Firing Rate Of Neurons Research Articles

Effects of NALCN-Encoded Na+ Leak Currents on the Repetitive Firing Properties of SCN Neurons Depend on K+-Driven Rhythmic Changes in Input Resistance.

Neurons in the suprachiasmatic nucleus (SCN) generate circadian changes in the rates of spontaneous action potential firing that regulate and synchronize daily rhythms in physiology and behavior. Considerable evidence suggests that daily rhythms in the repetitive firing rates (higher during the day than at night) of SCN neurons are mediated by changes in subthreshold potassium (K+) conductance(s). An alternative "bicycle" model for circadian regulation of membrane excitability in clock neurons, however, suggests that an increase in NALCN-encoded sodium (Na+) leak conductance underlies daytime increases in firing rates. The experiments reported here explored the role of Na+ leak currents in regulating daytime and nighttime repetitive firing rates in identified adult male and female mouse SCN neurons: vasoactive intestinal peptide-expressing (VIP+), neuromedin S-expressing (NMS+) and gastrin-releasing peptide-expressing (GRP+) cells. Whole-cell recordings from VIP+, NMS+, and GRP+ neurons in acute SCN slices revealed that Na+ leak current amplitudes/densities are similar during the day and at night, but have a larger impact on membrane potentials in daytime neurons. Additional experiments, using an in vivo conditional knockout approach, demonstrated that NALCN-encoded Na+ currents selectively regulate daytime repetitive firing rates of adult SCN neurons. Dynamic clamp-mediated manipulation revealed that the effects of NALCN-encoded Na+ currents on the repetitive firing rates of SCN neurons depend on K+ current-driven changes in input resistances. Together, these findings demonstrate that NALCN-encoded Na+ leak channels contribute to regulating daily rhythms in the excitability of SCN neurons by a mechanism that depends on K+ current-mediated rhythmic changes in intrinsic membrane properties.SIGNIFICANCE STATEMENT Elucidating the ionic mechanisms responsible for generating daily rhythms in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, is an important step toward understanding how the molecular clock controls circadian rhythms in physiology and behavior. While numerous studies have focused on identifying subthreshold K+ channel(s) that mediate day-night changes in the firing rates of SCN neurons, a role for Na+ leak currents has also been suggested. The results of the experiments presented here demonstrate that NALCN-encoded Na+ leak currents differentially modulate daily rhythms in the daytime/nighttime repetitive firing rates of SCN neurons as a consequence of rhythmic changes in subthreshold K+ currents.

Nucleus accumbens shell neurons’ early sensitivity to cocaine is associated with future increases in drug intake

The striatum, both dorsal and ventral, is strongly implicated in substance use disorder. Chronic consumption of abused substances, such as cocaine, can cause an oversaturation of mesostriatal dopamine, which results in alterations in the firing of striatal neurons. While most preclinical studies of drug self-administration (S-A) are focused on these alterations, individual differences in a subject's early responses to drugs can also account for substantial differences in addiction susceptibility. In this study, we modeled longitudinal pharmacokinetics using data from a previous longitudinal study (Coffey et al., 2015) and aimed to determine if firing in specific dorsal and ventral striatal subregions was subject to changes across chronic cocaine S-A, and if individual animal differences in striatal firing in response to early drug exposure correlated with increases in drug intake. We observed that the firing patterns of nucleus accumbens (NAc) core and shell neurons exhibited increasing sensitivity to cocaine over the first 6 S-A sessions and maintained a strong negative correlation between drug intake and neuronal firing rates across chronic S-A. Moreover, we observed that the early sensitivity of NAc shell neurons to cocaine correlated with future increases in drug intake. Specifically, rats whose NAc shell neurons were most inhibited by increasing levels of cocaine upon first exposure exhibited the strongest increases in cocaine intake over time. If this difference can be linked to a genetic difference, or druggable targets, it may be possible to screen for similar addiction susceptibility in humans or develop novel preemptive pharmacotherapies.

Spike-frequency adaptation inhibits the pairwise spike correlation.

