Firing Activity Of Neurons Research Articles

GABA-Induced Seizure-Like Events Caused by Multi-ionic Interactive Dynamics.

Experimental evidence showed that an increase in intracellular chloride concentration [Formula: see text] caused by gamma-aminobutyric acid (GABA) input can promote epileptic firing activity, but the actual mechanisms remain elusive. Here in this theoretical work, we show that influx of chloride and concomitant bicarbonate ion [Formula: see text] efflux upon GABA receptor activation can induce epileptic firing activity by transition of GABA from inhibition to excitation. We analyzed the intrinsic property of neuron firing states as a function of [Formula: see text] We found that as [Formula: see text] increases, the system exhibits a saddle-node bifurcation, above which the neuron exhibits a spectrum of intensive firing, periodic bursting interrupted by depolarization block (DB) state, and eventually a stable DB through a Hopf bifurcation. We demonstrate that only GABA stimuli together with [Formula: see text] efflux can switch GABA's effect to excitation which leads to a series of seizure-like events (SLEs). Exposure to a low [Formula: see text] can drive neurons with high concentrations of [Formula: see text] downward to lower levels of [Formula: see text], during which it could also trigger SLEs depending on the exchange rate with the bath. Our analysis and simulation results show how the competition between GABA stimuli-induced accumulation of [Formula: see text] and [Formula: see text] application-induced decrease of [Formula: see text] regulates the neuron firing activity, which helps to understand the fundamental ionic dynamics of SLE.

Abstract P436: Prorenin Increases the Firing Activity of Hypothalamic Arcuate Nucleus AgRP Neurons

The arcuate nucleus of the hypothalamus (ARC) serves as a key regulator of the cardiovascular and sympathetic regulating center. While neurons in the ARC expressing agouti-related peptide (AgRP) are implicated in the regulation of energy- and glucose homeostasis, our recent findings show that acute chemogenic activation of ARC AgRP neurons reduces blood pressure (BP), whereas inhibition of these neurons has the opposite effect. Together, these observations indicate ARC AgRP neuronal activity as a determinant of basal BP and suggest that tonic activity of these neurons may be required to maintain BP in the normal range. Importantly, most AgRP neurons express the (pro)renin receptor (PRR), a pivotal component of the brain renin-angiotensin system critical for BP regulation. Accordingly, we hypothesized that prorenin may regulate AgRP neuron activity through PRR, and thereby contributing to the autonomic regulation of BP. This study employed whole-cell patch clamp methodology in brain slices of ARC to investigate the effect of prorenin on AgRP neuron firing activity and understand mechanisms. Male and female mice expressing tdTomato in the AgRP neurons were used. Prorenin (2.5 nM) depolarized the resting membrane potential (-41.9 ± 8.7 mV vs. -47.2 ± 7.8 mV, P < 0.001) and increased the frequency of action potential (AP) (2.3 ± 1.3 Hz vs. 1.2 ± 0.8 Hz, P < 0.001) compared with the control (artificial cerebrospinal fluid (aCSF), n=10 neurons from 7mice). Analysis of AP waveforms revealed that prorenin decreased the amplitude of AP (61.0 ± 14.4 mV vs. 70.2 ± 14.3 mV, P < 0.001) and threshold potential (-31.8 ± 6.0 mV vs. -35.5 ± 4.8 mV, P < 0.001), and increased the rise time (2.3 ± 0.7 ms vs. 1.9 ± 0.6 ms, P < 0.001), decay time (2.6 ± 1.1 ms vs. 2.0 ± 0.9 ms, P < 0.01) and half-width (2.2 ± 0.7 ms vs. 1.8 ± 0.6 ms, P <0.01) compared with the control. These changes suggest that alterations in the intrinsic conductance underlying the AP waveform likely coincide with the observed decrease in resting membrane potentials, while the ion channels involved remained to be determined. In summary, prorenin increases the firing activity of the ARC AgRP neurons by depolarizing the resting membrane potential, implicating that activation of PRR in the ARC AgRP neurons may reduce BP and protect against hypertension development.

