Phasic Firing Research Articles

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Cell-type-specific origins of locomotor rhythmicity at different speeds in larval zebrafish.

Different speeds of locomotion require heterogeneous spinal populations, but a common mode of rhythm generation is presumed to exist. Here, we explore the cellular versus synaptic origins of spinal rhythmicity at different speeds by performing electrophysiological recordings from premotor excitatory interneurons in larval zebrafish. Chx10-labeled V2a neurons are divided into at least two morphological subtypes proposed to play distinct roles in timing and intensity control. Consistent with distinct rhythm generating and output patterning functions within the spinal V2a population, we find that descending subtypes are recruited exclusively at slow or fast speeds and exhibit intrinsic cellular properties suitable for rhythmogenesis at those speeds, while bifurcating subtypes are recruited more reliably at all speeds and lack appropriate rhythmogenic cellular properties. Unexpectedly, however, phasic firing patterns during locomotion in rhythmogenic and non-rhythmogenic V2a neurons alike are best explained by distinct modes of synaptic inhibition linked to cell type and speed. At fast speeds reciprocal inhibition in descending V2a neurons supports phasic firing, while recurrent inhibition in bifurcating V2a neurons helps pattern motor output. In contrast, at slow speeds recurrent inhibition in descending V2a neurons supports phasic firing, while bifurcating V2a neurons rely on reciprocal inhibition alone to pattern output. Our findings suggest cell-type-specific, not common, modes of rhythmogenesis generate and coordinate different speeds of locomotion.

Electrophysiological properties of neurons in the visual sensory layers of the superior colliculus in early postnatal mice

Objective: To investigate the action potential firing patterns of neurons in the visual sensory layers of the superior colliculus in early postnatal mice and the electrophysiological characteristics of neurons with different firing patterns. Methods: This experimental study utilized whole-cell patch-clamp recordings performed on neurons in the visual sensory layers of the superior colliculus using brain slices from 57 healthy male C57BL/6J mice aged 14 to 20 days (weighing 5.0 to 8.9 g) using brain slices. In current-clamp mode, action potential characteristics were analyzed based on the first action potential generated by depolarizing current, and the firing patterns of neurons were recorded using step depolarizing currents. Neuronal firing patterns were analyzed using hierarchical clustering, and the active electrical properties of neurons with different firing patterns were compared. Results: A total of 135 neurons from the visual sensory layers of the superior colliculus were successfully recorded. Cluster analysis of the neuronal firing patterns identified three types of firing patterns: tonic firing (97, 72%), phasic firing (26, 19%), and single firing (12, 9%). The number of action potentials for each firing pattern was 13.30±7.38, 3.73±3.61, and 0.83±0.39, respectively, with significant differences (P<0.001). There was no significant difference in the membrane potential response to step currents among the three firing pattern types (P>0.05). The action potential amplitudes were (60.45±12.22), (53.67±13.20), and (44.04± 12.92) mV, and the afterhyperpolarization amplitudes were (13.45±13.79), (12.02±13.11), and (20.75±2.85) mV, respectively. The maximum rising slopes were (171.29±77.46), (130.14±61.83), and (78.89±37.08) V/s, and the maximum falling slopes were (-76.33±33.61), (-68.17±31.65), and (-47.97±13.92) V/s, respectively, with all differences being statistically significant (all P<0.05). There were no significant differences in the resting membrane potential, action potential threshold, half-width, and afterhyperpolarization duration among the three firing pattern types (all P>0.05). Conclusions: In the early postnatal mice, neurons in the visual sensory layers of the superior colliculus exhibit three distinct firing patterns: tonic, phasic, and single firing. These firing pattern types show significant differences in action potential amplitude, afterhyperpolarization amplitude, maximum rising slopes, and maximum falling slopes.

Circadian Rhythms in Conditioned Threat Extinction Reflect Time-of-Day Differences in Ventromedial Prefrontal Cortex Neural Processing.

