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The ability to target and manipulate specific neuronal populations is crucial for understanding brain function. In this report, the authors describe a novel virus that restricts gene expression to telencephalic GABAergic interneurons, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in mice and in non-genetically tractable species. A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.

Nat. Neurosci. 19, 1743–1749 (2016); published online 31 October 2016; corrected after print 29 November 2016 In the version of this article initially published, authors Joshua S. Grimley, Anne-Rachel Krostag and Ajamete Kaykas were missing. These authors have been inserted into the author list after Jianhua Chu; they are at the Allen Institute for Brain Science, Seattle, Washington, USA, and performed experiments related to hESCs.

High signal-to-noise ratio (SNR) electromyography (EMG) recordings are essential for identifying and analyzing single motor unit activity. While high-density electrodes allow for greater spatial resolution, the smaller electrode area translates to a higher impedance and lower SNR. In this study, we developed an implantable and flexible 3D microelectrode array (MEA) with low impedance that enables high-quality EMG recording. With polyimide micro-cones realized by standard photolithography process and PEDOT:PSS coating, this design can increase effective surface area by up to 250% and significantly improve electrical performance for electrode sites with various geometric surface areas, where the electrode impedance is at most improved by 99.3%. Acute EMG activity from mice was recorded by implanting the electrodes in vivo, and we were able to detect multiple individual motor units simultaneously and with high resolution (SNR >> 100). The charge storage capacity was measured to be 34.2 mC/cm^2, indicating suitability of the electrodes for stimulation applications as well. Competing Interest Statement The authors have declared no competing interest.

Recent developments in electrode technology have demonstrated the power of flexible microelectrode arrays (FMEAs) for measuring muscle activity at high resolution. We recently introduced the Myomatrix array, a FMEA optimized for measuring the activity of individual motor units (the collection of muscle fibers innervated by a single motor neuron) [1] in freely behaving animals. Although FMEAs are fundamentally changing the way EMG is acquired, the number of recording channels is limited by the size of the plug that interfaces with the digital amplifier hardware and the density of electrode connections on the array. Increasing EMG channel count and supporting electrophysiological studies in smaller animals depends on two seemingly incompatible goals: reducing device size while increasing the number of recording channels. The solution to this is to increase channel density, which is currently limited by requiring that separate headstage and FMEA components be used simultaneously. In our prior devices [1], each FMEA had a dedicated wire output for every electrode input, creating a channel density is 1 : 1. To improve this channel density, we have developed a novel device integrating a digital amplifier (bare-die RHD2216 chip, Intan, Inc. [6]) directly onto an FMEA. This new design reduces the device’s backend footprint by 74% and relocates the intan bare die from the headstage to the FMEA itself, creating a channel density of 1 : 3.2. Our methodology combines standard FMEA microfabrication with wire-bonding and surface-mounted components, enabling direct integration into a Serial Peripheral Interface (SPI) connection into the device itself, without any separate headstage. With this initial device we see a 1 : 3.2 channel density, but our method allows for using other bare die amplifiers (Intan, Inc., USA) for a channel density of 1 : 12.8. Our findings present a robust technique for chip embedding in custom FMEAs, applicable to in-vivo electrophysiology

ArfGAP, with dual PH domain-containing protein 1/Centaurin-α(ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. An increased level of CentA1 and its association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest a role for this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 KO mice with the J20 mouse model of AD. We evaluated the behavioral and neuropathological hallmarks of AD and the gene expression profiles in J20 and J20 crossed with CentA1 KO mice (J20 x CentA1 KO) to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris Water Maze test showed significant impairment in J20 mice, which was rescued in J20 x CentA1 KO. Moreover, neuropathological hallmarks of AD, such as deposits of amyloid plaques and neuroinflammation, were significantly reduced in J20 x CentA1 KO. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes (DEGs) between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20 x CentA1 KO vs J20) were anti-correlated with changes caused by APP overexpression (J20 vs WT), consistent with the rescues of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes and that targeting CentA1 signaling at mitochondria might have therapeutic potential for AD prevention or treatment.Competing Interest StatementThe authors have declared no competing interest.

Dopamine is hypothesized to convey important error information in reinforcement learning tasks with explicit appetitive or aversive cues. However, during motor skill learning the only available feedback signal is typically an animal's evaluation of the sensory feedback arising from its own behavior, rather than any external reward or punishment. It has previously been shown that intact dopaminergic signaling from the ventral tegmental area / substantia nigra compacta complex (VTA/SNc) is necessary for vocal learning in response to an external aversive auditory cue in songbirds. However, the role of dopamine in learning in the absence of explicit external cues is still unclear. Here we used male Bengalese finches (Lonchura striata var. domestica) to test the hypothesis that dopamine signaling is necessary for self-evaluation driven sensorimotor learning. We combined 6-hydroxydopamine (6-OHDA) lesions of dopaminergic terminals within Area X, a songbird basal ganglia nucleus critical for vocal learning, with a headphones learning paradigm that shifted the birds' auditory feedback and compared their learning to birds without lesions. We found that 6-OHDA lesions affected song behavior in two ways. First, over a period of days lesioned birds systemically lowered their pitch regardless of the presence or absence of auditory errors. Second, 6-OHDA lesioned birds also displayed severe deficits in sensorimotor learning as measured by their adaptive change in pitch in response to the pitch-shifted auditory error. Our results suggest roles for dopamine both in motor production and in auditory error processing during vocal learning.