The auditory midbrain mediates tactile vibration sensing.

Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissues and processed by the somatosensory system, while sound waves traveling through air are captured by the cochlea and encoded in the auditory system. Here, we report that mechanical vibrations detected by the body's Pacinian corpuscle neurons, which are unique in their ability to entrain to high frequency (40-1000 Hz) environmental vibrations, are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the midbrain. Remarkably, most LCIC neurons receive convergent Pacinian and auditory input and respond more strongly to coincident tactile-auditory stimulation than to either modality alone. Moreover, the LCIC is required for behavioral responses to high frequency mechanical vibrations. Thus, environmental vibrations captured by Pacinian corpuscles are encoded in the auditory midbrain to mediate behavior.

A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.

The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.

Central circuitry and function of the cochlear efferent systems.

The cochlear efferent system comprises multiple populations of brainstem neurons whose axons project to the cochlea, and whose responses to acoustic stimuli lead to regulation of auditory sensitivity. The major groups of efferent neurons are found in the superior olivary complex and are likely activated by neurons of the cochlear nucleus, thus forming a simple reflex pathway back to the cochlea. The peripheral actions of only one of these efferent cell types has been well described. Moreover, the efferent neurons are not well understood at the cellular- and circuit-levels. For example, ample demonstration of descending projections to efferent neurons raises the question of whether these additional inputs constitute a mechanism for modulation of relay function or instead play a more prominent role in driving the efferent response. Related to this is the question of synaptic plasticity at these synapses, which has the potential to differentially scale the degree of efferent activation across time, depending on the input pathway. This review will explore central nervous system aspects of the efferent system, the physiological properties of the neurons, their synaptic inputs, their modulation, and the effects of efferent axon collaterals within the brainstem.

Distinct forms of synaptic plasticity during ascending vs descending control of medial olivocochlear efferent neurons.

Activity in each brain region is shaped by the convergence of ascending and descending axonal pathways, and the balance and characteristics of these determine the neural output. The medial olivocochlear (MOC) efferent system is part of a reflex arc that critically controls auditory sensitivity. Multiple central pathways contact MOC neurons, raising the question of how a reflex arc could be engaged by diverse inputs. We examined functional properties of synapses onto brainstem MOC neurons from ascending (ventral cochlear nucleus, VCN) and descending (inferior colliculus, IC) sources in mice using an optogenetic approach. We found that these pathways exhibited opposing forms of short-term plasticity, with the VCN input showing depression and the IC input showing marked facilitation. By using a conductance-clamp approach, we found that combinations of facilitating and depressing inputs enabled firing of MOC neurons over a surprisingly wide dynamic range, suggesting an essential role for descending signaling to a brainstem nucleus.

Identification of an inhibitory neuron subtype, the L-stellate cell of the cochlear nucleus.

Auditory processing depends upon inhibitory signaling by interneurons, even at its earliest stages in the ventral cochlear nucleus (VCN). Remarkably, to date only a single subtype of inhibitory neuron has been documented in the VCN, a projection neuron termed the D-stellate cell. With the use of a transgenic mouse line, optical clearing, and imaging techniques, combined with electrophysiological tools, we revealed a population of glycinergic cells in the VCN distinct from the D-stellate cell. These multipolar glycinergic cells were smaller in soma size and dendritic area, but over ten-fold more numerous than D-stellate cells. They were activated by auditory nerve and T-stellate cells, and made local inhibitory synaptic contacts on principal cells of the VCN. Given their abundance, combined with their narrow dendritic fields and axonal projections, it is likely that these neurons, here termed L-stellate cells, play a significant role in frequency-specific processing of acoustic signals.

Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters.

AMPARs mediate the briefest synaptic currents in the brain by virtue of their rapid gating kinetics. However, at the mossy fiber-to-unipolar brush cell synapse in the cerebellum, AMPAR-mediated EPSCs last for hundreds of milliseconds, and it has been proposed that this time course reflects slow diffusion from a complex synaptic space. We show that upon release of glutamate, synaptic AMPARs were desensitized by transmitter by >90%. As glutamate levels subsequently fell, recovery of transmission occurred due to the presence of the AMPAR accessory protein stargazin that enhances the AMPAR response to low levels of transmitter. This gradual increase in receptor activity following desensitization accounted for the majority of synaptic transmission at this synapse. Moreover, the amplitude, duration, and shape of the synaptic response was tightly controlled by plasma membrane glutamate transporters, indicating that clearance of synaptic glutamate during the slow EPSC is dictated by an uptake process.