Circadian rhythms in conditioned threat extinction emerge from a tissue-level circadian timekeeper, or local clock, in the ventromedial prefrontal cortex (vmPFC). Yet it remains unclear how this local clock contributes to extinction-dependent adaptations. Here we used single-unit and local field potential analyses to interrogate neural activity in the male rat vmPFC during repeated extinction sessions at different times of day. In association with superior recall of a remote extinction memory during the circadian active phase, vmPFC putative principal neurons exhibited phasic firing that was amplified for cue presentations and diminished at transitions in freezing behavior. Coupling of vmPFC gamma amplitude to the phase of low-frequency oscillations was greater during freezing than mobility, and this difference was augmented during the active phase, highlighting a time-of-day dependence in the organization of freezing- versus mobility-associated cell assemblies. Additionally, a greater proportion of vmPFC neurons were phase-locked to low-frequency oscillations during the active phase, consistent with heightened neural excitability at this time of day. Our results suggest that daily fluctuations in vmPFC excitability precipitate enhanced neural recruitment into extinction-based cell assemblies during the active phase, providing a potential mechanism by which the vmPFC local clock modulates circuit and behavioral plasticity during conditioned threat extinction.

Dopamine Release in the Nucleus Accumbens Core Encodes the General Excitatory Components of Learning.

Dopamine release in the nucleus accumbens core (NAcC) is generally considered to be a proxy for phasic firing of the ventral tegmental area dopamine (VTADA) neurons. Thus, dopamine release in NAcC is hypothesized to reflect a unitary role in reward prediction error signaling. However, recent studies reveal more diverse roles of dopamine neurons, which support an emerging idea that dopamine regulates learning differently in distinct circuits. To understand whether the NAcC might regulate a unique component of learning, we recorded dopamine release in NAcC while male rats performed a backward conditioning task where a reward is followed by a neutral cue. We used this task because we can delineate different components of learning, which include sensory-specific inhibitory and general excitatory components. Furthermore, we have shown that VTADA neurons are necessary for both the specific and general components of backward associations. Here, we found that dopamine release in NAcC increased to the reward across learning while reducing to the cue that followed as it became more expected. This mirrors the dopamine prediction error signal seen during forward conditioning and cannot be accounted for temporal-difference reinforcement learning. Subsequent tests allowed us to dissociate these learning components and revealed that dopamine release in NAcC reflects the general excitatory component of backward associations, but not their sensory-specific component. These results emphasize the importance of examining distinct functions of different dopamine projections in reinforcement learning.

Using microdialysis to monitor dopaminergic support of limb-use control following mesencephalic neurosphere transplantation in a rodent model of Parkinson's Disease

Controlled nigrostriatal dopamine release supports effective limb use during locomotion coordination that becomes compromised after this pathway deteriorates in Parkinson’s Disease (PD). How dopamine release relates to active ongoing behavior control remains unknown. Restoring proper release strategy appears important to successful PD treatment with transplanted dopamine-producing stem cells. This is suggested by apparently distinct behavioral support from tonic or phasic release and corresponding requirements of requisite afferent control exhibited by intact nigrostriatal neurons. Our laboratory previously demonstrated that transplanted dopaminergic cells can elicit skilled movement recovery known to depend on phasic dopamine release. However, efforts to measure this movement-related dopamine release yielded seemingly paradoxical, incongruent results. In response, here we explored whether those previous observations derived from rapid reuptake transport into either transplanted cells or residual, lesion-surviving terminals. We confirmed this using minimal reuptake blockade during intrastriatal microdialysis. After unilateral dopamine depletion, rats received transplants and were subjected to our swimming protocol. Among dopamine-depleted and transplanted rats, treatment supported restoration of limb movement symmetry. Interestingly, subsequent reuptake-restricted microdialysis confirmed distinct swimming-induced dopamine increases clearly occurred among these lesioned/transplanted subjects. Thus, phasic firing control appears to contribute to transplant-derived recovery in Parkinsonian animals.

