Distinct Neuronal Subpopulations Research Articles

Contingent adaptation in masking and surround suppression

Adaptation is the process that changes a neuron’s response based on recent inputs. In the traditional model, a neuron’s state of adaptation depends on the recent input to that neuron alone, whereas in a recently introduced model (Hebbian normalization), adaptation depends on the structure of neural correlated firing. In particular, increased response products between pairs of neurons leads to increased mutual suppression. We test a psychophysical prediction of this model: adaptation should depend on 2nd-order statistics of input stimuli. That is, if two stimuli excite two distinct sub-populations of neurons, then presenting those stimuli simultaneously during adaptation should strengthen mutual suppression between those subpopulations. We confirm this prediction in two experiments. In the first, pairing two gratings synchronously during adaptation (i.e., a plaid) rather than asynchronously (interleaving the two gratings in time) leads to increased effectiveness of one pattern for masking the other. In the second, pairing the gratings in a center-surround configuration results in reduced apparent contrast for the central grating when paired with the same surround (as compared with a condition in which the central grating appears with a different surround at test than during adaptation). These results are consistent with the prediction that an increase in response covariance leads to greater mutual suppression between neurons. This effect is detectable both at threshold (masking) and well above threshold (apparent contrast).

Pharmacological Antagonism of T-Type Calcium Channels Constrains Rebound Burst Firing in Two Distinct Subpopulations of GABA Neurons in the Rat Ventral Tegmental Area: Implications for α-Lipoic Acid.

The ventral tegmental area (VTA) is a midbrain region highly involved in motivation and reward. A large body of work has investigated synaptic plasticity and ion channel excitability in this area, which has strong implication in drug abuse. We recently provided electrophysiological and pharmacological evidence that the CaV3.1 isoform of T-type voltage-gated calcium channels contributes to the excitability of VTA dopamine (DA) neurons. However, the role of T-channels in excitability of VTA gamma-amino-butyric acid (GABA) neurons remained unaddressed. Here, with a population study of rat VTA GABA neurons, we provide evidence that T-channels contribute to rebound spiking activity in two phenotypically distinct subpopulations of GABAergic neurons, each with differing electrophysiological characteristics. Additionally, we provide the first study to investigate the effect of α-lipoic acid (ALA) on ion channels in mesolimbic reward circuitry. Taken together, our population study and pharmacology experiments implicate T-channels as a target for therapies aimed at tempering VTA and mesolimbic circuit excitability.

ERRγ is downregulated in injured motor neuron subpopulations following brachial plexus root avulsion.

Estrogen-related receptor γ (ERRγ) is a member of a small group of orphan nuclear receptor transcription factors that have been implicated in several physiological and pathological processes, including placental development, regulation of metabolic genes or disease. The pattern of expression of ERRγ, its role in neuronal injury and its co-localization with other transcription factors in the spinal cord of rats with brachial plexus injury has not been determined. The expression profile of ERRγ and its co-localization with RNA binding protein fox-1 homolog 3 (NeuN) or cyclic AMP-dependent transcription factor 3 (ATF-3) in the motor neurons of rats that underwent brachial plexus root avulsion were assessed using western blot analysis, immunohistochemistry and immunofluorescence. Fluorogold (FG) was used to mark neurons whose axons were severed. ATF-3 was expressed in the nuclei of motor neurons whose axons were severed by root avulsion. On day 3 post-avulsion, FG and ATF-3 were all co-localized in the injured motor neurons. The level of ERRγ protein in the ipsilateral half of injured spinal cords was significantly decreased compared with that in the contralateral half on days 3, 14 and 28 post-avulsion (all P<0.05). The numbers of ERRγ-positive motor neurons (ERRγon) were also notably decreased in the ipsilateral side compared with that in the contralateral side on days 14 and 28 post-avulsion, implying that the expression occurred in α motor neurons that were progressively being lost, a phenomenon that was expected post-brachial plexus avulsion. Almost all large and small ERRγ-positive motor neurons were also NeuN-positive (NeuNon). However, a few of these were ERRγon/NeuNoff (no NeuN signal). Therefore, these results suggested that ERRγ is a non-specific marker of γ motor neurons in rats, and therefore, this specific transcriptional program cannot be used to define functionally distinct motor neuron sub-populations. However, its downregulation on the injured side suggests that it is an important component of the response to injury in motor neurons.

