Persistent Firing Research Articles

Towards the PET radiotracer for p75 neurotrophin receptor: [11C]LM11A-24 shows biological activity in vitro, but unfavorable ex vivo and in vivo profile

Mature neurotrophins as well as their pro forms are critically involved in the regulation of neuronal functions. They are signaling through three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75NTR) and sortilin. Aberrant expression of p75NTR in the CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease. The goal of this work was to evaluate one of the very few reported p75NTR small molecule ligands as a lead compound for development of novel PET radiotracers for in vivo p75NTR imaging. Here we report that previously described ligand LM11A-24 shows significant inhibition of carbachol-induced persistent firing (PF) of entorhinal cortex (EC) pyramidal neurons in wild-type mice via selective interaction with p75NTR. Based on this electrophysiological assay, the compound has very high potency with an EC50<10nM. We optimized the radiosynthesis of [11C]LM11A-24 as the first attempt to develop PET radioligand for in vivo imaging of p75NTR. Despite some weak interaction with CNS tissues, the radiolabeled compound showed unfavorable in vivo profile presumably due to high hydrophilicity.

Cell-Specific Cholinergic Modulation of Excitability of Layer 5B Principal Neurons in Mouse Auditory Cortex.

The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neurons. Using in vitro electrophysiology and optogenetics in mouse brain slices, we found that ACh generated nicotinic ACh receptor (nAChR)-mediated depolarizing potentials and muscarinic ACh receptor (mAChR)-mediated hyperpolarizing potentials in AC L5B corticocallosal neurons. In corticocollicular neurons, ACh release also generated nAChR-mediated depolarizing potentials. However, in contrast to the mAChR-mediated hyperpolarizing potentials in corticocallosal neurons, ACh generated prolonged mAChR-mediated depolarizing potentials in corticocollicular neurons. These prolonged depolarizing potentials generated persistent firing in corticocollicular neurons, whereas corticocallosal neurons lacking mAChR-mediated depolarizing potentials did not show persistent firing. We propose that ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. Acetylcholine (ACh) is crucial for cognitive functions. Whereas in most cases the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) corticocollicular neurons projecting from layer 5B to the inferior colliculus are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Our results suggest that cell-specific ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. Moreover, our results provide synaptic mechanisms via which ACh may mediate its effects on AC receptive fields.

MGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions

Cognitive deficits in psychiatric and age-related disorders generally involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), but there are few treatments for these debilitating symptoms. Group II metabotropic glutamate receptors (mGluR2/3), which couple to Gi/Go, have been a focus of therapeutics based on rodent research, where mGluR2/3 have been shown to reduce axonal glutamate release and increase glial glutamate uptake. However, this strategy has had mixed results in patients, and understanding mGluR2/3 mechanisms in primates will help guide therapeutic interventions. The current study examined mGluR2/3 localization and actions in the primate dlPFC layer III circuits underlying working memory, where the persistent firing of ‘Delay cells’ is mediated by N-methyl-d-aspartate receptors and weakened by cAMP-PKA-potassium channel signaling in dendritic spines. Immunoelectron microscopy identified postsynaptic mGluR2/3 in the spines, in addition to the traditional presynaptic and astrocytic locations. In vivo iontophoretic application of the mGluR2/3 agonists (2R, 4R)-APDC or LY379268 onto dlPFC Delay cells produced an inverted-U effect on working memory representation, with enhanced neuronal firing following low doses of mGluR2/3 agonists. The enhancing effects were reversed by an mGluR2/3 antagonist or by activating cAMP signaling, consistent with mGluR2/3 inhibiting postsynaptic cAMP signaling in spines. Systemic administration of these agonists to monkeys performing a working memory task also produced an inverted-U dose–response, where low doses improved performance but higher doses, similar to clinical trials, had mixed effects. Our data suggest that low doses of mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function.

Opposing presynaptic roles of BDNF and ProBDNF in the regulation of persistent activity in the entorhinal cortex.