Adolescent alcohol exposure persistently alters orbitofrontal cortical encoding of Pavlovian conditional stimulus components in female rats

Exposure to alcohol during adolescence impacts cortical and limbic brain regions undergoing maturation. In rodent models, long-term effects on behavior and neurophysiology have been described after adolescent intermittent ethanol (AIE), especially in males. We hypothesized that AIE in female rats increases conditional approach to a reward-predictive cue and corresponding neuronal activity in the orbitofrontal cortex (OFC) and nucleus accumbens (NAc). We evaluated behavior and neuronal firing after AIE (5 g/kg intragastric) or water (CON) in adult female rats. Both AIE and CON groups expressed a ST phenotype, and AIE marginally increased sign-tracking (ST) and decreased goal-tracking (GT) metrics. NAc neurons exhibited phasic firing patterns to the conditional stimulus (CS), with no differences between groups. In contrast, neuronal firing in the OFC of AIE animals was greater at CS onset and offset than in CON animals. During reward omission, OFC responses to CS offset normalized to CON levels, but enhanced OFC firing to CS onset persisted in AIE. We suggest that the enhanced OFC neural activity observed in AIE rats to the CS could contribute to behavioral inflexibility. Ultimately, AIE persistently impacts the neurocircuitry of reward-motivated behavior in female rats.

Decreased GABAergic Neurotransmission Promotes Breathing Upon Emergence From Hibernation

The respiratory network must produce reliable output for an animal to survive. Although respiratory motor plasticity is well appreciated, how plasticity mechanisms work to promote robustness following environmental perturbations that disrupt breathing is less clear. During underwater hibernation, respiratory neurons of bullfrogs remain inactive for months, triggering a suite of compensatory mechanisms that aim to maintain respiratory function. We hypothesized that GABAergic inhibition would decrease following hibernation. In control animals, respiratory frequency was under control of GABAAR signaling. Specifically, block of GABAARs dose-dependently decreased respiratory burst frequency in the in vitro brainstem preparation (n=5 preparations). After hibernation, GABAA receptor block had little to no impact on respiratory burst frequency, suggesting the network was no longer reliant on GABAergic inhibition to maintain normal frequency (n=5 preparations). The loss of inhibition was specific to the respiratory network because non-respiratory motor activity and large seizure-like bursts were similarly triggered by GABAA receptor blockade in intact brainstem preparations from controls and hibernators. We next used a semi-intact preparation that maintains functional respiratory-synaptic input onto rhythmic motor neurons to identify compensatory changes in GABAergic tone at the level of the motor neuron. In controls, the firing rate of respiratory motoneurons was constrained by a phasic GABAAR tone because focal application of bicuculline, a GABAAR antagonist, led to an increase in phasic firing frequency (n=12 cells). After hibernation, this bicuculline-mediated increase in phasic firing frequency was attenuated suggesting phasic inhibition onto the motor neuron had decreased (n=9 cells). Brain slice recordings of identified vagal motor neurons revealed that postsynaptic GABAA receptor strength was unchanged following hibernation (n=16 control cells; n=16 hibernation cells). Taken together, our results suggest that GABAergic activity is decreased in premotor networks following hibernation. Despite this dramatic loss of GABAergic function, respiratory output from control preparations was indistinguishable from hibernators. To elucidate the functional impacts of loss of GABAergic activity, we tested the network’s ability to produce output at colder temperatures. In controls, respiratory output slowed as temperature decreased, with most networks nearly silent at 8 degrees Celsius (n=5 preparations). Interestingly, in controls low dose block of GABAA receptors promoted respiratory activity at cold temperatures, with frequency not statistically different than baseline at any temperature tested (n=4 preparations). This suggests that the loss of premotor GABAergic activity we observed could work to promote motor output at colder temperatures, which works adaptively for the animal when emerging from hibernation. NIH R01NS114514 (JS). 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.

