Tonic Firing Research Articles

Subpopulations of PKCγ interneurons within the medullary dorsal horn revealed by electrophysiologic and morphologic approach.

Mechanical allodynia, a cardinal symptom of persistent pain, is associated with the unmasking of usually blocked local circuits within the superficial spinal or medullary dorsal horn (MDH) through which low-threshold mechanical inputs can gain access to the lamina I nociceptive output neurons. Specific interneurons located within inner lamina II (IIi) and expressing the gamma isoform of protein kinase C (PKCγ⁺) have been shown to be key elements for such circuits. However, their morphologic and electrophysiologic features are still unknown. Using whole-cell patch-clamp recordings and immunohistochemical techniques in slices of adult rat MDH, we characterized such lamina IIi PKCγ⁺ interneurons and compared them with neighboring PKCγ⁻ interneurons. Our results reveal that PKCγ⁺ interneurons display very specific activity and response properties. Compared with PKCγ⁻ interneurons, they exhibit a smaller membrane input resistance and rheobase, leading to a lower threshold for action potentials. Consistently, more than half of PKCγ⁺ interneurons respond with tonic firing to step current. They also receive a weaker excitatory synaptic drive. Most PKCγ⁺ interneurons express Ih currents. The neurites of PKCγ⁺ interneurons arborize extensively within lamina IIi, can spread dorsally into lamina IIo, but never reach lamina I. In addition, at least 2 morphologically and functionally different subpopulations of PKCγ⁺ interneurons can be identified: central and radial PKCγ⁺ interneurons. The former exhibit a lower membrane input resistance, rheobase and, thus, action potential threshold, and less PKCγ⁺ immunoreactivity than the latter. These 2 subpopulations might thus differently contribute to the gating of dorsally directed circuits within the MDH underlying mechanical allodynia.

Functional heterogeneity of calretinin-expressing neurons in the mouse superficial dorsal horn: implications for spinal pain processing.

The superficial spinal dorsal horn contains a heterogeneous population of neurons that process sensory inputs. Information on the properties of excitatory interneurons in this region is limited. As calretinin is a protein thought to be restricted to an excitatory population in this region, the aim of this study was to characterize calretinin-expressing neurons. Most calretinin cells (85%) exhibited large A-type potassium currents and delayed firing action potential discharge, and received strong excitatory synaptic input, whereas the remainder exhibited hyperpolarization-activated cation currents and low threshold T-type calcium currents, and tonic- or initial bursting firing patterns, and received weak excitatory synaptic input. These respective features are consistent with properties of excitatory and inhibitory interneuron populations in this region of the spinal cord. Our findings have resolved a previously unidentified population of inhibitory interneurons. Furthermore, the contrasting excitability patterns of excitatory and inhibitory calretinin-expressing neurons suggest that they play distinct roles in spinal sensory processing circuits. Neurons in the superficial dorsal horn (SDH) of the spinal cord play an important role in nociceptive, thermal, itch and light touch sensations. Excitatory interneurons comprise ∼65% of all SDH neurons but surprisingly few studies have investigated their role in spinal sensory processing. Here we use a transgenic mouse to study putative excitatory SDH neurons that express the calcium binding protein calretinin (CR). Our immunocytochemical, morphological and electrophysiological analysis identified two distinct populations of CR-expressing neurons, which we termed 'Typical' and 'Atypical'. Typical CR-expressing neurons comprised ∼85% of the population and exhibited characteristic excitatory interneuron properties including delayed firing discharge, large rapid A-type potassium currents, and central, radial or vertical cell morphologies. Atypical neurons exhibited properties consistent with inhibitory interneurons, including tonic firing or initial bursting discharge, Ih currents, and islet cell morphology. Although both Typical and Atypical CR-expressing neurons responded to noxious peripheral stimulation, the excitatory drive onto Typical CR-expressing neurons was much stronger. Furthermore, Atypical CR-expressing cells comprise at least two functionally distinct subpopulations based on their responsiveness to noxious peripheral stimulation and neurochemical profile. Together our data suggest CR expression is not restricted to excitatory neurons in the SDH. Under normal conditions, the contribution of 'Typical' excitatory CR-expressing neurons to overall SDH excitability may be limited by the presence of A-type potassium currents, which limit the effectiveness of their strong excitatory input. Their contribution may, however, be increased in pathological situations where A-type potassium currents are decreased. By contrast, 'Atypical' inhibitory neurons with their excitable phenotype but weak excitatory input may be more easily recruited during increased peripheral stimulation.

