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[Display omitted] • LTD occurs reliably at cortical inputs into the amygdala. • The plasticity of synaptic connections is an evolving and dynamic process. • Pyramidal neurons exhibit similar LTD despite different spiking patterns. • The LTD in the amygdala is progressively stronger upon recurrent stimuli. • Gradually stronger LTD exhibits similitude to that of LTP. The convergence of conditioned and unconditioned stimuli (CS and US) into the lateral amygdala (LA) serves as a substrate for an adequate fear response in vivo. This well-known Pavlovian paradigm modulates the synaptic plasticity of neurons, as can be proved by the long-term potentiation (LTP) phenomenon in vitro. Although there is an increasing body of evidence for the existence of LTP in the amygdala, only a few studies were able to show a reliable long-term depression (LTD) of excitation in this structure. We have used coronal brain slices and conducted patch-clamp recordings in pyramidal neurons of the lateral amygdala (LA). After obtaining a stable baseline excitatory postsynaptic current (EPSC) response at a holding potential of −70 mV, we employed a paired-pulse paradigm at 1 Hz at the same membrane potential and could observe a reliable LTD. The different durations of stimulation (ranging between 1.5–24 min) were tested first in the same neuron, but the intensity was kept constant. The latter paradigm resulted in a step-wise LTD with a gradually increasing magnitude under these conditions. [ABSTRACT FROM AUTHOR]

• DMV contains cardiac and pulmonary parasympathetic motoneurons controlling ventricular function and airways secretion. • DMV pulmonary motoneurons are more depolarized and excitable than cardiac. • DMV pulmonary motoneurons have both lower magnitude of A-type K+ currents and level of Kv4.2 expression than cardiac. • DMV pulmonary motoneurons receive greater excitatory synaptic inputs and have highly dendritic complexity than cardiac. The dorsal motor nucleus of the vagus (DMV) contains parasympathetic motoneurons that project to the heart and lungs. These motoneurons control ventricular excitability/contractility and airways secretions/blood flow, respectively. However, their electrophysiological properties, morphology and synaptic input activity remain unknown. One important ionic current described in DMV motoneurons controlling their electrophysiological behaviour is the A-type mediated by voltage-dependent K+ (Kv) channels. Thus, we compared the electrophysiological properties, synaptic activity, morphology, A-type current density, and single cell expression of Kv subunits, that contribute to macroscopic A-type currents, between DMV motoneurons projecting to either the heart or lungs of adult male rats. Using retrograde labelling, we visualized distinct DMV motoneurons projecting to the heart or lungs in acutely prepared medullary slices. Subsequently, whole cell recordings, morphological reconstruction and single motoneuron qRT-PCR studies were performed. DMV pulmonary motoneurons were more depolarized, electrically excitable, presented higher membrane resistance, broader action potentials and received greater excitatory synaptic inputs compared to cardiac DMV motoneurons. These differences were in part due to highly branched dendritic complexity and lower magnitude of A-type K+ currents. By evaluating expression of channels that mediate A-type currents from single motoneurons, we demonstrated a lower level of Kv4.2 in pulmonary versus cardiac motoneurons, whereas Kv4.3 and Kv1.4 levels were similar. Thus, with the distinct electrical, morphological, and molecular properties of DMV cardiac and pulmonary motoneurons, we surmise that these cells offer a new vista of opportunities for genetic manipulation providing improvement of parasympathetic function in cardiorespiratory diseases such heart failure and asthma. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cph is the Drosophila homologue of BCL11A (CTIP1) and BCL11B (CTIP2) • Cph knockdown results in crawling disabilities in larvae. • Cph knockdown flies show loss of co-ordination and motor activity. • Evoked signalling is reduced and irregular in these animals. • Cph expressing neurons are glutamatergic. Functioning of the nervous system requires proper formation and specification of neurons as well as accurate connectivity and signalling between them. Locomotor behaviour depends upon these events that occur during neural development, and any aberration in them could result in motor disorders. Transcription factors are believed to be master regulators that control these processes, but very few linked to behaviour have been identified so far. The Drosophila homologue of BCL11A (CTIP1) and BCL11B (CTIP2), Chronophage (Cph), was recently shown to be involved in temporal patterning of neural stem cells but its role in post-mitotic neurons is not known. We show that knockdown of Cph in neurons during development results in animals with locomotor defects at both larval and adult stages. The defects are more severe in adults, with inability to stand, uncoordinated behaviour and complete loss of ability to walk, climb, or fly. These defects are similar to the motor difficulties observed in some patients with mutations in BCL11A and BCL11B. Electrophysiological recordings showed reduced evoked activity and irregular neuronal firing. All Cph -expressing neurons in the ventral nerve cord are glutamatergic. Our results imply that Cph modulates primary locomotor activity through configuration of glutamatergic neurons. Thus, this study ascribes a hitherto unknown role to Cph in locomotor behaviour of Drosophila melanogaster. [ABSTRACT FROM AUTHOR]

[Display omitted] • Whole-cell sensory-evoked responses were explored in VPM thalamic neurons of rat pups. • Principal whisker stimulation evoked a group of large-amplitude EPSPs. • Large EPSPs evoked spike bursts and plateau potentials. • Large EPSPs nested gamma-barrages of IPSPs. • IPSPs prevented the inactivation of action potentials. During the critical period of postnatal development, brain maturation is extremely sensitive to external stimuli. Newborn rodents already have functional somatosensory pathways and the thalamus, but the cortex is still forming. Immature thalamic synapses may produce large postsynaptic potentials in immature neurons, while non-synaptic membrane currents remain relatively weak and slow. The thalamocortical system generates spontaneous and evoked early gamma and spindle-burst oscillations in newborn rodents. How relatively strong synapses and weak intrinsic currents interact with each other and how they contribute to early thalamic activities remains largely unknown. Here, we performed local field potential (LFP), juxtacellular, and patch-clamp recordings in the somatosensory thalamus of urethane-anesthetized rat pups at postnatal days 6–7 with one whisker stimulation. We removed the overlying cortex and hippocampus to reach the thalamus with electrodes. Deflection of only one (the principal) whisker induced spikes in a particular thalamic cell. Whisker deflection evoked a group of large-amplitude excitatory events, likely originating from lemniscal synapses and multiple inhibitory postsynaptic events in thalamocortical cells. Large-amplitude excitatory events produced a group of spike bursts and could evoke a depolarization block. Juxtacellular recordings confirmed the partial inactivation of spikes. Inhibitory events prevented inactivation of action potentials and gamma-modulated neuronal firing. We conclude that the interplay of strong excitatory and inhibitory synapses and relatively weak intrinsic currents produces sensory-evoked early gamma oscillations in thalamocortical cells. We also propose that sensory-evoked large-amplitude excitatory events contribute to evoked spindle-bursts. [ABSTRACT FROM AUTHOR]

[Display omitted] • FLV is inhibitor of cholesterol biosynthesis. • FLV could inhibit I K(erg) and I h. • FLV could regulate the firings and afterhyperpolarization. Fluvastatin (FLV), the first synthetically derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, is a potent inhibitor of cholesterol biosynthesis. While its primary mechanism of action is to reduce cholesterol levels, there is some evidence suggesting that it may also have effects on K+ channels. However, the overall effects of fluvastatin on ionic currents are not yet well understood. The whole-cell clamp recordings were applied to evaluate the ionic currents and action potentials of cells. Here, we have demonstrated that FLV can effectively inhibit the amplitude of erg-mediated K+ current (I K(erg)) in pituitary tumor (GH 3) cells, with an IC 50 of approximately 3.2 µM. In the presence of FLV, the midpoint in the activation curve of I K(erg) was distinctly shifted to a less negative potential by 10 mV, with minimal modification of the gating charge. However, the magnitude of hyperpolarization-activated cation current (I h) elicited by long-lasting membrane hyperpolarization was progressively decreased, with an IC 50 value of 8.7 µM, upon exposure to FLV. More interestingly, we also found that FLV (5 µM) could regulate the action potential and afterhyperpolarization properties in primary embryonic mouse cortical neurons. Our study presents compelling evidence indicating that FLV has the potential to impact both the amplitude and gating of the ion channels I K(erg) and I h. We also provide credible evidence suggesting that this drug has the potential to modify the properties of action potentials and the afterhyperpolarization current in electrically excitable cells. However, the assumption that these findings translate to similar in-vivo results remains unclear. [ABSTRACT FROM AUTHOR]

