Multishank Thin-Film Neural Probes and Implantation System for High-Resolution Neural Recording Applications

Abstract Silicon probes have played a key role in studying the brain. However, the stark mechanical mismatch between these probes and the brain leads to chronic damage in the surrounding neural tissue, limiting their application in research and clinical translation. Mechanically flexible probes made of thin plastic shanks offer an attractive tissue‐compatible alternative but are difficult to implant into the brain. They also struggle to achieve the electrode density and layout necessary for the high‐resolution applications their silicon counterparts excel at. Here, a multishank high‐density flexible neural probe design is presented, which emulates the functionality of stiff silicon arrays for recording from neural population across multiple sites within a given region. The flexible probe is accompanied by a detachable 3D printed implanter, which delivers the probe by means of hydrophobic‐coated shuttles. The shuttles can then be retracted with minimal movement and the implanter houses the electronics necessary for in vivo recording applications. Validation of the probes through extracellular recordings from multiple brain regions and histological evidence of minimal foreign body response opens the path to long‐term chronic monitoring of neural ensembles

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.Fil: Dedic, Nina. Max Planck Institute Of Psychiatry; AlemaniaFil: Kühne, Claudia. Max Planck Institute Of Psychiatry; AlemaniaFil: Jakovcevski, Mira. Max Planck Institute Of Psychiatry; AlemaniaFil: Hartmann, Jakob. Max Planck Institute Of Psychiatry; AlemaniaFil: Genewsky, Andreas J.. Max Planck Institut Of Psychiatry; AlemaniaFil: Gomes, Karina S.. Max Planck Institute Of Psychiatry; AlemaniaFil: Anderzhanova, Elmira. Max Planck Institute Of Psychiatry; AlemaniaFil: Pöhlmann, Max L.. Max Planck Institute Of Psychiatry; AlemaniaFil: Chang, Simon. Max Planck Institute Of Psychiatry; AlemaniaFil: Kolarz, Adam. Max Planck Institute Of Psychiatry; AlemaniaFil: Vogl, Annette M.. Max Planck Institute Of Psychiatry; AlemaniaFil: Dine, Julien. Max Planck Institute Of Psychiatry; AlemaniaFil: Metzger, Michael W.. Max Planck Institute of Psychiatry; ArmeniaFil: Schmid, Bianca. Max Planck Institute Of Psychiatry; AlemaniaFil: Almada, Rafael C.. Max Planck Institute Of Psychiatry; AlemaniaFil: Ressler, Kerry J.. Harvard Medical School; Estados UnidosFil: Wotjak, Carsten T.. Max Planck Institute Of Psychiatry; AlemaniaFil: Grinevich, Valery. University of Heidelberg; AlemaniaFil: Chen, Alon. Max Planck Institute Of Psychiatry; AlemaniaFil: Schmidt, Mathias V.. Institute Of Developmental Genetics, Helmholtz Zentrum; AlemaniaFil: Wurst, Wolfgang. German Center for Neurodegenerative Diseases; AlemaniaFil: Refojo, Damian. Max Planck Institute Of Psychiatry; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Deussing, Jan M.. Max Planck Institute Of Psychiatry; Alemani

A simplified microwave-based motion detector for home cage activity monitoring in mice

Background: Locomotor activity of rodents is an important readout to assess well-being and physical health, and is pivotal for behavioral phenotyping. Measuring homecage-activity with standard and cost-effective optical methods in mice has become difficult, as modern housing conditions (e.g. individually ventilated cages, cage enrichment) do not allow constant, unobstructed, visual access. Resolving this issue either makes greater investments necessary, especially if several experiments will be run in parallel, or is at the animals' expense. The purpose of this study is to provide an easy, yet satisfying solution for the behavioral biologist at novice makers level. Results: We show the design, construction and validation of a simplified, low-cost, radar-based motion detector for home cage activity monitoring in mice. In addition we demonstrate that mice which have been selectively bred for low levels of anxiety-related behavior (LAB) have deficits in circadian photoentrainment compared to CD1 control animals. Conclusion: In this study we have demonstrated that our proposed low-cost microwave-based motion detector is well-suited for the study of circadian rhythms in mice