Measuring effects of different noises in a model using ISI-distance methods

This paper examines the effects of current and conductance noises in a minimal Hodgkin–Huxley type model of a cold receptor neuron. Current noise enters the membrane equation directly while conductance noise is propagated through the activation variables. Compared with common used interspike interval method, ISI-distance is a simple complementary approach to measure the different effects of current and conductance noises. ISI-distance extracts information from the interspike intervals by evaluating the ratio of instantaneous firing rates, which is parameter-free, time scale-independent and easy to visualize. Simulation results show that the most significant differences between different noise implementations in a pacemaker-like tonic firing regime at the transition to chaotic burst discharges.

Changes in Activity of the Same Thalamic Neurons to Repeated Nociception in Behaving Mice

The sensory thalamus has been reported to play a key role in central pain sensory modulation and processing, but its response to repeated nociception at thalamic level is not well known. Current study investigated thalamic response to repeated nociception by recording and comparing the activity of the same thalamic neuron during the 1st and 2nd formalin injection induced nociception, with a week interval between injections, in awake and behaving mice. Behaviorally, the 2nd injection induced greater nociceptive responses than the 1st. Thalamic activity mirrored these behavioral changes with greater firing rate during the 2nd injection. Analysis of tonic and burst firing, characteristic firing pattern of thalamic neurons, revealed that tonic firing activity was potentiated while burst firing activity was not significantly changed by the 2nd injection relative to the 1st. Likewise, burst firing property changes, which has been consistently associated with different phases of nociception, were not induced by the 2nd injection. Overall, data suggest that repeated nociception potentiated responsiveness of thalamic neurons and confirmed that tonic firing transmits nociceptive signals.

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats.

In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORD-expressing putative dopamine neurons in midbrain. In Exp. 3, we used a 'retro-DREADD' dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior.

Distinct ensembles of medial prefrontal cortex neurons are activated by threatening stimuli that elicit excitation vs. inhibition of movement.

Neural circuits controlling defensive behavior were investigated by recording single units in medial prefrontal cortex (mPFC) and dorsolateral periaqueductal gray (dlPAG) while rats expressed conditioned fear responses to an auditory conditioned stimulus (CS; 20-s train of white noise pips) previously paired with an aversive unconditioned stimulus (US; 2-s train of periorbital shocks). The CS elicited conditioned movement inhibition (CMI; characterized by decreased movement speed and freezing) when rats had not recently encountered the US, whereas the CS elicited conditioned movement excitation (CME; characterized by increased movement speed and flight behavior) after recent US encounters. Many mPFC neurons were "strategy-selective" cells that changed their firing rates only when the CS elicited CME (15/71) or CMI (13/71) responses, whereas few mPFC cells (4/71) responded nonselectively to the CS during either response. By contrast, many dlPAG neurons (20/74) responded nonselectively to the CS, but most (40/74) were excited by the CS selectively during CME trials (and none during CMI trials). CME-selective neurons in dlPAG responded phasically after CS pips that elicited CME responses, whereas CME-selective neurons in mPFC showed tonically elevated activity before and after pips that evoked CME responses. These findings suggest that, at the time when the CS occurs, tonic firing rates of CME- and CMI-selective mPFC neurons may bias the rat's choice of whether to express CME vs. CMI responses, perhaps via projections to downstream structures (such as amygdala and PAG) that influence how sensory stimuli are mapped onto motor circuits that drive the expression of competing behaviors.

Interspike interval correlation in a stochastic exponential integrate-and-fire model with subthreshold and spike-triggered adaptation.

We study the spike statistics of an adaptive exponential integrate-and-fire neuron stimulated by white Gaussian current noise. We derive analytical approximations for the coefficient of variation and the serial correlation coefficient of the interspike interval assuming that the neuron operates in the mean-driven tonic firing regime and that the stochastic input is weak. Our result for the serial correlation coefficient has the form of a geometric sequence and is confirmed by the comparison to numerical simulations. The theory predicts various patterns of interval correlations (positive or negative at lag one, monotonically decreasing or oscillating) depending on the strength of the spike-triggered and subthreshold components of the adaptation current. In particular, for pure subthreshold adaptation we find strong positive ISI correlations that are usually ascribed to positive correlations in the input current. Our results i) provide an alternative explanation for interspike-interval correlations observed in vivo, ii) may be useful in fitting point neuron models to experimental data, and iii) may be instrumental in exploring the role of adaptation currents for signal detection and signal transmission in single neurons.