• Neuroscience needs analytical frameworks for understanding across levels of biology. • Information asymmetric signaling game theory can apply to neuroscientific problems. • Game theory uses local utilities, but global utility for information maximization. • Neurons do not know input information types, so can be deceived about those types. • Game theory equilibria are signaling conventions for information processing modes. We consider the possibility of applying game theory to analysis and modeling of neurobiological systems. Specifically, the basic properties and features of information asymmetric signaling games are considered and discussed as having potential to explain diverse neurobiological phenomena; we focus on neuronal action potential discharge that can represent cognitive variables in memory and purposeful behavior. We begin by arguing that there is a pressing need for conceptual frameworks that can permit analysis and integration of information and explanations across many scales of biological function including gene regulation, molecular and biochemical signaling, cellular and metabolic function, neuronal population, and systems level organization to generate plausible hypotheses across these scales. Developing such integrative frameworks is crucial if we are to understand cognitive functions like learning, memory, and perception. The present work focuses on systems neuroscience organized around the connected brain regions of the entorhinal cortex and hippocampus. These areas are intensely studied in rodent subjects as model neuronal systems that undergo activity-dependent synaptic plasticity to form neuronal circuits and represent memories and spatial knowledge used for purposeful navigation. Examples of cognition-related spatial information in the observed neuronal discharge of hippocampal place cell populations and medial entorhinal head-direction cell populations are used to illustrate possible challenges to information maximization concepts. It may be natural to explain these observations using the ideas and features of information asymmetric signaling games. [ABSTRACT FROM AUTHOR]

[Display omitted] • The initial electrophysiological characterization of pallidal cholinergic neurons was performed. • Their firing resembles that of some type of basal forebrain cholinergic neurons. • Dopamine receptors activity sustain their membrane resting potential and excitability. • The blockade of D 2 -class receptors hyperpolarizes them and reduces their excitability. • The blockade of D 2 -class receptors changes their induced firing pattern. We employed the whole-cell patch-clamp method and ChAT-Cre mice to study the electrophysiological attributes of cholinergic neurons in the external globus pallidus. Most neurons were inactive, although approximately 20% displayed spontaneous firing, including burst firing. The resting membrane potential, the whole neuron input resistance, the membrane time constant and the total neuron membrane capacitance were also characterized. The current–voltage relationship showed time-independent inward rectification without a "sag". Firing induced by current injections had a brief initial fast adaptation followed by tonic firing with minimal accommodation. Intensity-frequency plots exhibited maximal average firing rates of about 10 Hz. These traits are similar to those of some cholinergic neurons in the basal forebrain. Also, we examined their dopamine sensitivity by acutely blocking dopamine receptors. This action demonstrated that the membrane potential, excitability, and firing pattern of pallidal cholinergic neurons rely on the constitutive activity of dopamine receptors, primarily D 2 -class receptors. The blockade of these receptors induced a resting membrane potential hyperpolarization, a decrease in firing for the same stimulus, the disappearance of fast adaptation, and the emergence of a depolarization block. This shift in physiological characteristics was evident even when the hyperpolarization was corrected with D.C. current. Neither the currents that generate the action potentials nor those from synaptic inputs were responsible. Instead, our findings suggest, that subthreshold slow ion currents, that require further investigation, are the target of this novel dopaminergic signaling. [ABSTRACT FROM AUTHOR]

• In wakefulness, theta-locked spike sequences resemble flash-evoked sequences. • During anesthesia, spontaneous UP state and flash-evoked sequences are different. • Sequences show higher reliability and longer latency when evoked during DOWN state. • Deep anesthesia suppresses inhibitory neuron firing, altering all spike sequences. • Cortical firing changes during desflurane may influence visual information processing. Recurring spike sequences are thought to underlie cortical computations and may be essential for information processing in the conscious state. How anesthesia at graded levels may influence spontaneous and stimulus-related spike sequences in visual cortex has not been fully elucidated. We recorded extracellular single-unit activity in the rat primary visual cortex in vivo during wakefulness and three levels of anesthesia produced by desflurane. The latencies of spike sequences within 0–200 ms from the onset of spontaneous UP states and visual flash-evoked responses were compared. During wakefulness, spike latency patterns linked to the local field potential theta cycle were similar to stimulus-evoked patterns. Under desflurane anesthesia, spontaneous UP state sequences differed from flash-evoked sequences due to the recruitment of low-firing excitatory neurons to the UP state. Flash-evoked spike sequences showed higher reliability and longer latency when stimuli were applied during DOWN states compared to UP states. At deeper levels, desflurane altered both UP state and flash-evoked spike sequences by selectively suppressing inhibitory neuron firing. The results reveal desflurane-induced complex changes in cortical firing sequences that may influence visual information processing. [ABSTRACT FROM AUTHOR]

[Display omitted] • LncRNA FTX is poorly-expressed in MGF epileptiform discharge hippocampal neurons. • FTX overexpression inhibits death of epileptiform discharge hippocampal neurons. • FTX inhibits GABPB1 expression as ceRNA of miR-142-5p. • miR-142-5p overexpression partially annuls inhibition of FTX on ferroptosis. • FTX inhibits MGF-induced neuronal ferroptosis via miR-142-5p/GABPB1 axis. Epilepsy is a disabling and drug-refractory neurological disorder. Long non-coding RNAs (lncRNAs) play a vital role in neuronal function and central nervous system development. This study aimed to explore the regulatory mechanism of lncRNA five prime to Xist (FTX) in cell ferroptosis following epilepsy to provide a theoretical foundation for epilepsy management. Hippocampal neurons were isolated from brain tissues of healthy male SD rats, and an in vitro cell model of epilepsy was established using magnesium-free (MGF) induction. Patch-clamp technique was used to determine the action potentials of neurons. Neuronal viability and apoptosis were assessed by CCK-8 assay and flow cytometry. Levels of FTX, miR-142-5p, and GABPB1 were determined by RT-qPCR and Western blot, respectively. The cellular location of FTX was predicted and validated by RNA immunoprecipitation. Dual-luciferase assay verified targeting relationships among FTX, miR-142-5p, and GAPBP1. Levels of ferroptosis indicators and ferroptosis-related proteins were measured using Western blot and corresponding kits. Neuronal ferroptosis and apoptosis increased after MGF induction, and FTX was weakly-expressed in MGF-induced neurons. FTX overexpression attenuated ferroptosis and apoptosis of MGF-induced neurons. miR-142-5p was upregulated after MGF induction and downregulated after FTX overexpression, and FTX targeted miR-142-5p. miR-142-5p overexpression partially negated the inhibitory action of FTX overexpression on ferroptosis of MGF-induced neurons. FTX regulated GABPB1 expression by targeting miR-142-5p. In conclusion, FTX overexpression mitigated ferroptosis of MGF-induced neurons through the miR-142-5p/GABPB1 axis. In conclusion, lncRNA FTX inhibited ferroptosis of MGF-induced rat hippocampal neurons via the miR-142-5p/GABPB1 axis. [ABSTRACT FROM AUTHOR]

• Nucleus accumbens shell neurons reflect kinematics during reward approach. • Nucleus accumbens shell neuronal firing correlates with speed. • Nucleus accumbens shell neuronal activity predicts changes in speed. • Nucleus accumbens shell neuronal firing correlates with path completion. The nucleus accumbens (NAc) is considered an interface between motivation and action, with NAc neurons playing an important role in promoting reward approach. However, the encoding by NAc neurons that contributes to this role remains unknown. We recorded 62 NAc neurons in male Wistar rats (n = 5) running towards rewarded locations in an 8-arm radial maze. Variables related to locomotor approach kinematics were the best predictors of the firing rate for most NAc neurons. Nearly 18% of the recorded neurons were inhibited during the entire approach run (locomotion-off cells), suggesting that reduction in firing of these neurons promotes initiation of locomotor approach. 27% of the neurons presented a peak of activity during acceleration followed by a valley during deceleration (acceleration-on cells). Together, these neurons accounted for most of the speed and acceleration encoding identified in our analysis. In contrast, a further 16% of neurons presented a valley during acceleration followed by a peak just prior to or after reaching reward (deceleration-on cells). These findings suggest that these three classes of NAc neurons influence the time course of speed changes during locomotor approach to reward. [ABSTRACT FROM AUTHOR]

[Display omitted] • Enlarged excitatory postsynaptic potentials in ACC-CS neurons during neuropathic pain. • Neuropathic pain did not change the intrinsic excitability of ACC-CS neurons. • Enhanced synaptic transmission was coupled to increased firing of ACC-CS neurons. Maladaptive neuronal plasticity is a main mechanism for the development and maintenance of pathological pain. Affective, motivational and cognitive deficits that are comorbid with pain involve cellular and synaptic modifications in the anterior cingulate cortex (ACC), a major brain mediator of pain perception. Here we use a model of neuropathic pain (NP) in male mice and ex-vivo electrophysiology to investigate whether layer 5 caudal ACC (cACC) neurons projecting to the dorsomedial striatum (DMS), a critical region for motivational regulation of behavior, are involved in aberrant neuronal plasticity. We found that while the intrinsic excitability of cortico-striatal cACC neurons (cACC-CS) was preserved in NP animals, excitatory postsynaptic potentials (EPSP) induced after stimulation of distal inputs were enlarged. The highest synaptic responses were evident both after single stimuli and in each of the EPSP that compose responses to trains of stimuli, and were accompanied by increased synaptically-driven action potentials. EPSP temporal summation was intact in ACC-CS neurons from NP mice, suggesting that the plastic changes were not due to alterations in dendritic integration but rather through synaptic mechanisms. These results demonstrate for the first time that NP affects cACC neurons that project to the DMS and reinforce the notion that maladaptive plasticity of the cortico-striatal pathway may be a key factor in sustaining pathological pain. [ABSTRACT FROM AUTHOR]