The spike train output correlation with pairwise neurons determines the neural population coding, which depends on the average firing rate of individual neurons. Spike frequency adaptation (SFA), which serves as an essential cellular encoding strategy, modulates the firing rates of individual neurons. However, the mechanism by which the SFA modulates the output correlation of the spike trains remains unclear. We introduce a pairwise neuron model that receives correlated inputs to generate spike trains, and the output correlation is qualified using Pearson correlation coefficient. The SFA is modeled using adaptation currents to examine its effect on the output correlation. Moreover, we use dynamic thresholds to explore the effect of SFA on output correlation. Furthermore, a simple phenomenological neuron model with a threshold-linear transfer function is utilized to confirm the effect of SFA on decreasing the output correlation. The results show that the adaptation currents decreased the output correlation by reducing the firing rate of a single neuron. At the onset of a correlated input, a transient process shows a decrease in interspike intervals (ISIs), resulting in a temporary increase in the correlation. When the adaptation current is sufficiently activated, the correlation reached a steady state, and the ISIs are maintained at higher values. The enhanced adaptation current achieved by increasing the adaptation conductance further reduces the pairwise correlation. While the time and slide windows influence the correlation, they make no difference in the effect of SFA on decreasing the output correlation. Moreover, SFA simulated by dynamic thresholds also decreases the output correlation. Furthermore, the simple phenomenological neuron model with a threshold-linear transfer function confirms the effect of SFA on decreasing the output correlation. The strength of the signal input and the slope of the linear component of the transfer function, the latter of which can be decreased by SFA, could together modulate the strength of the output correlation. Stronger SFA will decrease the slope and hence decrease the output correlation. The results reveal that the SFA reduces the output correlation with pairwise neurons in the network by reducing the firing rate of individual neurons. This study provides a link between cellular non-linear mechanisms and network coding strategies.

A Review of Neural Data and Modelling to Explain How a Semicircular Canal Dehiscence (SCD) Causes Enhanced VEMPs, Skull Vibration Induced Nystagmus (SVIN), and the Tullio Phenomenon

Angular acceleration stimulation of a semicircular canal causes an increased firing rate in primary canal afferent neurons that result in nystagmus in healthy adult animals. However, increased firing rate in canal afferent neurons can also be caused by sound or vibration in patients after a semicircular canal dehiscence, and so these unusual stimuli will also cause nystagmus. The recent data and model by Iversen and Rabbitt show that sound or vibration may increase firing rate either by neural activation locked to the individual cycles of the stimulus or by slow changes in firing rate due to fluid pumping (“acoustic streaming”), which causes cupula deflection. Both mechanisms will act to increase the primary afferent firing rate and so trigger nystagmus. The primary afferent data in guinea pigs indicate that in some situations, these two mechanisms may oppose each other. This review has shown how these three clinical phenomena—skull vibration-induced nystagmus, enhanced vestibular evoked myogenic potentials, and the Tullio phenomenon—have a common tie: they are caused by the new response of semicircular canal afferent neurons to sound and vibration after a semicircular canal dehiscence.

Multi-channel microelectrode arrays for detection of single-cell level neural information in the hippocampus CA1 under general anesthesia induced by low-dose isoflurane

Timely monitoring of anesthesia status during surgery is important to prevent an overdose of isoflurane anesthesia. Therefore, in-depth studies of the neural mechanisms of anesthetics are warranted. Hippocampal CA1 plays an important role during anesthesia. Currently, a high spatiotemporal resolution microdevice technology for the accurate detection of deep brain nuclei is lacking. In this research, four-shank 32-channel implantable microelectrode arrays (MEAs) were developed for the real-time recording of single-cell level neural information in rat hippocampal CA1. Platinum nanoparticles were modified onto the microelectrodes to substantially enhance the electrical properties of the microelectrode arrays. The modified MEAs exhibited low impedance (11.5 ± 1 kΩ) and small phase delay (-18.5 ± 2.54°), which enabled the MEAs to record single-cell level neural information with a high signal-to-noise ratio. The MEAs were implanted into the CA1 nuclei of the anesthetized rats, and the electrophysiological signals were recorded under different degrees of anesthesia mediated by low-dose concentrations of isoflurane. The recorded signals were analyzed in depth. Isoflurane caused an inhibition of spike firing rate in hippocampal CA1 neurons, while inducing low-frequency oscillations in CA1, thus enhancing the low-frequency power of local field potentials. In this manner, the spike firing rate and the power of local field potentials in CA1 could characterize the degree of isoflurane anesthesia. The present study provides a technical tool to study the neural mechanisms of isoflurane anesthesia and a research method for monitoring the depth of isoflurane anesthesia in clinical practice.