Opposing actions of co-released GABA and neurotensin on the activity of preoptic neurons and on body temperature.

Neurotensin (Nts) is a neuropeptide acting as a neuromodulator in the brain. Pharmacological studies have identified Nts as a potent hypothermic agent. The medial preoptic area, a region that plays an important role in the control of thermoregulation, contains a high density of neurotensinergic neurons and Nts receptors. The conditions in which neurotensinergic neurons play a role in thermoregulation are not known. In this study, optogenetic stimulation of preoptic Nts neurons induced a small hyperthermia. In vitro, optogenetic stimulation of preoptic Nts neurons resulted in synaptic release of GABA and net inhibition of the preoptic pituitary adenylate cyclase-activating polypeptide (Adcyap1) neurons firing activity. GABA-A receptor antagonist or genetic deletion of Slc32a1 (VGAT) in Nts neurons unmasked also an excitatory effect that was blocked by a Nts receptor 1 antagonist. Stimulation of preoptic Nts neurons lacking Slc32a1 resulted in excitation of Adcyap1 neurons and hypothermia. Mice lacking Slc32a1 expression in Nts neurons presented changes in the fever response and in the responses to heat or cold exposure as well as an altered circadian rhythm of body temperature. Chemogenetic activation of all Nts neurons in the brain induced a 4-5°C hypothermia, which could be blocked by Nts receptor antagonists in the preoptic area. Chemogenetic activation of preoptic neurotensinergic projections resulted in robust excitation of preoptic Adcyap1 neurons. Taken together, our data demonstrate that endogenously released Nts can induce potent hypothermia and that excitation of preoptic Adcyap1 neurons is the cellular mechanism that triggers this response.

Distinct Neuromodulatory Effects of Endogenous Orexin and Dynorphin Corelease on Projection-Defined Ventral Tegmental Dopamine Neurons.

Dopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues, and circuit-specific signaling drives different aspects of motivated behavior. Orexin (ox; also known as hypocretin) and dynorphin (dyn) are coexpressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the coreleased peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LHox/dyn neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregate based on VTADA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch-clamp electrophysiology in male and female orexincre mice, we showed a diverse response of LHox/dyn optical stimulation on VTADA neuronal firing, which is not mediated by fast transmitter release and is blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA-projecting VTADA neurons, optical stimulation of LHox/dyn inputs in the VTA bidirectionally affects firing of either lAcbSh- or mAchSh-projecting VTADA neurons. These findings indicate that LHox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking.

Implication of locus coeruleus dysfunction in Prader–Willi syndrome: Insights from a mouse model

Prader–Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/−p) animals. Compared to WT mice, Ndn + m/−p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/−p and WT mice, but Ndn + m/−p mice were less anxious. After acute restraint, Ndn + m/−p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/−p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/−p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Blockade of pre- and post-synaptic GABAB receptors in the anteroventral bed nucleus of stria terminalis produces anxiolytic-like and anxiety-like effects in parkinsonian rats respectively