Dual and Opposing Functions of the Central Amygdala in the Modulation of Pain

SUMMARYPain perception is essential for survival and can be amplified or suppressed by expectations, experiences, and context. The neural mechanisms underlying bidirectional modulation of pain remain largely unknown. Here, we demonstrate that the central nucleus of the amygdala (CeA) functions as a pain rheostat, decreasing or increasing pain-related behaviors in mice. This dual and opposing function of the CeA is encoded by opposing changes in the excitability of two distinct subpopulations of GABAergic neurons that receive excitatory inputs from the parabrachial nucleus (PB). Thus, cells expressing protein kinase C-delta (CeA-PKCδ) are sensitized by nerve injury and increase pain-related responses. In contrast, cells expressing somatostatin (CeA-Som) are inhibited by nerve injury and their activity drives antinociception. Together, these results demonstrate that the CeA can amplify or suppress pain in a cell-type-specific manner, uncovering a previously unknown mechanism underlying bidirectional control of pain in the brain.

Calcium-Binding Proteins as Determinants of Central Nervous System Neuronal Vulnerability to Disease.

Neuronal subpopulations display differential vulnerabilities to disease, but the factors that determine their susceptibility are poorly understood. Toxic increases in intracellular calcium are a key factor in several neurodegenerative processes, with calcium-binding proteins providing an important first line of defense through their ability to buffer incoming calcium, allowing the neuron to quickly achieve homeostasis. Since neurons expressing different calcium-binding proteins have been reported to be differentially susceptible to degeneration, it can be hypothesized that rather than just serving as markers of different neuronal subpopulations, they might actually be a key determinant of survival. In this review, we will summarize some of the evidence that expression of the EF-hand calcium-binding proteins, calbindin, calretinin and parvalbumin, may influence the susceptibility of distinct neuronal subpopulations to disease processes.

(245) Electrophysiological and Morphological Characterization of Genetically Distinct Nociceptive Neurons in the Central Amygdala

The central amygdala (CeA) has key functions in modulating pain-related behaviors and exhibits experience-dependent plasticity in the context of chronic pain. Recent work from our lab has further revealed that distinct CeA cell types contribute differently to behavioral outcomes in pathological pain states in mice. Cells expressing Protein Kinase C delta (CeA-PKCδ), for example, promote hypersensitivity and display increased excitability following injury. By contrast, somatostatin-expressing CeA (CeA-Som) neurons contribute to an endogenous analgesic tone at baseline and display suppressed excitability during nerve-injury. The cellular mechanisms driving this opposing modulation of pain-related behaviors are still poorly understood. We hypothesized that the convergence of genetic identity, intrinsic membrane properties and morphological characteristics of distinct subpopulations of neurons contributes to the functional heterogeneity in the CeA. Here, we begin to test this hypothesis by characterizing the electrophysiological and morphological properties of CeA-PKCδ and CeA-Som neurons. Preliminary results from whole-cell patch-clamp electrophysiology experiments in acute amygdala slices show that the electrophysiological properties of CeA-PKCδ and CeA-Som neurons are distinct. Firing properties in CeA-PKCδ neurons, for example, are highly heterogeneous, with spontaneously active, accommodating, and non-accommodating cells found among this population. In contrast, the overwhelming majority of CeA-Som neurons are either spontaneously active or non-accommodating. Notably, non-accommodating CeA-Som neurons are more excitable than non-accommodating CeA-PKCδ neurons, displaying increased firing responses to depolarizing current injection, reduced latencies to first spike and after hyperpolarizations and changes in resting membrane potentials. Ongoing experiments are evaluating the morphological properties of these genetically distinct cells, with the end goal of correlating pain-related behaviors with morphological properties, genetic identity and firing properties. Altogether, our results demonstrate that the output gain of CeA-Som cells is significantly greater than that of CeA-PKCδ neurons, suggesting that cell-type-specific differences in neuronal excitability might contribute to functional heterogeneity in the CeA.

Divergent medial amygdala projections regulate approach-avoidance conflict behavior.

Avoidance of innate threats is often conflicted by motivations to engage in exploratory approach behavior. The neural pathways that mediate this approach-avoidance conflict are not well resolved. Here, we isolated a population of dopamine D1 receptor (D1R) expressing neurons within the posteroventral region of the medial amygdala (MeApv) in mice that are activated either during approach or during avoidance of an innate threat stimulus. Distinct subpopulations of MeApv-D1R neurons differentially innervate the ventromedial hypothalamus (VMH) and bed nucleus of the stria terminalis (BNST) and these projections have opposing effects on investigation or avoidance of threatening stimuli. These projections are potently modulated through opposite actions of D1R signaling that bias approach behavior. These data demonstrate divergent pathways in the MeApv that can be differentially weighted towards exploration or evasion of threats.