BackgroundSustained, persistent firing (PF) of cortical pyramidal neurons following a short depolarization is a crucial cellular mechanism required for spatial and working memory. Pyramidal neurons in the superficial and deep layers of the medial and lateral entorhinal cortex (EC) display this property of prolonged firing activity. Here, we focused on the regulation of this activity in EC neurons by mature brain derived neurotrophic factor (BDNF) and its precursor proBDNF.ResultsUsing patch clamp electrophysiology in acute mouse cortical slices, we observed that BDNF facilitates cholinergic PF in pyramidal neurons in layer V of the medial EC. Inhibition of TrkB with K252a blocks the potentiating effect of BDNF whereas inhibition of p75NTR with function-blocking antibodies does not. By recording spontaneous excitatory post-synaptic currents (sEPSC), we find that BDNF acts pre-synaptically via TrkB to increase glutamate release whereas proBDNF acting via p75NTR acts to reduce it. MPEP abolished the facilitating effect of BDNF on PF, demonstrating that the metabotropic glutamate receptor mGluR5 plays a critical role in the BDNF effect. In contrast, paired pulse ratio and EPSC measurements indicated that proBDNF, via presynaptic p75NTR, is a negative regulator of glutamate release in the EC.ConclusionsTaken together, our findings demonstrate that the BDNF/TrkB pathway facilitates persistent activity whereas the proBDNF/p75NTR pathway inhibits this mnemonic property of entorhinal pyramidal neurons.

海馬における内因性持続性発火とその役割

海馬における内因性持続性発火とその役割

Short Stimulus, Long Response: Sodium and Calcium Dynamics Explain Persistent Neuronal Firing.

A neuron fires in response to a stimulus, and in most cases, becomes refractory to further firing while returning to its resting state. In some neurons, however, a brief stimulus induces prolonged firing, lasting many seconds or even minutes. What mechanisms underlie this persistent response? One hypothesis has been that the neuron is linked into circuits that feed back onto it, providing a long-lasting secondary source of excitation. But models of such systems suggest they are much more susceptible to perturbation than is found in the neurons that actually exhibit prolonged firing. One such set of neurons are the mitral cells of the accessory olfactory bulb (AOB). In rodents and many other mammals (though not humans), the AOB processes pheromonal stimuli received by the vomeronasal organ, helping to regulate social interactions. In a new study in PLOS Biology, Asaph Zylbertal and colleagues show that the prolonged firing of the AOB’s mitral cells is independent of circuit-level control and is instead due to an unusually slow decay in the intracellular concentration of sodium ions. The authors have previously shown that mitral cells respond to a brief but intense stimulus by firing for up to several minutes. Here, they combined electrophysiology, cellular imaging, and computational modeling to tease apart the mechanism underlying that persistent firing. Recall that a resting neuron maintains a variety of ionic gradients across its plasma membrane. Importantly, the concentration of sodium is high outside the cell and low inside. At the dendrite, stimulation of the neuron opens sodium channels and sodium ions come flooding into the cell. The influx of sodium (combined with other ion changes) depolarizes the membrane, a change that then propagates down the axon as an action potential. The dendritic sodium channels then close and sodium is pumped out of the cell, restoring the gradient and the resting membrane potential. Among the other ions in flux during neuronal firing is calcium. By injecting a calcium-sensitive dye into the mitral cells, the authors showed that the level of calcium in the tip of a dendritic branch (the “tuft”) rose quickly in response to stimulation, and then decayed very slowly, a phenomenon not observed in other regions of the cell. Furthermore, they found that the level of calcium was dependent on the strength of the stimulus received by the neuron. Intracellular calcium is removed by two mechanisms: a calcium pump, and a sodium-calcium exchanger, in which the intake of extracellular sodium is coupled with the extrusion of calcium. But the activity of the exchanger and, hence, the rate of calcium extrusion depends on the strength of the sodium gradient. That, in turn, depends on the density of the major sodium exporter, the sodium/potassium ATPase. Thus, the authors reasoned, at low enough densities of the ATPase, intracellular sodium could remain high enough to reduce the activity of the exchanger or even reverse it, like a revolving door spinning backwards. This reversal could account for the prolonged elevation of intracellular calcium, which in turn could explain the prolonged firing of the mitral cells. To test this idea, they built a model involving three membrane proteins: the sodium/calcium exchanger, the calcium pump, and the sodium/potassium ATPase. By incorporating details of intracellular diffusion and the varying density of membrane proteins among cellular compartments, they showed that the intracellular sodium concentration was a major determinant of the slow decay in calcium levels. While the calcium pump removed calcium from the cell, the exchanger, driven by high sodium to run in reverse, let it back in (Fig 1). Critically, the effect depended on having relatively few sodium/potassium pumps available, in order to keep sodium elevated. The model predicted, and in vitro measurements confirmed, that blocking the exchanger allowed calcium to fall faster and abolished the prolonged firing of mitral cells. Fig 1 The ionic machinery behind prolonged firing. The mechanism described here is unlikely to be limited to the accessory olfactory bulb’s mitral cells. Further experiments will test whether it also contributes to long-lasting firing in other brain areas, including those involved in working memory, which involves persistent firing in response to limited stimuli. In addition, given calcium’s critical role as an intracellular signaling molecule, activity-dependent prolonged elevation of calcium may contribute to changes in synaptic plasticity, gene expression, and other processes, at time scales previously unrecognized.