The anteroventral bed nucleus of stria terminalis (avBNST) is a limbic forebrain region involved in the regulation of anxiety, and expresses GABAB receptors, which are located at both pre- and post-synaptic sites. However, it is unclear how blockade of these receptors affects anxiety-like behaviors, particularly in Parkinson's disease (PD)-related anxiety. In the present study, unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta in rats induced anxiety-like behaviors, and increased GABA release and decreased glutamate release in the avBNST, as well as decreased level of dopamine (DA) in the basolateral amygdala (BLA). Intra-avBNST injection of pre-synaptic GABAB receptor antagonist CGP36216 produced anxiolytic-like effects, while the injection of post-synaptic GABAB receptor antagonist CGP35348 induced anxiety-like responses in both sham and 6-OHDA rats. Intra-avBNST injection of CGP36216 inhibited the GABAergic neurons and increased GABA/glutamate ratio in the avBNST and increased levels of DA and serotonin (5-HT) in the BLA; conversely, CGP35348 produced opposite effects on the firing activity of avBNST GABAergic neurons and levels of the neurotransmitters in the avBNST and BLA. Moreover, the doses of the antagonists producing significant behavioral effects in 6-OHDA rats were lower than those in sham rats, and the duration of action of the antagonists on the firing rate of the neurons and release of the neurotransmitters was prolonged in 6-OHDA rats. Altogether, these findings suggest that pre- and post-synaptic GABAB receptors in the avBNST are implicated in PD-related anxiety-like behaviors, and degeneration of the nigrostriatal pathway enhances functions and/or upregulates expression of these receptors.

Altered firing activity of intracardiac neurons isolated from mice carrying the Scn5a-1798insD mutation

Abstract Funding Acknowledgements None. Background Dysfunction of the cardiac sodium channel Nav1.5 (encoded by SCN5A) is associated with arrhythmias and sudden cardiac death, the mechanisms of which have been extensively studied in cardiomyocytes. However, patients carrying an SCN5A mutation often display clinical symptoms which are not readily explained solely by alterations in cardiomyocyte electrophysiology. For instance, carriers of the SCN5A-1795insD mutation, which is associated with features of Brugada syndrome and Long QT syndrome type 3 (LQT3), display severe bradycardia leading to excessive QT-prolongation and sudden death especially occurring at rest or during the night, suggesting autonomic triggers. Interestingly, SCN5A is not only present in cardiomyocytes, but also in intracardiac neurons (ICN). ICN modulate cardiac electrophysiological properties and their dysregulation may contribute to arrhythmogenesis. Purpose To explore whether ICN from mice carrying the Scn5a-1798insD mutation (the murine equivalent of SCN5A-1795insD) display electrophysiological alterations that may (in part) contribute to the arrhythmogenic phenotype. Methods and Results ICN were isolated by enzymatic dissociation from fat pads located in the pulmonary veins and sinoatrial node regions of the hearts of wild-type (WT) and Scn5a-1798insD mice. Immunodetection of the cholinergic marker ChAT confirmed the prominent cholinergic phenotype of ICN. In agreement with previous reports in other species, we also detected the presence of Nav1.5 in murine ICN. Nav1.5 expression was mainly observed in ChAT positive cells. To evoke repetitive action potential (AP) firing in single ICN, 500 ms-sustained depolarizing current pulses were applied of increasing amplitude (from 0 pA to 150 pA). Two types of neurons were identified on the basis of firing pattern characteristics: accommodating (neurons that discharged multiple APs decrementing in frequency during the pulse) and tonic (neurons that discharged multiple APs at a high frequency). APs firing frequency did not differ between WT and Scn5a-1798insD accommodating ICN, while it was significantly increased in Scn5a-1798insD tonic ICN as compared to WT (at 100 pA, AP count/500ms in WT CMs: 29.5±1.7, n=24; at 100 pA, AP count/500ms in Scn5a-1798insD: 36.2±2.0, n=18, p=0.02). Conclusions The impact of SCN5A mutations on ICN function are unexplored, but may play an essential role in arrhythmogenesis. The increased AP firing frequency observed in Scn5a-1798insD ICN may lead to increased release of neurotransmitters, such as acetylcholine, that in turn may contribute to the bradycardia observed in patients. Overall, further elucidation of the electrophysiological consequences of inherited Nav1.5 dysfunction in ICN might provide novel therapeutic targets to prevent lethal arrhythmias.

A large-scale neuronal network modelling study: Stimulus size modulates gamma oscillations in the primary visual cortex by long-range connections.

