The Mauthner cells are a pair of large reticulospinal neurons that organize sensory-evoked tail flip responses in fishes. An identifiable group of auditory “mixed” (electrical and chemical) synaptic contacts known as “Large Myelinated Club Endings” on these cells have provided a valuable model for the study of synaptic transmission in the vertebrate brain. While most of studies were performed in adult fish, we describe here methods that make possible recording synaptic transmission from these contacts in developing zebrafish, a genetically tractable vertebrate species which is uniquely amenable for combining synaptic physiology with live imaging and behavioral analysis. Significance statement An identifiable type of “mixed” synaptic contacts on the fish Mauthner cells provide a valuable model for the study of synaptic transmission in the vertebrate brain. We describe here methods to record synaptic potentials from these contacts in developing zebrafish. The approach makes possible to explore the molecul...

Intracranial neurophysiological recordings require chronic implants to provide transcranial access to the brain. Especially in larger animals, which participate in experiments over extended periods of time, implants should match the skull curvature to promote osseointegration and avoid tissue and bacterial ingress over time. Proposed CAD methods for designing implants to date have focused on naïve animals with continuous and even skull surfaces and calculate Boolean differences between implant and skull surface to fit the implant to the skull curvature. However, custom-fitting by calculating the difference fails, if a discontinuous skull surface needs to be matched. Also, the difference method does not allow designs with constant material thickness along the skull curvature, e.g. to allow fixed screw lengths. We present a universal step-by-step guide for custom-fitting implants which overcomes these limitations. It is suited for unusual skull conditions, like surface discontinuities or irregularities and i...

People with photosensitive epilepsy (PSE) are prone to seizures elicited by visual stimuli. The possibility of inducing epileptiform activity in a reliable way makes PSE a useful model to understand epilepsy, with potential applications for the development of new diagnostic methods and new treatments for epilepsy. A relationship has been demonstrated between PSE and both occipital and more widespread cortical hyperexcitability using various types of stimulation. Here we aimed to test whether hyperexcitability could be inferred from resting interictal electroencephalographic (EEG) data without stimulation. We considered a cohort of 46 individuals with idiopathic generalised epilepsy (IGE) that underwent EEG during intermittent photic stimulation (IPS): 26 had a photoparoxysmal response (PPR), the PPR group, and 20 did not, the non-PPR group. For each individual, we computed functional networks from the resting EEG data prior to stimulation. We then placed a computer model of ictogenicity into the networks a...

Postingestive signals are important for shaping appetitive and consummatory responses, but the brain mechanisms required to assimilate interoceptive events with those at the frontlines of ingestion (taste-guided) are poorly understood. Here, we investigated whether an insular cortex (IC) region, which receives viscerosensory input, including gustatory, is required to modify taste-elicited consummatory reactions in response to a real-time interoceptive change using a serial taste reactivity (TR) test where the rats’ oromotor and somatic reactions to intraoral infusions of sucrose were periodically assessed over 45 minutes following Lithium Chloride (LiCl) administration. Results showed that neurally-intact rats shifted from an ingestive repertoire to an aversive one as LiCl took effect. Overall, this hedonic shift was delayed in rats with bilateral neurotoxic IC lesions. Rats with greater neuronal loss in posterior gustatory IC displayed fewer aversive reactions to sucrose following this initial LiCl inject...

Transactivating response element DNA-binding protein of 43 kDa (TDP-43), which is encoded by the TARDBP gene, is an RNA-binding protein with fundamental RNA processing activities, and its loss-of-function (LOF) has a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TARDBP mutations are postulated to inactivate TDP-43 functions, leading to impaired RNA processing. However, it has not been fully examined how mutant TDP-43 affects global RNA regulation, especially in human cell models. Here, we examined global RNA processing in forebrain cortical neurons derived from human induced pluripotent stem cells (iPSCs) with a pathogenic TARDBP mutation encoding the TDP-43K263E protein. In neurons expressing mutant TDP-43, we detected disrupted RNA regulation, including global changes in gene expression, missplicing, and aberrant polyadenylation, all of which were highly similar to those induced by TDP-43 knockdown. This mutation-induced TDP-43 LOF w...

