable events by temporarily blocking output from the striatum. Understanding how cholinergic interneurons work will help reveal how the striatum drives behavior. It may also lead to treatments for diseases caused by cholinergic system dysfunction. Many patients with Parkinson’s disease or schizophrenia take medicines to block the effects of acetylcholine. Understanding how acetylcholine affects the striatum may help clarify how these treatments work.

Large scale transitions between active (up) and silent (down) states during quiet wakefulness or NREM sleep regulate fundamental cortical functions and are known to involve both excitatory and inhibitory cells. However, if and how inhibition regulates these activity transitions is unclear. Using fluorescence-targeted electrophysiological recording and cell-specific optogenetic manipulation in both anesthetized and non-anesthetized mice, we found that two major classes of interneurons, the parvalbumin and the somatostatin positive cells, tightly control both up-to-down and down-to-up state transitions. Inhibitory regulation of state transition was observed under both natural and optogenetically-evoked conditions. Moreover, perturbative optogenetic experiments revealed that the inhibitory control of state transition was interneuron-type specific. Finally, local manipulation of small ensembles of interneurons affected cortical populations millimetres away from the modulated region. Together, these results demonstrate that inhibition potently gates transitions between cortical activity states, and reveal the cellular mechanisms by which local inhibitory microcircuits regulate state transitions at the mesoscale.

This paper evaluates the performance of the Rubin reduction methods, enhanced with static modal derivatives, for vibration analysis of geometrically nonlinear structures with friction contact. Static modal derivatives are computed numerically based on Rubin reduction, which includes free interface normal modes and residual flexibility attachment modes, by introducing a finite displacement around these modes. Then, the most relevant static modal derivatives are selected using an improved strategy that incorporates weighting factors derived from both a nonlinear static analysis and a geometrically linear transient run. This enhanced Rubin method is also compared with the previously used enhanced Craig–Bampton method, which is based on fixed normal modes, constraint modes, and their static derivatives. The effectiveness of these methods is demonstrated through vibration analysis of a geometrically nonlinear beam in different contact configurations. Both methods proved their robustness, achieving accurate results with a relatively small number of modes in the reduced space, thus ensuring low online computation times. Furthermore, the analyses show the significant impact of using a geometrically nonlinear model on the accurate prediction of a contact state.

This paper presents a novel test rig to study the effect of fretting wear and of the contact surface evolution on the forced response of systems with dry friction contact. This rig allows simulating contacts similar to the type of contacts present between the shrouds at the blade tip. Several research groups have been studying how fretting wear affects the dynamic response of mechanical systems, developing numerical prediction tools that consider dry friction contact and nonlinearity. The aim of this work is to experimentally study the evolution of contact interfaces and how this evolution affects the system dynamics. Experimental results will aid to validate the numerical predictions. The test rig developed for this activity is made of a cantilever beam fixed at one end and with a friction contact at the free end. The contact couple is made of two replaceable specimens. The contact is loaded via a lifting mechanism through a screw with fine thread. Fretting wear test was performed at a constant frequency and force amplitude, exciting the beam with an electromagnetic shaker. To emphasize the change of the dynamic response, frequency sweeps were performed at various intervals during the wear test. The full range test with ‘changing preload’ due to progressing wear was performed until a full loss of contact. This paper describes the test rig design, intent, set-up, instrumentation, test plan and results. Results include the frequency response curves for unworn contact, wear profiles at multiple intervals and the effect of wear on the frequency response. Though energy dissipation per cycle is quite small, wear leads to material loss at the contact with a sufficiently large number of cumulative cycles and substantially affects the dynamic response. Results collected in this research activity are of particular importance to validate numerical tool that aim to simulate the dynamic behaviour of systems with dry friction contacts that undergo material loss caused by wear.