A commentary on: "Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli".

Each time there is an interaction with the environment, we select one among many, equally possible, actions. How is it done? In the classical view, to access motor resources, many cortical action plans compete in the basal ganglia: a set of subcortical neuron populations, whose output constantly inhibits specific thalamic targets. In the basal ganglia, one cortical plan is selected, the corresponding thalamic inhibition is disabled, finally producing the action (Albin et al., 1989). The classical view of action selection is now extended, including thalamic afferents. And, in the current view, a key role as modulators of action selection has been assigned to cholinergic interneurons of the striatum, the largest basal ganglia structure (Ding et al., 2010). Striatum is divided in two major populations of GABAergic medium spiny neurons (MSNs) according to different expression of D1 and D2 dopamine receptors. These two populations and their downstream pathways are respectively addressed as direct and indirect, for their connections with output basal structures (Tepper and Bolam, 2004). More than 90% of striatal neurons are MSNs while the remaining 5–10% are two types of interneurons, cholinergic, and GABAergic. These are providing the lateral inhibition that can actually implement the competition among cortical plans and therefore are a key to understand action selection. Cholinergic interneurons are known as tonically active neurons (TANs) for their spontaneous activity (>4 Hz). They receive glutamatergic afferents from cortex and thalamus, forming more synapses with thalamic than cortical terminals (Doig et al., 2014), and dopaminergic afferents from substantia nigra pars compacta. Locally, they branch dendritic arborization up to a millimeter in diameter, and they innervate GABAergic interneurons, other TANs and MSNs (Tepper and Bolam, 2004). Under resting conditions, MSNs are hyperpolarized by TANs spontaneous tonic firing (Tepper and Bolam, 2004). Morris et al. (2004) showed that increased cortical activity makes TANs respond with a brief burst, an afterhyperpolarization pause in their firing, and a rebound burst. In addition, Ding et al. (2010) have shown, in vitro, that also thalamic stimuli elicit TAN burst-pause pattern response. The work of Doig et al. (2014) aims at functionally distinguish thalamic and cortical contributions to action selection. Using different stimuli (single-, paired-pulse, and pulse trains) selectively delivered in the cortex and thalamus of rats, they were able to identify two temporal TAN response patterns. As in Morris et al. (2004), they used peri-stimulus time histogram (PSTH) analysis to identify the three main phases in TAN response: burst, pause and rebound. Applying pulse trains, which mimic the timing of motivationally salient stimuli (Ding et al., 2010), they were able to discriminate cortical and thalamic stimuli, predicting the whole TAN response based only on the initial phase. In fact, the number of spikes in the burst correlated positively with pause length and negatively with the magnitude of rebound: thalamic source was identified by high initial phase, long pause and low rebound, while cortical source was marked by lower initial phase, short pause, and higher rebound (Figure 1A).

Thalamic Kv 7 channels: pharmacological properties and activity control during noxious signal processing.

The existence of functional K(v)7 channels in thalamocortical (TC) relay neurons and the effects of the K(+)-current termed M-current (I(M)) on thalamic signal processing have long been debated. Immunocytochemical evidence suggests their presence in this brain region. Therefore, we aimed to verify their existence, pharmacological properties and function in regulating activity in neurons of the ventrobasal thalamus (VB). Characterization of K(v)7 channels was performed by combining in vitro, in vivo and in silico techniques with a pharmacological approach. Retigabine (30 μM) and XE991 (20 μM), a specific K(v)7 channel enhancer and blocker, respectively, were applied in acute brain slices during electrophysiological recordings. The effects of intrathalamic injection of retigabine (3 mM, 300 nL) and/or XE991 (2 mM, 300 nL) were investigated in freely moving animals during hot-plate tests by recording behaviour and neuronal activity. K(v)7.2 and K(v)7.3 subunits were found to be abundantly expressed in TC neurons of mouse VB. A slow K(+)-current with properties of IM was activated by retigabine and inhibited by XE991. K(v)7 channel activation evoked membrane hyperpolarization, a reduction in tonic action potential firing, and increased burst firing in vitro and in computational models. Single-unit recordings and pharmacological intervention demonstrated a specific burst-firing increase upon I(M) activation in vivo. A K(v)7 channel-mediated increase in pain threshold was associated with fewer VB units responding to noxious stimuli, and increased burst firing in responsive neurons. K(v)7 channel enhancement alters somatosensory activity and may reflect an anti-nociceptive mechanism during acute pain processing.