The Effects of Diabetes and High-Fat Diet on Polymodal Nociceptor and Cold Thermoreceptor Nerve Terminal Endings in the Corneal Epithelium.

There is a substantial body of evidence indicating that corneal sensory innervation is affected by pathology in a range of diseases. However, there are no published studies that have directly assessed whether the nerve fiber density of the different subpopulations of corneal sensory neurons are differentially affected. The present study explored the possibility that the intraepithelial nerve fiber density of corneal polymodal nociceptors and cold thermoreceptors are differentially affected in mice fed with a high-fat high cholesterol (HFHC; 21% fat, 2% cholesterol) diet and in those that also have diabetes. The mice were fed the HFHC diet for the duration of the experiment (up to 40 weeks). Mice in the diabetes group had hyperglycaemia induced with streptozotocin after 15 weeks on the HFHC diet. Age-matched control animals were fed a standard diet. All corneal nerve fibers were labeled with a pan neuronal antibody (antiprotein gene product 9.5), and polymodal nociceptors and cold thermoreceptors were labeled with antibodies directed against transient receptor potential cation channel, subfamily V, member 1 and transient receptor potential cation channel subfamily M member 8, respectively. The mice fed a HFHC diet and those that in addition have hyperglycemia have similar reductions in corneal nerve fiber density consistent with small fiber neuropathy. Importantly, both treatments more markedly affected the intraepithelial axons of cold thermoreceptors than those of polymodal nociceptors. The results provide evidence that distinct subpopulations of corneal sensory neurons can be differentially affected by pathology.

Contingent adaptation in masking and surround suppression

Adaptation is the process that changes a neuron's response based on recent inputs. In the traditional model, a neuron's state of adaptation depends on the recent input to that neuron alone, whereas in a recently introduced model (Hebbian normalization), adaptation depends on the structure of neural correlated firing. In particular, increased response products between pairs of neurons leads to increased mutual suppression. We test a psychophysical prediction of this model: adaptation should depend on 2nd-order statistics of input stimuli. That is, if two stimuli excite two distinct sub-populations of neurons, then presenting those stimuli simultaneously during adaptation should strengthen mutual suppression between those subpopulations. We confirm this prediction in two experiments. In the first, pairing two gratings synchronously during adaptation (i.e., a plaid) rather than asynchronously (interleaving the two gratings in time) leads to increased effectiveness of one pattern for masking the other. In the second, pairing the gratings in a center-surround configuration results in reduced apparent contrast for the central grating when paired with the same surround (as compared with a condition in which the central grating appears with a different surround at test than during adaptation). These results are consistent with the prediction that an increase in response covariance leads to greater mutual suppression between neurons. This effect is detectable both at threshold (masking) and well above threshold (apparent contrast).

Linkage between hypothalamic homeostatic and midbrain motivation circuits and habenula enabling sex steroid modulation of motivation and behavior

It is well‐established that the lateral habenula (LHb) plays a key role in integrating a variety of neural circuits associated with reward and aversive behaviors, yet there is limited information about how neuronal circuits within the LHb might serve to coordinate motivational, hormonal and homeostatic states to elicit environmentally appropriate behaviors.We have identified a population of phenotypically GABAergic cell type in the medial division of the LHb (LHbM) that is apparently also endowed with estrogen responsivity, i.e., cells express Esr1 mRNA, and are immunopositive for ERα. These neurons express receptors for vasopressin, serotonin, dopamine and orexin, and project (as identified by in vivo juxtacellular labeling) both locally within LHb and to midbrain cell groups including those in dorsal raphe and impingent upon ventral tegmental area (VTA). They also appear to receive afferents from midbrain reward (dopamine and serotonin) and hypothalamic water and energy homeostasis (vasopressin and orexin) cell groups: these afferents are excitatory (VGLUT2‐expressing) and capable of converting testosterone to estrogen (express aromatase, or estrogen synthase at both the soma and the axon terminals). We have also demonstrated dynamic changes in LHbM VGAT+ cell density that are dependent upon gonadal functional status, and closely correlate with changes in hormone‐dependent vasopressinergic input, and with motivational behavior in response to predator and forced swim stressors.These findings provide a neurochemical and neuroanatomical basis for convergent projecting pathways to LHbMC that employ a localized neurosteroid signaling mechanism to convey altered homeostasic and gonadal hormone status to habenular output controlling motivated behaviors.Magnocellular vasopressinergic neurons of the paraventricular nucleus (PVN) have been observed to send projections not only to the lateral habenula (Zhang et al., 2016) but also to the central nucleus of the amygdala (Hernández et al., 2016). As for the habenular projections, vasopressinergic terminals in amygdala arising from cell bodies in PVN synapse upon GABAergic neurons, and are involved in the linkage of water and thirst homeostatic balance to anxiety and stress coping (Hernández et al., 2016). We are currently examining whether or not vasopressinergic projections to the lateral habenula and to the central amygdala are the same, or distinct neuronal sub‐populations, and whether or not amygdalar target neurons, like those in lateral habenula, are endowed with estrogen responsivity as well.Support or Funding InformationSupported by: CONACYT‐CB‐238744 (LZ), PAPIIT‐IN216918 (LZ) and MH002386 (LEE).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Circadian expression and functional characterization of PEA-15 within the mouse suprachiasmatic nucleus.