A low-power artificial spiking neuron based on ionic memristor for modulated frequency coding

Neurons encode information through firing spikes with rich spatiotemporal dynamics. Using artificial neuron hardware based on memristors to emulate neuronal firing is of great significance for advancing the development of brain-like computing and artificial intelligence. However, it is still challenging to achieve low power frequency coding in memristive artificial neurons. Here, a low-power ionic memristor based on Pt/HfO2/Ag is reported for artificial spiking neurons. The device is driven by a low bias current and the filament dynamically ruptures and forms, producing oscillated voltage spikes that resemble neuronal spikes. The oscillation frequency increases from 0.5 Hz to ∼2.18 Hz with the stimulation current increasing from 1 nA to 5 nA, enabling the emulation of neuronal frequency-coding function. The low power consumption of ∼70 pJ per pulse indicates that the device is promising for energy-efficient neuromorphic computing applications. In addition, the device is found to be capable of simulating the phasic,adaptive, and burst firing modes of neurons.

Current Review of the Function and Regulation of Tuberoinfundibular Dopamine Neurons.

Tuberoinfundibular dopamine (TIDA) neurons have cell bodies located in the arcuate nucleus of the mediobasal hypothalamus. They project to the external zone of the median eminence, and the dopamine (DA) released there is carried by the hypophysial portal vasculature to the anterior pituitary. The DA then activates D2 receptors to inhibit prolactin (PRL) secretion from lactotrophs. The TIDA neuronal population is the principal regulatory factor controlling PRL secretion. The neuroendocrine role subserved by TIDA neurons sets them apart from other dopaminergic populations like the nigrostriatal and mesolimbic DA neurons. TIDA neurons exhibit intrinsic oscillatory fluctuations in their membrane potential that give rise to phasic firing and bursting activity. TIDA neuronal activity is sexually differentiated and modulated by gonadal hormones and PRL, as well as an array of small molecule and peptide neurotransmitters. This review covers these characteristics.

Techniques for Measurement of Serotonin: Implications in Neuropsychiatric Disorders and Advances in Absolute Value Recording Methods.

Serotonin (5-HT) is a monoamine neurotransmitter in the peripheral, enteric, and central nervous systems (CNS). Within the CNS, serotonin is principally involved in mood regulation and reward-seeking behaviors. It is a critical regulator in CNS pathologies such as major depressive disorder, addiction, and schizophrenia. Consequently, in vivo serotonin measurements within the CNS have emerged as one of many promising approaches to investigating the pathogenesis, progression, and treatment of these and other neuropsychiatric conditions. These techniques vary in methods, ranging from analyte sampling with microdialysis to voltammetry. Provided this diversity in approach, inherent differences between techniques are inevitable. These include biosensor size, temporal/spatial resolution, and absolute value measurement capabilities, all of which must be considered to fit the prospective researcher's needs. In this review, we summarize currently available methods for the measurement of serotonin, including novel voltammetric absolute value measurement techniques. We also detail serotonin's role in various neuropsychiatric conditions, highlighting the role of phasic and tonic serotonergic neuronal firing within each where relevant. Lastly, we briefly review the present clinical application of these techniques and discuss the potential of a closed-loop monitoring and neuromodulation system utilizing deep brain stimulation (DBS).

Afferent neurons of the kidney with impaired firing pattern in inflammation - role of sodium currents?

Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5nmol/ml) for 12h. We characterized neurons as "tonic," i.e., sustained action potential (AP) firing, or "phasic," i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na+ and K+ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na+ and K+ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6ms, P < 0.01). In neurons incubated with CXCL1, Na+ and K+ peak current density increased in phasic (Na+: - 969 ± 47 vs. - 758 ± 47 nA/pF, P < 0.01; K+: 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na+ currents ([- 365- - 1429 nA] vs. [- 412- - 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na+ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions.

Expression of hyperpolarization-activated current (Ih) in zonally defined vestibular calyx terminals of the crista.