Potentiation of NMDA receptor-mediated transmission in striatal cholinergic interneurons.

Pauses in the tonic firing of striatal cholinergic interneurons (CINs) emerge during reward-related learning in response to conditioning of a neutral cue. We have previously reported that augmenting the postsynaptic response to cortical afferents in CINs is coupled to the emergence of a cell-intrinsic afterhyperpolarization (AHP) underlying pauses in tonic activity. Here we investigated in a bihemispheric rat-brain slice preparation the mechanisms of synaptic plasticity of excitatory afferents to CINs and the association with changes in the AHP. We found that high frequency stimulation (HFS) of commissural corticostriatal afferents from the contralateral hemisphere induced a robust long-term depression (LTD) of postsynaptic potentials (PSP) in CINs. Depression of the PSP of smaller magnitude and duration was observed in response to HFS of the ipsilateral white matter or cerebral cortex. In Mg2+-free solution HFS induced NMDA receptor-dependent potentiation of the PSP, evident in both the maximal slope and amplitude of the PSP. The increase in maximal slope corroborates previous findings, and was blocked by antagonism of either D1-like dopamine receptors with SCH23390 or D2-like dopamine receptors with sulpiride during HFS in Mg2+-free solution. Potentiation of the slower PSP amplitude component was due to augmentation of the NMDA receptor-mediated potential as this was completely reversed on subsequent application of the NMDA receptor antagonist AP5. HFS similarly potentiated NMDA receptor currents isolated by blockade of AMPA/kainate receptors with CNQX. The plasticity-induced increase in the slow PSP component was directly associated with an increase in the subsequent AHP. Thus plasticity of cortical afferent synapses is ideally suited to influence the cue-induced firing dynamics of CINs, particularly through potentiation of NMDA receptor-mediated synaptic transmission.

Tonic Firing Rate Controls Dendritic Ca2+Signaling and Synaptic Gain in Substantia Nigra Dopamine Neurons

Substantia nigra dopamine neurons fire tonically resulting in action potential backpropagation and dendritic Ca(2+) influx. Using Ca(2+) imaging in acute mouse brain slices, we find a surprisingly steep relationship between tonic firing rate and dendritic Ca(2+). Increasing the tonic rate from 1 to 6 Hz generated Ca(2+) signals up to fivefold greater than predicted by linear summation of single spike-evoked Ca(2+)-transients. This "Ca(2+) supralinearity" was produced largely by depolarization of the interspike voltage leading to activation of subthreshold Ca(2+) channels and was present throughout the proximal and distal dendrites. Two-photon glutamate uncaging experiments show somatic depolarization enhances NMDA receptor-mediated Ca(2+) signals >400 μm distal to the soma, due to unusually tight electrotonic coupling of the soma to distal dendrites. Consequently, we find that fast tonic firing intensifies synaptically driven burst firing output in dopamine neurons. These results show that modulation of background firing rate precisely tunes dendritic Ca(2+) signaling and provides a simple yet powerful mechanism to dynamically regulate the gain of synaptic input.

Mechanisms of gain control by voltage-gated channels in intrinsically-firing neurons.