• Mice exposed in the EOP produced the SIH in response to mechanical stimulation. • The SIH was strongly prevented by lesioning the bilateral ACC. • The stress altered evoked glutamatergic currents within the ACC. • The LFS produced the STD in the ACC of the stress model. Stress can be categorized according to physical, psychological and social factors. Exposure to stress produces stress-induced hypersensitivity and forms negative emotions such as anxiety and depression. For example, acute physical stress induced by the elevated open platform (EOP) causes prolonged mechanical hypersensitivity. The anterior cingulate cortex (ACC) is a cortical region involved in pain and negative emotions. Recently, we showed that mice exposed to the EOP changed spontaneous excitatory, but not inhibitory transmission in layer II/III pyramidal neurons of the ACC. However, it is still unclear whether the ACC is involved in the EOP induced mechanical hypersensitivity, and how the EOP alters evoked synaptic transmission on excitatory and inhibitory synaptic transmission in the ACC. In this study, we injected ibotenic acid into the ACC to examine if it was involved in stress-induced mechanical hypersensitivity induced by EOP exposure. Next, by using whole-cell patch-clamp recording from brain slice preparation, we analyzed action potentials and evoked synaptic transmission from layer II/III pyramidal neurons within the ACC. Lesion of the ACC completely blocked the stress-induced mechanical hypersensitivity induced by EOP exposure. Mechanistically, EOP exposure mainly altered evoked excitatory postsynaptic currents such as input–output and paired pulse ratio. Intriguingly, the mice exposed in the EOP also produced low-frequency stimulation induced short-term depression on excitatory synapses in the ACC. These results suggest that the ACC plays a critical role in the modulation of stress-induced mechanical hypersensitivity, possibly through synaptic plasticity on excitatory transmission. [ABSTRACT FROM AUTHOR]

• Honokiol increased spontaneous post-synaptic activities on SG neurons. • Honokiol increased both glycinergic and GABAergic miniature post-synaptic currents. • Honokiol mediated postsynaptic effect on SG neurons involved in both GABA and glycine receptors. • Honokiol potentiated both GABA A - and glycine receptor-mediated responses on SG neurons. • Honokiol suppressed spontaneous neuronal firing on SG neurons in inflammatory pain model mice. Inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine are known to be abundant in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc). Thus, it has been recognized as an initial synaptic site for regulating orofacial nociceptive stimuli. Honokiol, a principal active ingredient derived from the bark of Magnolia officinalis, has been exploited in traditional remedies with multiple biological effects, including anti-nociception on humans. However, the anti-nociceptive mechanism of honokiol on SG neurons of the Vc remains fully elusive. In this study, effects of honokiol on SG neurons of the Vc in mice were investigated using the whole-cell patch-clamp method. In a concentration-dependent manner, honokiol significantly enhanced frequencies of spontaneous postsynaptic currents (sPSCs) that were independent of action potential generation. Notably, honokiol-induced increase in the frequency of sPSCs was attributed to the release of inhibitory neurotransmitters through both glycinergic and GABAergic pre-synaptic terminals. Furthermore, higher concentration of honokiol induced inward currents that were noticeably attenuated in the presence of picrotoxin (a GABA A receptor antagonist) or strychnine (a glycine receptor antagonist). Honokiol also exhibited potentiation effect on glycine- and GABA A receptor-mediated responses. In inflammatory pain model, the increase in frequency of spontaneous firing on SG neurons induced by formalin was significantly inhibited by the application of honokiol. Altogether, these findings indicate that honokiol might directly affect SG neurons of the Vc to facilitate glycinergic and GABAergic neurotransmissions and modulate nociceptive synaptic transmission against pain. Consequently, the inhibitory effect of honokiol in the central nociceptive system contributes to orofacial pain management. [ABSTRACT FROM AUTHOR]

• Reflex-mediated finger force changes are stabilized by intra-muscle synergies. • No synergies in the space of individual finger force stabilized the force changes. • Effects of dominance are seen in inter-finger but not intra-muscle synergies. • Effects of motor equivalence are seen during reflex-induced force changes. We used the framework of the uncontrolled manifold hypothesis to explore force-stabilizing synergies and motor equivalence in the spaces of individual motor unit (MU) firing frequencies. Healthy subjects performed steady force production tasks by pressing with one finger or three fingers of a hand. Surface EMG was used to identify individual MU action potentials. MUs formed stable groups (MU-modes) with parallel scaling of the firing frequency in both flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) that allowed identifying them with the reciprocal and coactivation commands. Smooth lifting of the fingers by an "inverse piano" device led to an unintentional, reflex-based force increase. There was significantly larger motion in the space of MU-modes that kept the force unchanged (motor equivalent) compared to motion that changed force (non-motor equivalent). The force change was stabilized by co-varying contributions of the MU-modes defined separately for FDS and EDC. In contrast, analysis of the three-finger task in the space of individual finger forces showed no synergies stabilizing total force change. Effects of hand dominance were seen on multi-finger synergies but not intra-muscle synergies. We conclude that spinal mechanisms, such as recurrent inhibition and reflex loops from proprioceptors, contribute significantly to intra-muscle synergies, while multi-finger synergies reflect supra-spinal processes. These results provide methods to explore the contributions of spinal vs supraspinal circuitry to changed motor synergies in populations with a variety of neurological disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Spire2 is decreased in the brains of epileptic individuals. • Spire2 has an inhibitory role on epilepsy development and progression. • In mice, Spire2 knock-down aggravated abnormal firing. • In mice, Spire2 overexpression normalized firing. Epilepsy is a neurological disorder caused by abnormally elevated neuronal firing and excitability. Spire2, also known as the nucleating factor of F-actin, plays an important role in long-range vesicle transport. This study showed that Spire2 was highly expressed in neurons in the cortex and hippocampus. Its knockdown significantly reduced the initiation current of the evoked action potential and the frequency of action potential, suggesting that Spire2 knockdown inhibits the threshold current of the neuron. In the cortex of patients with refractory temporal lobe epilepsy (TLE), Spire2 expression was significantly reduced. Decreased expression levels of Spire2 were also observed in kainic acid (KA) and pentylenetetrazole (PTZ) animal models. In the KA and PTZ models, Spire2-knockdown mice showed significantly increased seizures and shortened intervals between seizures, with a tendency to increase seizure duration. In contrast, Spire2-overexpressing mice showed reduced numbers of spontaneous seizures. In conclusion, this study revealed a significantly decreased expression of Spire2 in the brain tissues of epileptic individuals and an inhibitory role for this protein in the development of epilepsy. In addition, knockdown of Spire2 aggravated abnormal firing in epileptic mice, while its overexpression had the opposite effect. These findings provide new insights into the mechanism of epileptogenesis. [ABSTRACT FROM AUTHOR]

• Looming visual stimuli induced defense responses, whereas dimming visual stimuli did not. • Superior colliculus and lateral posterior thalamic nuclei played a role in visually evoked defense behaviors. • The theta frequency band played a key role during fear visual stimulation. Animals perceive threat information mainly from vision, and the subcortical visual pathway plays a critical role in the rapid processing of fear visual information. The superior colliculus (SC) and lateral posterior (LP) nuclei of the thalamus are key components of the subcortical visual pathway; however, how animals encode and transmit fear visual information is unclear. To evaluate the response characteristics of neurons in SC and LP thalamic nuclei under fear visual stimuli, extracellular action potentials (spikes) and local field potential (LFP) signals were recorded under looming and dimming visual stimuli. The results showed that both SC and LP thalamic nuclei were strongly responsive to looming visual stimuli but not sensitive to dimming visual stimuli. Under the looming visual stimulus, the theta (θ) frequency bands of both nuclei showed obvious oscillations, which markedly enhanced the synchronization between neurons. The functional network characteristics also indicated that the network connection density and information transmission efficiency were higher under fear visual stimuli. These findings suggest that both SC and LP thalamic nuclei can effectively identify threatening fear visual information and rapidly transmit it between nuclei through the θ frequency band. This discovery can provide a basis for subsequent coding and decoding studies in the subcortical visual pathways. [ABSTRACT FROM AUTHOR]