Calyx terminals make afferent synapses with type I hair cells in vestibular epithelia and express diverse ionic conductances that influence action potential generation and discharge regularity in vestibular afferent neurons. Here we investigated the expression of hyperpolarization-activated current (Ih) in calyx terminals in central and peripheral zones of mature gerbil crista slices, using whole cell patch-clamp recordings. Slowly activating Ih was present in >80% calyces tested in both zones. Peak Ih and half-activation voltages were not significantly different; however, Ih activated with a faster time course in peripheral compared with central zone calyces. Calyx Ih in both zones was blocked by 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD7288; 100 µM), and the resting membrane potential became more hyperpolarized. In the presence of dibutyryl-cAMP (dB-cAMP), peak Ih was increased, activation kinetics became faster, and the voltage of half-activation was more depolarized compared with control calyces. In current clamp, calyces from both zones showed three different categories of firing: spontaneous firing, phasic firing where a single action potential was evoked after a hyperpolarizing pulse, or a single evoked action potential followed by membrane potential oscillations. In the absence of Ih, the latency to peak of the action potential increased; Ih produces a small depolarizing current that facilitates firing by driving the membrane potential closer to threshold. Immunostaining showed the expression of HCN2 subunits in calyx terminals. We conclude that Ih is found in calyx terminals across the crista and could influence conventional and novel forms of synaptic transmission at the type I hair cell-calyx synapse.NEW & NOTEWORTHY Calyx afferent terminals make synapses with vestibular hair cells and express diverse conductances that impact action potential firing in vestibular primary afferents. Conventional and nonconventional synaptic transmission modes are influenced by hyperpolarization-activated current (Ih), but regional differences were previously unexplored. We show that Ih is present in both central and peripheral calyces of the mammalian crista. Ih produces a small depolarizing resting current that facilitates firing by driving the membrane potential closer to threshold.

Structure and dynamics that specialize neurons for high-frequency coincidence detection in the barn owl nucleus laminaris.

A principal cue for sound source localization is the difference in arrival times of sounds at an animal's two ears (interaural time difference, ITD). Neurons that process ITDs are specialized to compare the timing of inputs with submillisecond precision. In the barn owl, ITD processing begins in the nucleus laminaris (NL) region of the auditory brain stem. Remarkably, NL neurons are sensitive to ITDs in high-frequency sounds (kilohertz-range). This contrasts with ITD-based sound localization in analogous regions in mammals where ITD sensitivity is typically restricted to lower-frequency sounds. Guided by previous experiments and modeling studies of tone-evoked responses of NL neurons, we propose NL neurons achieve high-frequency ITD sensitivity if they respond selectively to the small-amplitude, high-frequency oscillations in their inputs, and remain relatively non-responsive to mean input level. We use a biophysically based model to study the effects of soma-axon coupling on dynamics and function in NL neurons. First, we show that electrical separation of the soma from the axon region in the neuron enhances high-frequency ITD sensitivity. This soma-axon coupling configuration promotes linear subthreshold dynamics and rapid spike initiation, making the model more responsive to input oscillations, rather than mean input level. Second, we provide new evidence for the essential role of phasic dynamics for high-frequency neural coincidence detection. Transforming our model to the phasic firing mode further tunes the model to respond selectively to the oscillating inputs that carry ITD information. Similar structural and dynamical mechanisms specialize mammalian auditory brain stem neurons for ITD sensitivity, and thus, our work identifies common principles of ITD processing and neural coincidence detection across species and for sounds at widely different frequencies.

Temporal interference current stimulation in peripheral nerves is not driven by envelope extraction

Background. Electrical neuromodulation remains an effective therapy for multiple neurological disorders. One strategy to electrically stimulate nerves utilizes the interference of multiple high frequency waveforms. This technique, known as temporal interference stimulation or interferential current stimulation, has recently gained significant attention as a method to improve the state-of-the-art in neurostimulation in both animal studies and human clinical trials. Objective. Here we report our investigation into the fundamental properties of the neuronal response to these types of waveforms—the effects of carrier and envelope frequencies, thresholds, firing behavior, and phase and asymmetric interference patterns. Methods. We utilized a cuff electrode on the rat sciatic nerve to apply a variety of interferential signals. We recorded muscle activity in the plantar muscles and biceps femoris, which are proxies for activity on two of the major branches of the sciatic, which are spatially distinct in the target volume. We tested both fundamental recruitment properties as well as spatial techniques to selectively activate either muscle group. Results. Our data suggest, contrary to the currently accepted explanation, that neurons do not extract envelopes at all, and that the response to these signals is well explained by a resistor–capacitor (i.e. integrator) membrane with a fixed firing threshold. Basic interference techniques do not change recruitment far from electrodes. Techniques can produce regions of both phasic activation and tonic activation/conduction block. Conclusions. An integrator model suggests that interference techniques are less capable of minimally invasive stimulation for a subcortical brain target than previously thought. Human clinical trials using these techniques should reevaluate their methods. Interference stimulation allows significant target selectivity in a peripheral cuff electrode with targets near electrodes. These techniques can allow spatially distinct regions of phasic firing, tonic firing, conduction block, and no effect.