Prolonged Intracellular Na+ Dynamics Govern Electrical Activity in Accessory Olfactory Bulb Mitral Cells.

Persistent activity has been reported in many brain areas and is hypothesized to mediate working memory and emotional brain states and to rely upon network or biophysical feedback. Here, we demonstrate a novel mechanism by which persistent neuronal activity can be generated without feedback, relying instead on the slow removal of Na+ from neurons following bursts of activity. We show that mitral cells in the accessory olfactory bulb (AOB), which plays a major role in mammalian social behavior, may respond to a brief sensory stimulation with persistent firing. By combining electrical recordings, Ca2+ and Na+ imaging, and realistic computational modeling, we explored the mechanisms underlying the persistent activity in AOB mitral cells. We found that the exceptionally slow inward current that underlies this activity is governed by prolonged dynamics of intracellular Na+ ([Na+]i), which affects neuronal electrical activity via several pathways. Specifically, elevated dendritic [Na+]i reverses the Na+-Ca2+ exchanger activity, thus modifying the [Ca2+]i set-point. This process, which relies on ubiquitous membrane mechanisms, is likely to play a role in other neuronal types in various brain regions.

Mathematical modelling of ICAN-mediated persistent firing in hippocampal neurons

Persistent neural activity has been the focus of neuroscientific research since it was first associated with complex cognitive behaviours. In particular, persistent firing has long been thought to be the neural mechanisms underlying short-term memory encoding and storage [1]. This activity is often elicited by short transient stimuli that have to be retained in memory for long delay periods, in the order of several seconds, after the original stimulus disappeared. In this scenario, the brain stores information for future execution of action depending on that information. Persistent activity elicited in a recurrent network comprising strong excitation in the local circuit has been extensively described in the literature (for a review see [2]). However, recent findings have shown that memory can also be encoded in brain regions which do not display such recurrent connection topology, including the CA1 hippocampal area [3]. Emerging studies are pointing towards intrinsic neural mechanisms independent of synaptic connections, as a complementary mechanism for the maintenance of persistent activity in the hippocampus [4]. These include various cytoplasmic currents flowing through the membrane, characterised by slow ion channel kinetics, and particular neurotransmitter modulation. Our work investigates persistent firing activity in networks of hippocampal neurons, elicited by leveraging intrinsic currents rather than network dynamics. Building on previous findings [5], we model a hippocampal pyramidal neuron using the Hodgkin-Huxley model, with low-threshold Ca2+ currents governing the inward flow of calcium ions in the cell membrane. The intracellular calcium concentration mediates the opening of calcium-activated non-specific (CAN) ion channels [6], which causes an increase in the ionic flow through the cell membrane. Therefore the CAN channels equip the neuron with an after-spike depolarisation mechanism, which enables it to emit action potentials in the absence of external stimulation. Given a transient 250ms 200pA current injection, the neuron is capable of eliciting and maintaining persistent activity with a firing rate of 6Hz for long delay periods (~30s). Moreover, this behaviour is in accord with that displayed in neural recordings of hippocampal slice preparations [4]. Connecting these persistent firing neurons in a network comprising strong local excitation yields a wide range of behaviours depending on the interaction between CAN and synaptic currents. Indeed, our network model is capable of displaying rhythmic behaviour in the form of short synchronised bursts with intra-burst frequencies of 20-40Hz and inter-burst frequencies of 3Hz. These results hint towards a possible mechanism for the generation of memory-related oscillatory activity in the hippocampus.

