Extracellular Recordings Research Articles

Lights at night mediate depression-like behavioral and molecular phenotypes in a glucocorticoid-dependent manner in male rats

Nocturnal light pollution, an underappreciated mood manipulator, disturbs the circadian rhythms of individuals in modern society. Preclinical and clinical studies have suggested that exposure to lights at night (LANs) results in depression-like phenotypes. However, the mechanism underlying the action of LANs remains unclear. Therefore, this study explored the potential influence of LANs on depression-related brain regions by testing brain-derived neurotrophic factor (BDNF), synaptic transmission, and plasticity in male Sprague-Dawley rats. Depression-related behavioral tests, enzyme-linked immunosorbent assays, and intracellular and extracellular electrophysiological recordings were performed. Resultantly, rats exposed to either white or blue LAN for 5 or 21 days exhibited depression-like behaviors. Both white and blue LANs reduced BDNF expression in the medial prefrontal cortex (mPFC) and ventrolateral periaqueductal gray (vlPAG). Moreover, both lights at night (LANs) elevated the plasma corticosterone levels. Pharmacologically, the activation of glucocorticoid receptors mimics the LAN-mediated effects on depression-like behaviors and reduces BDNF levels, whereas the inhibition of glucocorticoid receptors blocks LAN-mediated behavioral and molecular actions. Electrophysiologically, both LANs attenuated the stimulation-response curve, increased the paired-pulse ratio, and decreased the frequency and amplitude of miniature excitatory postsynaptic currents in the vlPAG. In the mPFC, LANs attenuate long-term potentiation and long-term depression. Collectively, these results suggested that white and blue LANs disturbed BDNF expression, synaptic transmission, and plasticity in the vlPAG and mPFC in a glucocorticoid-dependent manner. The results of the present study provide a theoretical basis for understanding the effects of nocturnal light exposure on depression-like phenotypes.

Dual Extracellular Recordings in the Mouse Hippocampus and Prefrontal Cortex.

The technique of recording local field potentials (LFPs) is an electrophysiological method used to measure the electrical activity of localized neuronal populations. It serves as a crucial tool in cognitive research, particularly in brain regions like the hippocampus and prefrontal cortex. Dual LFP recordings between these areas are of particular interest as they allow the exploration of interregional signal communication. However, methods for performing these recordings are rarely described, and most commercial recording devices are either expensive or lack adaptability to accommodate specific experimental designs. This study presents a comprehensive protocol for performing dual-electrode LFP recordings in the mouse hippocampus and the prefrontal cortex to investigate the effects of antipsychotic drugs and potassium channel modulators on LFP properties in these areas. The technique enables the measurement of LFP properties, including power spectra within each brain region and coherence between the two. Additionally, a low-cost, custom-designed recording device has been developed for these experiments. In summary, this protocol provides a means to record signals with high signal-to-noise ratios in different brain regions, facilitating the investigation of interregional information communication within the brain.

A7 CANNABINOID 1 AND 2 RECEPTOR AGONISTS AND MU-OPIOID RECEPTOR AGONISTS SYNERGISTICALLY INHIBIT COLONIC NOCICEPTION DURING ACUTE COLITIS