The postnatal development of D-serine in the retinas of two mouse strains, including a mutant mouse with a deficiency in D-amino acid oxidase and a serine racemase knockout mouse.

D-Serine, an N-methyl D-aspartate receptor coagonist, and its regulatory enzymes, D-amino acid oxidase (DAO; degradation) and serine racemase (SR; synthesis), have been implicated in crucial roles of the developing central nervous system, yet the functional position that they play in regulating the availability of d-serine throughout development of the mammalian retina is not well-known. Using capillary electrophoresis and a sensitive method of enantiomeric amino acid separation, we were able to determine total levels of d-serine at specific ages during postnatal development of the mouse retina in two different strains of mice, one of which contained a loss-of-function point mutation for DAO while the other was a SR knockout line. Each mouse line was tested against conspecific wild type (WT) mice for each genetic strain. The universal trend in all WT and transgenic mice was a large amount of total retinal d-serine at postnatal age 2 (P2), followed by a dramatic decrease as the mice matured into adulthood (P70-80). SR knockout mice retinas had 41% less D-serine than WT retinas at P2, and 10 times less as an adult. DAO mutant mice retinas had significantly elevated levels of d-serine when compared to WT retinas at P2 (217%), P4 (223%), P8 (194%), and adulthood (227%).

Head movement: a novel serotonin-sensitive behavioral endpoint for tail suspension test analysis.

The tail suspension test (TST) as an antidepressant and depression-related behavior screen, has many advantages over the forced swim test (FST) in terms of procedural simplicity and consistent SSRI response. However, the FST has traditionally offered more specific neuromodulatory information by differentiating between serotonin (5-HT) and norepinephrine sensitive behavior categories. Head movement is a newly characterized behavior endpoint in the FST and TST with a selective 5-HT sensitivity. In this investigation, we show that the baseline and drug response profile of head movement previously found in the 129S6 strain of mice (Lockridge et al., 2010) is reproducible in the C57 strain. Head movement is inversely correlated to FST swimming and elevated in the TST by SSRI administration. The use of a weighted bin sample analysis method differentiates TST behaviors into fluoxetine-responsive head movement and desipramine-responsive struggling. The use of 5-HT subtype receptor agonists, after depleting endogenous 5-HT with pCPA, shows the head movement suppressing effect of 5-HT2A and 5-HT2C postsynaptic receptor activation. 5-HT1A and 5-HT1B agonists were ineffective. We propose that a head movement focused analysis can add sensitive and reliable 5-HT detection capability to mouse TST testing with minimal effort but significant reward.

Serine racemase deletion abolishes light-evoked NMDA receptor currents in retinal ganglion cells.

Glycine and/or D-serine are obligatory coagonists of the N-methyl-D-aspartate receptor (NMDAR). Serine racemase, the D-serine-synthesizing enzyme, is expressed by astrocytes and Müller cells of the retina, but little is known about its role in retinal signalling. In this study, we utilize a serine racemase knockout (SRKO) mouse to explore the contribution of D-serine to inner-retinal function. Retinal tissue levels of D-serine in SRKO mice are reduced by 85%. Whole-cell recordings from SRKO retinal ganglion cells showed markedly reduced coagonist occupancy of NMDARs and consequently a dramatic reduction in the NMDAR component of light-evoked responses. NMDAR currents in SRKOs could be rescued by applying exogenous coagonist, but SRKO ganglion cells still displayed lower NMDA/AMPA receptor ratios than wild-type (WT) controls when the coagonist site was saturated. Despite having abnormalities in synaptic glutamatergic transmission, SRKO mice displayed no obvious signs of visual impairment in behavioural testing. These findings raise interesting questions about the role of D-serine in inner-retinal function and development.

High-resolution optical angle sensors: approaching the diffraction limit to the sensitivity.

We carry out a detailed analysis of angle-sensitive devices based on the critical-angle effect. We consider their use in measuring small angular deflections of a laser beam. We establish the diffraction limit to the sensitivity for optical-angle sensors based on reflection and transmission of a laser beam. We find that this limit is identical to that of the triangulation scheme when using a position-sensitive detector or the autocollimation scheme. We analyze the main proposals to date of optical-angle sensors based on the critical-angle effect, focusing on their maximum sensitivity and their polarization dependence in practical conditions. We propose and analyze theoretically a novel and simple angle-sensitive device for sensing optical-beam deflections with very low polarization dependence and a maximum sensitivity close to the diffraction limit when used with typical laser beams. We discuss the basic principles for designing this type of device, provide numerical results, and point out a convenient fabrication procedure.