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Neurotrophic factors (NTFs) hold potential as disease-modifying therapies for neurodegenerative disorders like Parkinson’s disease. Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown neuroprotective and restorative effects on nigral dopaminergic neurons in various animal models of Parkinson’s disease. To date, however, their effects on brain neurochemistry have not been compared using in vivo microdialysis. We measured extracellular concentration of dopamine and activity of dopamine neurochemistry-regulating enzymes in the nigrostriatal system of rat brain. NTFs were unilaterally injected into the striatum of intact Wistar rats. Brain microdialysis experiments were performed 1 and 3 weeks later in freely-moving animals. One week after the treatment, we observed enhanced stimulus-evoked release of dopamine in the striatum of MANF-treated rats, but not in rats treated with GDNF or CDNF. MANF also increased dopamine turnover. Although GDNF did not affect the extracellular level of dopamine, we found significantly elevated tyrosine hydroxylase (TH) and catechol-O-methyltransferase (COMT) activity and decreased monoamine oxidase A (MAO-A) activity in striatal tissue samples 1 week after GDNF injection. The results show that GDNF, CDNF, and MANF have divergent effects on dopaminergic neurotransmission, as well as on dopamine synthetizing and metabolizing enzymes. Although the cellular mechanisms remain to be clarified, knowing the biological effects of exogenously administrated NTFs in intact brain is an important step towards developing novel neurotrophic treatments for degenerative brain diseases. Electronic supplementary material The online version of this article (10.1007/s12035-018-0872-8) contains supplementary material, which is available to authorized users.

Neuromodulation technologies are progressing from pacemaking and sensory operations to full closed-loop control. In particular, optogenetics—the genetic modification of light sensitivity into neural tissue allows for simultaneous optical stimulation and electronic recording. This paper presents a neural interface application-specified integrated circuit (ASIC) for intelligent optoelectronic probes. The architecture is designed to enable simultaneous optical neural stimulation and electronic recording. It provides four low noise (2.08 μ V $_{\text{rms}}$ ) recording channels optimized for recording local field potentials (LFPs) (0.1–300 Hz bandwidth, $\pm$ 5 mV range, sampled 10-bit@4 kHz), which are more stable for chronic applications. For stimulation, it provides six independently addressable optical driver circuits, which can provide both intensity (8-bit resolution across a 1.1 mA range) and pulse-width modulation for high-radiance light emitting diodes (LEDs). The system includes a fully digital interface using a serial peripheral interface (SPI) protocol to allow for use with embedded controllers. The SPI interface is embedded within a finite state machine (FSM), which implements a command interpreter that can send out LFP data whilst receiving instructions to control LED emission. The circuit has been implemented in a commercially available 0.35 μ m CMOS technology occupying a 1.95 mm $\times$ 1.10 mm footprint for mounting onto the head of a silicon probe. Measured results are given for a variety of bench-top, in vitro and in vivo experiments, quantifying system performance and also demonstrating concurrent recording and stimulation within relevant experimental models.

Optogenetic manipulations are widely used for investigating the contribution of genetically identified cell types to behavior. Simultaneous electrophysiological recordings are less common, although they are critical for characterizing the specific impact of optogenetic manipulations on neural circuits in vivo. This is at least in part because combining photostimulation with large-scale electrophysiological recordings remains technically challenging, which also poses a limitation for performing extracellular identification experiments. Currently available interfaces that guide light of the appropriate wavelength into the brain combined with an electrophysiological modality suffer from various drawbacks such as a bulky size, low spatial resolution, heat dissipation, or photovoltaic artifacts. To address these challenges, we have designed and fabricated an integrated ultrathin neural interface with 12 optical outputs and 24 electrodes. We used the device to measure the effect of localized stimulation in the anterior olfactory cortex, a paleocortical structure involved in olfactory processing. Our experiments in adult mice demonstrate that because of its small dimensions, our novel tool causes far less tissue damage than commercially available devices. Moreover, optical stimulation and recording can be performed simultaneously, with no measurable electrical artifact during optical stimulation. Importantly, optical stimulation can be confined to small volumes with approximately single-cortical layer thickness. Finally, we find that even highly localized optical stimulation causes inhibition at more distant sites. NEW & NOTEWORTHY In this study, we establish a novel tool for simultaneous extracellular recording and optogenetic photostimulation. Because the device is built using established microchip technology, it can be fabricated with high reproducibility and reliability. We further show that even very localized stimulation affects neural firing far beyond the stimulation site. This demonstrates the difficulty in predicting circuit-level effects of optogenetic manipulations and highlights the importance of closely monitoring neural activity in optogenetic experiments.

Neurons sensitive to visual motion change their response properties during prolonged motion stimulation. These changes have been interpreted as adaptive and were concluded, for instance, to adjust the sensitivity of the visual motion pathway to velocity changes or to increase the reliability of encoding of motion information. These conclusions are based on experiments with experimenter-designed motion stimuli that differ substantially with respect to their dynamical properties from the optic flow an animal experiences during normal behavior. We analyze for the first time motion adaptation under natural stimulus conditions. The experiments are done on the H1-cell, an identified neuron in the blowfly visual motion pathway that has served in many previous studies as a model system for visual motion computation. We reconstructed optic flow perceived by a blowfly in free flight and used this behaviorally generated optic flow to study motion adaptation. A variety of measures (variability in spike count, response latency, jitter of spike timing) suggests that the coding quality does not improve with prolonged stimulation. However, although the number of spikes decreases considerably during stimulation with natural optic flow, the amount of information that is conveyed stays nearly constant. Thus the information per spike increases, and motion adaptation leads to parsimonious coding without sacrificing the reliability with which behaviorally relevant information is encoded.

SUMMARY In the mammalian brain, calcium signals in dendritic spines are involved in many neuronal functions, particularly in the induction of synaptic plasticity. Recent studies have identified sensory stimulationevoked spine calcium signals in cortical neurons in vivo. However, spine signaling during ongoing cortical activity in the absence of sensory input, which is essential for important functions like memory consolidation, is not well understood. Here, by using in vivo two-photon imaging of auditory cortical neurons, we demonstrate that subthreshold, NMDAreceptor-dependent spine calcium signals are abundant during up states, but almost absent during down states. In each neuron, about 500 nonclustered spines, which are widely dispersed throughout the dendritic field, are on average active during an up state. The same subset of spines is reliably active during both sensory stimulation and up states. Thus, spontaneously recurring up states evoke in these spines ‘‘patterned’’ calcium activity that may control consolidation of synaptic strength following epochs of sensory stimulation.