Abstract Background Abdominal pain is a debilitating symptom in patients with inflammatory bowel disease. Previously we have shown that combining sub-analgesic doses of cannabinoid 1 receptor (CB1R), but not cannabinoid 2 receptor (CB2R), and mu-opioid receptor (MOR) agonists synergistically inhibits colonic nociception in healthy mice. However, it is unknown whether this combination has analgesic efficacy in a pre-clinical model of colitis. Aims To determine the effects of combining sub-analgesic doses of CBR and MOR agonists on colonic nociception during acute colitis. Methods Colitis was induced in male and female C57BL/6 mice with 2.5% dextran sulfate sodium in drinking water. Extracellular afferent nerve recordings were obtained from ex vivo flat sheet preparations of mouse distal colon. Mechanosensitivity of single afferent axons was assessed via probing of the colon with a 1g von Frey hair before and after superfusion of agonists of CB1R or CB2R plus MOR. To examine effects in vivo, visceromotor response (VMR) to colorectal distention (volume range 20-80 µL) was measured via electromyography. Mice were injected intraperitoneally with vehicle, or a combination of CB1R or CB2R agonist plus morphine 30-minutes prior to VMR experiment. Data were analyzed using a one or two-way ANOVA with Bonferroni test. N denotes number of mice; n denotes number of single afferent axons. Results In afferent nerve recordings, in contrast to healthy mice, the CB2R agonist HU-308 (1 µM and 3 µM) inhibited colonic mechanosensitivity in mice with colitis (1 µM: p<0.01, N=5, n=12; 3 µM: p<0.01, N=7, n=10); a lower concentration (300 nM) had no effect (p=0.52, N=6, n=10). The CB1R agonist ACEA (10 µM) reduced mechanosensitivity during acute colitis (p<0.05, n=11, N=6), whereas 100 nM (p>0.99, n=7, N=5) and 1 µM (p=0.25, n=10, N=6) had no effect. A combination of sub-analgesic concentrations of ACEA (100 nM) and DAMGO (MOR agonist, 1 nM) inhibited colonic mechanosensitivity in healthy mice (p<0.01, N=4, n=8) and during acute colitis (p<0.05, N=6, n=8). While a combination of sub-analgesic concentrations of HU-308 (300 nM) and DAMGO (1 nM) had no effect in healthy mice (p=0.70, N=4, n=8), it inhibited colonic mechanosensitivity during acute colitis (p<0.01, N=8, n=15). In VMR experiments, a combination of a sub-analgesic dose of ACEA (0.3 mg/kg) with morphine (0.3 mg/kg) reduced VMR (p<0.01, N=7) during acute colitis. Similarly, a combination of a sub-analgesic dose of HU-308 (1 mg/kg) and morphine (0.3 mg/kg) reduced VMR (p<0.01, N=6) during acute colitis. Conclusions A CB2R agonist inhibits colonic nociception during acute colitis, but not in healthy mice. A sub-analgesic combination of CB1R and MOR agonists can inhibit pain in healthy and inflamed mice, while combining sub-analgesic CB2R and MOR agonists is only inhibitory during acute colitis. Funding Agencies NRC

Discovering optimal features for neuron-type identification from extracellular recordings.

Advancements in multichannel recordings of single-unit activity (SUA) in vivo present an opportunity to discover novel features of spatially-varying extracellularly-recorded action potentials (EAPs) that are useful for identifying neuron-types. Traditional approaches to classifying neuron-types often rely on computing EAP waveform features based on conventions of single-channel recordings and thus inherit their limitations. However, spatiotemporal EAP waveforms are the product of signals from underlying current sources being mixed within the extracellular space. We introduce a machine learning approach to demix the underlying sources of spatiotemporal EAP waveforms. Using biophysically realistic computational models, we simulate EAP waveforms and characterize them by the relative prevalence of these sources, which we use as features for identifying the neuron-types corresponding to recorded single units. These EAP sources have distinct spatial and multi-resolution temporal patterns that are robust to various sampling biases. EAP sources also are shared across many neuron-types, are predictive of gross morphological features, and expose underlying morphological domains. We then organize known neuron-types into a hierarchy of latent morpho-electrophysiological types based on differences in the source prevalences, which provides a multi-level classification scheme. We validate the robustness, accuracy, and interpretations of our demixing approach by analyzing simulated EAPs from morphologically detailed models with classification and clustering methods. This simulation-based approach provides a machine learning strategy for neuron-type identification.

Multielectrode array use in insect auditory neuroscience to unravel the spatio-temporal response pattern in the prothoracic ganglion of Mecopoda elongata.

Mechanoreceptors in hearing organs transduce sound-induced mechanical responses into neuronal signals, which are further processed and forwarded to the brain along a chain of neurons in the auditory pathway. Bushcrickets (katydids) have their ears in the front leg tibia, and the first synaptic integration of sound-induced neuronal signals takes place in the primary auditory neuropil of the prothoracic ganglion. By combining intracellular recordings of the receptor activity in the ear, extracellular multichannel array recordings on top of the prothoracic ganglion and hook electrode recordings at the neck connective, we mapped the timing of neuronal responses to tonal sound stimuli along the auditory pathway from the ears towards the brain. The use of the multielectrode array allows the observation of spatio-temporal patterns of neuronal responses within the prothoracic ganglion. By eliminating the sensory input from one ear, we investigated the impact of contralateral projecting interneurons in the prothoracic ganglion and added to previous research on the functional importance of contralateral inhibition for binaural processing. Furthermore, our data analysis demonstrates changes in the signal integration processes at the synaptic level indicated by a long-lasting increase in the local field potential amplitude. We hypothesize that this persistent increase of the local field potential amplitude is important for the processing of complex signals, such as the conspecific song.

