Neural oscillations play critical roles in information processing, communication between brain areas, learning, and memory. We have recently discovered that familiar visual stimuli can robustly induce 5 Hz oscillations in the primary visual cortex (V1) of awake mice after the visual experience. To gain more mechanistic insight into this phenomenon, we utilized in vivo patch-clamp recordings to monitor the subthreshold activity of individual neurons during these oscillations. We analyzed the visual tuning properties of V1 neurons in naive and experienced mice to assess the effect of visual experience on the orientation and direction selectivity. Using optogenetic stimulation through the patch pipette in vivo, we measured the synaptic strength of specific intracortical and thalamocortical projections in vivo in the visual cortex before and after the visual experience. We found 5 Hz oscillations in membrane potential (Vm) and firing rates evoked in single neurons in response to the familiar stimulus, consiste...

Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson’s patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared to neighbouring protected SN GABAergic neurons, which correlated with the accumulation of α-synuclein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient iPSC-derived dopaminergic neurons carrying the SNCA-Triplication mutation, which accumulated α-synuclein oligomers and mitochondrial damage, and displayed REST target gene dysregulation. ...

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...

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...

Brainstem median raphe (MR) neurons expressing the serotonergic regulator gene Pet1 send collateralized projections to forebrain regions to modulate affective, memory-related, and circadian behaviors. Some Pet1 neurons express a surprisingly incomplete battery of serotonin pathway genes, with somata lacking transcripts for tryptophan hydroxylase 2 (Tph2 ) encoding the rate-limiting enzyme for serotonin (5-hydroxytryptamine, 5-HT) synthesis, but abundant for vesicular glutamate transporter 3 ( Vglut3 ) encoding a synaptic-vesicle associated glutamate transporter. Genetic fate maps show these non-classical, putatively glutamatergic Pet1 neurons in the MR arise embryonically from the same progenitor cell compartment – hindbrain rhombomere 2 (r2) – as serotonergic TPH2+ MR Pet1 neurons. Well established is the distribution of efferents en masse from r2- derived, Pet1 -neurons; unknown is the relationship between these efferent targets and the specific constituent source-neuron subgroups identified as r2- Pet1T...