15Most existing multi-compartment, mammalian neuron models are built from rodent data. However, 16 our increasing knowledge of differences between human and rodent neurons suggests that, to 17 understand the cellular basis of human brain function, we should build models from human data. 18 Here, we present the first full spiking, multi-compartment model of a human layer 5 cortical 19 pyramidal neuron. Model development balanced prioritizing current clamp data from the neuron 20 providing the model's morphology, while also ensuring the model's generalizability via preservation 21 of spiking properties observed in a secondary population of neurons, by "cycling" between these 22 data sets. The model was successfully validated against electrophysiological data not used in 23 model development, including experimentally observed subthreshold resonance characteristics. 24 Our model highlights kinetic differences in the h-current across species, with the unique 25 relationship between the model and experimental data allowing for a detailed investigation of the 26 relationship between the h-current and subthreshold resonance. 27 28 30 (Womelsdorf et al., 2014) within the six-layered neocortex stems from invasive and in vitro studies 31 in rodents and non-human primates. Whether or not such principles can be extended to human 32 neocortex remains speculative at best. Despite the significant transcriptomic convergence of 33 human and mouse neurons (Hodge et al., 2019), significant differences between human and rodent 34 cell-type properties exist. In vitro studies have identified differences between mouse and human 35 neurons in morphology (Mohan et al., 2015), dendritic integration (Beaulieu-Laroche et al., 2018; 36 Eyal et al., 2016), synaptic properties (Verhoog et al., 2013), and collective dynamics (McGinn and 37 Valiante, 2014; Molnár et al., 2008; Florez et al., 2013). However, less explored are the active 38 1 of 36 Manuscript submitted to eLife membrane properties of human cortical neurons, which together with their passive and synaptic 39 properties underlie oscillations which are of likely physiological relevance (Akam and Kullmann, 40 2014; Womelsdorf et al., 2014; Fries, 2005; Anastassiou et al., 2011; Hanslmayr et al., 2019; Vaz 41 et al., 2019). 42 Recently it has been shown that increased expression of hyperpolarization activated cation chan-43 nels (h-channels) contribute to the observed subthreshold resonance in supragranular layer human 44 pyramidal cells not seen in their rodent counterparts (Kalmbach et al., 2018). Such differential 45 expression of h-channels also appears to be present between superficial and deep layer neurons 46 of human cortex, with layer 5 (L5) pyramidal cells demonstrating a larger sag voltage mediated 47 65 et al., 2013; Beaulieu-Laroche et al., 2018) leads to two important questions for computational 66neuroscientists: in what settings is it appropriate to utilize rodent neuron models to glean insights 67 into the human brain, and when such approximations are u...

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Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein‐coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure‐related hyperexcitability.

. Significance: Light-sheet fluorescence microscopy (LSFM) is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. We demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Aim: Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. Approach: We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200-mm-diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed, in vitro , and in vivo mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. Results: The probes had 5 to 10 addressable sheets and average sheet thicknesses for propagation distances up to in free space. Imaging areas were as large as in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. Conclusions: The neural probes can lead to new variants of LSFM for deep brain imaging and experiments in freely moving animals.

2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways. Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism. Tonic-clonic seizures were induced by an injection of Pentylenetetrazol (80 mg/kg, i.p.) in adult male Wistar rats. Delay and duration for the seizure stages were considered for analysis. Monoacylglycerol lipase blocker (JJKK048; 1 mg/kg) or alpha/beta hydroxylase domain 6 blocker (WWL70; 5 mg/kg) were administrated alone or with 2-AG to evaluate the anticonvulsive potential of these enzymes. To determine the CB1 receptor involvement, its blocker (MJ15; 3 mg/kg) was administrated associated with JJKK048 or WWL70. To assess anandamide anticonvulsive effect, anandamide membrane transporter blocker (LY21813240; 2.5 mg/kg) was used alone or associated with MJ15. Also, fatty acid amide hydrolase blocker (URB597; 1 mg/kg; to prevent intracellular anandamide hydrolysis) were used alone or with AMG21629 (transient receptor potential vanilloid; TRPV1 antagonist; 3 mg/kg). All compounds were dissolved in DMSO and injected i.p., before the Pentylenetetrazol. Both JJKK048 and WWL70 revealed anticonvulsive effect. Anticonvulsive effect of JJKK048 but not WWL70 was CB1 receptor dependent. LY2183240 showed CB1 receptor dependent anticonvulsive effect. However, URB597 revealed a TRPV1 dependent proconvulsive effect. It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.

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We demonstrate the first implantable nanophotonic neural probes with integrated silicon nitride phased arrays. Coherent beam-steering is achieved in brain tissue by wavelength tuning. Beam profiles, optogenetic stimulation, and functional imaging are validated in vitro.

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