Spontaneous slow wave oscillations in extracellular field potential recordings reflect the alternating dominance of excitation and inhibition.

In the resting state, cortical neurons can fire action potentials spontaneously but synchronously (Up state), followed by a quiescent period (Down state) before the cycle repeats. Extracellular recordings in the infragranular layer of cortex with a micro-electrode display a negative deflection (depth-negative) during Up states and a positive deflection (depth-positive) during Down states. The resulting slow wave oscillation (SWO) has been studied extensively during sleep and under anaesthesia. However, recent research on the balanced nature of synaptic excitation and inhibition has highlighted our limited understanding of its genesis. Specifically, are excitation and inhibition balanced during SWOs? We analyse spontaneous local field potentials (LFPs) during SWOs recorded from anaesthetised rats via a multi-channel laminar micro-electrode and show that the Down state consists of two distinct synaptic states: a Dynamic Down state associated with depth-positive LFPs and a prominent dipole in the extracellular field, and a Static Down state with negligible ( ) LFPs and a lack of dipoles extracellularly. We demonstrate that depth-negative and -positive LFPs are generated by a shift in the balance of synaptic excitation and inhibition from excitation dominance (depth-negative) to inhibition dominance (depth-positive) in the infragranular layer neurons. Thus, although excitation and inhibition co-tune overall, differences in their timing lead to an alternation of dominance, manifesting as SWOs. We further show that Up state initiation is significantly faster if the preceding Down state is dynamic rather than static. Our findings provide a coherent picture of the dependence of SWOs on synaptic activity. KEY POINTS: Cortical neurons can exhibit repeated cycles of spontaneous activity interleaved with periods of relative silence, a phenomenon known as 'slow wave oscillation' (SWO). During SWOs, recordings of local field potentials (LFPs) in the neocortex show depth-negative deflection during the active period (Up state) and depth-positive deflection during the silent period (Down state). Here we further classified the Down state into a dynamic phase and a static phase based on a novel method of classification and revealed non-random, stereotypical sequences of the three states occurring with significantly different transitional kinetics. Our results suggest that the positive and negative deflections in the LFP reflect the shift of the instantaneous balance between excitatory and inhibitory synaptic activity of the local cortical neurons. The differences in transitional kinetics may imply distinct synaptic mechanisms for Up state initiation. The study may provide a new approach for investigating spontaneous brain rhythms.

A Modular Implementation to Handle and Benchmark Drift Correction for High-Density Extracellular Recordings.

High-density neural devices are now offering the possibility to record from neuronal populations in vivo at unprecedented scale. However, the mechanical drifts often observed in these recordings are currently a major issue for "spike sorting," an essential analysis step to identify the activity of single neurons from extracellular signals. Although several strategies have been proposed to compensate for such drifts, the lack of proper benchmarks makes it hard to assess the quality and effectiveness of motion correction. In this paper, we present a benchmark study to precisely and quantitatively evaluate the performance of several state-of-the-art motion correction algorithms introduced in the literature. Using simulated recordings with induced drifts, we dissect the origins of the errors performed while applying a motion correction algorithm as a preprocessing step in the spike sorting pipeline. We show how important it is to properly estimate the positions of the neurons from extracellular traces in order to correctly estimate the probe motion, compare several interpolation procedures, and highlight what are the current limits for motion correction approaches.

