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Micro-Graphitic Single Crystal Diamond Multi Electrode Arrays (μG-SCD-MEAs) have so far been used as amperometric sensors to detect catecholamines from chromaffin cells and adrenal gland slices. Besides having time resolution and sensitivity that are comparable with carbon fiber electrodes, that represent the gold standard for amperometry, μG-SCD-MEAs also have the advantages of simultaneous multisite detection, high biocompatibility and implementation of amperometric/potentiometric protocols, aimed at monitoring exocytotic events and neuronal excitability. In order to adapt diamond technology to record neuronal activity, the μG-SCD-MEAs in this work have been interfaced with cultured midbrain neurons to detect electrical activity as well as quantal release of dopamine (DA). μG-SCD-MEAs are based on graphitic sensing electrodes that are embedded into the diamond matrix and are fabricated using MeV ion beam lithography. Two geometries have been adopted, with 4 × 4 and 8 × 8 microelectrodes (20 μm × 3.5 μm exposed area, 200 μm spacing). In the amperometric configuration, the 4 × 4 μG-SCD-MEAs resolved quantal exocytosis from midbrain dopaminergic neurons. KCl-stimulated DA release occurred as amperometric spikes of 15 pA amplitude and 0.5 ms half-width, at a mean frequency of 0.4 Hz. When used as potentiometric multiarrays, the 8 × 8 μG-SCD-MEAs detected the spontaneous firing activity of midbrain neurons. Extracellularly recorded action potentials (APs) had mean amplitude of ∼-50 μV and occurred at a mean firing frequency of 0.7 Hz in 67% of neurons, while the remaining fired at 6.8 Hz. Comparable findings were observed using conventional MEAs (0.9 and 6.4 Hz, respectively). To test the reliability of potentiometric recordings with μG-SCD-MEAs, the D -autoreceptor modulation of firing was investigated by applying levodopa (L-DOPA, 20 μM), and comparing μG-SCD-MEAs, conventional MEAs and current-clamp recordings. In all cases, L-DOPA reduced the spontaneous spiking activity in most neurons by 70%, while the D -antagonist sulpiride reversed this effect. Cell firing inhibition was generally associated with increased APs amplitude. A minority of neurons was either insensitive to, or potentiated by L-DOPA, suggesting that AP recordings originate from different midbrain neuronal subpopulations and reveal different modulatory pathways. Our data demonstrate, for the first time, that μG-SCD-MEAs are multi-functional biosensors suitable to resolve real-time DA release and AP firing in neuronal networks.

Changes in striatal cholinergic interneuron (ChI) activity are thought to contribute to Parkinson’s disease pathophysiology and dyskinesia from chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, but the physiological basis of these changes is unknown. We find that dopamine lesion decreases the spontaneous firing rate of ChIs, whereas chronic treatment with L-DOPA of lesioned mice increases baseline ChI firing rates to levels beyond normal activity. The effect of dopamine loss on ChIs was due to decreased currents of both hyperpolarization-activated cyclic nucleotide-gated (HCN) and small conductance calcium-activated potassium (SK) channels. L-DOPA reinstatement of dopamine normalized HCN activity, but SK current remained depressed. Pharmacological blockade of HCN and SK activities mimicked changes in firing, confirming that these channels are responsible for the molecular adaptation of ChIs to dopamine loss and chronic L-DOPA treatment. These findings suggest that targeting ChIs with channel-specific modulators may provide therapeutic approaches for alleviating L-DOPA-induced dyskinesia in PD patients.

The glucagon-like peptide-1 (GLP-1) plays important roles in the regulation of food intake and energy metabolism. Peripheral or central GLP-1 suppresses food intake and reduces body weight. The electrophysiological properties of neurons in the mammalian central nervous system reflect the neuronal excitability and the functional organization of the brain. Recent studies focus on elucidating GLP-1-induced suppression of feeding behaviors and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that activation of GLP-1 receptor (GLP-1R) suppresses food intake and induces postsynaptic depolarization of membrane potential and/or presynaptic modulation of glutamatergic or GABAergic neurotransmission in brain nuclei located within the medulla oblongata, pons, mesencephalon, diencephalon, and telencephalon. This review may provide a background to guide future research about the cellular mechanisms of GLP-1-induced feeding inhibition.