Developing a 3-D computational model of neurons in the central amygdala to understand pharmacological targets for pain.

Neuropathic and nociplastic pain are major causes of pain and involve brain areas such as the central nucleus of the amygdala (CeA). Within the CeA, neurons expressing protein kinase c-delta (PKCδ) or somatostatin (SST) have opposing roles in pain-like modulation. In this manuscript, we describe our progress towards developing a 3-D computational model of PKCδ and SST neurons in the CeA and the use of this model to explore the pharmacological targeting of these two neural populations in modulating nociception. Our 3-D model expands upon our existing 2-D computational framework by including a realistic 3-D spatial representation of the CeA and its subnuclei and a network of directed links that preserves morphological properties of PKCδ and SST neurons. The model consists of 13,000 neurons with cell-type specific properties and behaviors estimated from laboratory data. During each model time step, neuron firing rates are updated based on an external stimulus, inhibitory signals are transmitted between neurons via the network, and a measure of nociceptive output from the CeA is calculated as the difference in firing rates of pro-nociceptive PKCδ neurons and anti-nociceptive SST neurons. Model simulations were conducted to explore differences in output for three different spatial distributions of PKCδ and SST neurons. Our results show that the localization of these neuron populations within CeA subnuclei is a key parameter in identifying spatial and cell-type pharmacological targets for pain.

Increased cortical plasticity leads to memory interference and enhanced hippocampal-cortical interactions.

Our brain is continuously challenged by daily experiences. Thus, how to avoid systematic erasing of previously encoded memories? While it has been proposed that a dual-learning system with 'slow' learning in the cortex and 'fast' learning in the hippocampus could protect previous knowledge from interference, this has never been observed in the living organism. Here, we report that increasing plasticity via the viral-induced overexpression of RGS14414 in the prelimbic cortex leads to better one-trial memory, but that this comes at the price of increased interference in semantic-like memory. Indeed, electrophysiological recordings showed that this manipulation also resulted in shorter NonREM-sleep bouts, smaller delta-waves and decreased neuronal firing rates. In contrast, hippocampal-cortical interactions in form of theta coherence during wake and REM-sleep as well as oscillatory coupling during NonREM-sleep were enhanced. Thus, we provide the first experimental evidence for the long-standing and unproven fundamental idea that high thresholds for plasticity in the cortex protect preexisting memories and modulating these thresholds affects both memory encoding and consolidation mechanisms.

Systems-level analysis of local field potentials reveals differential effects of lysergic acid diethylamide and ketamine on neuronal activity and functional connectivity.

Psychedelic substances have in recent years attracted considerable interest as potential treatments for several psychiatric conditions, including depression, anxiety, and addiction. Imaging studies in humans point to a number of possible mechanisms underlying the acute effects of psychedelics, including changes in neuronal firing rates and excitability as well as alterations in functional connectivity between various brain nodes. In addition, animal studies using invasive recordings, have suggested synchronous high-frequency oscillations involving several brain regions as another key feature of the psychedelic brain state. To better understand how the imaging data might be related to high-resolution electrophysiological measurements, we have here analyzed the aperiodic part of the local field potential (LFP) in rodents treated with a classic psychedelic (LSD) or a dissociative anesthetic (ketamine). In addition, functional connectivity, as quantified by mutual information measures in the LFP time series, has been assessed with in and between different structures. Our data suggest that the altered brain states of LSD and ketamine are caused by different underlying mechanisms, where LFP power shifts indicate increased neuronal activity but reduced connectivity following ketamine, while LSD also leads to reduced connectivity but without an accompanying change in LFP broadband power.

FGF2 activity regulates operant alcohol self-administration and mesolimbic dopamine transmission

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol self-administration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

5-HT1B receptors in the basolateral amygdaloid nucleus regulate anxiety-like behaviors through AC-PKA signal pathway in a rat model of Parkinson’s disease

