Multifocal fluorescence microscope for fast optical recordings of neuronal action potentials.

In recent years, optical sensors for tracking neural activity have been developed and offer great utility. However, developing microscopy techniques that have several kHz bandwidth necessary to reliably capture optically reported action potentials (APs) at multiple locations in parallel remains a significant challenge. To our knowledge, we describe a novel microscope optimized to measure spatially distributed optical signals with submillisecond and near diffraction-limit resolution. Our design uses a spatial light modulator to generate patterned illumination to simultaneously excite multiple user-defined targets. A galvanometer driven mirror in the emission path streaks the fluorescence emanating from each excitation point during the camera exposure, using unused camera pixels to capture time varying fluorescence at rates that are ∼1000 times faster than the camera's native frame rate. We demonstrate that this approach is capable of recording Ca(2+) transients resulting from APs in neurons labeled with the Ca(2+) sensor Oregon Green Bapta-1 (OGB-1), and can localize the timing of these events with millisecond resolution. Furthermore, optically reported APs can be detected with the voltage sensitive dye DiO-DPA in multiple locations within a neuron with a signal/noise ratio up to ∼40, resolving delays in arrival time along dendrites. Thus, the microscope provides a powerful tool for photometric measurements of dynamics requiring submillisecond sampling at multiple locations.

Plug-and-play control of a brain-computer interface through neural map stabilization.

Brain-computer interfaces (BCIs) enable control of assistive devices in individuals with severe motor impairments. A limitation of BCIs that has hindered real-world adoption is poor long-term reliability and lengthy daily recalibration times. To develop methods that allow stable performance without recalibration, we used a 128-channel chronic electrocorticography (ECoG) implant in a paralyzed individual, which allowed stable monitoring of signals. We show that long-term closed-loop decoder adaptation, in which decoder weights are carried across sessions over multiple days, results in consolidation of a neural map and 'plug-and-play' control. In contrast, daily reinitialization led to degradation of performance with variable relearning. Consolidation also allowed the addition of control features over days, that is, long-term stacking of dimensions. Our results offer an approach for reliable, stable BCI control by leveraging the stability of ECoG interfaces and neural plasticity.

Cortistatin-expressing interneurons require TrkB signaling to suppress neural hyper-excitability.

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis.

A model of temporal scaling correctly predicts that motor timing improves with speed.

Timing is fundamental to complex motor behaviors: from tying a knot to playing the piano. A general feature of motor timing is temporal scaling: the ability to produce motor patterns at different speeds. One theory of temporal processing proposes that the brain encodes time in dynamic patterns of neural activity (population clocks), here we first examine whether recurrent neural network (RNN) models can account for temporal scaling. Appropriately trained RNNs exhibit temporal scaling over a range similar to that of humans and capture a signature of motor timing, Weber's law, but predict that temporal precision improves at faster speeds. Human psychophysics experiments confirm this prediction: the variability of responses in absolute time are lower at faster speeds. These results establish that RNNs can account for temporal scaling and suggest a novel psychophysical principle: the Weber-Speed effect.

Neurocomputational Models of Interval and Pattern Timing.

Most of the computations and tasks performed by the brain require the ability to tell time, and process and generate temporal patterns. Thus, there is a diverse set of neural mechanisms in place to allow the brain to tell time across a wide range of scales: from interaural delays on the order of microseconds to circadian rhythms and beyond. Temporal processing is most sophisticated on the scale of tens of milliseconds to a few seconds, because it is within this range that the brain must recognize and produce complex temporal patterns-such as those that characterize speech and music. Most models of timing, however, have focused primarily on simple intervals and durations, thus it is not clear whether they will generalize to complex pattern-based temporal tasks. Here, we review neurobiologically based models of timing in the subsecond range, focusing on whether they generalize to tasks that require placing consecutive intervals in the context of an overall pattern, that is, pattern timing.

Antidepressant-like Effects of Electroconvulsive Seizures Require Adult Neurogenesis in a Neuroendocrine Model of Depression.

BACKGROUND: Neurogenesis continues throughout life in the hippocampal dentate gyrus. Chronic treatment with monoaminergic antidepressant drugs stimulates hippocampal neurogenesis, and new neurons are required for some antidepressant-like behaviors. Electroconvulsive seizures (ECS), a laboratory model of electroconvulsive therapy (ECT), robustly stimulate hippocampal neurogenesis. HYPOTHESIS: ECS requires newborn neurons to improve behavioral deficits in a mouse neuroendocrine model of depression. METHODS: We utilized immunohistochemistry for doublecortin (DCX), a marker of migrating neuroblasts, to assess the impact of Sham or ECS treatments (1 treatment per day, 7 treatments over 15 days) on hippocampal neurogenesis in animals receiving 6 weeks of either vehicle or chronic corticosterone (CORT) treatment in the drinking water. We conducted tests of anxiety- and depressive-like behavior to investigate the ability of ECS to reverse CORT-induced behavioral deficits. We also determined whether adult neurons are required for the effects of ECS. For these studies we utilized a pharmacogenetic model (hGFAPtk) to conditionally ablate adult born neurons. We then evaluated behavioral indices of depression after Sham or ECS treatments in CORT-treated wild-type animals and CORT-treated animals lacking neurogenesis. RESULTS: ECS is able to rescue CORT-induced behavioral deficits in indices of anxiety- and depressive-like behavior. ECS increases both the number and dendritic complexity of adult-born migrating neuroblasts. The ability of ECS to promote antidepressant-like behavior is blocked in mice lacking adult neurogenesis. CONCLUSION: ECS ameliorates a number of anxiety- and depressive-like behaviors caused by chronic exposure to CORT. ECS requires intact hippocampal neurogenesis for its efficacy in these behavioral indices.

Atrophy of pyramidal neurons and increased stress-induced glutamate levels in CA3 following chronic suppression of adult neurogenesis.

Following their birth in the adult hippocampal dentate gyrus, newborn progenitor cells migrate into the granule cell layer where they differentiate, mature, and functionally integrate into existing circuitry. The hypothesis that adult hippocampal neurogenesis is physiologically important has gained traction, but the precise role of newborn neurons in hippocampal function remains unclear. We investigated whether loss of new neurons impacts dendrite morphology and glutamate levels in area CA3 of the hippocampus by utilizing a human GFAP promoter-driven thymidine kinase genetic mouse model to conditionally suppress adult neurogenesis. We found that chronic ablation of new neurons induces remodeling in CA3 pyramidal cells and increases stress-induced release of the neurotransmitter glutamate. The ability of persistent impairment of adult neurogenesis to influence hippocampal dendrite morphology and excitatory amino acid neurotransmission has important implications for elucidating newborn neuron function, and in particular, understanding the role of these cells in stress-related excitoxicity.