• Mechanisms of NE on spinal lamina X assessed in inflammatory pain model rats. • Spontaneous neuronal firing on spinal lamina X was enhanced under inflammatory pain. • NE facilitates presynaptic inhibitory transmission and induces hyperpolarization. • These actions of NE on spinal lamina X cause analgesia against inflammatory pain. Norepinephrine (NE) acts directly on the inhibitory interneurons of spinal lamina X and may act on spinal lamina X neurons for inhibiting nociceptive synaptic transmission against pain. We investigated this mechanism within inflammatory pain model rats. Using immunohistochemical staining and in vivo extracellular recording, the increased number of phosphorylated extracellular signal-regulated kinase profiles in lamina X (n = 6/group) and increased frequency of spontaneous neuronal firing on putative lamina X (n = 14) under the inflammatory pain were significantly suppressed by the direct application of NE (P < 0.01). Following in vivo observation of enhanced spontaneous neuronal firing, we tested the impact of NE on this discharge using an in vitro spinal slice preparation. Using in vitro patch-clamps recording, the baseline level of miniature inhibitory postsynaptic currents (mIPSCs) frequency on spinal lamina X neurons cord is decreased under inflammatory pain. Direct application of NE to spinal lamina X neurons in inflammatory pain model rats facilitates mIPSCs frequency and induces an outward current (n = 8; P < 0.05), and these responses are inhibited by α1A- and α2-receptor antagonists (n = 8; P > 0.05). Considering these results and those of our previous study (Ohashi et al., 2019), NE might act on inhibitory interneurons of spinal lamina X to facilitate inhibitory transmission and induces neurons located in or around lamina X membrane hyperpolarization. These NE-mediated responses acted through α1A- and α2-receptors. These mechanisms of NE on spinal lamina X might contribute to analgesia against inflammatory pain. [ABSTRACT FROM AUTHOR]

[Display omitted] • High glucose changed electrophysiological properties and caused neuronal injury. • High glucose decreased the expression of PSD-95. • Rapamycin protected against neuronal injury caused by high glucose. • Rapamycin increased the expression of PSD-95 caused by high glucose. Diabetic neuropathy is one of the most common complications in patients with diabetes and leads to cognitive impairment. It is suggested that protracted hyperglycemia is the main trigger of cognitive deficits in diabetes and causes hippocampal abnormalities. Rapamycin, an inhibitor of mammalian target of rapamycin complex 1 (mTORC1), can significantly ameliorate cognitive deficits in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and Huntington disease. We employed whole-cell patch clamping to examine the effects of rapamycin on neuronal electrophysiological characteristics of the hippocampal dentate gyrus in mice under the condition of high glucose. We recorded the action potentials (APs) and the miniature excitatory postsynaptic currents (mEPSCs) of dentate gyrus neurons. We found that high glucose increased the half-width, the duration and decreased the peak amplitude of Aps as well as the inter-event interval (IEI) of mEPSCs in hippocampal dentate gyrus neurons. However, rapamycin pre-treatment reversed the changes induced by high glucose. Moreover, we demonstrated that rapamycin pre-treatment reversed the down-regulation of postsynaptic density protein 95 (PSD-95) expression caused by high glucose. Therefore, pre-treatment with rapamycin could ameliorate high glucose-induced alteration of synaptic transmission in the hippocampal dentate gyrus. [ABSTRACT FROM AUTHOR]

• Dendrites exhibit a diverse repertoire of spikes. • We surveyed the full range of dendritic spikes of the neocortex and hippocampus. • We discuss the broader role of dendritic spikes in single-cell computation. Half a century since their discovery by Llinás and colleagues, dendritic spikes have been observed in various neurons in different brain regions, from the neocortex and cerebellum to the basal ganglia. Dendrites exhibit a terrifically diverse but stereotypical repertoire of spikes, sometimes specific to subregions of the dendrite. Despite their prevalence, we only have a glimpse into their role in the behaving animal. This article aims to survey the full range of dendritic spikes found in excitatory and inhibitory neurons, compare them in vivo versus in vitro , and discuss new studies describing dendritic spikes in the human cortex. We focus on neocortical and hippocampal neurons and present a roadmap to identify and understand the broader role of dendritic spikes in single-cell computation. [ABSTRACT FROM AUTHOR]

• Enucleation triggers degeneration of retinal outputs to the visual thalamus. • Retinal axons in the visual thalamus cease transmission one week post-injury. • Enucleation enhances relay neurons spiking in the visual thalamus. • Relay neuron dendrites are re-organized following enucleation. • Findings point to structural and functional circuit changes resulting from injury. Within the nervous system, plasticity mechanisms attempt to stabilize network activity following disruption by injury, disease, or degeneration. Optic nerve injury and age-related diseases can induce homeostatic-like responses in adulthood. We tested this possibility in the thalamocortical (TC) neurons in the dorsolateral geniculate nucleus (dLGN) using patch-clamp electrophysiology, optogenetics, immunostaining, and single-cell dendritic analysis following loss of visual input via bilateral enucleation. We observed progressive loss of vGlut2-positive retinal terminals in the dLGN indicating degeneration post-enucleation that was coincident with changes in microglial morphology indicative of microglial activation. Consistent with the decline of vGlut2 puncta, we also observed loss of retinogeniculate (RG) synaptic function assessed using optogenetic activation of RG axons while performing whole-cell voltage clamp recordings from TC neurons in brain slices. Surprisingly, we did not detect any significant changes in the frequency of miniature post-synaptic currents (mEPSCs) or corticothalamic feedback synapses. Analysis of TC neuron dendritic structure from single-cell dye fills revealed a gradual loss of dendrites proximal to the soma, where TC neurons receive the bulk of RG inputs. Finally, analysis of action potential firing demonstrated that TC neurons have increased excitability following enucleation, firing more action potentials in response to depolarizing current injections. Our findings show that degeneration of the retinal axons/optic nerve and loss of RG synaptic inputs induces structural and functional changes in TC neurons, consistent with neuronal attempts at compensatory plasticity in the dLGN. [ABSTRACT FROM AUTHOR]

• The firing rate of putative CA1 neurons was assessed in freely behaving inbred mice. • 129S CA1 pyr and int units have lower firing rate scores than B6 neurons. • 129S CA1 putative int show significant FR variability. • The detectability index for putative pyr/int pairs is significantly lower in 129S CA1. A spontaneous mutation of the disrupted in schizophrenia 1 (Disc1) gene is carried by the 129S inbred mouse strain. Truncated DISC1 protein in 129S mouse synapses impairs the scaffolding of excitatory postsynaptic receptors and leads to progressive spine dysgenesis. In contrast, C57BL/6 inbred mice carry the wild-type Disc1 gene and exhibit more typical cognitive performance in spatial exploration and executive behavioral tests. Because of the innate Disc1 mutation, adult 129S inbred mice exhibit the behavioral phenotypes of outbred B6 Disc1 knockdown (Disc1 −/−) or Disc1-L-100P mutant strains. Recent studies in Disc1 −/− and L-100P mice have shown that impaired excitation-driven interneuron activity and low hippocampal theta power underlie the behavioral phenotypes that resemble human depression and schizophrenia. The current study compared the firing rate and connectivity profile of putative neurons in the CA1 of freely behaving inbred 129S and B6 mice, which have mutant and wild-type Disc1 genes, respectively. In cognitive behavioral tests, 129S mice had lower exploration scores than B6 mice. Furthermore, the mean firing rate for 129S putative pyramidal (pyr) cells and interneurons (int) was significantly lower than that for B6 CA1 neurons sampled during similar tasks. Analysis of pyr/int connectivity revealed a significant delay in synaptic transmission for 129S putative pairs. Sampled 129S pyr/int pairs also had lower detectability index scores than B6 putative pairs. Therefore, the spontaneous Disc1 mutation in the 129S strain attenuates the firing of putative pyr CA1 neurons and impairs spike timing fidelity during cognitive tasks. [ABSTRACT FROM AUTHOR]

• Neuronal firing rates are altered by corticohippocampal GluN2B deletion, both in the cortex and dorsal striatum. • GluN2B deletion disrupts communication between the orbital frontal cortex and dorsal striatum driving the continuation of unrewarded responses. • Our data demonstrate corticostriatal coordination is necessary for optimal behavioral flexibility. • These results suggest GluN2B containing NMDARs are a key molecular component in mediating neuronal timing. A common feature across neuropsychiatric disorders is inability to discontinue an action or thought once it has become detrimental. Reversal learning, a hallmark of executive control, requires plasticity within cortical, striatal and limbic circuits and is highly sensitive to disruption of N -methyl- d -aspartate receptor (NMDAR) function. In particular, selective deletion or antagonism of GluN2B containing NMDARs in cortical regions including the orbitofrontal cortex (OFC), promotes maladaptive perseveration. It remains unknown whether GluN2B functions to maintain local cortical activity necessary for reversal learning, or if it exerts a broader influence on the integration of neural activity across cortical and subcortical systems. To address this question, we utilized in vivo electrophysiology to record neuronal activity and local field potentials (LFP) in the orbitofrontal cortex and dorsal striatum (dS) of mice with deletion of GluN2B in neocortical and hippocampal principal cells while they performed touchscreen reversal learning. Reversal impairment produced by corticohippocampal GluN2B deletion was paralleled by an aberrant increase in functional connectivity between the OFC and dS. These alterations in coordination were associated with alterations in local OFC and dS firing activity. These data demonstrate highly dynamic patterns of cortical and striatal activity concomitant with reversal learning, and reveal GluN2B as a molecular mechanism underpinning the timing of these processes. [ABSTRACT FROM AUTHOR]