Peripheral Neuropathy Induces HCN Channel Dysfunction in Pyramidal Neurons of the Medial Prefrontal Cortex.

Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its molecular basis. The cationic current Ih mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays an important role in pain by facilitating ectopic firing and hyperexcitability in DRG neurons, however little is known regarding the role of Ih in supraspinal pain pathways. The medial prefrontal cortex (mPFC), which is reported to be involved in the affective aspects of pain, exhibits high HCN channel expression. Using the spared nerve injury (SNI) model of neuropathic pain in Long-Evans rats and patch-clamp recordings in layer II/III pyramidal neurons of the contralateral mPFC, we observed a hyperpolarizing shift in the voltage-dependent activation of Ih in SNI neurons, whereas maximal Ih remained unchanged. Accordingly, SNI mPFC pyramidal neurons exhibited increased input resistance and excitability, as well as facilitated glutamatergic mGluR5-mediated persistent firing, compared with sham neurons. Moreover, intracellular application of bromo-cAMP abolished the hyperpolarizing shift in the voltage-dependent activation of Ih observed in SNI neurons, whereas protein kinase A (PKA) inhibition further promoted this shift in both SNI and sham neurons. Behaviorally, acute HCN channel blockade by local injection of ZD7288 in the mPFC of SNI rats induced a decrease in cold allodynia. These findings suggest that changes in the cAMP/PKA axis in mPFC neurons underlie alterations to HCN channel function, which can influence descending inhibition of pain pathways in neuropathic conditions. Significance statement: Recent studies investigating the role of the medial prefrontal cortex (mPFC) in neuropathic pain have led to an increased awareness of how affective and cognitive factors can influence pain perception. It is therefore imperative that we advance our understanding of the involvement of supraspinal pain pathways. Our electrophysiological and behavioral results support an important role for hyperpolarization-activated cyclic nucleotide-gated channels and the cAMP/protein kinase A signaling axis in promoting hyperexcitability and persistent firing in pyramidal neurons of the mPFC in neuropathic animals. These findings offer novel insights, with potential therapeutic implications, into pathophysiological mechanisms underlying the abnormal contribution of layer II/III prefrontal pyramidal neurons to chronic pain states.

Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells.

Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.

ProBDNF and p75NTR Control Excitability and Persistent Firing of Cortical Pyramidal Neurons.

Persistent firing of entorhinal cortex (EC) pyramidal neurons is required for working memory. We report here that pro-brain-derived neurotrophic factor (proBDNF) activates p75NTR to induce a Rac1-dependent and phosphatidylinositol 4,5-bisphosphate-dependent signaling cascade that suppresses persistent activity. Conversely, using loss-of-function approaches, we find that endogenous proBDNF or p75NTR activation strongly decreases pyramidal neuron excitability and persistent firing, suggesting that a physiological role of this proBDNF-p75NTR cascade may be to regulate working memory in vivo. Consistent with this, mice rendered null for p75NTR during adulthood show improvements in working memory but also display an increased propensity for severe seizures. We propose that by attenuating EC network performance, the proBDNF-p75NTR signaling cascade reduces the probability of epileptogenesis.

A Top-Down Cortical Circuit for Accurate Sensory Perception

A fundamental issue in cortical processing of sensory information is whether top-down control circuits from higher brain areas to primary sensory areas not only modulate but actively engage in perception. Here, we report the identification of a neural circuit for top-down control in the mouse somatosensory system. The circuit consisted of a long-range reciprocal projection between M2 secondary motor cortex and S1 primary somatosensory cortex. Invivo physiological recordings revealed that sensory stimulation induced sequential S1 to M2 followed by M2 to S1 neural activity. The top-down projection from M2 to S1 initiated dendritic spikes and persistent firing of S1 layer 5 (L5) neurons. Optogenetic inhibition of M2 input to S1 decreased L5 firing and the accurate perception of tactile surfaces. These findings demonstrate that recurrent input to sensory areas is essential for accurate perception and provide a physiological model for one type of top-down control circuit.