The circadian timing system influences the functional properties of most, if not all, physiological processes. Central to themammalian timing system is the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN functions as a 'master clock' that sets the phasing of ancillary circadian oscillator populations found throughout the body. Further, via an entraining input from the retina, the SCN ensures that the clock oscillators are synchronized to the daily light/dark cycle. A critical component of the SCN timing and entrainment systems is the p44/42 mitogen-activated protein kinase (ERK/MAPK) pathway. Here, we examined the expression and function of phosphoprotein-enriched in astrocytes (PEA-15), an ERK scaffold proteinthat serves as a key regulator of MAPK signaling. A combination of immunolabeling and Western blotting approaches revealed high levels of PEA-15 within the SCN. PEA-15 expression was enriched in distinct subpopulations of SCN neurons, including arginine vasopressin (AVP)-positive neurons of the SCN shell region. Further, expression profiling detected a significant circadian oscillation in PEA-15 expression within the SCN. Brief photic stimulation during the early subjective night led to a significant increase in PEA-15 phosphorylation, an event that can trigger ERK/PEA-15 dissociation. Consistent withthis, co-immunoprecipitation assays revealed that PEA-15 is directly bound to ERK in the SCN and that photic stimulation leads to their dissociation. Finally, we show that PEA-15 regulates ERK/MAPK-dependent activation of the coreclock gene period1. Together, these data raise the prospect that PEA-15 functions as a key regulator of the SCN timing system.

Complementary expression of calcium binding proteins delineates the functional organization of the locomotor network

Neuronal networks in the spinal cord generate and execute all locomotor-related movements by transforming descending signals from supraspinal areas into appropriate rhythmic activity patterns. In these spinal networks, neurons that arise from the same progenitor domain share similar distribution patterns, neurotransmitter phenotypes, morphological and electrophysiological features. However, subgroups of them participate in different functionally distinct microcircuits to produce locomotion at different speeds and of different modalities. To better understand the nature of this network complexity, here we characterized the distribution of parvalbumin (PV), calbindin D-28 k (CB) and calretinin (CR) which are regulators of intracellular calcium levels and can serve as anatomical markers for morphologically and potential functionally distinct neuronal subpopulations. We observed wide expression of CBPs in the adult zebrafish, in several spinal and reticulospinal neuronal populations with a diverse neurotransmitter phenotype. We also found that several spinal motoneurons express CR and PV. However, only the motoneuron pools that are responsible for generation of fast locomotion were CR-positive. CR can thus be used as a marker for fast motoneurons and might potentially label the fast locomotor module. Moreover, CB was mainly observed in the neuronal progenitor cells that are distributed around the central canal. Thus, our results suggest that during development the spinal neurons utilize CB and as the neurons mature and establish a neurotransmitter phenotype they use CR or/and PV. The detailed characterization of CBPs expression, in the spinal cord and brainstem neurons, is a crucial step toward a better understanding of the development and functionality of neuronal locomotor networks.

Precision of Discrete and Rhythmic Forelimb Movements Requires a Distinct Neuronal Subpopulation in the Interposed Anterior Nucleus

The deep cerebellar nuclei (DCN) represent output channels of the cerebellum, and they transmit integrated sensorimotor signals to modulate limb movements. But the functional relevance of identifiable neuronal subpopulations within the DCN remains unclear. Here, we examine a genetically tractable population of neurons in the mouse interposed anterior nucleus (IntA). We show that these neurons represent a subset of glutamatergic neurons in the IntA and constitute a specific element of an internal feedback circuit within the cerebellar cortex and cerebello-thalamo-cortical pathway associated with limb control. Ablation and optogenetic stimulation of these neurons disrupt efficacy of skilled reach and locomotor movement and reveal that they control positioning and timing of the forelimb and hindlimb. Together, our findings uncover the function of a distinct neuronal subpopulation in the deep cerebellum and delineate the anatomical substrates and kinematic parameters through which it modulates precision of discrete and rhythmic limb movements.

