Repetitive behavior is a widely observed neuropsychiatric symptom. Abnormal dopaminergic signaling in the striatum is one of the factors associated with behavioral repetition; however, the molecular mechanisms underlying the induction of repetitive behavior remain unclear. Here, we demonstrated that the NOX1 isoform of the superoxide-producing enzyme NADPH oxidase regulated repetitive behavior in mice by facilitating excitatory synaptic inputs in the central striatum (CS). In male C57Bl/6J mice, repeated stimulation of D2 receptors induced abnormal behavioral repetition and perseverative behavior. Nox1 deficiency or acute pharmacological inhibition of NOX1 significantly shortened repeated D2 receptor stimulation-induced repetitive behavior without affecting motor responses to a single D2 receptor stimulation. Among brain regions, Nox1 showed enriched expression in the striatum, and repeated dopamine D2 receptor stimulation further increased Nox1 expression levels in the CS, but not in the dorsal striatum. ...

P2X7 receptors (P2X7Rs) are associated with numerous pathophysiological mechanisms, and this promotes them as therapeutic targets for certain neurodegenerative conditions. However, the identity of P2X7R-expressing cells in the nervous system remains contentious. Here we examined P2X7R functionality in auditory nerve cells from rodents of either sex, and determined their functional and anatomical expression pattern. In whole-cell recordings from rat spiral ganglion cultures, the purinergic agonist 2’,3’-O-(4-benzoylbenzoyl)-ATP (BzATP) activated desensitizing currents in spiral ganglion neurons (SGNs), but non-desensitizing currents in glia that were blocked by P2X7R-specific antagonists. In imaging experiments, BzATP gated sustained Ca2+ entry into glial cells. BzATP-gated uptake of the fluorescent dye YO-PRO-1 was reduced and slowed by P2X7R-specific antagonists. In rats, P2X7Rs were immuno-localized predominantly within satellite glial cells (SGCs) and Schwann cells (SCs). P2X7R expression was not detect...

In this short review, I describe from personal experience how every step in the career of any scientist, no matter how disjointed and pragmatic each might seem at the time, will almost inevitably meld together, to help us all tackle novel projects. My postdoctoral research in Paul Greengard’s lab, where I investigated neurotransmitter-mediated phosphorylation of Synapsin I, was instrumental in my career progression, and Paul’s support was instrumental in my ability to make a leap into independent research.

Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG delta power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy ( Slp ) mutation in the salt-inducible kinase 3 ( Sik3 ) gene, which produces the mutant SIK3 (SLP) protein, leads to an increase in NREMS EEG delta power and sleep amount. Since Sik3Slp mice express SIK3 (SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3Slp mice remains to be elucidated. Here, we generated two mouse lines, synapsin1CreERT2 and Sik3ex13flox mice, which enable inducible Cre-mediated, conditional expression of...

The human motor system can rapidly adapt its motor output in response to errors. The prevailing theory of this process posits that the motor system adapts an internal forward model that predicts the consequences of outgoing motor commands and uses this forward model to plan future movements. However, despite clear evidence that adaptive forward models exist and are used to help track the state of the body, there is no definitive evidence that such models are used in movement planning. An alternative to the forward-model-based theory of adaptation is that movements are generated based on a learned policy that is adjusted over time by movement errors directly (“direct policy learning”). This learning mechanism could act in parallel with, but independent of, any updates to a predictive forward model. Forward-model-based learning and direct policy learning generate very similar predictions about behavior in conventional adaptation paradigms. However, across three experiments with human participants (N=47, 26 f...

Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R). Defective pruning of calyces of Held and significant reduction of the mature astrocyte marker glial fibrillary acidic protein (GFAP) were observed after hearing onset. Here, we investigated the time course required for microglia to populate the mouse MNTB after cessation of CSF1R inhibitor treatment. We then examined whether defects seen after microglial depletion were rectified by microglial repopulation. We found that microglia returned to control levels at 4 weeks (wk) of age (18 days post cessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at 4 wk, and GFAP expression recovered by 7 wk. We further investigated the effects of microglia elimination ...

The dorsal cochlear nucleus (DCN) is a region of particular interest for auditory and tinnitus research. Yet, lack of useful genetic markers for in vivo manipulations hinders elucidation of the DCN contribution to tinnitus pathophysiology. This work assesses whether adeno-associated viral vectors (AAV) containing the calcium/calmodulin-dependent protein kinase 2 alpha (CaMKII α ) promoter and a mouse line of nicotinic acetylcholine receptor alpha 2 subunit (Chrna2)-Cre can target specific DCN populations. We found that CaMKII α cannot be used to target excitatory fusiform DCN neurons as labelled cells showed diverse morphology indicating they belong to different classes of DCN neurons. Light stimulation after driving Channelrhodopsin2 by the CaMKII α promoter generated spikes in some units but firing rate decreased when light stimulation coincided with sound. Expression and activation of CaMKII α -eArchaerhodopsin3.0 in the DCN produced inhibition in some units but sound-driven spikes were delayed by conco...

Perception improves with repeated exposure. Evidence has shown object recognition can be improved by training for multiple days in adults. In particular, a study of Amar-Halpert et al. (2017) has compared the learning effect of repetitive and brief, at-threshold training on a discrimination task and reported similar improvement in both groups. The finding is interpreted as evidence that memory reactivation benefits discrimination learning. This raises the question how this process might influence different perceptual tasks, including tasks with more complex visual stimuli. Here, this preregistered study investigates whether reactivation induces improvements in a visual object learning task that includes more complex visual stimuli. Participants were trained to recognize a set of objects during five days of training. After the initial training, a group was trained with repeated practice, the other with brief, near-threshold reactivation trials. In both groups we found improved object recognition at brief ex...