A robust in vivo-like persistent firing supported by a hybrid of intracellular and synaptic mechanisms.

Persistent firing is believed to support short-term information retention in the brain. Established hypotheses make use of the recurrent synaptic connectivity to support persistent firing. However, this mechanism is known to suffer from a lack of robustness. On the other hand, persistent firing can be supported by an intrinsic cellular mechanism in multiple brain areas. However, the consequences of having both the intrinsic and the synaptic mechanisms (a hybrid model) on persistent firing remain largely unknown. The goal of this study is to investigate whether a hybrid neural network model with these two mechanisms has advantages over a conventional recurrent network based model. Our computer simulations were based on in vitro recordings obtained from hippocampal CA3 pyramidal cells under cholinergic receptor activation. Calcium activated non-specific cationic (CAN) current supported persistent firing in the Hodgkin-Huxley style cellular models. Our results suggest that the hybrid model supports persistent firing within a physiological frequency range over a wide range of different parameters, eliminating parameter sensitivity issues generally recognized in network based persistent firing. In addition, persistent firing in the hybrid model is substantially more robust against distracting inputs, can coexist with theta frequency oscillations, and supports pattern completion.

Persistent discharges in dentate gyrus perisoma-inhibiting interneurons require hyperpolarization-activated cyclic nucleotide-gated channel activation.

Parvalbumin (PV)-expressing perisoma-inhibiting interneurons (PIIs) of the dentate gyrus integrate rapidly correlated synaptic inputs and generate short-duration action potentials that propagate along the axon to their output synapses, supporting fast inhibitory signaling onto their target cells. Here we show that PV-PIIs in rat and mouse dentate gyrus (DG) integrate their intrinsic activity over time and can turn into a persistent firing mode characterized by the ability to generate long-lasting trains of action potentials at ∼50 Hz in the absence of additional inputs. Persistent firing emerges in the axons remote from the axon initial segment and markedly depends on hyperpolarization-activated cyclic nucleotide-gated channel (HCNC) activation. Persistent firing properties are modulated by intracellular Ca(2+) levels and somatic membrane potential. Detailed computational single-cell PIIs models reveal that HCNC-mediated conductances can contribute to persistent firing during conditions of a shift in their voltage activation curve to more depolarized potentials. Paired recordings from PIIs and their target granule cells show that persistent firing supports strong inhibitory output signaling. Thus, persistent firing may emerge during conditions of intense activation of the network, thereby providing silencing to the circuitry and the maintenance of sparse activity in the dentate gyrus.

Contribution of NMDA receptors to dorsolateral prefrontal cortical networks in primates.

Cognitive disorders such as schizophrenia and Alzheimer's disease are associated with dysfunction of the highly evolved dorsolateral prefrontal cortex (dlPFC), and with changes in glutamatergic N-methyl-D-aspartate receptors (NMDARs). Recent research on the primate dlPFC discovered that the pyramidal cell circuits that generate the persistent firing underlying spatial working memory communicate through synapses on spines containing NMDARs with NR2B subunits (GluN2B) in the post-synaptic density. This contrasts with synapses in the hippocampus and primary visual cortex, where GluN2B receptors are both synaptic and extrasynaptic. Blockade of GluN2B in the dlPFC markedly reduces the persistent firing of the Delay cells needed for neuronal representations of visual space. Cholinergic stimulation of nicotinic α7 receptors within the glutamate synapse is necessary for NMDAR actions. In contrast, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors have only subtle effects on the persistent firing of Delay cells, but contribute substantially to the firing of Cue and Response cells. Systemic administration of the NMDAR antagonist ketamine reduces the persistent firing of Delay cells, but increases the firing of some Response cells. The reduction in persistent firing produced by ketamine may explain why this drug can mimic or worsen the cognitive symptoms of schizophrenia. Similar actions in the medial PFC circuits representing the emotional aspects of pain may contribute to the rapid analgesic and anti-depressant actions of ketamine.

Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

BackgroundPsychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cyclic adenosine monophosphate signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect. MethodsA variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current, while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance. ResultsImmunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased HCN channel current, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation. ConclusionsThese findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses.

Spatial Patterns of Persistent Neural Activity Vary with the Behavioral Context of Short-Term Memory

A short-term memory can be evoked by different inputs and control separate targets in different behavioral contexts. To address the circuit mechanisms underlying context-dependent memory function, we determined through optical imaging how memory is encoded at the whole-network level in two behavioral settings. Persistent neural activity maintaining a memory of desired eye position was imaged throughout the oculomotor integrator after saccadic or optokinetic stimulation. While eye position was encoded by the amplitude of network activity, the spatial patterns of firing were context dependent: cells located caudally generally were most persistent following saccadic input, whereas cells located rostrally were most persistent following optokinetic input. To explain these data, we computationally identified four independent modes of network activity and found these were differentially accessed by saccadic and optokinetic inputs. These results show how a circuit can simultaneously encode memory value and behavioral context, respectively, in its amplitude and spatial pattern of persistent firing.

Transient and sustained afterdepolarizations in accessory olfactory bulb mitral cells are mediated by distinct mechanisms that are differentially regulated by neuromodulators

Social interactions between mammalian conspecifics rely heavily on molecular communication via the main and accessory olfactory systems. These two chemosensory systems show high similarity in the organization of information flow along their early stages: social chemical cues are detected by the sensory neurons of the main olfactory epithelium and the vomeronasal organ. These neurons then convey sensory information to the main (MOB) and accessory (AOB) olfactory bulbs, respectively, where they synapse upon mitral cells that project to higher brain areas. Yet, the functional difference between these two chemosensory systems remains unclear. We have previously shown that MOB and AOB mitral cells exhibit very distinct intrinsic biophysical properties leading to different types of information processing. Specifically, we found that unlike MOB mitral cells, AOB neurons display persistent firing responses to strong stimuli. These prolonged responses are mediated by long-lasting calcium-activated non-selective cationic current (Ican). In the current study we further examined the firing characteristics of these cells and their modulation by several neuromodulators. We found that AOB mitral cells display transient depolarizing afterpotentials (DAPs) following moderate firing. These DAPs are not found in MOB mitral cells that show instead robust hyperpolarizing afterpotentials. Unlike Ican, the DAPs of AOB mitral cells are activated by low levels of intracellular calcium and are relatively insensitive to flufenamic acid. Moreover, the cholinergic agonist carbachol exerts opposite effects on the persistent firing and DAPs of AOB mitral cells. We conclude that these phenomena are mediated by distinct biophysical mechanisms that may serve to mediate different types of information processing in the AOB at distinct brain states.

Modeling Neuromorphic Persistent Firing Networks

Neurons are believed to be the brain computational engines of the brain. A recent discovery in neurophysiology reveals that interneurons can slowly integrate spiking, share the output across a coupled network of axons and respond with persistent firing even in the absence of input to the soma or dendrites, which has not been understood and could be very important for exploring the mechanism of human cognition. The conventional models are incapable of simulating the important newly-discovered phenomenon of persistent firing induced by axonal slow integration. In this paper, we propose a computationally efficient model of neurons through modeling the axon as a slow leaky integrator, which captures almost all-known neural behaviors. The model controls the switching of axonal firing dynamics between passive conduction mode and persistent firing mode. The interplay between the axonal integrated potential and its multiple thresholds in axon precisely determines the persistent firing dynamics of neurons. We also present a persistent firing polychronous spiking network which exhibits asynchronous dynamics indicating that this computationally efficient model is not only bio-plausible, but also suitable for large scale spiking network simulations. The implications of this network and the analog circuit design for exploring the relationship between working memory and persistent firing enable developing a spiking network-based memory and bio-inspired computer systems.