Stimulus size modulation of neuronal firing activity is a fundamental property of the primary visual cortex. Numerous biological experiments have shown that stimulus size modulation is affected by multiple factors at different spatiotemporal scales, but the exact pathways and mechanisms remain incompletely understood. In this paper, we establish a large-scale neuronal network model of primary visual cortex withlayer 2/3 to study how gamma oscillation properties are modulated by stimulus size and especially how long-range connections affect the modulation as realistic neuronal properties and spatial distributions of synaptic connections are considered. It is shown that long-range horizontal synaptic connections are sufficient to produce dimensional modulation of firing rates and gamma oscillations. In particular, with increasing grating stimulus size, the firing rate increases and then decreases, the peak frequency of gamma oscillations decreases and the spectral power increases. These are consistent with biological experimental observations. Furthermore, we explain in detail how the number and spatial distribution of long-range connections affect the size modulation of gamma oscillations by using the analysis of neuronal firing activity and synaptic current fluctuations. Our results provide a mechanism explanation for size modulation of gamma oscillations in the primary visual cortex and reveal the important and unique role played by long-range connections, which contributes to a deeper understanding of the cognitive function of gamma oscillations in visual cortex.

Glucocorticoid receptors regulate hypothalamic CRH neuron activity in primary hypertension

The hypothalamic-pituitary-adrenal axis is important in maintaining homeostasis in response to physical and psychological stressors. The corticotropin-releasing hormone (CRH) is a neuropeptide synthesized by CRH neurons in brain regions including paraventricular nucleus (PVN) of the hypothalamus. The glucocorticoids synthesized and released in adrenal gland act on hypothalamic CRH-expressing neurons inhibit the CRH production and maintain the level of glucocorticoids. The glucocorticoid receptor (GR) is critical for this negative feedback to regulate CRH synthesis and release. Hypertension is associated with high stress response and CRH mRNA levels. The number of CRH-expression neurons are significantly increased in PVN of the hypothalamus in primary hypertension patients. this study determined if the HPA axis negative feedback is altered and contribute to maintaining hypertension. We measured mRNA expression levels of GRs and MR in PVN tissue obtained from adult Wistar-Kyoto normotensive rats (WKYs) and spontaneously hypertensive rats (SHRs) and found that the GR mRNA expression level was significantly lower in SHRs that in WKY rats, while the MR gene expression did not differ between WKY rats and SHRs. Furthermore, we found that acute perfusion of dexamethasone (DEX), a synthetic glucocorticoid, significantly decreased frequency of spontaneous excitatory postsynaptic synaptic currents (EPSCs) in identified PVN-CRH expressing neurons in brain slices prepared from WKY and SHRs. DEX caused a greater reduction of frequency of EPSCs in SHRs was than in WKY rats. Acute perfusion of DEX significantly increased the firing rate of PVN-CRH neurons in WKY rats but did not change the firing rate in SHRs. In addition, incubation of brain slices with DEX for 1 hr significantly inhibited the firing activity of PVN-CRH neurons in WKY rats but did not change the firing activity of PVN CRH neurons in SHRs. These data suggested that the glucocorticoid excites PVN-CRH neurons in acute phase while inhibits these neurons in chronic phase in normotensive rat. In hypertension, downregulated GR may be responsible for impaired the HPA axis feedback and contribute to hypertension. HL139523, HL142133, and HL159157. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Maternal treatment with a selective delta-opioid receptor agonist during gestation has a sex-specific pro-cognitive action in offspring: mechanisms involved.

Background: There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Methods: Gestating Wistar rats were chronically treated with a selective delta-agonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by in vivo electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. Results: We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Conclusion: Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.

Short-term hyperoxia-induced functional and morphological changes in rat hippocampus.