BackgroundParkinson’s disease (PD) is commonly accompanied with anxiety, multiple studies indicate that the basolateral amygdaloid nucleus (BLA) is closely related to modulation of anxiety and expresses serotonin1B (5-HT1B) receptors, however, effects of BLA 5-HT1B receptors on anxiety-like behaviors are unclear, particularly in PD-related anxiety. MethodsThe open-field and elevated plus maze tests were used to examine anxiety-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of BLA neurons and GABA, glutamate, dopamine (DA) and 5-HT release in the BLA, respectively. Western blotting was used to analyze protein expression of 5-HT1B receptors, adenylate cyclase (AC) and phosphorylated protein kinase A at threonine 197 site (p-PKA-Thr197) in the BLA. ResultsIntra-BLA injection of 5-HT1B receptor agonist CP93129 produced anxiety-like effects and antagonist SB216641 induced anxiolytic-like responses in sham-operated and 6-hydroxydopamine-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129, respectively. Intra-BLA injection of CP93129 increased the firing rate of BLA glutamate neurons and decreased GABA/glutamate ratio and DA and 5-HT levels in the BLA of sham-operated and the lesioned rats, while SB216641 induced the opposite effects. Compared with sham-operated rats, effects of CP93129 and SB216641 on behaviors, electrophysiology and microdialysis were decreased in the lesioned rats, which were associated with decreased expression of 5-HT1B receptors, AC and p-PKA-Thr197 in the BLA. ConclusionThese findings suggest that 5-HT1B receptor-AC-PKA signal pathway in the BLA is involved in the regulation of PD-related anxiety.

Hypothalamic Corticotropin-Releasing Hormone Contributes to Hypertension in Spontaneously Hypertensive Rats.

Corticotropin-releasing hormone (CRH) is a neuropeptide regulating neuroendocrine and autonomic function. CRH mRNA and protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in primary hypertension. However, the role of CRH in elevated sympathetic outflow in primary hypertension remains unclear. CRHR1 proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar-Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor, Tat-N-dimer. Blocking CRHRs with astressin or CRHR1 with NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in primary hypertension.SIGNIFICANCE STATEMENT Our study found that corticotropin-releasing hormone receptor (CRHR)1 protein levels were increased in the paraventricular nucleus (PVN), and CRHR1 interacts with NMDA receptors (NMDARs) through postsynaptic density protein (PSD)-95 in the PVN neurons in primary hypertension. The increased CRHR1 and CRHR1-NMDAR-PSD-95 complex in the PVN contribute to the hyperactivity of the PVN presympathetic neurons and elevated sympathetic vasomotor tone in hypertension in SHRs. Thus, the antagonism of CRHR1 decreases sympathetic outflow and blood pressure in hypertension. These findings determine a novel role of CRHR1 in elevated sympathetic vasomotor tone in hypertension, which is useful for developing novel therapeutics targeting CRHR1 to treat elevated sympathetic outflow in primary hypertension. The CRHR1 receptor antagonists, which are used to treat health consequences resulting from chronic stress, are candidates to treat primary hypertension.

Modeling Instantaneous Firing Rate of Deep Brain Stimulation Target Neuronal Ensembles in the Basal Ganglia and Thalamus

ObjectiveDeep brain stimulation (DBS) is an effective treatment for movement disorders, including Parkinson disease and essential tremor. However, the underlying mechanisms of DBS remain elusive. Despite the capability of existing models in interpreting experimental data qualitatively, there are very few unified computational models that quantitatively capture the dynamics of the neuronal activity of varying stimulated nuclei—including subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and ventral intermediate nucleus (Vim)—across different DBS frequencies. Materials and MethodsBoth synthetic and experimental data were used in the model fitting; the synthetic data were generated by an established spiking neuron model that was reported in our previous work, and the experimental data were provided using single-unit microelectrode recordings (MERs) during DBS (microelectrode stimulation). Based on these data, we developed a novel mathematical model to represent the firing rate of neurons receiving DBS, including neurons in STN, SNr, and Vim—across different DBS frequencies. In our model, the DBS pulses were filtered through a synapse model and a nonlinear transfer function to formulate the firing rate variability. For each DBS-targeted nucleus, we fitted a single set of optimal model parameters consistent across varying DBS frequencies. ResultsOur model accurately reproduced the firing rates observed and calculated from both synthetic and experimental data. The optimal model parameters were consistent across different DBS frequencies. ConclusionsThe result of our model fitting was in agreement with experimental single-unit MER data during DBS. Reproducing neuronal firing rates of different nuclei of the basal ganglia and thalamus during DBS can be helpful to further understand the mechanisms of DBS and to potentially optimize stimulation parameters based on their actual effects on neuronal activity.