Implantation of Flexible Electrodes for Simultaneous in-vivo Extracellular Recording and Two-Photon Imaging

Introduction: Rigid silicon electrodes like Utah array grids and Neuropixel probes have been used in human and animal brain models to understand the dynamics of neural computation, treat neurodegenerative disorders, and act as brain-machine-interfaces. However, when implanted chronically, glial proliferation can rapidly disrupt the interaction between neurons and electrodes, drastically reducing recording fidelity. The development of flexible electrodes has the potential to minimize tissue damage and inflammation, which allows for long-term recordings over several months. In line with this objective, the Nano-neurotechnology Lab at Purdue University has developed a 6-µm thick, flexible, and biocompatible Parylene probe to facilitate chronic recordings in awake mice. However, flexible electrodes present a unique engineering challenge as the force required to insert into the brain causes the probe to buckle and fail during insertion. 
 Methods and Results: Here, I designed a micropipette shuttle using a glass micropipette and custom insertion system which provided reproducible probe implantation into the cortex. The implantation device was designed in CAD software and 3D-printed for rapid prototyping. The procedure was developed on brain phantoms made of 0.6% agarose with a comparable Young’s modulus to mouse brain tissue. Utilizing 3D-printed pieces and the surface tension of diluted poly-vinyl-acrylate adhesive to align the probe to a micropipette, insertion of the electrode and retraction of the shuttle was accomplished in awake mice. 
 Conclusion: The implications of flexible recording electrodes are extensive. Long-term implantation opens the door for understanding behavioral and learning dynamics over time. Moreover, the flexibility of these probes allows for the combination of 2-photon optical microscopy, thus enabling multi-modal investigation of neuronal physiology. A low-cost, consistent procedure is the first step in the implementation of these flexible probes for further advancements in fundamental neuroscience research and its potential applications in human and animal studies.

Multiformity of extracellular microelectrode recordings from Aδ neurons in the dorsal root ganglia: a computational modeling study.

Microelectrodes serve as a fundamental tool in electrophysiology research throughout the nervous system, providing a means of exploring neural function with a high resolution of neural firing information. We constructed a hybrid computational model using the finite element method and multicompartment cable models to explore factors that contribute to extracellular voltage waveforms that are produced by sensory pseudounipolar neurons, specifically smaller A-type neurons, and that are recorded by microelectrodes in dorsal root ganglia. The finite element method model included a dorsal root ganglion, surrounding tissues, and a planar microelectrode array. We built a multicompartment neuron model with multiple trajectories of the glomerular initial segment found in many A-type sensory neurons. Our model replicated both the somatic intracellular voltage profile of Aδ low-threshold mechanoreceptor neurons and the unique extracellular voltage waveform shapes that are observed in experimental settings. Results from this model indicated that tortuous glomerular initial segment geometries can introduce distinct multiphasic properties into a neuron's recorded waveform. Our model also demonstrated how recording location relative to specific microanatomical components of these neurons, and recording distance from these components, can contribute to additional changes in the multiphasic characteristics and peak-to-peak voltage amplitude of the waveform. This knowledge may provide context for research employing microelectrode recordings of pseudounipolar neurons in sensory ganglia, including functional mapping and closed-loop neuromodulation. Furthermore, our simulations gave insight into the neurophysiology of pseudounipolar neurons by demonstrating how the glomerular initial segment aids in increasing the resistance of the stem axon and mitigating rebounding somatic action potentials.NEW & NOTEWORTHY We built a computational model of sensory neurons in the dorsal root ganglia to investigate factors that influence the extracellular waveforms recorded by microelectrodes. Our model demonstrates how the unique structure of these neurons can lead to diverse and often multiphasic waveform profiles depending on the location of the recording contact relative to microanatomical neural components. Our model also provides insight into the neurophysiological function of axon glomeruli that are often present in these neurons.

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats

BackgroundIndividuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats.MethodsIn vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains.ResultsOur results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered.ConclusionsThese results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Laser-patterned epoxy-based 3D microelectrode arrays for extracellular recording.