Gain modulation is a key feature of neural information processing, but underlying mechanisms remain unclear. In single neurons, gain can be measured as the slope of the current-frequency (input-output) relationship over any given range of inputs. While much work has focused on the control of basal firing rates and spike rate adaptation, gain control has been relatively unstudied. Of the limited studies on gain control, some have examined the roles of synaptic noise and passive somatic currents, but the roles of voltage-gated channels present ubiquitously in neurons have been less explored. Here, we systematically examined the relationship between gain and voltage-gated ion channels in a conductance-based, tonically-active, model neuron. Changes in expression (conductance density) of voltage-gated channels increased (Ca2+ channel), reduced (K+ channels), or produced little effect (h-type channel) on gain. We found that the gain-controlling ability of channels increased exponentially with the steepness of their activation within the dynamic voltage window (voltage range associated with firing). For depolarization-activated channels, this produced a greater channel current per action potential at higher firing rates. This allowed these channels to modulate gain by contributing to firing preferentially at states of higher excitation. A finer analysis of the current-voltage relationship during tonic firing identified narrow voltage windows at which the gain-modulating channels exerted their effects. As a proof of concept, we show that h-type channels can be tuned to modulate gain by changing the steepness of their activation within the dynamic voltage window. These results show how the impact of an ion channel on gain can be predicted from the relationship between channel kinetics and the membrane potential during firing. This is potentially relevant to understanding input-output scaling in a wide class of neurons found throughout the brain and other nervous systems.

Inflammatory-induced changes in synaptic drive and postsynaptic AMPARs in lamina II dorsal horn neurons are cell-type specific.

Persistent peripheral inflammation alters trafficking of AMPA receptors (AMPARs) at the synapses between primary afferents and dorsal horn (DH) neurons that contribute to the maintenance of inflammatory pain. However, whether peripheral inflammation changes the synaptic activity within the DH circuitry and how it modulates synaptic AMPARs in different neuronal types still remain unknown. We find that complete Freund adjuvant (CFA)-induced peripheral inflammation prominently augments excitatory neurotransmission in rat lamina II neurons characterized by intrinsic adapting firing properties and apparently decreases it in the tonic firing lamina II neurons, suggesting different roles of these types of interneurons in pain processing. Peripheral inflammation also differentially changes inhibitory neurotransmission in these neuronal types, shifting the balance between neuronal excitation and inhibition toward excitation of the adapting firing, but toward inhibition of the tonic firing lamina II neurons. Synaptic AMPARs were differentially changed in the adapting firing and the tonic firing neurons, implying different mechanisms of AMPAR adjustment at the synapses in these types of interneurons during persistent inflammation. The inflammatory-induced, neuron-type specific changes in synaptic drive within the DH circuitry and synaptic AMPAR functioning in lamina II neurons may contribute to the persistent pain maintenance.

Serotonergic neurons signal reward and punishment on multiple timescales.

Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We 'tagged' serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales.

Implementation of Linear Sensory Signaling via Multiple Coordinated Mechanisms at Central Vestibular Nerve Synapses

Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations.

Contribution of persistent sodium currents to the excitability of tonic firing substantia gelatinosa neurons of the rat

The roles of persistent Na+ currents (INaP) in intrinsic membrane properties were examined in rat substantia gelatinosa (SG) neurons of the trigeminal subnucleus caudalis using a conventional whole-cell patch clamp technique. In a voltage-clamp mode, riluzole inhibited the slow voltage ramp-induced INaP but had little effect on the peak amplitude of transient Na+ currents in SG neurons. In a current-clamp mode, most SG neurons exhibited spontaneous action potentials and tonic firing pattern. Riluzole reduced both spontaneous and elicited action potentials in a concentration-dependent manner. The present results suggest that the riluzole-sensitive INaP plays an important role in the excitability of SG neurons and are thus, likely to contribute to the modulation of nociceptive transmission from the orofacial tissues.

Diverse cortical codes for scene segmentation in primate auditory cortex.

The temporal coherence of amplitude fluctuations is a critical cue for segmentation of complex auditory scenes. The auditory system must accurately demarcate the onsets and offsets of acoustic signals. We explored how and how well the timing of onsets and offsets of gated tones are encoded by auditory cortical neurons in awake rhesus macaques. Temporal features of this representation were isolated by presenting otherwise identical pure tones of differing durations. Cortical response patterns were diverse, including selective encoding of onset and offset transients, tonic firing, and sustained suppression. Spike train classification methods revealed that many neurons robustly encoded tone duration despite substantial diversity in the encoding process. Excellent discrimination performance was achieved by neurons whose responses were primarily phasic at tone offset and by those that responded robustly while the tone persisted. Although diverse cortical response patterns converged on effective duration discrimination, this diversity significantly constrained the utility of decoding models referenced to a spiking pattern averaged across all responses or averaged within the same response category. Using maximum likelihood-based decoding models, we demonstrated that the spike train recorded in a single trial could support direct estimation of stimulus onset and offset. Comparisons between different decoding models established the substantial contribution of bursts of activity at sound onset and offset to demarcating the temporal boundaries of gated tones. Our results indicate that relatively few neurons suffice to provide temporally precise estimates of such auditory "edges," particularly for models that assume and exploit the heterogeneity of neural responses in awake cortex.