The Endocannabinoid System Differentially Regulates Escape Behavior in Mice

Among the hardwired behaviors, fear or survival responses certainly belong to the most evolutionary conserved ones. However, higher animals possess the ability to adapt to certain environments (e.g., novel foraging grounds), and, therefore, those responses need to be plastic. Previous studies revealed a cell-type specific role of the endocannabinoid system in novelty fear, conditioned fear and active vs. passive avoidance in a shuttle box paradigm. In this study we aim to investigate, whether knocking-out the cannabinoid receptor type-1 (CB1) on cortical glutamatergic (Glu-CB1−/−) or GABAergic (GABA-CB1−/−) neurons differentially affects the level of behavioral inhibition, which could ultimately lead to differences in escape behavior. In this context, we developed a novel behavioral paradigm, the Moving Wall Box (MWB). Using the MWB task we could show that Glu-CB1−/− mice have higher levels of behavioral inhibition over the course of repeated testing. GABA-CB1−/− mice, in contrast, showed significantly lower levels of behavioral inhibition compared to wild-type controls and more escape behavior. These changes in behavioral inhibition and escape behavior cannot be explained by altered levels of arousal, as repeated startle measurements revealed general habituation irrespective of the line and genotype of the animals. Taken together, we could show that CB1 on cortical glutamatergic terminals is important for the acquisition of active avoidance, as the absence of CB1 on these neurons creates a bias toward inhibitory avoidance. This is the case in situations without punishment such as electric footshocks. On the contrary CB1 receptors on GABAergic neurons mediate the acquisition of passive avoidance, as the absence of CB1 on those neurons establishes a strong bias toward escape behavior

Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line

We characterized phenotype and function of a fetal human mesencephalic cell line (LUHMES, Lund human mesencephalic) as neuronal model system. Neurodevelopmental profiling of the proliferation stage (d0, day 0) of these conditionally-immortalized cells revealed neuronal features, expressed simultaneously with some early neuroblast and stem cell markers. An optimized 2-step differentiation procedure, triggered by shut-down of the myc transgene, resulted in uniformly post-mitotic neurons within 5 days (d5). This was associated with down-regulation of some precursor markers and further up-regulation of neuronal genes. Neurite network formation involved the outgrowth of 1–2, often > 500 μm long projections. They showed dynamic growth cone behavior, as evidenced by time-lapse imaging of stably GFP-over-expressing cells. Voltage-dependent sodium channels and spontaneous electrical activity of LUHMES continuously increased from d0 to d11, while levels of synaptic markers reached their maximum on d5. The developmental expression patterns of most genes and of the dopamine uptake- and release-machinery appeared to be intrinsically predetermined, as the differentiation proceeded similarly when external factors such as dibutyryl-cAMP and glial cell derived neurotrophic factor were omitted. Only tyrosine hydroxylase required the continuous presence of cAMP. In conclusion, LUHMES are a robust neuronal model with adaptable phenotype and high value for neurodevelopmental studies, disease modeling and neuropharmacology

Stimulation of the Nigrotectal Pathway at the Level of the Superior Colliculus Reduces Threat Recognition and Causes a Shift From Avoidance to Approach Behavior

Defensive behavioral responses are essential for survival in threating situations. The superior colliculus (SC) has been implicated in the generation of defensive behaviors elicited by visual, tactile and auditory stimuli. Furthermore, substantia nigra pars reticulata (SNr) neurons are known to exert a modulatory effect on midbrain tectum neural substrates. However, the functional role of this nigrotectal pathway in threating situations is still poorly understood. Using optogenetics in freely behaving mice, we activated SNr projections at the level of the SC, and assessed consequences on behavioral performance in an open field test (OFT) and the beetle mania task (BMT). The latter confronts a mouse with an erratic moving robo-beetle and allows to measure active and passive defensive responses upon frequent encounter of the threatening object. Channelrhodopsin-2 (ChR2)-mediated activation of the inhibitory nigrotectal pathway did not affect anxiety-like and exploratory behavior in the OFT, but increased the number of contacts between robo-beetle and test mouse in the BMT. Depending on the size of the arena, active avoidance responses were reduced, whereas tolerance and close following of the robo-beetle were significantly increased. We conclude from the data that the nigrotectal pathway plays holds the potential to modulate innate fear by attenuating threat recognition and causing a shift from defensive to approach behavior