Excess oxygen (O2) levels may have a stimulating effect, but in the long term, and at high concentrations of O2, it is harmful to the nervous system. The hippocampus is very sensitive to pathophysiological changes and altered O2 concentrations can interfere with hippocampus-dependent learning and memory functions. In this study, we investigated the hyperoxia-induced changes in the rat hippocampus to evaluate the short-term effect of mild and severe hyperoxia. Wistar male rats were randomly divided into control (21% O2), mild hyperoxia (30% O2), and severe hyperoxia groups (100% O2). The O2 exposure lasted for 60 min. Multi-channel silicon probes were used to study network oscillations and firing properties of hippocampal putative inhibitory and excitatory neurons. Neural damage was assessed using the Gallyas silver impregnation method. Mild hyperoxia (30% O2) led to the formation of moderate numbers of silver-impregnated "dark" neurons in the hippocampus. On the other hand, exposure to 100% O2 was associated with a significant increase in the number of "dark" neurons located mostly in the hilus. The peak frequency of the delta oscillation decreased significantly in both mild and severe hyperoxia in urethane anesthetized rats. Compared to normoxia, the firing activity of pyramidal neurons under hyperoxia increased while it was more heterogeneous in putative interneurons in the cornu ammonis area 1 (CA1) and area 3 (CA3). These results indicate that short-term hyperoxia can change the firing properties of hippocampal neurons and network oscillations and damage neurons. Therefore, the use of elevated O2 concentration inhalation in hospitals (i.e., COVID treatment and surgery) and in various non-medical scenarios (i.e., airplane emergency O2 masks, fire-fighters, and high altitude trekkers) must be used with extreme caution.

Dynamic prediction of goal location by coordinated representation of prefrontal-hippocampal theta sequences

Prefrontal (PFC) and hippocampal (HPC) sequences of neuronal firing modulated by theta rhythms could represent upcoming choices during spatial memory-guided decision-making. How the PFC-HPC network dynamically coordinates theta sequences to predict specific goal locations and how it is interrupted in memory impairments induced by amyloid beta (Aβ) remain unclear. Here, we detected theta sequences of firing activities of PFC neurons and HPC place cells during goal-directed spatial memory tasks. We found that PFC ensembles exhibited predictive representation of the specific goal location since the starting phase of memory retrieval, earlier than the hippocampus. High predictive accuracy of PFC theta sequences existed during successful memory retrieval and positively correlated with memory performance. Coordinated PFC-HPC sequences showed PFC-dominant prediction of goal locations during successful memory retrieval. Furthermore, we found that theta sequences of both regions still existed under Aβ accumulation, whereas their predictive representation of goal locations was weakened with disrupted spatial representation of HPC place cells and PFC neurons. These findings highlight the essential role of coordinated PFC-HPC sequences in successful memory retrieval of a precise goal location.

Firing behaviors of memristor-based Rulkov neuron map using energy method

Neural firing behavior is essentially the energy transmission between neurons, which can represent the information process of nervous system. Consequently, it is crucial to delve deeply into the intricate firing activity and energy characteristics of neurons. The Helmholtz theorem offers an accurate energy description for continuous neurons. However, the energy of discrete neurons remains under-explored due to lacking an effective theoretical framework. In this paper, we introduce a novel Rulkov neuron map that incorporates a charge-controlled memristor for imitating the effect of electromagnetic radiation. The Hamilton energy method is utilized to investigate the firing behaviors of this neuron map. A pivotal step in our analysis is meticulously scaling the parameters and variables to transform the neuron map into a continuous oscillator, which is essential for obtaining its energy function. In the exploration of the Rulkov neuron map, a range of intricate firing behaviors, including mixed-mode firing, bursting firing and coexistence firing, are observed. Notably, the occurrence of coherence resonance is detected under noise excitation. These behaviors are characterized by the time evolution of membrane potential and Hamilton energy spectrum. Furthermore, FPGA-based experiments are conducted to confirm the numerical results.

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9–39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.

Alpha herpesvirus exocytosis from neuron cell bodies uses constitutive secretory mechanisms, and egress and spread from axons is independent of neuronal firing activity.