Microelectrode arrays are commonly used to study the electrophysiological behavior of cells. Recently, there has been a growing interest in fabricating three-dimensional microelectrode arrays. Here, we present a novel process for the fast fabrication of epoxy-based 3D microelectrode array platforms with the assistance of laser-patterning technology. To this end, we photopatterned 3D pillars as scaffolds using epoxy-based dry films. Electrodes and conductor traces were fabricated by laser patterning of sputtered platinum films on top of the 3D structures, followed by deposition of parylene-C for insulation. Microelectrodes at the tip of the 3D structures were exposed using a vertical laser ablation process. The final electrodes demonstrated a low impedance of ∼10 kΩ at 1 kHz in electrochemical impedance spectroscopy measurements under physiological conditions. We investigated the maximum compression force of the 3D structures, which could withstand approximately 0.6 N per pillar. The 3D microelectrode arrays were used to record extracellular signals from HL-1 cells in culture as a proof of principle. Our results show regular firing of action potentials recorded at the tip of the 3D structures, demonstrating the possibility of recording cell signals in non-planar environments.

An Efficient Brain-Switch for Asynchronous Brain-Computer Interfaces.

Intracortical brain computer interfaces (iBCIs) utilizing extracellular recordings mainly employ in vivo signal processing application-specific integrated circuits (ASICs) to detect action potentials (spikes). Conventionally, "brain-switches" based on spiking activity have been employed to realize asynchronous (self-paced) iBCIs, estimating when the user involves in the underlying BCI task. Several studies have demonstrated that local field potentials (LFPs) can effectively replace action potentials, drastically reducing the power consumption and processing requirements of in vivo ASICs. This article presents the first LFP-based brain-switch design and implementation using gated recurrent neural networks (RNNs). Compared to the previously reported brain-switches, our design requires no exhaustive learning phase for the estimation of optimal recording channels or frequency band selection, making it more applicable to practical asynchronous iBCIs. The synthesized ASIC of the designed in vivo LFP-based feature extraction unit, in a standard 180-nm CMOS process, occupies only 0.09 mm2 of silicon area, and the post place-and-route synthesis results indicate that it consumes 91.87 nW of power while operating at 2 kHz. Compared to the previously published ASICs, the proposed LFP-based brain-switch consumes the least power for in vivo digital signal processing and achieves comparable state estimation performance to that of spike-based brain-switches.

Effect of lidocaine on salicylate-induced tinnitus in guinea pigs: A focus on the auditory cortex.

This study aimed to investigate the effects of the intravenous administration of lidocaine in the auditory cortex after the systemic administration of salicylate. Healthy male albino Hartley guinea pigs were divided into two groups. The control group received only lidocaine, whereas the experimental group received lidocaine after checking for the effects of salicylate. Extracellular recordings of spikes in the primary auditory cortex and dorsocaudal areas in healthy albino Hartley guinea pigs were continuously documented (pre- and post-lidocaine, pre- and post-salicylate, and post-salicylate after adding lidocaine to post-salicylate). We recorded 160 single units in the primary auditory cortex from five guinea pigs and 155 single units in the dorsocaudal area from another five guinea pigs to confirm the effects of lidocaine on untreated animals. No significant change was detected in either the threshold or Q10dB value after lidocaine administration in the primary auditory cortex and dorsocaudal areas. Spontaneous firing activity significantly decreased after lidocaine administration in the primary auditory cortex and dorsocaudal areas. Next, we recorded 160 single units in the primary auditory cortex from five guinea pigs and 137 single units in the dorsocaudal area from another five guinea pigs to determine the effects of lidocaine on salicylate-treated animals. The threshold was significantly elevated after salicylate administration; however, no additional change was detected after adding lidocaine to the primary auditory cortex and dorsocaudal areas. Regarding the Q10dB value, lidocaine negated the significant changes induced by salicylate in the primary auditory cortex and dorsocaudal areas. Moreover, lidocaine negated the significant changes in spontaneous firing activities induced by salicylate in the primary auditory cortex and dorsocaudal areas. In conclusion, changes in the Q10dB value and spontaneous firing activities induced by salicylate administration are abolished by lidocaine administration, suggesting that these changes are related to the presence of tinnitus.

Left Barrel Cortical Neurons Activity following Transplantation of Stem Cells into Right Lesioned-Barrel Cortex in Rats.