• Locus Coeruleus phasic response facilitated prefrontal network activation. • Transient NA release sustained depolarization and enhanced spiking probability in the mPFC. • Effect of LC stimulation depended on excitability level of prefrontal network. • Functional role for the coerulear–prefrontal interactions for promoting plasticity is proposed. Cortical slow rhythmic activity, a hallmark of deep sleep, is observed under urethane anesthesia. Synchronized fluctuations of the membrane excitability of a large neuronal population are reflected in the extracellular Local Field Potential (LFP), as high-amplitude slow (∼1 Hz) oscillations (SO). The SO-phase indicates the presence (Up) or absence (Down) of neuronal spiking. The cortical state is controlled by the input from thalamic and neuromodulatory centers, including the brainstem noradrenergic nucleus Locus Coeruleus (LC). The bidirectional modulation of neuronal excitability by noradrenaline (NA) is well known. We have previously shown that LC phasic activation caused transient excitability increase in the medial prefrontal cortex (mPFC). In the present study, we characterized the effect of LC phasic activation on the prefrontal population dynamics at a temporal scale of a single SO cycle. We applied short (0.2 s) trains of electric pulses (0.02–0.05 mA at 20–50 Hz) to the LC cell bodies and monitored a broadband (0.1 Hz–8 kHz) mPFC LFP in urethane-anesthetized rats. The direct electrical stimulation of LC (LC-DES), applied during the Up-phase, enhanced the firing probability in the mPFC by ∼20% and substantially prolonged Up-states in 56% of trials. The LC-DES applied during Down-phase caused a rapid Down-to-Up transition in 81.5% of trials. The LC-DES was more effective at a higher frequency, but not at a higher current. Our results suggest that transient NA release, coupled to SO, may promote synaptic plasticity and memory consolidation by sustaining a depolarized state in the mPFC neurons. [ABSTRACT FROM AUTHOR]

• D11399 a Citrus sinensis -containing extract reduces stress-related responses in mice. • The effects of D11399 in mice involve, at least in part, the olfactory epithelium. • Modulating sensorial modalities in mice might relieve depressive endophenotypes. In the present study, we examined the neurobehavioral effects of a sensory functional food ingredient mainly based on Citrus sinensis extracts (D11399) using a battery of tests recapitulating various endophenotypes of depression such as anxiety in the open field (OF), the elevated plus-maze (EPM), and the novelty suppressed feeding (NSF), self-care in the splash test (ST), despair in the forced swimming task (FST) but also anhedonia in the sucrose preference test (SPT) in mice. A one-week oral administration of D11399 promoted anxiolytic- and antidepressant-like responses in naïve mice subjected to the NSF and FST. In a marked contrast, the administration of D11399 by oral gavage or the inhibition of olfaction by methimazole prevented such beneficial effects. We further investigated the neurobehavioral properties of a ten-week oral administration of D11399 in the corticosterone (CORT) mouse model of depression. Interestingly, D11399 also elicited anxiolytic- and antidepressant-like effects in various paradigms. To characterize the putative underpinning neurobiological mechanisms in CORT mice, we investigated whether cellular and molecular processes commonly associated with antidepressant responses such as monoaminergic neurotransmission and neuronal maturation in the hippocampus were impacted. Although D11399 did not modify the hippocampal extracellular levels of monoamines (i.e. serotonin and norepinephrine), it reversed the ability of CORT to decrease serotonin neurons firing rate in the dorsal raphe and neuronal maturation in the hippocampus. These findings suggest that the anxiolytic- and antidepressant-like effects of this sensory functional food ingredient are closely related with olfaction and likely a concomitant change in the activity of the central serotonergic system. Further experiments are warranted to precise the neuronal circuits linking sensorial and emotional modalities and identify innovative therapeutic strategies aimed to relieve depressive endophenotypes. [ABSTRACT FROM AUTHOR]

• Recording from feline interneurons during fictive locomotion or scratch. • Focus on neurons firing during extension and excited by extensor gr I afferents. • These interneurons are located in the intermediate nucleus and the ventral horn. • They may mediate "resetting to extension" and be part of the rhythm generator. Sensory information arising from limb movements controls the spinal locomotor circuitry to adapt the motor pattern to demands of the environment. Stimulation of extensor group (gr) I afferents during fictive locomotion in decerebrate cats prolongs the ongoing extension, and terminates ongoing flexion with an initiation of the subsequent extension, i. e. "resetting to extension". Moreover, instead of the classical Ib non-reciprocal inhibition, stimulation of extensor gr I afferents produces a polysynaptic excitation in extensor motoneurons with latencies (∼3.5–4.0 ms) compatible with 3 interposed interneurons. We assume that some interneurons in this pathway actually belong to the rhythm-generating layer of the locomotor Central Pattern Generator (CPG), since their activity was correlated to a resetting of the rhythm. In the present work fictive locomotion was (mostly) induced by i.v. injection of nialamide followed by l -DOPA in paralyzed cats following decerebration and spinalization at C1 level. In some experiments, we extended previous observations during fictive locomotion on the emergence and locomotor state-dependence of polysynaptic excitatory postsynaptic potentials from extensor gr I afferents to ankle extensor motoneurons. However, the main focus was to record location and properties of interneurons (n = 62) that (i) were active during the extensor phase of fictive locomotion and (ii) received short-latency excitation (mono-, di- or polysynaptic) from extensor gr I afferents. We conclude that the interneurons recorded fulfill the characteristics to belong to the neuronal pathway activated by extensor gr I afferents during locomotion, and may contribute to the 'resetting to extension' as part of the locomotor CPG. [ABSTRACT FROM AUTHOR]

While chronic pain is a main symptom in endometriosis, the underlying mechanisms and effective therapy remain elusive. We developed an animal model enabling the exploration of ectopic endometrium as a source of endometriosis pain. Rats were surgically implanted with autologous uterus in the gastrocnemius muscle. Within two weeks, visual inspection revealed the presence of a reddish-brown fluid-filled cystic structure at the implant site. Histology demonstrated cystic glandular structures with stromal invasion of the muscle. Immunohistochemical studies of these lesions revealed the presence of markers for nociceptor nerve fibers and neuronal sprouting. Fourteen days after surgery rats exhibited persistent mechanical hyperalgesia at the site of the ectopic endometrial lesion. Intralesional, but not contralateral, injection of progesterone was dose-dependently antihyperalgesic. Systemic administration of leuprolide also produced antihyperalgesia. In vivo electrophysiological recordings from sensory neurons innervating the lesion revealed a significant increase in their response to sustained mechanical stimulation. These results are consistent with clinical and pathological findings observed in patients with endometriosis, compatible with the ectopic endometrium as a source of pain. This model of endometriosis allows mechanistic exploration at the lesion site facilitating our understanding of endometriosis pain.