Alpha herpesviruses naturally infect the peripheral nervous system, and can spread to the central nervous system, causing severe debilitating or deadly disease. Because alpha herpesviruses spread along synaptic circuits, and infected neurons exhibit altered electrophysiology and increased spontaneous activity, we hypothesized that alpha herpesviruses use activity-dependent synaptic vesicle-like regulated secretory mechanisms for egress and spread from neurons. Using live-cell fluorescence microscopy, we show that Pseudorabies Virus (PRV) particles use the constitutive Rab6 post-Golgi secretory pathway to exit from the cell body of primary neurons, independent of local calcium signaling. Some PRV particles colocalize with Rab6 in the proximal axon, but we did not detect colocalization/co-transport in the distal axon. Thus, the specific secretory mechanisms used for viral egress from axons remains unclear. To address the role of neuronal activity more generally, we used a compartmentalized neuron culture system to measure the egress and spread of PRV from axons, and pharmacological and optogenetics approaches to modulate neuronal activity. Using tetrodotoxin to silence neuronal activity, we observed no inhibition, and using potassium chloride or optogenetics to elevate neuronal activity, we also show no increase in virus spread from axons. We conclude that PRV egress from neurons uses constitutive secretory mechanisms: generally, activity-independent mechanisms in axons, and specifically, the constitutive Rab6 post-Golgi secretory pathway in cell bodies.

Serotonergic regulation of cortical neurovascular coupling and hemodynamics upon awakening from sleep in mice

Neurovascular coupling (NVC) is the functional hyperemia of the brain responding to local neuronal activity. It is mediated by astrocytes and affected by subcortical ascending pathways in the cortex that convey information, such as sensory stimuli and the animal condition. Here, we investigate the influence of the raphe serotonergic system, a subcortical ascending arousal system in animals, on the modulation of cortical NVC and cerebral blood flow (CBF). Raphe serotonergic neurons were optogenically activated for 30 s, which immediately awakened the mice from non-rapid eye movement sleep. This caused a biphasic cortical hemodynamic change: a transient increase for a few seconds immediately after photostimulation onset, followed by a large progressive decrease during the stimulation period. Serotonergic neuron activation increased intracellular Ca2+ levels in cortical pyramidal neurons and astrocytes, demonstrating its effect on the NVC components. Pharmacological inhibition of cortical neuronal firing activity and astrocyte metabolic activity had small hypovolemic effects on serotonin-induced biphasic CBF changes, while blocking 5-HT1B receptors expressed primarily in cerebral vasculature attenuated the decreasing CBF phase. This suggests that serotonergic neuron activation leading to animal awakening could allow the NVC to exert a hyperemic function during a biphasic CBF response, with a predominant decrease in the cortex.

Synaptic mechanisms underlying the elevated sympathetic outflow in fructose-induced hypertension.

Metabolic syndrome is associated with cardiovascular dysfunction, including elevated sympathetic outflow. However, the underlying brain mechanisms are unclear. The nucleus tractus solitarius (NTS) critically regulates autonomic reflexes related to cardiovascular function and contains neurons projecting to the caudal ventrolateral medulla (CVLM). Nitric oxide (NO) is a diffusible free-radical messenger in the vascular, immune, and nervous systems. In this study, we determine if NO in the NTS is involved in the synaptic plasticity underlying the elevated sympathetic outflow in fructose-induced hypertension. We retrogradely labeled CVLM-projecting NTS neurons through the injection of FluoSpheres into the CVLM in a fructose-fed rat model to determine the cellular mechanism involved in increased sympathetic outflow. Fructose feeding increased the blood pressure and glucose levels, which represent metabolic syndrome. We found that fructose feeding reduces the NO precursor L-arginine-induced increase in the firing activity of CVLM-projecting NTS neurons. Furthermore, fructose feeding reduces the L-arginine-induced increase in presynaptic spontaneous glutamatergic synaptic inputs to NTS neurons, while NO donor DEA/NO produces an increase in glutamatergic synaptic inputs in fructose-fed rats similar to that in vehicle-treated rats. In addition, fructose feeding reduces the NO-induced depressor response and sympathoinhibition. These data suggested that fructose feeding reduced NO production and, thus, the subsequent NO-induced glutamate releases in the NTS and depressor response. The findings of this study provide new insights into the central mechanisms involved in the neural control of cardiovascular and autonomic functions in the NTS in metabolic syndrome.