Disinhibition of the medial prefrontal cortex increases cardiorespiratory output and firing rate of neurons in the ventral respiratory column in anesthetized mice

During wakefulness, breathing is frequently voluntarily modulated to facilitate various behaviors including vocalization, feeding, and whisking. Breathing also correlates highly with changes in behavioral arousal such as during sleep ( Physiol 36: 203, 2021) , periods of high emotionality ( Neuroimage 134: 305, 2016), or recovery from anesthesia ( Curr Biol 28: 2145, 2018). The medial prefrontal cortex (mPFC) alters voluntary executive function ( Brain Stimul 13: 582, 2020) and arousal ( Trends Neurosci 45: 722, 2022). Additionally, previous studies have shown that the mPFC has the capacity to modulate breathing ( Resp Physiol Neurobiol 303: 103924, 2022). This modulation occurs via top-down influence of cortical and subcortical nuclei and hinges on a balance of excitatory and inhibitory activity within the mPFC ( Int Rev Neurobiol 158: 337, 2021). Furthermore, there are direct and indirect connections from the mPFC to the pontine and ventral respiratory column (VRC) neurons that control breathing ( J Comp Neurol 492: 145, 2005). Taken together, these data suggest a tripartite relationship among the mPFC, behavioral arousal, and breathing, however, the exact neuronal mechanisms underlying the mPFC modulation of breathing are unknown. To address this gap, this study is testing the hypothesis that administration of the GABAA receptor antagonist gabazine into the mPFC of mice increases breathing and heart rate, as well as neuronal activity of the respiratory neurons in the VRC. All procedures were reviewed and approved by the SCRI Institutional Animal Care and Use Committee and adhered to the ARRIVE guidelines. We recorded diaphragmatic activity and heart rate in response to unilateral microinjection (50.6nL) of gabazine (0.13nmol, 47ng) into the mPFC of female and male, urethane (1.5mg/kg) anesthetized mice (n = 5, mean age: 20wks). In 1 of the 5 mice, a Neuropixel high-density electrode was inserted into the VRC along the rostro caudal axis to simultaneously record neuronal activity. Paired, two-tailed t-test revealed gabazine delivered to the mPFC significantly (p<0.05) increased respiratory rate and heart rate. Firing rate of the neurons in the VRC also significantly increased as confirmed by a Wilcoxon Rank-Sum test. These data indicate that blocking inhibitory neurotransmission in the mPFC increases cardiorespiratory output and neuronal activity in the VRC. This result is consistent with data from rats ( J Physiol 591: 6069, 2013) and supports the interpretation that the mPFC participates in the neurobehavioral control of breathing. Ongoing studies are increasing sample size and phenotyping specific populations of mPFC neurons that modulate breathing and heart rate. This work is funded by the National Institutes of Health R01-HL151389, R01-HL126523, R01-HL144801, P01-HL090554 This is the full abstract presented at the American Physiology Summit 2023 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.

Spinal neuromodulation by intrathecal oxytocin administration mitigates the myocardial ischemia induced sympathoexcitation by suppressing the ischemia-related spinal neural hyperactivity