• K3 transgenic mouse models the pathology of frontotemporal lobar degeneration. • Discharge profile of neurons in the K3 striatum shifted towards burst firing. • K3 striatal neurons show enhanced subthreshold activity. • Altered medium spiny neurons in K3 mice show increased sensitivity. • K3s have early deficits in goal directed behaviour attributed to striatal function. Pathological forms of the microtubule-associated protein tau are involved in a large group of neurodegenerative diseases named tauopathies, including frontotemporal lobar degeneration (FTLD-tau). K369I mutant tau transgenic mice (K3 mice) recapitulate neural and behavioural symptoms of FTLD, including tau aggregates in the cortex, alterations to nigrostriatum, memory deficits and parkinsonism. The aim of this study was to further characterise the K3 mouse model by examining functional alterations to the striatum. Whole-cell patch-clamp electrophysiology was used to investigate the properties of striatal neurons in K3 mice and wildtype controls. Additionally, striatal-based instrumental learning tasks were conducted to assess goal-directed versus habitual behaviours (i.e., by examining sensitivity to outcome devaluation and progressive ratios). The K3 model demonstrated significant alterations in the discharge properties of striatal neurons relative to wildtype mice, which manifested as a shift in neuronal output towards a burst firing state. K3 mice acquired goal-directed responding faster than control mice and were goal-directed at test unlike wildtype mice, which is likely to indicate reduced capacity to develop habitual behaviour. The observed pattern of behaviour in K3 mice is suggestive of deficits in dorsal lateral striatal function and this was supported by our electrophysiological findings. Thus, both the electrophysiological and behavioural alterations indicate that K3 mice have early deficits in striatal function. This finding adds to the growing literature which indicate that the striatum is impacted in tau-related neuropathies such as FTLD, and further suggests that the K3 model is a unique mouse model for investigating FTLD especially with striatal involvement. [ABSTRACT FROM AUTHOR]

• VTA dopamine and glutamate terminals are mapped to specific anatomical layers in the DG, CA3, and CA1. • The distribution of VTA dopamine presynaptic terminals is robust in the CA1 stratum oriens and reduces putative pyramidal burst firing. • VTA glutamate terminals innervate all CA1 layers and promote burst firing in putative pyramidal units. Reciprocal connection between the ventral tegmental area (VTA) and the hippocampus forms a loop that controls information entry into long-term memory. Compared with the widely studied VTA dopamine system, VTA glutamate terminals are anatomically dominant in the hippocampus and less understood. The current study employs anterograde and retrograde labeling of VTA dopamine and glutamate neurons to map the distribution of their terminals within the layers of the hippocampus. Also, functional tracing of VTA dopamine and glutamate projections to the hippocampus was performed by photostimulation of VTA cell bodies during CA1 extracellular voltage sampling in vivo. VTA dopamine terminals predominantly innervate the CA1 basal dendrite layer and modulate the firing rate of active putative neurons. In contrast, anatomical dominance of VTA glutamate terminals in the CA1 pyramidal cell and apical dendrite layers suggests the possible involvement of these terminals in excitability regulation. In support of these outcomes, photostimulation of VTA dopamine neurons increased the firing rate but not intrinsic excitability parameters for putative pyramidal units. Conversely, activation of VTA glutamate neurons increased CA1 network firing rate and burst rate. In addition, VTA glutamate inputs reduced the interspike and interburst intervals for putative CA1 neurons. Taken together, we deduced that layer-specific distribution of presynaptic dopamine and glutamate terminals in the hippocampus determinines VTA modulation (dopamine) or regulation (glutamate) of excitability in the CA1 neural network. [ABSTRACT FROM AUTHOR]

• A complex link between spreading depolarization (SD) and epileptiform burst discharges has been observed. • The effect of SD on the interictal-to-ictal transitions in low-Mg2+ model of seizure was studied in rat hippocampus. • SD significantly accelerates the interictal-to-ictal transitions and facilitates development of ictaform discharges. • SD may play a potential role in seizure initiation in temporal lobe epilepsy. The transition of neuronal burst firing from the interictal to ictal state contributes to seizure initiation in human temporal lobe epilepsy. The low-Mg2+ model of seizure is characterized by initial spontaneous interictal bursting events, which later developed into ictaform discharges. Both experimental and clinical studies point to a complex link between spreading depolarization (SD) and epileptiform field potentials (EFP), including SD-induced epileptic seizures. To investigate the mechanism of SD and EFP interactions, the effect of SD on the transition of interictal to ictal state in low-Mg2+ model of seizure was studied in the rat hippocampus in vitro. After the appearance of interictal activities, SD was elicited by local application of KCl. SD significantly increased the amplitude and duration of action potentials and after-hyperpolarization, and hyperpolarized the membrane potential. Furthermore, SD significantly increased the duration of interictal activities and the threshold potentials of interictal activities. In addition, SD significantly accelerated the transition from interictal to ictal state compared to the control tissues. Ictal activities after induction of SD exhibited a significantly longer duration. This study revealed that SD accelerates interictal-to-ictal transitions and facilitates development of ictaform discharges, possibly via the enhancement of neural synchronization, and points to the potential role of SD in seizure initiation. [ABSTRACT FROM AUTHOR]

• Extra-hippocampal regions might participate in the expression of sharp-wave ripples (SPW-Rs). • We found two neuronal populations in the lSuM: SPW-R-active (increased firing during SPW-Rs), and SPW-R-unchanged neurons. • lSuM SPW-R-active neurons increased their firing prior to SPW-Rs peak power and hippocampal excitatory neurons. • lSuM SPW-R-active neurons showed a higher firing during theta and slow oscillations compared to SPW-R-unchanged neurons. • These results provide new insight on the interaction between a lSuM neuronal population and hippocampus during SPW-Rs. The extent of the networks that control the genesis and modulation of hippocampal sharp-wave ripples (SPW-Rs), which are involved in memory consolidation, remains incompletely understood. Here, we performed a detailed in vivo analysis of single cell firing in the lateral supramammillary nucleus (lSuM) during theta and slow oscillations, including SPW-Rs, in anesthetized rats. We classified neurons as SPW-R-active and SPW-R-unchanged according to whether or not they increased their firing during SPW-Rs. We show that lSuM SPW-R-active neurons increase their firing prior to SPW-Rs peak power and prior to hippocampal excitatory cell activation. Moreover, lSuM SPW-R-active neurons show increased firing activity during theta and slow oscillations as compared to unchanged neurons. These results suggest that a sub-population of lSuM neurons can interact with the hippocampus during SPW-Rs, raising the possibility that the lSuM may modulate memory consolidation. [ABSTRACT FROM AUTHOR]

• Intravenous metoclopramide does not affect the neurogenic dural vasodilation in rats. • The drug inhibits excitability of the second-order trigeminovascular neurons. • The central inhibitory effect of metoclopramide is dose-dependent. Metoclopramide is widely used as an abortive migraine therapy due to the advantage of having not only antiemetic, but also analgesic properties. Despite the proven clinical efficacy of metoclopramide in acute migraine, the mechanism of its anti-cephalalgic action has not been entirely elucidated. Taking into account the key role of the trigeminovascular system activation in migraine pathophysiology, we aimed to investigate metoclopramide effects on the excitability of central trigeminovascular neurons and neurogenic dural vasodilation using valid electrophysiological and neurovascular models of trigeminovascular nociception. Extracellular recordings of the activity of second-order dura-sensitive neurons were made in the trigeminocervical complex (TCC) of 16 anaesthetised rats. Cumulative metoclopramide infusion (three steps in 30 min intervals, 5 mg/kg i.v. per step, n = 8) significantly and dose-dependently suppressed both ongoing firing of the TCC neurons and their responses to dural electrical stimulation, maximally to 30%[0–49%] (median[Q1-Q3]) and 4%[0–30%] of the initial level, respectively (both p = 0.001, compared to saline (n = 8)). By contrast, the neurogenic dural vasodilation studied in a separate group of 12 rats was not significantly affected by cumulative infusion of metoclopramide (5 mg/kg i.v. per step, n = 6) compared to both baseline values and the vehicle group (n = 6) (all p > 0.05). These results provide evidence that metoclopramide is unable to affect the peripheral response to trigeminovascular activation, but it does suppress the central response, which is highly predictive of anti-migraine action. Thus, here we show the neurophysiological mechanism underlying the therapeutic efficacy of metoclopramide in migraine. [ABSTRACT FROM AUTHOR]

• Nerve terminals in both the PNS and CNS have large number of active zones (AZs). • The probability of quantal neurotransmitter release is different among these AZs. • Functional interaction among these AZs may be fundamental for synaptic plasticity. It has long been known that each neuron in both the central and peripheral nervous system has a large number of active zones. Nonetheless, how active zones are regulated to maintain a homeostatic release state and response to the constantly changing environment remains poorly understood. Due to its relatively simple structure and easy accessibility, the neuromuscular synapse (NM-synapse) continues to be used as a model synapse to examine the basic nature of synaptic neurotransmission. In the NM-synapse, quantal neurotransmitter release can occur spontaneously or triggered by invading nerve impulses. Past research has indicated that some active zones tend to be involved more with spontaneous quantal release than evoked quantal release. Furthermore, evoked quantal release has been shown to be highly non-uniform between active zones along nerve terminal branches. How these large numbers of active zones along the same nerve terminal are functionally correlated remains unclear. This review starts with the basic features of quantal neurotransmitter release, then progresses to the current knowledge on how the active zones interact with each other along the same nerve terminal. [ABSTRACT FROM AUTHOR]