[This corrects the article DOI: 10.3389/fncel.2023.1078550.].

The aim of this work was to monitor the effects of extracellular α-synuclein on the firing activity of midbrain neurons dissociated from substantia nigra TH-GFP mice embryos and cultured on microelectrode arrays (MEA). We monitored the spontaneous firing discharge of the network for 21 days after plating and the role of glutamatergic and GABAergic inputs in regulating burst generation and network synchronism. Addition of GABA A , AMPA and NMDA antagonists did not suppress the spontaneous activity but allowed to identify three types of neurons that exhibited different modalities of firing and response to applied L-DOPA: high-rate (HR) neurons, low-rate pacemaking (LR-p), and low-rate non-pacemaking (LR-np) neurons. Most HR neurons were insensitive to L-DOPA, while the majority of LR-p neurons responded with a decrease of the firing discharge; less defined was the response of LR-np neurons. The effect of exogenous α-synuclein (α-syn) on the firing discharge of midbrain neurons was then studied by varying the exposure time (0–48 h) and the α-syn concentration (0.3–70 μM), while the formation of α-syn oligomers was monitored by means of AFM. Independently of the applied concentration, acute exposure to α-syn monomers did not exert any effect on the spontaneous firing rate of HR, LR-p, and LR-np neurons. On the contrary, after 48 h exposure, the firing activity was drastically altered at late developmental stages (14 days in vitro , DIV, neurons): α-syn oligomers progressively reduced the spontaneous firing discharge (IC 50 = 1.03 μM), impaired burst generation and network synchronism, proportionally to the increased oligomer/monomer ratio. Different effects were found on early-stage developed neurons (9 DIV), whose firing discharge remained unaltered, regardless of the applied α-syn concentration and the exposure time. Our findings unravel, for the first time, the variable effects of exogenous α-syn at different stages of midbrain network development and provide new evidence for the early detection of neuronal function impairment associated to aggregated forms of α-syn.

Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN. Some neurons in the brain produce electrical signals (or “fire”) spontaneously, without receiving any other signals from the senses or from other neurons. This spontaneous activity has a number of important roles. For example, in a part of the brain known as the substantia nigra pars reticulata (SNr), spontaneously active neurons frequently produce electrical signals that reduce electrical activity in other brain areas. A current of positively charged ions constantly flows into the spontaneously active SNr neurons and enables them to fire constantly. Ions enter neurons through proteins called ion channels that are embedded in the surface of the neuron. Like all proteins, ion channels are made by “transcribing” genes to form molecules of RNA that are then “translated” to produce the basic sequence of the protein. Lutas et al. have now used single-cell RNA sequencing to study SNr neurons from mice and investigate which ion channel the positive ion current flows through. The RNA sequences revealed that the neurons have the gene for an ion channel known as NALCN. Recordings of the firing rate of neurons in slices of mouse brain showed that SNr neurons without this channel did not fire as often as SNr neurons with the channel. In addition, neurotransmitters (chemicals that alter the ability of neurons to fire) and changes in cell metabolism had less of an effect on the firing rate of SNr neurons that lacked the NALCN channel than they do on normal neurons. These findings may help explain why people with mutations in the NALCN gene have movement disorders, as the substantia nigra pars reticulata plays an important role in orchestrating complex movements. Future work is now needed to understand how a change in NALCN activity affects the other brain areas that SNr neurons connect to.