Human multisensory grasping movements (i.e., seeing and feeling a handheld object while grasping it with the contralateral hand) are superior to movements guided by each separate modality. This multisensory advantage might be driven by the integration of vision with either the haptic position only or with both position and size cues. To contrast these two hypotheses, we manipulated visual uncertainty (central vs. peripheral vision) and the availability of haptic cues during multisensory grasping. We showed a multisensory benefit irrespective of the degree of visual uncertainty suggesting that the integration process involved in multisensory grasping can be flexibly modulated by the contribution of each modality. Increasing visual uncertainty revealed the role of the distinct haptic cues. The haptic position cue was sufficient to promote multisensory benefits evidenced by faster actions with smaller grip apertures, whereas the haptic size was fundamental in fine-tuning the grip aperture scaling. These resul...

The posterior parietal cortex (PPC) plays a key role in integrating sensory inputs from different modalities to support adaptive behavior. Neuronal activity in PPC reflects perceptual decision making across behavioral tasks, but the mechanistic involvement of PPC is unclear. In an audiovisual change detection task, we tested the hypothesis that PPC is required to arbitrate between the noisy inputs from the two different modalities and help decide in which modality a sensory change occurred. In trained male mice, we found extensive single-neuron and population-level encoding of task-relevant visual and auditory stimuli, trial history, as well as upcoming behavioral responses. However, despite these rich neural correlates, which would theoretically be sufficient to solve the task, optogenetic inactivation of PPC did not affect visual or auditory performance. Thus, in spite of neural correlates faithfully tracking sensory variables and predicting behavioral responses, PPC was not relevant for audiovisual chan...

Reading words aloud is a fundamental aspect of literacy. The rapid rate at which multiple distributed neural substrates are engaged in this process can only be probed via techniques with high spatiotemporal resolution. We probed this with direct intracranial recordings covering most of the left hemisphere in 46 humans (26 male, 20 female) as they read aloud regular, exception and pseudo-words. We used this to create a spatiotemporal map of word processing and to derive how broadband γ activity varies with multiple word attributes critical to reading speed: lexicality, word frequency, and orthographic neighborhood. We found that lexicality is encoded earliest in mid-fusiform (mFus) cortex, and precentral sulcus, and is represented reliably enough to allow single-trial lexicality decoding. Word frequency is first represented in mFus and later in the inferior frontal gyrus (IFG) and inferior parietal sulcus (IPS), while orthographic neighborhood sensitivity resides solely in IPS. We thus isolate the neural co...

The subthalamic nucleus (STN) has been implicated in motor and non-motor tasks, and is an effective target of deep brain stimulation (DBS) for the treatment of Parkinson's disease, likely in part due to the STN’s projections outside of the basal ganglia to other brain regions. While there is some evidence of a disynaptic connection between the STN and the cerebellum via the pontine nuclei (PN), how the STN modulates the activity of the neurons in the PN remains unknown. Here we addressed this question using a combination of anatomical tracings, optogenetics, and in vivo electrophysiology in both wild-type and transgenic mice of both sexes. Approximately half of recorded neurons in the PN, which were located primarily in the medial area, responded with short latency to both single pulses and trains of optogenetic stimulation of channelrhodopsin (ChR2)-expressing STN axons in awake, head-restrained mice. Furthermore, the increase in the activity of PN neurons correlated with the strength of activation of STN...

Zn2+ is an important contributor to ischemic brain injury and recent studies support the hypothesis that mitochondria are key sites of its injurious effects. In murine hippocampal slices (both sexes) subjected to oxygen glucose deprivation (OGD), we found that Zn2+ accumulation and its entry into mitochondria precedes and contributes to the induction of acute neuronal death. In addition, if the ischemic episode is short (and sublethal), there is ongoing Zn2+ accumulation in CA1 mitochondria after OGD that may contribute to their delayed dysfunction. Using this slice model of sublethal OGD, we have now examined Zn2+ contributions to the progression of changes evoked by OGD and occurring over 4-5 hours. We detected progressive mitochondrial depolarization occurring from ∼ 2 hours after ischemia, a large increase in spontaneous synaptic activity between 2-3 hours, and mitochondrial swelling and fragmentation at 4 hours. Blockade of the primary route for Zn2+ entry, the mitochondrial Ca2+ uniporter (MCU; with ...