The Role of Human Primary Motor Cortex in the Production of Skilled Finger Sequences.

Human primary motor cortex (M1) is essential for producing dexterous hand movements. Although distinct subpopulations of neurons are activated during single-finger movements, it remains unknown whether M1 also represents sequences of multiple finger movements. Using novel multivariate functional magnetic resonance imaging (fMRI) analysis techniques and combining evidence from both 3T and 7T fMRI data, we found that after 5 d of intense practice, premotor and parietal areas encoded the different movement sequences. There was little or no evidence for a sequence representation in M1. Instead, activity patterns in M1 could be fully explained by a linear combination of patterns for the constituent individual finger movements, with the strongest weight on the first finger of the sequence. Using passive replay of sequences, we show that this first-finger effect is due to neuronal processes involved in the active execution, rather than to a hemodynamic nonlinearity. These results suggest that M1 receives increased input from areas with sequence representations at the initiation of a sequence, but that M1 activity itself relates to the execution of component finger presses only. These results improve our understanding of the representation of finger sequences in the human neocortex after short-term training and provide important methodological advances for the study of long-term skill development.SIGNIFICANCE STATEMENT There is clear evidence that human primary motor cortex (M1) is essential for producing individuated finger movements, such as pressing a button. Over and above its involvement in movement execution, it is less clear whether M1 also plays a role in learning and controlling sequences of multiple finger movements, such as when playing the piano. Using cutting-edge multivariate fMRI analysis and carefully controlled experiments, we demonstrate here that, while premotor areas clearly show a sequence representation, activity patterns in M1 can be fully explained from the patterns for individual finger movements. The results provide important new insights into the interplay of M1 and premotor cortex for learning of sequential movements.

Dynamic nuclear envelope phenotype in rats overexpressing mutated human torsinA protein.

ABSTRACTA three-base-pair deletion in the human TOR1A gene is causative for the most common form of primary dystonia: the early-onset dystonia type 1 (DYT1 dystonia). The pathophysiological consequences of this mutation are still unknown. To study the pathology of the mutant torsinA (TOR1A) protein, we have generated a transgenic rat line that overexpresses the human mutant protein under the control of the human TOR1A promoter. This new animal model was phenotyped with several approaches, including behavioral tests and neuropathological analyses. Motor phenotype, cellular and ultrastructural key features of torsinA pathology were found in this new transgenic rat line, supporting that it can be used as a model system for investigating the disease’s development. Analyses of mutant TOR1A protein expression in various brain regions also showed a dynamic expression pattern and a reversible nuclear envelope pathology. These findings suggest the differential vulnerabilities of distinct neuronal subpopulations. Furthermore, the reversibility of the nuclear envelope pathology might be a therapeutic target to treat the disease.

A New Behavioral Test and Associated Genetic Tools Highlight the Function of Ventral Abdominal Muscles in Adult Drosophila.

The function of the nervous system in complex animals is reflected by the achievement of specific behaviors. For years in Drosophila, both simple and complex behaviors have been studied and their genetic bases have emerged. The neuromuscular junction is maybe one of the prototypal simplest examples. A motor neuron establishes synaptic connections on its muscle cell target and elicits behavior: the muscle contraction. Different muscles in adult fly are related to specific behaviors. For example, the thoracic muscles are associated with flight and the leg muscles are associated with locomotion. However, specific tools are still lacking for the study of cellular physiology in distinct motor neuron subpopulations. Here we decided to use the abdominal muscles and in particular the ventral abdominal muscles (VAMs) in adult Drosophila as new model to link a precise behavior to specific motor neurons. Hence, we developed a new behavioral test based on the folding movement of the adult abdomen. Further, we performed a genetic screen and identify two specific Gal4 lines with restricted expression patterns to the adult motor neurons innervating the VAMs or their precursor cells. Using these genetic tools, we showed that the lack of the VAMs or the loss of the synaptic transmission in their innervating motor neurons lead to a significant impairment of the abdomen folding behavior. Altogether, our results allow establishing a direct link between specific motor neurons and muscles for the realization of particular behavior: the folding behavior of the abdomen in Drosophila.