Background: Myocardial ischemia can lead to fatal ventricular arrhythmias by disrupting the cardiospinal neural network which controls the sympathoexcitation. Spinal neuromodulation techniques could decrease myocardial ischemia-induced sympathoexcitation by modulating the spinal neural network. Hypothesis: We hypothesize that spinal oxytocin (OXT) administration decreases myocardial ischemia-induced sympathoexcitation by suppressing spinal neural hyperactivity in the dorsal horn (DH) and intermediolateral nucleus regions (IML). Materials and Methods: Anesthetized pigs underwent laminectomy to expose the spinal T2 section and a sternotomy to expose the heart for performing left anterior descending coronary artery ischemia (LAD) with and without intrathecal oxytocin (90ug) treatment. Electrocardiograms were recorded using a 56-channel mesh electrode to evaluate the activation recovery interval (ARI) and dispersion of repolarization (DOR) which are the markers for sympathoexcitation and arrhythmogenecity. Extracellular in-vivo spinal neural recordings were done by using a 64-channel microelectrode array inserted at the T2 segment of the spinal cord to record the activity of DH and IML neurons. Oxytocin was administered intrathecally at T1-T3. Spinal neural activity, ARI, and DOR were evaluated during myocardial ischemia with vs. without intrathecal oxytocin administration. Results: Sixteen Yorkshire pigs entered into this study. In 13 animals (LAD:7, LAD+OXT:6) ARI and DOR were evaluated during long LAD ischemia (1hr). ARI shortening due to LAD was mitigated by OXT (LAD:-33 ± 4 ms; LAD+OXT: -15 ± 1 ms, P=0.001). OXT decreased the LAD-induced augmented DOR (LAD: 2194± 310 ms2; LAD+OXT: 1099± 305 ms2, P=0.029). We have further evaluated the effect of OXT on short LAD ischemia (5 mins) and the impact of intrathecal OXT agonist on the spinal cord neural processing of myocardial ischemia in 3 pigs. Out of 88 recorded neurons, LAD increased the firing rate of more neurons than the LAD+OXT (LAD: increased 52, decreased 12 neurons; LAD+OXT: increased 16, decreased 14 neurons, P=0.007). The LAD-induced spinal cord hyperactivity was mitigated after intrathecal OXT administration (LAD:1.57 ± 0.52 Hz to LAD+OXT: 0.02 ± 0.22 Hz, P=0.0001). OXT also mitigated the reperfusion-induced spinal neuronal hyperactivity (LAD:2.16 ± 0.59 Hz to LAD+OXT: -0.36 ± 0.28 Hz, P<0.0001). OXT showed a similar effect in reducing the LAD-induced sympathoexcitation in these three animals (ARI shortening: LAD: -69 ± 14 ms; LAD+OXT: -38 ± 8 ms, P=0.035). Conclusion: Myocardial ischemia induces sympathoexcitation by increasing the spinal neural activity. OXT mitigates the adverse effect of myocardial ischemia by suppressing spinal neural hyperactivity. Funding: NIH (R01) HL136836 (Dr.Mahajan) and University of Pittsburgh Medical Center Competitive Medical Research Fund (Dr.Salavatian). This is the full abstract presented at the American Physiology Summit 2023 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.

Ethanol depresses neurons in the lateral parabrachial nucleus by potentiating pre- and postsynaptic GABAA receptors.

As a psychoactive substance, ethanol is widely used in people's life. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on the lateral parabrachial nucleus (LPB), which is a novel component related to sedation. Coronal brain slices (280 μm thick) containing the LPB were prepared from C57BL/6J mice. The spontaneous firing and membrane potential of LPB neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch-clamp recordings. Drugs were applied through superfusion. The LPB neurons exhibited a regular spontaneous discharge at a rate of 1.5-3 Hz without burst firing. Brief superfusion of ethanol (30, 60, and 120 mM) concentration-dependently and reversibly suppressed the spontaneous firing of the neurons in LPB. In addition, when synaptic transmission was blocked by tetrodotoxin (TTX) (1 μM), ethanol (120 mM) caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents, which were abolished in the presence of the GABAA receptor (GABAA-R) antagonist picrotoxin (100 μM). In addition, the inhibitory effect of ethanol on the firing rate of LPB neurons was completely abolished by picrotoxin. Ethanol inhibits the excitability of LPB neurons in mouse slices, possibly via potentiating GABAergic transmission onto the neurons at pre- and postsynaptic sites.

Detecting change points in neural population activity with contrastive metric learning.

Finding points in time where the distribution of neural responses changes (change points) is an important step in many neural data analysis pipelines. However, in complex and free behaviors, where we see different types of shifts occurring at different rates, it can be difficult to use existing methods for change point (CP) detection because they can't necessarily handle different types of changes that may occur in the underlying neural distribution. Additionally, response changes are often sparse in high dimensional neural recordings, which can make existing methods detect spurious changes. In this work, we introduce a new approach for finding changes in neural population states across diverse activities and arousal states occurring in free behavior. Our model follows a contrastive learning approach: we learn a metric for CP detection based on maximizing the Sinkhorn divergences of neuron firing rates across two sides of a labeled CP. We apply this method to a 12-hour neural recording of a freely behaving mouse to detect changes in sleep stages and behavior. We show that when we learn a metric, we can better detect change points and also yield insights into which neurons and sub-groups are important for detecting certain types of switches that occur in the brain.