Heightened sympathetic neuron activity and altered cardiomyocyte properties in spontaneously hypertensive rats during the postnatal period.

The Spontaneously Hypertensive Rat (SHR) has increased sympathetic drive to the periphery that precedes and contributes to the development of high blood pressure, making it a useful model for the study of neurogenic hypertension. Comparisons to the normotensive Wistar Kyoto (WKY) rat have demonstrated altered active and intrinsic properties of SHR sympathetic neurons shortly before the onset of hypertension. Here we examine the structural and functional plasticity of postnatal SHR and WKY sympathetic neurons cultured alone or co-cultured with cardiomyocytes under conditions of limited extrinsic signaling. SHR neurons have an increased number of structural synaptic sites compared to age-matched WKY neurons, measured by the co-localization of presynaptic vesicular acetylcholine transporter and postsynaptic shank proteins. Whole cell recordings show that SHR neurons have a higher synaptic charge than WKY neurons, demonstrating that the increase in synaptic sites is associated with increased synaptic transmission. Differences in synaptic properties are not associated with altered firing rates between postnatal WKY and SHR neurons and are not influenced by interactions with target cardiomyocytes from either strain. Both SHR and WKY neurons show tonic firing patterns in our cultures, which are depleted of non-neuronal ganglionic cells and provide limited neurotrophic signaling. This suggests that the normal mature, phasic firing of sympathetic neurons requires extrinsic signaling, with potentially differential responses in the prehypertensive SHR, which have been reported to maintain tonic firing at later developmental stages. While cardiomyocytes do not drive neuronal differences in our cultures, SHR cardiomyocytes display decreased hypertrophy compared to WKY cells and altered responses to co-cultured sympathetic neurons. These experiments suggest that altered signaling in SHR neurons and cardiomyocytes contributes to changes in the cardiac-sympathetic circuit in prehypertensive rats as early as the postnatal period.

More than the end: OFF response plasticity as a mnemonic signature of a sound's behavioral salience.

In studying how neural populations in sensory cortex code dynamically varying stimuli to guide behavior, the role of spiking after stimuli have ended has been underappreciated. This is despite growing evidence that such activity can be tuned, experience-and context-dependent and necessary for sensory decisions that play out on a slower timescale. Here we review recent studies, focusing on the auditory modality, demonstrating that this so-called OFF activity can have a more complex temporal structure than the purely phasic firing that has often been interpreted as just marking the end of stimuli. While diverse and still incompletely understood mechanisms are likely involved in generating phasic and tonic OFF firing, more studies point to the continuing post-stimulus activity serving a short-term, stimulus-specific mnemonic function that is enhanced when the stimuli are particularly salient. We summarize these results with a conceptual model highlighting how more neurons within the auditory cortical population fire for longer duration after a sound’s termination during an active behavior and can continue to do so even while passively listening to behaviorally salient stimuli. Overall, these studies increasingly suggest that tonic auditory cortical OFF activity holds an echoic memory of specific, salient sounds to guide behavioral decisions.

Flexible Glassy Carbon Multielectrode Array for In Vivo Multisite Detection of Tonic and Phasic Dopamine Concentrations.