• TRPV3 mRNA is expressed in the cerebellum of rat. • Cerebellar Purkinje neurons are equipped with TRPV3 ion channel. • TRPV3-ir in the cerebellum showed developmental-stage dependent expression. • TRPV3 inhibitor reduced stride length and increased footprints length. • Cerebellar TRPV3 regulate motor coordination function of the cerebellum. Thermosensitive transient receptor potential vanilloid (TRPV) channels are widely expressed in the brain and known to profoundly influence Ca2+-signaling, neurotransmitter release and behavior. While these channels are expressed in the cerebellum, neuronal firing and hyperactivity/reflexes seem associated with cerebellar temperature modulation. However, the distribution and functional significance of TRPV-equipped elements in the cerebellum has remained unexplored. Among TRPV sub-family, TRPV3 is regulated by temperature within physiological range and its transcript highly expressed in the brain. The study aims at exploring the relevance of TRPV3 in the cerebellum of developing and adult rat. RT-PCR analysis showed expression of N- and C-terminal fragments of TRPV3 mRNA in the adult rat cerebellum. Using double immunofluorescence, TRPV3-immunoreactivity was observed in Calbindin D28K-labeled Purkinje neurons. The sections of cerebellum from the postnatal rats (P4, P8, P16 and P42) were processed for TRPV3-immunofluorescence. Compared to P4 and P8, the percent fluorescent area of TRPV3-immunoreactivity significantly increased in the cerebellum of P16 and P42 rats. With a view to test the significance of TRPV3 in cerebellar function, TRPV3-agonist (eugenol) or -inhibitors [ruthenium red or isopentenyl pyrophosphate (IPP)] were administered stereotaxically intra-cerebellum and motor responses analyzed. Compared to controls, rats injected with TRPV3 inhibitor significantly reduced the stride length (P < 0.001), locomotor activity (P < 0.001), and rotarod retention time (P < 0.001), but increased footprints length (P < 0.01) and escape latency (P < 0001). TRPV3-agonist treatment, however, had no effect on these behaviors. We suggest that TRPV3 in Purkinje neurons may serve as novel molecular component for Ca2+-signaling and motor coordination function of the cerebellum. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone's abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide's levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide's expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration. Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide's expression in the hypothalamus is influenced by neuroendocrine challenges.

An important prerequisite for the analysis of spike synchrony in extracellular recordings is the extraction of single-unit activity from the multi-unit signal. To identify single units, potential spikes are separated with respect to their potential neuronal origins ('spike sorting'). However, different sorting algorithms yield inconsistent unit assignments, which seriously influences subsequent spike train analyses. We aim to identify the best sorting algorithm for subthalamic nucleus recordings of patients with Parkinson's disease (experimental data ED). Therefore, we apply various prevalent algorithms offered by the 'Plexon Offline Sorter' and evaluate the sorting results. Since this evaluation leaves us unsure about the best algorithm, we apply all methods again to artificial data (AD) with known ground truth. AD consists of pairs of single units with different shape similarity embedded in the background noise of the ED. The sorting evaluation depicts a significant influence of the respective methods on the single unit assignments. We find a high variability in the sortings obtained by different algorithms that increases with single units shape similarity. We also find significant differences in the resulting firing characteristics. We conclude that Valley-Seeking algorithms produce the most accurate result if the exclusion of artifacts as unsorted events is important. If the latter is less important ('clean' data) the K-Means algorithm is a better option. Our results strongly argue for the need of standardized validation procedures based on ground truth data. The recipe suggested here is simple enough to become a standard procedure. • Different spike sorting methods yield highly variable single unit assignments. • Thus, there are significant differences in the resulting dynamical properties. • Valley-seeking yields the most accurate result if there are many perturbations. • K-Means is a better option if perturbations are of less importance. [ABSTRACT FROM AUTHOR]

Many, or most, tinnitus models rely on increased central gain in the auditory pathway as all or part of the explanation, in that central auditory neurones deprived of their usual sensory input maintain homeostasis by increasing the rate at which they fire in response to any given strength of input, including amplifying spontaneous firing which forms the basis of tinnitus. However, dramatic gain changes occur in response to damage to the auditory periphery, irrespective of whether tinnitus occurs. This article considers gain in its broadest sense, summarizes its contributory processes, neural manifestations, behavioral effects, techniques for its measurement, pitfalls in attributing gain changes to tinnitus, a discussion of the minimum evidential requirements to implicate gain as a necessary and/or sufficient basis to explain tinnitus, and the extent of existing evidence in this regard. Overall there is compelling evidence that peripheral auditory insults induce changes in neuronal firing rates, synchrony and neurochemistry and thus increase gain, but specific attribution of these changes to tinnitus is generally hampered by the absence of hearing-matched human control groups or insult-exposed non-tinnitus animals. A few studies show changes specifically attributable to tinnitus at group level, but the limited attempts so far to classify individual subjects based on gain metrics have not proven successful. If gain turns out to be unnecessary or insufficient to cause tinnitus, candidate additional mechanisms include focused attention, resetting of sensory predictions, failure of sensory gating, altered sensory predictions, formation of pervasive memory traces and/or entry into global perceptual networks. This article is part of a Special Issue entitled: Hearing Loss, Tinnitus, Hyperacusis, Central Gain. • Gain changes comprise changes in synaptic properties, neuronal excitability and neural synchrony. • Dramatic gain changes, at all levels of the central auditory pathway, follow damage to the peripheral auditory system. • Lack of hearing-matched control groups has been the main factor preventing attribution of gain changes to tinnitus. • For gain to be a sufficient explanation of tinnitus, it must provide accurate classification at the individual subject level. • Alternative/additional processes are summarized to explain tinnitus if gain changes are non-contributory or insufficient. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea patients face episodes of chronic intermittent hypoxia (CIH), which has been suggested as a causative factor for increased sympathetic activity (SNA) and hypertension. Female rats exposed to CIH develop hypertension and exhibit changes in respiratory–sympathetic coupling, marked by an increase in the inspiratory modulation of SNA. We tested the hypothesis that enhanced inspiratory-modulation of SNA is dependent on carotid bodies (CBs) and are associated with changes in respiratory network activity. For this, in CIH-female rats we evaluated the effect of CBs ablation on respiratory–sympathetic coupling, recorded from respiratory neurons in the working heart–brainstem preparation and from NTS neurons in brainstem slices. CIH-female rats had an increase in peripheral chemoreflex response and in spontaneous excitatory neurotransmission in NTS. CBs ablation prevents the increase in inspiratory modulation of SNA in CIH-female rats. Pre-inspiratory/inspiratory (Pre-I/I) neurons of CIH-female rats have a reduced firing frequency. Post-inspiratory neurons are active for a longer period during expiration in CIH-female rats. Further, using the computational model of a brainstem respiratory–sympathetic network, we demonstrate that a reduction in Pre-I/I neuron firing frequency simulates the enhanced inspiratory SNA modulation in CIH-female rats. We conclude that changes in respiratory–sympathetic coupling in CIH-female rats is dependent on CBs and it is associated with changes in firing properties of specific respiratory neurons types. • Peripheral chemoreflex response is increased CIH-female rats. • Excitatory neurotransmission is increased in NTS neurons of CIH-female rats. • Enhanced respiratory–sympathetic coupling depends on the integrity of carotid bodies in CIH-female rats • Pre-inspiratory (Pre-I/I) and Post-inspiratory neurons have changed their firing properties in CIH-female rats. • Reduction in the conductance of I NaP in Pre-I/I neurons simulates respiratory–sympathetic coupling in CIH-female rats. [ABSTRACT FROM AUTHOR]

Gap junctions mediate electrical coupling between neurons and modulate their firing activity. In mouse neocortical layer 5, the major types of pyramidal neurons organize into cell type-specific microcolumns that exhibit modular neuronal activity. During cortical development, microcolumn neurons are electrically coupled in a cell type-specific manner at the stage of synaptogenesis, forming a dense network of gap junctions. However, modulation of neuronal activity by the gap junction network has not been examined. Here, we show that the electrical coupling induces amplification and slow synchronization of action potentials. This slow synchronization is mediated by electrical transmission that is an order of magnitude slower than that of gap junction-coupled neurons of other types. Theoretical and structural analyses suggested that apical dendrites are a major site of electrical coupling, providing slow electrical transmission. These results suggest that the gap junction network organizes neuronal activity of developing cortical circuit modules with unique slow dynamics. • Microcolumnar gap junction network amplifies and synchronizes firing activity of developing neocortical pyramidal neurons. • Synchronization and electrical transmission are markedly slower than those of previously known electrical coupling. • Apical dendritic shafts are suggested to be a major site of gap junctions providing uniquely slow electrical transmission. [ABSTRACT FROM AUTHOR]