Background Tinnitus, a self‐reported perceptual disorder, is currently believed to arise from maladaptive plasticity due to reduced sensory input. While deep brain stimulation (DBS) has shown promise in alleviating tinnitus‐related behaviors, its effects on neuronal activity remain unclear. This study aimed to evaluate the spontaneous firing rates (SFRs) of the primary auditory cortex (A1) before and after DBS of the external cortex of the inferior colliculus (ECIC) in a rat model of tinnitus. Methods Tinnitus was induced in rats through sodium salicylate injections for 14 consecutive days, while the control group received normal saline injections over the same period. We conducted tinnitus and hearing assessments using the gap pre‐pulse inhibition of the acoustic startle (GPIAS) and pre‐pulse inhibition (PPI) tests. From day 14, both groups underwent DBS of the ECIC and single unit recordings from the A1. Results Before ECIC stimulation, A1 neurons in rats with potential tinnitus exhibited significantly higher spontaneous activity compared to controls. Following ECIC stimulation, the SFRs in the group displaying abnormal GPIAS responses significantly decreased, and the difference between the tinnitus and control groups was no longer significant. Additionally, inter‐spike interval (ISI) analysis revealed a higher frequency of short ISIs (<5 ms) in rats with potential tinnitus, which decreased after DBS, aligning with values observed in the control group. Conclusion ECIC stimulation effectively modulates A1 hyperactivity, highlighting its role in tinnitus pathophysiology. These findings warrant further research into ECIC's role in tinnitus regulation, which could inform future therapeutic interventions and enhance mathematical models of tinnitus mechanisms. Deep brain stimulation of the inferior colliculus (ICx) significantly reduces auditory cortex hyperactivity in a rat model of tinnitus. This study highlights ICx stimulation as a promising therapeutic approach for tinnitus‐related neural dysregulation.

The authors investigate the physical and mechanical properties of hornstone, gabbro-dolerite and rich chalcopyrite–pyrrhotine ore subjected to flooding at the Oktyabrsky deposit in the Talnakh ore province. The analysis of the petrography, chemistry and mineralogy of the test samples showed no substantial differences in their properties after flooding. The comparison of the strength and deformation characteristics of rocks from the uniaxial compression and tension testing results demonstrate the decrease of both in water-saturated rocks and the increase in the room-temperature dried samples. The limit strength, elasticity modulus and internal friction angles have smaller values in rocks after drying than in the initial samples.

Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound similarities with neocortical circuits. CPGs can produce meaningful functional output in the absence of sensory inputs. Neocortical circuits could be considered analogous to CPGs as they have rich spontaneous dynamics that, similar to CPGs, are powerfully modulated or engaged by sensory inputs, but can also generate output in their absence. We find compelling evidence for this argument at the anatomical, biophysical, developmental, dynamic and pathological levels of analysis. Although it is possible that cortical circuits are particularly plastic types of CPG ('learning CPGs'), we argue that present knowledge about CPGs is likely to foretell the basic principles of the organization and dynamic function of cortical circuits.

With electrical stimulation, retinal prostheses bypass dysfunctional photoreceptors and activate the surviving bipolar or retinal ganglion cells (RGCs). Therefore, the effective modulation of RGCs is crucial for developing retinal prostheses. Substantial research has been performed on the ability of an electrical stimulus to generate a reliable RGC response. However, different experimental conditions show varying levels of how well the electrical stimulation evokes RGC spikes. Therefore, in this study, we attempted to extract an indicator to understand how the electrical stimulation effectively evokes RGC spikes. Six cynomolgus monkeys were used: three as controls and three as an N-methyl-N-nitrosourea (MNU)-induced retinal degeneration model. The retinal recordings were performed using 8 × 8 multi-electrode arrays (MEAs). Electrical stimulation consisted of symmetrical biphasic pulses of varying amplitudes and durations. The number of stimulation conditions that resulted in significantly higher post-stimulation firing rates than pre-stimulus firing rates was defined as the modulation efficiency ratio (MER). The MER was significantly lower in degenerated retinas than in normal retinas. We investigated the relationship between the variables and the MER in normal and degenerated primate RGCs. External variables, such as duration and inter-electrode distance, and internal variables, such as average firing rates and statistics (mean, standard deviation, and coefficient of variation [CV]) of inter-spike intervals (ISIs) of spontaneous spikes, were used. External variables had similar effects on MER in normal and degenerated RGCs. In contrast, internal variables affected MER differently in normal and degenerated RGCs. While in normal RGCs, they were not related to MER, in degenerated RGCs, the mean ISIs were positively correlated with MER, and the CV of ISIs was negatively correlated with MER. The most important variable affecting MER was the mean ISI. A shorter ISI indicates hyperactive firing in the degenerated retina, which prevents electrical stimulation from evoking more RGCs. We believe that this hyperactivity in degenerated retinas results in a lower MER than that in the normal retina. Our findings can be used to optimize the selection of stimulation channels for in vitro MEA experiments and practical calibration methods to achieve higher efficiency when testing retinal prostheses.