Bifurcations to bursting oscillations in memristor-based FitzHugh-Nagumo circuit

To characterize neuronal firing activities and elucidate its bifurcation mechanisms, a memristor-based FitzHugh-Nagumo (FHN) circuit is designed based on the FHN circuit architecture combined with a first-order memristive simulator, and its normalized system with periodic and quasi-periodic bursting oscillations is established. With the change of externally applied excitation, the memristor-based FHN system has the time-varying equilibrium point where the number, position and stability evolve slowly over time. In an evolution period of the time-domain waveform, different fold and/or Hopf bifurcations are triggered, resulting in periodic or quasi-periodic bursting oscillations. To explain the intrinsic bifurcation mechanisms, the fold and Hopf bifurcation sets are built and the transitions between the resting and spiking states are demonstrated, thus identifying the Hopf/fold and Hopf/Hopf bursting oscillations. Finally, based on the circuit simulation model, analog circuit simulations and hardware circuit measurements are developed for the memristor-based FHN circuit to confirm MATLAB numerical simulations. In addition, it is worth noting that the proposed circuit is a simple non-autonomous memristive neuron circuit that is particularly easy to physically implement.

Tau reduction with artificial microRNAs modulates neuronal physiology and improves tauopathy phenotypes in mice

Abnormal tau accumulation is the hallmark of several neurodegenerative diseases, named tauopathies. Strategies aimed at reducing tau in the brain are promising therapeutic interventions, yet more precise therapies would require targeting specific nuclei and neuronal subpopulations affected by disease, while avoiding global reduction of physiological tau. Here we developed artificial microRNAs directed against the human MAPT mRNA to dwindle tau protein by engaging the endogenous RNA interference pathway. In human differentiated neurons in culture, microRNAs-mediated tau reduction diminished neuronal firing without affecting neuronal morphology or impairing axonal transport. In the htau mouse model of tauopathy, we locally expressed artificial microRNAs in the prefrontal cortex (PFC), an area particularly vulnerable to initiating tau pathology in this model. Tau knockdown prevented the accumulation of insoluble and hyperphosphorylated tau, modulated firing activity of putative pyramidal neurons, and improved glucose uptake in the PFC. Moreover, such tau reduction prevented cognitive decline in aged htau mice. Our results suggest target engagement of designed tau-microRNAs to effectively reduce tau pathology, providing a proof of concept for a potential therapeutic approach based on local tau knockdown to rescue tauopathy-related phenotypes.

A critical review of ethanol effects on neuronal firing: A metabolic perspective.

Ethanol metabolism is relatively understudied in neurons, even though changes in neuronal metabolism are known to affect their activity. Recent work demonstrates that ethanol is preferentially metabolized over glucose as a source of carbon and energy, and it reprograms neurons to a state of reduced energy potential and diminished capacity to utilize glucose once ethanol is exhausted. Ethanol intake has been associated with changes in neuronal firing and specific brain activity (EEG) patterns have been linked with risk for alcohol use disorder (AUD). Furthermore, a haplotype of the inwardly rectifying potassium channel subunit, GIRK2, which plays a critical role in regulating excitability of neurons, has been linked with AUD and shown to be directly regulated by ethanol. At the same time, overexpression of GIRK2 prevents ethanol-induced metabolic changes. Based on the available evidence, we conclude thatthe mechanisms underlying the effects of ethanol on neuronal metabolism are a novel target for developing therapies for AUD.