Amyloid-β Protein Precursor Regulates Electrophysiological Properties in the Hippocampus via Altered Kv1.4 Expression and Function in Mice.

Amyloid-β protein precursor (AβPP) is enriched in neurons. However, the mechanism underlying AβPP regulation of neuronal activity is poorly understood. Potassium channels are critically involved in neuronal excitability. In hippocampus, A-type potassium channels are highly expressed and involved in determining neuronal spiking. We explored hippocampal local field potential (LFP) and spiking in the presence and absence of AβPP, and the potential involvement of an A-type potassium channel. We used in vivo extracellular recording and whole-cell patch-clamp recording to determine neuronal activity, current density of A-type potassium currents, and western blot to detect changes in related protein levels. Abnormal LFP was observed in AβPP-/- mice, including reduced beta and gamma power, and increased epsilon and ripple power. The firing rate of glutamatergic neurons reduced significantly, in line with an increased action potential rheobase. Given that A-type potassium channels regulate neuronal firing, we measured the protein levels and function of two major A-type potassium channels and found that the post-transcriptional level of Kv1.4, but not Kv4.2, was significantly increased in the AβPP-/- mice. This resulted in a marked increase in the peak time of A-type transient outward potassium currents in both glutamatergic and gamma-aminobutyric acid-ergic (GABAergic) neurons. Furthermore, a mechanistic experiment using human embryonic kidney 293 (HEK293) cells revealed that the AβPP deficiency-induced increase in Kv1.4 may not involve protein-protein interaction between AβPP and Kv1.4. This study suggests that AβPP modulates neuronal firing and oscillatory activity in the hippocampus, and Kv1.4 may be involved in mediating the modulation.

Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus–thalamus circuitry

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets

The perineuronal nets (PNNs) are sugar coated protein structures that encapsulate certain neurons in the brain, such as parvalbumin positive (PV) inhibitory neurons. As PNNs are theorized to act as a barrier to ion transport, they may effectively increase the membrane charge-separation distance, thereby affecting the membrane capacitance. Tewari et al. (2018) found that degradation of PNNs induced a 25%-50% increase in membrane capacitance c_text {m} and a reduction in the firing rates of PV-cells. In the current work, we explore how changes in c_text {m} affects the firing rate in a selection of computational neuron models, ranging in complexity from a single compartment Hodgkin-Huxley model to morphologically detailed PV-neuron models. In all models, an increased c_text {m} lead to reduced firing, but the experimentally reported increase in c_text {m} was not alone sufficient to explain the experimentally reported reduction in firing rate. We therefore hypothesized that PNN degradation in the experiments affected not only c_text {m}, but also ionic reversal potentials and ion channel conductances. In simulations, we explored how various model parameters affected the firing rate of the model neurons, and identified which parameter variations in addition to c_text {m} that are most likely candidates for explaining the experimentally reported reduction in firing rate.

Neurogenic Background for Emotional Stress-Associated Hypertension.

The response to natural stressors involves both cardiac stimulation and vascular changes, primarily triggered by increases in sympathetic activity. These effects lead to immediate flow redistribution that provides metabolic support to priority target organs combined with other key physiological responses and cognitive strategies, against stressor challenges. This extremely well-orchestrated response that was developed over millions of years of evolution is presently being challenged, over a short period of time. In this short review, we discuss the neurogenic background for the origin of emotional stress-induced hypertension, focusing on sympathetic pathways from related findings in humans and animals. The urban environment offers a variety of psychological stressors. Real or anticipatory, emotional stressors may increase baseline sympathetic activity. From routine day-to-day traffic stress to job-related anxiety, chronic or abnormal increases in sympathetic activity caused by emotional stressors can lead to cardiovascular events, including cardiac arrhythmias, increases in blood pressureand even sudden death. Among the various alterations proposed, chronic stress could modify neuroglial circuits or compromise antioxidant systems that may alter the responsiveness of neurons to stressful stimuli. These phenomena lead to increases in sympathetic activity, hypertension and consequent cardiovascular diseases. The link between anxiety, emotional stress, and hypertension may result from an altered neuronal firing rate in central pathways controlling sympathetic activity. The participation of neuroglial and oxidative mechanisms in altered neuronal function is primarily involved in enhanced sympathetic outflow. The significance of the insular cortex-dorsomedial hypothalamic pathway in the evolution of enhanced overall sympathetic outflow is discussed.