Dopamine (DA) plays a central role in the modulation of various physiological brain functions, including learning, motivation, reward, and movement control. The DA dynamic occurs over multiple timescales, including fast phasic release, as a result of neuronal firing and slow tonic release, which regulates the phasic firing. Real-time measurements of tonic and phasic DA concentrations in the living brain can shed light on the mechanism of DA dynamics underlying behavioral and psychiatric disorders and on the action of pharmacological treatments targeting DA. Current state-of-the-art in vivo DA detection technologies are limited in either spatial or temporal resolution, channel count, longitudinal stability, and ability to measure both phasic and tonic dynamics. We present here an implantable glassy carbon (GC) multielectrode array on a SU-8 flexible substrate for integrated multichannel phasic and tonic measurements of DA concentrations. The GC MEA demonstrated in vivo multichannel fast-scan cyclic voltammetry (FSCV) detection of electrically stimulated phasic DA release simultaneously at different locations of the mouse dorsal striatum. Tonic DA measurement was enabled by coating GC electrodes with poly(3,4-ethylenedioxythiophene)/carbon nanotube (PEDOT/CNT) and using optimized square-wave voltammetry (SWV). Implanted PEDOT/CNT-coated MEAs achieved stable detection of tonic DA concentrations for up to 3 weeks in the mouse dorsal striatum. This is the first demonstration of implantable flexible MEA capable of multisite electrochemical sensing of both tonic and phasic DA dynamics in vivo with chronic stability.

Carbon Fiber Microelectrode pH Sensors with Voltammetry and Field Effect Transistors

Graphitic carbon fiber microelectrodes (CFMEs) have been used as biosensors for the detection of biomolecules such as neurotransmitters using fast scan cyclic voltammetry (FSCV). The electrodes are relatively small (7 microns in diameter), biocompatible, have high spatiotemporal resolution, and do not generally illicit an immune response. Traditionally, CFMEs have been used to detect neurotransmitters such as dopamine, serotonin, norepinephrine, and others. The shape and position of the cyclic voltammogram (CV) is a chemical fingerprint for neurotransmitter detection with the peak oxidative current being proportional to concentration. The method is ideal for measuring fast, subsecond changes of neurotransmitters such as the phasic firing of dopaminergic neurons. Recently, the method has been expanded to measure other molecules such as metals, amino acids, peptides (including neuropeptides), hormones, proteins, neuromodulators, and other biomolecules.In this study, we demonstrate the use of CFMEs as both FSCV sensors and field-effect transistor (FET) transducers for dynamic pH measurements. The electrochemical oxidation and reduction of functional groups on the surface of CFMEs affect their response over a physiologically relevant pH range. When measured with FET transducers, the sensitivity of the measurements over the measured pH range was found to be (101 ± 18) mV, which exceeded the Nernst value at room temperature of 59 mV by approximately 70 %. Finally, we validated the functionality of CFMEs as pH sensors with FSCV ex vivo in rat brain coronal slices with exogenously applied solutions of varying pH indicating that potential in vivo study is feasible. The sensitive, fast, biocompatible, and selective detection of pH fluctuations provides for a multitude of potential future applications such as the optimization of biomolecule measurement and measurement of pH in specific extracellular tumor microenvironments for cancer studies in addition to many others.

Temporal Pattern Coding in Ionic Memristor‐Based Spiking Neurons for Adaptive Tactile Perception

AbstractBiological neurons encode signals through firing voltage spike trains having unique temporal patterns, enabling efficient information representation and processing. Realization of these rich neuronal firing characteristics in a single electronic device, without circuitry and software assistance, promise compact and functional neuromorphic hardware for advanced artificial intelligence applications. Here, a Pt/Co3O4‐x/ITO‐based ionic memristor is reported that can faithfully produce voltage spike trains exhibiting diverse temporal patterns of biological neurons, under electric current stimulation. The spiking behaviors stem from the redistribution of ions in the device, governed by the current induced electric field and Joule heating effects. Tonic, phasic, burst, and adaptive firing patterns of neurons are demonstrated. Particularly, the adaptive firing characteristics allow the memristor to reduce the response to invariant current stimulation and to respond to current changes with enhanced sensitivity, implementing neuronal adaptive coding function. Integrating such memristors with pressure sensors yields an artificial tactile sensory system that can adaptively perceive small pressure variations in the presence of strong static pressure backgrounds, enabling accurate identification of touched objects in ever‐changing environments. This work opens up an avenue toward advanced neuromorphic hardware for smart neural prosthetics and bionic robotics applications.