The role of mesoaccumbens dopamine in nicotine dependence.

There is abundant evidence that the dopamine (DA) neurons that project to the nucleus accumbens play a central role in neurobiological mechanisms underpinning drug dependence. This chapter considers the ways in which these projections facilitate the addiction to nicotine and tobacco. It focuses on the complimentary roles of the two principal subdivisions of the nucleus accumbens, the accumbal core and shell, in the acquisition and maintenance of nicotine-seeking behavior. The ways in which tonic and phasic firing of the neurons contributes to the ways in which the accumbens mediate the behavioral responses to nicotine are also considered. Experimental studies suggest that nicotine has relatively weak addictive properties which are insufficient to explain the powerful addictive properties of tobacco smoke. This chapter discusses hypotheses that seek to explain this conundrum. They implicate both discrete sensory stimuli closely paired with the delivery of tobacco smoke and contextual stimuli habitually associated with the delivery of the drug. The mechanisms by which each type of stimulus influence tobacco dependence are hypothesized to depend upon the increased DA release and overflow, respectively, in the two subdivisions of the accumbens. It is suggested that a majority of pharmacotherapies for tobacco dependence are not more successful because they fail to address this important aspect of the dependence.

One-Dimensional Population Density Approaches to Recurrently Coupled Networks of Neurons with Noise

Mean-field systems have been previously derived for networks of coupled, two-dimensional, integrate-and-fire neurons such as the Izhikevich, adapting exponential (AdEx) and quartic integrate and fire (QIF), among others. Unfortunately, the mean-field systems have a degree of frequency error and the networks analyzed often do not include noise when there is adaptation. Here, we derive a one-dimensional partial differential equation (PDE) approximation for the marginal voltage density under a first order moment closure for coupled networks of integrate-and-fire neurons with white noise inputs. The PDE has substantially less frequency error than the mean-field system, and provides a great deal more information, at the cost of analytical tractability. The convergence properties of the mean-field system in the low noise limit are elucidated. A novel method for the analysis of the stability of the asynchronous tonic firing solution is also presented and implemented. Unlike previous attempts at stability analysis with these network types, information about the marginal densities of the adaptation variables is used. This method can in principle be applied to other systems with nonlinear partial differential equations.

Rapid development of Purkinje cell excitability, functional cerebellar circuit, and afferent sensory input to cerebellum in zebrafish.

The zebrafish has significant advantages for studying the morphological development of the brain. However, little is known about the functional development of the zebrafish brain. We used patch clamp electrophysiology in live animals to investigate the emergence of excitability in cerebellar Purkinje cells, functional maturation of the cerebellar circuit, and establishment of sensory input to the cerebellum. Purkinje cells are born at 3 days post-fertilization (dpf). By 4 dpf, Purkinje cells spontaneously fired action potentials in an irregular pattern. By 5 dpf, the frequency and regularity of tonic firing had increased significantly and most cells fired complex spikes in response to climbing fiber activation. Our data suggest that, as in mammals, Purkinje cells are initially innervated by multiple climbing fibers that are winnowed to a single input. To probe the development of functional sensory input to the cerebellum, we investigated the response of Purkinje cells to a visual stimulus consisting of a rapid change in light intensity. At 4 dpf, sudden darkness increased the rate of tonic firing, suggesting that afferent pathways carrying visual information are already active by this stage. By 5 dpf, visual stimuli also activated climbing fibers, increasing the frequency of complex spiking. Our results indicate that the electrical properties of zebrafish and mammalian Purkinje cells are highly conserved and suggest that the same ion channels, Nav1.6 and Kv3.3, underlie spontaneous pacemaking activity. Interestingly, functional development of the cerebellum is temporally correlated with the emergence of complex, visually-guided behaviors such as prey capture. Because of the rapid formation of an electrically-active cerebellum, optical transparency, and ease of genetic manipulation, the zebrafish has great potential for functionally mapping cerebellar afferent and efferent pathways and for investigating cerebellar control of motor behavior.