Monomeric Huntingtin Exon 1 Has Similar Overall Structural Features for Wild-Type and Pathological Polyglutamine Lengths.

Huntington’s disease is caused by expansion of a polyglutamine (polyQ) domain within exon 1 of the huntingtin gene (Httex1). The prevailing hypothesis is that the monomeric Httex1 protein undergoes sharp conformational changes as the polyQ length exceeds a threshold of 36–37 residues. Here, we test this hypothesis by combining novel semi-synthesis strategies with state-of-the-art single-molecule Förster resonance energy transfer measurements on biologically relevant, monomeric Httex1 proteins of five different polyQ lengths. Our results, integrated with atomistic simulations, negate the hypothesis of a sharp, polyQ length-dependent change in the structure of monomeric Httex1. Instead, they support a continuous global compaction with increasing polyQ length that derives from increased prominence of the globular polyQ domain. Importantly, we show that monomeric Httex1 adopts tadpole-like architectures for polyQ lengths below and above the pathological threshold. Our results suggest that higher order homotypic and/or heterotypic interactions within distinct sub-populations of neurons, which are inevitable at finite cellular concentrations, are likely to be the main source of sharp polyQ length dependencies of HD.

Calcium dynamics control K-ATP channel-mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study.

Burst firing in medial substantia nigra (mSN) dopamine (DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium (K-ATP) channels both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is unknown. We show experimentally that L-type calcium channel activity in mSN DA neurons enhances open probability of K-ATP channels. We then generate a mathematical model to study the role of Ca2+ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca2+ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, coapplication of NMDA and a selective K-ATP channel opener, NN414, is required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca2+ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca2+ buffering, as might be expected in the calbindin-positive SN DA neuron subpopulation, promote rhythmic bursting pattern, consistent with experimental observations in vivo. NEW & NOTEWORTHY Recently identified distinct subpopulations of midbrain dopamine neurons exhibit differences in their two primary activity patterns in vivo: tonic (single spike) firing and phasic bursting. This study elucidates the biophysical basis of bursts specific to dopamine neurons in the medial substantia nigra, enabled by ATP-sensitive K+ channels and necessary for novelty-induced exploration. A better understanding of how dopaminergic signaling differs between subpopulations may lead to therapeutic strategies selectively targeted to specific subpopulations.

Cortico-Accumbens Regulation of Approach-Avoidance Behavior Is Modified by Experience and Chronic Pain

Although optimizing decisions between drives to avoid pain and to obtain reward are critical for survival, understanding the neuronal circuit activity that regulates choice during approach-avoidance conflicts is limited. Here, we recorded neuronal activity in the infralimbic (IL) cortex and nucleus accumbens (NAc) during an approach-avoidance task. In this task, disruption of approach by a pain-predictive cue (PPC-avoidance) is extinguished by experience and reinstated in a model of chronic pain. In the IL-NAc circuit, the activity of distinct subpopulations of neurons predicts the extent of PPC-avoidance observed. Furthermore, chemogenetic and optogenetic manipulations establish that IL-NAc circuitry regulates PPC-avoidance behavior. Our results indicate that IL-NAc circuitry is engaged during approach-avoidance conflicts, and modifications of this circuit by experience and chronic pain determine whether approach or avoidance occurs.

Veratridine produces distinct calcium response profiles in mouse Dorsal Root Ganglia neurons

Nociceptors are a subpopulation of dorsal root ganglia (DRG) neurons that detect noxious stimuli and signal pain. Veratridine (VTD) is a voltage-gated sodium channel (VGSC) modifier that is used as an “agonist” in functional screens for VGSC blockers. However, there is very little information on VTD response profiles in DRG neurons and how they relate to neuronal subtypes. Here we characterised VTD-induced calcium responses in cultured mouse DRG neurons. Our data shows that the heterogeneity of VTD responses reflects distinct subpopulations of sensory neurons. About 70% of DRG neurons respond to 30–100 μM VTD. We classified VTD responses into four profiles based upon their response shape. VTD response profiles differed in their frequency of occurrence and correlated with neuronal size. Furthermore, VTD response profiles correlated with responses to the algesic markers capsaicin, AITC and α, β-methylene ATP. Since VTD response profiles integrate the action of several classes of ion channels and exchangers, they could act as functional “reporters” for the constellation of ion channels/exchangers expressed in each sensory neuron. Therefore our findings are relevant to studies and screens using VTD to activate DRG neurons.