Stem cells (SCs) can improve the functional defects of brain injury. Rodents use their whiskers to get tactile information from their surroundings. The aim of this study was to investigate whether the transplantation of SCs into the lesioned barrel cortex can help neuronal function in the contralateral cortex. Sixteen male Wistar rats (200-230 g) were used in this experimental study. We induced a mechanical lesion in the right barrel cortex area of rats by removing this area by a 3 mm skin punch. Four groups containing one intact group of rats: group 1: control, and three lesion groups, group 2: lesion+un-differentiated dental pulp SCs (U-DPSCs), group 3: lesion+differentiated dental pulp SCs (D-DPSCs), and group 4: cell medium (vehicle) that were injected in the lesion area. Three weeks after transplantation of SCs or cell medium, the rats' responses of left barrel cortical neurons to controlled deflections of right whiskers were recorded by using the extracellular single-unit recordings technique. The results showed that the neural spontaneous activity and response magnitude of intact barrel cortex neurons in the lesion group decreased significantly (P<0.05) compared to the control group while ON and OFF responses were improved in the D-DPSCs (P<0.001) group compared to the vehicle group three weeks after transplantation. Transplantation of dental pulp mesenchymal SCs significantly improved the neural responses of the left barrel cortex that was depressed in the vehicle group.

Step-by-step approach: Stereotaxic surgery for in vivo extracellular field potential recording at the rat Schaffer collateral-CA1 synapse using the eLab system

In vivo extracellular field potential recording is a commonly used technique in modern neuroscience research. The success of long-term electrophysiological recordings often depends on the quality of the implantation surgery. However, there is limited use of visually guided stereotaxic neurosurgery and the application of the eLab/ePulse electrophysiology system in rodent models. This study presents a practical and functional manual guide for surgical electrode implantation in rodent models using the eLab/ePulse electrophysiology system for recording and stimulation purposes to assess neuronal functionality and synaptic plasticity. The evaluation parameters included the input/output function (IO), paired-pulse facilitation or depression (PPF/PPD), long-term potentiation (LTP), and long-term depression (LTD).•Provides a detailed picture-guided procedure for conducting in vivo stereotaxic neurosurgery.•Specifically covers the insertion of hippocampal electrodes and the recording of evoked extracellular field potentials.

Improvements for recording retinal function with Microelectrode Arrays

A microelectrode array (MEA) is a configuration of multiple electrodes that enables the concurrent targeting of multiple sites for extracellular recording and stimulation. By utilizing light pulses or electrical stimulations, MEA recordings unveil the complex patterns of electrical activities that arise from the signaling processes within the retinal network. Here, we present a stepwise approach for using microelectrode arrays (MEAs) for recording action potentials from the mouse retina in response to electrical and light stimuli. We provide detailed techniques accompanied by description of a custom optical system, example recordings, troubleshooting guidelines, and data processing methods including spike sorting and code resources for analyzing light and electrical responses. The comprehensive nature of this paper aims to guide researchers in utilizing MEAs effectively for investigating retinal functionality. In particular, it can be easy to have a MEA experiment fail, but hard to identify the source of the failure. This paper is meant to demystify that process. It includes:•A description of MEA setup, recording, and spike data validation.•A troubleshooting guide for common failure modes in MEA recordings from mouse retina.•Spike detection and sorting to precisely extract distinctive action potential.

Blue light at night produces stress-evoked heightened aggression by enhancing brain-derived neurotrophic factor in the basolateral amygdala

Light is an underappreciated mood manipulator. People are often exposed to electronic equipment, which results in nocturnal blue light exposure in modern society. Light pollution drastically shortens the night phase of the circadian rhythm. Preclinical and clinical studies have reported that nocturnal light exposure can influence mood, such as depressive-like phenotypes. However, the effects of blue light at night (BLAN) on other moods and how it alters mood remain unclear. Here, we explored the impact of BLAN on stress-provoked aggression in male Sprague‒Dawley rats, focusing on its influence on basolateral amygdala (BLA) activity. Resident-intruder tests, extracellular electrophysiological recordings, and enzyme-linked immunosorbent assays were performed. The results indicated that BLAN produces stress-induced heightened aggressive and anxiety-like phenotypes. Moreover, BLAN not only potentiates long-term potentiation and long-term depression in the BLA but also results in stress-induced elevation of brain-derived neurotrophic factor (BDNF), mature BDNF, and phosphorylation of tyrosine receptor kinase B expression in the BLA. Intra-BLA microinfusion of BDNF RNAi, BDNF neutralizing antibody, K252a, and rapamycin blocked stress-induced heightened aggressive behavior in BLAN rats. In addition, intra-BLA application of BDNF and 7,8-DHF caused stress-induced heightened aggressive behavior in naïve rats. Collectively, these results suggest that BLAN results in stress-evoked heightened aggressive phenotypes, which may work by enhancing BLA BDNF signaling and synaptic plasticity. This study reveals that nocturnal blue light exposure may have an impact on stress-provoked aggression. Moreover, this study provides novel insights into the BLA BDNF-dependent mechanism underlying the impact of the BLAN on mood.