Abstract A common feature across neuropsychiatric disorders is inability to discontinue an action or thought once it has become detrimental. Reversal learning, a hallmark of executive control, requires plasticity within cortical, striatal and limbic circuits and is highly sensitive to disruption of N -methyl- D -aspartate receptor (NMDAR) function. In particular, selective deletion or antagonism of GluN2B containing NMDARs in cortical regions including the orbitofrontal cortex (OFC), promotes maladaptive perseveration. It remains unknown whether GluN2B functions to maintain local cortical activity necessary for reversal learning, or if it exerts a broader influence on the integration of neural activity across cortical and subcortical systems. To address this question, we utilized in vivo electrophysiology to record neuronal activity and local field potentials (LFP) in the orbitofrontal cortex and dorsal striatum (dS) of mice with deletion of GluN2B in neocortical and hippocampal principal cells while they performed touchscreen reversal learning. Reversal impairment produced by corticohippocampal GluN2B deletion was paralleled by an aberrant increase in functional connectivity between the OFC and dS. These alterations in coordination were associated with alterations in local OFC and dS firing activity. These data demonstrate highly dynamic patterns of cortical and striatal activity concomitant with reversal learning, and reveal GluN2B as a molecular mechanism underpinning the timing of these processes. Highlights • Neuronal firing rates are altered by corticohippocampal GluN2B deletion, both in the cortex and dorsal striatum. • GluN2B deletion disrupts communication between the orbital frontal cortex and dorsal striatum driving the continuation of unrewarded responses. • Our data demonstrate corticostriatal coordination is necessary for optimal behavioral flexibility. • These results suggest GluN2B containing NMDARs are a key molecular component in mediating neuronal timing. [ABSTRACT FROM AUTHOR]

Abstract Recent studies on the impact of Parkinson's disease (PD) on the thalamostriatal pathway have mainly focused on the structural and functional changes in the thalamus projection to the striatum. Alterations in the electrophysiological activity of the thalamostriatal circuit in PD have not been intensively studied. To further investigate this circuit, parafascicular nucleus (PF) single-unit spikes and dorsal striatum local field potential (LFP) activities were simultaneously recorded in control and 6-hydroxydopamine (6-OHDA)-lesioned rats during inattentive rest or treadmill walking states. We classified the PF neurons into two predominant subtypes (PF I and PF II). During rest state, after dopamine loss, increased PF I spike and striatal LFP coherence was observed in the beta-frequency (12–35 Hz), with changed PF I neuronal firing pattern and unchanged firing rates of the two neuron subtypes. However, in a treadmill walking state, PF II neurons displayed markedly increased coherence to striatal beta oscillations in the dopamine-depleted rats, as well as an altered PF II neuronal firing pattern and significantly decreased firing rates of the two neuron subtypes. The results indicate that in PD animals, state transition from rest to moving, such as treadmill walking, is associated with different PF neuron types and increased spike-LFP synchronization, which may provide new paradigms for understanding and treating PD. Highlights • PF neurons were classified into two predominant subtypes and dopamine loss altered PF neural firing activities. • The alterations of PF neural firing in PD are state-dependent. • Synchronization between single PF neurons with striatum β-frequency oscillations increased after dopamine loss. • The changes of synchronization are associated with different PF neuron subtypes in different states. [ABSTRACT FROM AUTHOR]

Whole-cell patch-clamp and extracellular field recordings were obtained from 450-microns-thick brain slices of infant rats (10-13 days postnatal) to determine the actions of corticotropin-releasing hormone on glutamate- and GABA-mediated synaptic transmission in the hippocampus. Synthetic corticotropin-releasing hormone (0.15 microM) reversibly increased the excitability of hippocampal pyramidal cells, as determined by the increase in the amplitude of the CA1 population spikes evoked by stimulation of the Schaffer collateral pathway. This increase in population spike amplitude could be prevented by the corticotropin-releasing hormone receptor antagonist alpha-helical (9-41)-corticotropin-releasing hormone (10 microM). Whole-cell patch-clamp recordings revealed that, in the presence of blockers of fast excitatory and inhibitory synaptic transmission, corticotropin-releasing hormone caused only a small (1-2 mV) depolarization of the resting membrane potential in CA3 pyramidal cells, and it did not significantly alter the input resistance. However, corticotropin-releasing hormone, in addition to decreasing the slow afterhyperpolarization, caused an increase in the number of action potentials per burst evoked by depolarizing current pulses. Corticotropin-releasing hormone did not significantly change the frequency, amplitude or kinetics of miniature excitatory postsynaptic currents. However, it increased the frequency of the spontaneous excitatory postsynaptic currents in CA3 pyramidal cells, without altering their amplitude and single exponential rise and decay time constants. Corticotropin-releasing hormone did not change the amplitude of the pharmacologically isolated (i.e. recorded in the presence of GABAA receptor antagonist bicuculline) excitatory postsynaptic currents in CA3 and CA1 pyramidal cells evoked by stimulation of the mossy fibers and the Schaffer collaterals, respectively. Current-clamp recordings in bicuculline-containing medium showed that, in the presence of corticotropin-releasing hormone, mossy fiber stimulation leads to large, synchronized, polysynaptically-evoked bursts of action potentials in CA3 pyramidal cells. In addition, the peptide caused a small, reversible decrease in the amplitude of the pharmacologically isolated (i.e. recorded in the presence of glutamate receptor antagonists) evoked inhibitory postsynaptic currents in CA3 pyramidal cells, but it did not significantly alter the frequency, amplitude, rise and decay time constants of spontaneous or miniature inhibitory postsynaptic currents. These data demonstrate that corticotropin-releasing hormone, an endogenous neuropeptide whose intracerebroventricular infusion results in seizure activity in immature rats, has diverse effects in the hippocampus which may contribute to epileptogenesis. It is proposed that the net effect of corticotropin-releasing hormone is a preferential amplification of those incoming excitatory signals which are strong enough to reach firing threshold in at least a subpopulation of CA3 cells. These findings suggest that the actions of corticotropin-releasing hormone on neuronal excitability in the immature hippocampus may play a role in human developmental epilepsies.

Highlights • IL-1β (1 µg, i.p.) induced sickness-like behavior in adult male Sprague–Dawley rats. • It increased the firing rate in the BLA complex acutely with a change in firing pattern. • The effect was more prominent in the basal nucleus of the BLA complex. • LPS (250 μg/kg, i.p.) increased BLA firing rate acutely and persistently. • Immunogen challenge increased BLA firing rate before serum IL-1β reached its peak. Abstract Peripheral inflammation often causes changes in mood and emergence of depressive behavior, and is characterized by a group of physical manifestations including lethargy, malaise, listlessness, decreased appetite, anhedonia, and fever. These behavioral changes are induced at the molecular level by pro-inflammatory cytokines like interleukin (IL)-1β, IL-6 and TNF-α. The basolateral amygdala (BLA) is a key brain region involved in mood and may mediate some of the behavioral effects of inflammation. However, it is unknown whether peripheral inflammatory state affects the activity of BLA neurons. To test this, adult male Sprague–Dawley rats were treated with IL-1β (1 μg, intraperitoneal (i.p.)), and behavioral and electrophysiological measures were obtained. IL-1β reduced locomotion in the open-field test and also reduced home-cage mobility, consistent with features of sickness-like behavior. Using in vivo single-unit extracellular electrophysiological recordings from anesthetized rats, we found that spontaneous BLA neuronal firing was acutely (<30 min) increased after IL-1β, followed by a return to baseline level, particularly in the basal nucleus of the BLA complex. To verify and expand on effects of peripheral inflammation, we tested whether another, long-lasting inflammagen also changes BLA neuronal firing. Lipopolysaccharide (250 μg/kg, i.p.) increased BLA firing rate acutely (<30 min) and persistently. The findings demonstrate a rapid effect of peripheral inflammation on BLA activity and suggest a link between BLA neuronal firing and triggering of behavioral consequences of peripheral inflammation. These findings are a first step toward understanding the neuronal basis of depressive behavior caused by acute peripheral inflammation. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) plays a key role in the initiation as well as the prolonged heightened pain sensitivity of the inflammatory response. Previously, we showed that NGF rapidly augmented both the excitability of isolated rat sensory neurons and the mechanical sensitivity of the rat’s hind paw. The increase in excitability and sensitivity was blocked by the myristoylated pseudosubstrate inhibitor of atypical PKCs (mPSI), suggesting that an atypical PKC may play a key regulatory role in generating this heightened sensitivity. Our findings raised the question as to whether NGF directs changes in translational control, as suggested for long-lasting long-term potentiation (LTP), or whether NGF leads to the activation of an atypical PKC by other mechanisms. The current studies demonstrate that enhanced action potential (AP) firing produced by NGF was blocked by inhibitors of translation, but not transcription. In parallel, in vitro studies showed that NGF elevated the protein levels of PKMζ, which was also prevented by inhibitors of translation. Intraplantar injection of NGF in the rat hind paw produced a rapid and maintained increase in mechanical sensitivity whose onset was delayed by translation inhibitors. Established NGF-induced hypersensitivity could be transiently reversed by injection of rapamycin or mPSI. These results suggest that NGF produces a rapid increase in the synthesis of PKMζ protein in the paw that augments neuronal sensitivity and that the ongoing translational expression of PKMζ plays a critical role in generating as well as maintaining the heightened sensitivity produced by NGF. [ABSTRACT FROM AUTHOR]