Consequences of Adaptation of Spike-Threshold-Accommodation

Event Abstract Back to Event Consequences of Adaptation of Spike-Threshold-Accommodation William J. Spain1, 2*, Nikolai C. Dembrow1, 2 and Gregory S. Newkirk1 1 University of Washington, Physiology & Biophysics, United States 2 VAPSHCS, Neurology, United States It has long been known that action potential threshold depends on the time-course of the rising trajectory of the underlying EPSCs, so called action potential threshold accommodation where some neurons are less excitable for more slowly rising inputs. By selective filtering of slower inputs, AP threshold accommodation restricts the “synaptic receptive field” of a neuron. Experimental results will be shown demonstrating a dynamic change in the amount of AP threshold accommodation that occurs in a neuron and its consequences for neuronal input selectivity. One of several mechanisms that can result in threshold accommodation is potassium channels located near the spike generating zone of a neuron. The potassium channels must have voltage dependence and kinetics that result in an increase in channel activation during the rising phase of an EPSP (e.g. Id or Kv1 type channels). In some neurons the depolarization of the mean inter-spike membrane potential during persistent firing results in slow inactivation of such K channels. The filtering of slower rising EPSCs decreases over time as K channel inactivation accumulates (all else being equal). In this manner, as synaptic activity persists, a broadening of the range of input frequencies that can efficiently drive action potentials occurs, causing an increase in firing rate. That is, the lessening of threshold accommodation makes the neurons less high pass. In addition to the increase in firing rate, spike-time precision decreases during a constant noisy input (or phase-locking to specific frequency components of the input decreases). A specific example from the auditory brainstem will be reviewed that supports the hypothesis that this form of neuronal adaptation underlies the adaptation of the ability to accurately locate moving sounds. Acknowledgements We thank M. Higgs, S. Slee, M. Kuznetsova, A. Brown and G. Stecker for prior experiments and discussions that formed the basis for this abstract. References Slee, S.L., Higgs, M.H., Fairhall, A.F. and Spain, W.J. Two-Dimensional Time Coding in the Auditory Brainstem. J. Neuroscience 25: 9978-9988, 2005. Kuznetsova, M.S. Higgs, M.H., and Spain, W.J. Adaptive Changes in Firing Rate and Spike Timing Precision in Neurons of the Chick Nucleus Magnocellularis. J. Neuroscience 28:11906-11915, 2008. Higgs, M.H. and Spain, W.J. Kv1 Channels control spike threshold dynamics and spike timing in cortical pyramidal neurons. J. Physiology 589: 5125-42, 2011. Brown, A.D., Kuznetsova, M.S., Spain, W.J. and Stecker, G.C. Frequency-specific, location-independent adaptation of interaural time difference sensitivity. Hearing Research 291: 53-6, 2012. Higgs, M.H. Kuznesova, M.S. and Spain, W.J. Adaptation of spike timing precision controls the sensitivity of sound localization J. Neuroscience 32: 32(44):15489-94, 2012. Keywords: Action potential threshold, Adaptation, Physiological, Potassium Channels, accommodation, Sound Localization, Inactivation, spike time precision, phase-locking Conference: Spike Initiation: Models & Experiments, Prague, Czechia, 22 Jul - 22 Jul, 2015. Presentation Type: Oral Presentation Topic: Neuroscience Citation: Spain WJ, Dembrow NC and Newkirk GS (2015). Consequences of Adaptation of Spike-Threshold-Accommodation . Front. Neurosci. Conference Abstract: Spike Initiation: Models & Experiments. doi: 10.3389/conf.fnins.2015.90.00006 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Jul 2015; Published Online: 08 Jul 2015. * Correspondence: Dr. William J Spain, University of Washington, Physiology & Biophysics, Seattle, Washington, 98195, United States, spain@u.washington.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers William J Spain Nikolai C Dembrow Gregory S Newkirk Google William J Spain Nikolai C Dembrow Gregory S Newkirk Google Scholar William J Spain Nikolai C Dembrow Gregory S Newkirk PubMed William J Spain Nikolai C Dembrow Gregory S Newkirk Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.