The neuronal implementation of representational geometry in primate prefrontal cortex

Modern neuroscience has seen the rise of a population-doctrine that represents cognitive variables using geometrical structures in activity space. Representational geometry does not, however, account for how individual neurons implement these representations. Leveraging the principle of sparse coding, we present a framework to dissect representational geometry into biologically interpretable components that retain links to single neurons. Applied to extracellular recordings from the primate prefrontal cortex in a working memory task with interference, the identified components revealed disentangled and sequential memory representations including the recovery of memory content after distraction, signals hidden to conventional analyses. Each component was contributed by small subpopulations of neurons with distinct spiking properties and response dynamics. Modeling showed that such sparse implementations are supported by recurrently connected circuits as in prefrontal cortex. The perspective of neuronal implementation links representational geometries to their cellular constituents, providing mechanistic insights into how neural systems encode and process information.

Compromised trigemino-coerulean coupling in migraine sensitization can be prevented by blocking beta-receptors in the locus coeruleus

BackgroundMigraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors.MethodsWe used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol.ResultsWe found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions’ interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity.ConclusionsAltogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol’s prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.

Cannabidiol Modifies the Glutamate Over-Release in Brain Tissue of Patients and Rats with Epilepsy: A Pilot Study.

Drug-resistant epilepsy (DRE) is associated with high extracellular levels of glutamate. Studies support the idea that cannabidiol (CBD) decreases glutamate over-release. This study focused on investigating whether CBD reduces the evoked glutamate release in cortical synaptic terminals obtained from patients with DRE as well as in a preclinical model of epilepsy. Synaptic terminals (synaptosomes) were obtained from the epileptic neocortex of patients with drug-resistant temporal lobe epilepsy (DR-TLE, n = 10) or drug-resistant extratemporal lobe epilepsy (DR-ETLE, n = 10) submitted to epilepsy surgery. Synaptosomes highly purified by Percoll-sucrose density gradient were characterized by confocal microscopy and Western blot. Synaptosomes were used to estimate the high KCl (33 mM)-evoked glutamate release in the presence of CBD at different concentrations. Our results revealed responsive tissue obtained from seven patients with DR-TLE and seven patients with DR-ETLE. Responsive tissue showed lower glutamate release (p < 0.05) when incubated with CBD at low concentrations (less than 100 µM) but not at higher concentrations. Tissue that was non-responsive to CBD (DR-TLE, n = 3 and DR-ELTE, n = 3) showed high glutamate release despite CBD exposure at different concentrations. Simultaneously, a block of the human epileptic neocortex was used to determine its viability through whole-cell and extracellular electrophysiological recordings. The electrophysiological evaluations supported that the responsive and non-responsive human epileptic neocortices used in the present study exhibited proper neuronal viability and stability to acquire electrophysiological responses. We also investigated whether the subchronic administration of CBD could reduce glutamate over-release in a preclinical model of temporal lobe epilepsy. Administration of CBD (200 mg/kg, p.o. every 24 h for 7 days) to rats with lithium-pilocarpine-evoked spontaneous recurrent seizures reduced glutamate over-release in the hippocampus. The present study revealed that acute exposure to low concentrations of CBD can reduce the glutamate over-release in synaptic terminals obtained from some patients with DRE. This effect is also evident when applied subchronically in rats with spontaneous recurrent seizures. An important finding was the identification of a group of patients that were non-responsive to CBD effects. Future studies are essential to identify biomarkers of responsiveness to CBD to control DRE.