Noise, vibration and harshness analyses are of great interest for the latest developments of the gearboxes of electric vehicles. Gearboxes are now the main source of vibrations, since electric powertrains are much quieter than internal combustion engines. Traditionally, the simulation of the non-linear gear dynamics is studied by first performing a series of preliminary static analyses to compute the static transmission error (STE). The STE (i.e., in the form of varying mesh stiffness) is then accepted as the system’s excitation source to compute the dynamic transmission error (DTE). This paper presents a novel approach to analyze the non-linear dynamics of gears which does not require any preliminary static analyses. The method consists of a frequency–domain approach based on the Harmonic Balance Method (HBM) and the Alternating Frequency–Time (AFT) scheme, allowing for much faster simulations when compared to the widely used direct–time integration (DTI). The contact between the teeth is modeled as intermittent and penalty based with a varying gap. The time–varying gap between the teeth is initially approximated to a step function that guarantees the design contact ratio. The methodology introduced is tested on a lumped parameter model of a spur–gear pair already proposed and simulated in the literature. The results obtained with the novel approach are compared with the DTI simulation of the model as a reference. The excellent match between the different approaches validates the reliability of developed methodology.

Genetically encoded calcium indicators and optogenetic actuators can report and manipulate the activity of specific neuronal populations. However, applying imaging and optogenetics simultaneously has been difficult to establish in the mammalian brain, even though combining the techniques would provide a powerful approach to reveal the functional organization of neural circuits. Here, we developed a technique based on patterned two-photon illumination to allow fast scanless imaging of GCaMP6 signals in the intact mouse brain at the same time as single-photon optogenetic inhibition with Archaerhodopsin. Using combined imaging and electrophysiological recording, we demonstrate that single and short bursts of action potentials in pyramidal neurons can be detected in the scanless modality at acquisition frequencies up to 1 kHz. Moreover, we demonstrate that our system strongly reduces the artifacts in the fluorescence detection that are induced by single-photon optogenetic illumination. Finally, we validated our technique investigating the role of parvalbumin-positive (PV) interneurons in the control of spontaneous cortical dynamics. Monitoring the activity of cellular populations on a precise spatiotemporal scale while manipulating neuronal activity with optogenetics provides a powerful tool to causally elucidate the cellular mechanisms underlying circuit function in the intact mammalian brain.

Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments, including real-time interaction with deep neural networks, and communication with behavioural and physiological measurement and manipulation devices.

The endogenous opioid system provides powerful control over emotions, nociception, and motivation among many other fundamental nervous system functions. Its major components include a panel of opioid peptides that activate four canonical inhibitory opioid receptors. However, its regulatory principles are not fully understood including the existence of additional receptors and other elements. In this study we report the identification of a receptor for the opioid peptide dynorphin. By conducting a screen of a custom library of neuropeptides, we found that orphan receptor GPR139 binds to and is activated by a series of dynorphin peptides. Unlike other opioid receptors, GPR139 couples to Gq/11 and avoids β-arrestin, providing excitatory signaling that homeostatically scales the inhibitory response of neurons to dynorphin. This introduces a non-canonical dynorphin receptor as an essential component of the opioid system. Li et al. identify dynorphin as an endogenous ligand for orphan receptor GPR139 introducing it as a non-canonical member of the opioid receptor family that triggers excitatory signaling to balance the inhibitory effects of opioids.

Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide–binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein–coupled receptor signaling principles.

Martinez-Rivera et al. investigated the role of cutaneous superficial neuromasts in controlling effective sperm transfer in Western mosquitofish (Gambusia affinis), showing impairment of gonopodial movements after neuromasts removal. [...]neural circuits for sexual cue processing have evolved together with those involved in the generation of courtship displays, with conserved and species-specific neural pathways across animals (Kelley et al.). [...]the type of established relationship can impact the processing of sensory information. Despite these advances in the field, the details of how the brain integrates these multimodal sexual cues in the context of mating are still unclear. [...]how these circuits adapt and change based on extrinsic and intrinsic factors, and the extent to which they are conserved in different animal species is largely unknown.