Vasoactive Intestinal Polypeptide Interneurons Research Articles

Hypersensitivity to Distractors in Fragile X Syndrome from Loss of Modulation of Cortical VIP Interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in humans and mice with FXS but not in typically developing controls. In both species, males and females were examined. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the poststimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1 -/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells could be a potential therapeutic target for attentional difficulties in FXS.SIGNIFICANCE STATEMENT Sensory hypersensitivity, impulsivity, and persistent inattention are among the most consistent clinical features of FXS, all of which impede daily functioning and create barriers to learning. However, the neural mechanisms underlying sensory over-reactivity remain elusive. To overcome a significant challenge in translational FXS research we demonstrate a compelling alignment of sensory over-reactivity in both humans with FXS and Fmr1 -/- mice (the principal animal model of FXS) using a novel analogous distractor task. Two-photon microscopy in mice revealed that lack of modulation by VIP cells contributes to susceptibility to distractors. Implementing research efforts we describe here can help identify dysfunctional neural mechanisms associated not only with sensory issues but broader impairments, including those in learning and cognition.

Cortex-wide response mode of VIP-expressing inhibitory neurons by reward and punishment.

Neocortex is classically divided into distinct areas, each specializing in different function, but all could benefit from reinforcement feedback to inform and update local processing. Yet it remains elusive how global signals like reward and punishment are represented in local cortical computations. Previously, we identified a cortical neuron type, vasoactive intestinal polypeptide (VIP)-expressing interneurons, in auditory cortex that is recruited by behavioral reinforcers and mediates disinhibitory control by inhibiting other inhibitory neurons. As the same disinhibitory cortical circuit is present virtually throughout cortex, we wondered whether VIP neurons are likewise recruited by reinforcers throughout cortex. We monitored VIP neural activity in dozens of cortical regions using three-dimensional random access two-photon microscopy and fiber photometry while mice learned an auditory discrimination task. We found that reward and punishment during initial learning produce rapid, cortex-wide activation of most VIP interneurons. This global recruitment mode showed variations in temporal dynamics in individual neurons and across areas. Neither the weak sensory tuning of VIP interneurons in visual cortex nor their arousal state modulation was fully predictive of reinforcer responses. We suggest that the global response mode of cortical VIP interneurons supports a cell-type-specific circuit mechanism by which organism-level information about reinforcers regulates local circuit processing and plasticity.

Disinhibitory circuit mediated by connections from vasoactive intestinal polypeptide to somatostatin interneurons underlies the paradoxical decrease in spike synchrony with increased border ownership selective neuron firing rate.

The activity of border ownership selective (BOS) neurons in intermediate-level visual areas indicates which side of a contour owns a border relative to its classical receptive field and provides a fundamental component of figure-ground segregation. A physiological study reported that selective attention facilitates the activity of BOS neurons with a consistent border ownership preference, defined as two neurons tuned to respond to the same visual object. However, spike synchrony between this pair is significantly suppressed by selective attention. These neurophysiological findings are derived from a biologically-plausible microcircuit model consisting of spiking neurons including two subtypes of inhibitory interneurons, somatostatin (SOM) and vasoactive intestinal polypeptide (VIP) interneurons, and excitatory BOS model neurons. In our proposed model, BOS neurons and SOM interneurons cooperate and interact with each other. VIP interneurons not only suppress SOM interneuron responses but also are activated by feedback signals mediating selective attention, which leads to disinhibition of BOS neurons when they are directing selective attention toward an object. Our results suggest that disinhibition arising from the synaptic connections from VIP to SOM interneurons plays a critical role in attentional modulation of neurons in intermediate-level visual areas.

Activation of VIP interneurons in the prefrontal cortex ameliorates neuropathic pain aversiveness.

SUMMARYWhile dysfunction of the medial prefrontal cortex (mPFC) has been implicated in chronic pain, the underlying neural circuits and the contribution of specific cellular populations remain unclear. Using in vivo Ca2+ imaging, we report that in both male and female mice, peripheral nerve injury-induced neuropathic pain causes a marked reduction of vasoactive intestinal polypeptide (VIP)-expressing interneuron activity in the prelimbic area of the mPFC, which contributes to decreased prefrontal cortical outputs. Moreover, prelimbic glutamatergic projections to GABAergic interneurons in the anterior cingulate cortex (ACC) are diminished, leading to loss of cortical-cortical inhibition and increased pyramidal neuron activity in the ACC. Chemogenetic activation of prelimbic VIP interneurons restores neuronal responses in the mPFC-ACC pathway and attenuates pain-like behaviors in mice. Furthermore, restoration of prelimbic outputs to the ACC reverses nerve injury-induced ACC hyperactivation. These findings reveal mPFC circuit changes associated with neuropathic pain and highlight VIP interneurons as potential therapeutic targets for pain treatment.

Modulation of epileptiform activity by three subgroups of GABAergic interneurons in mouse somatosensory cortex

4-Aminopyridine (4-AP) induces ictal-like epileptiform discharges in a variety of brain regions. These events are associated with enhanced inhibitory and excitatory synaptic neurotransmission. The relative contribution of specific subclasses of GABAergic interneurons (INs) to epileptiform activity in the 4-AP model is not well characterized. We have used genetically encoded channelrhodopsin (ChR) and Archaerhodopsin (Arch) expression in parvalbumin (PV), somatostatin (SST) and vasoactive intestinal polypeptide (VIP) INs to investigate the role of interneuron subclasses in 4-AP-induced epileptiform discharges. Whole-cell patch-clamp recordings were obtained from L5 pyramidal cells (PYRs) in somatosensory cortex of 30-to-70-day old mice. In the presence of 100 µM 4-AP, photostimulation of ChR in PV and SST, but not VIP INs, evoked epileptiform discharges similar to spontaneous and electrically evoked events. Light activation of Arch in PV INs was more effective in reducing epileptiform activity compared to SST and VIP INs. Epileptiform discharges were evoked at offset of Arch induced hyperpolarizations in PV and SST interneurons but not VIP INs. PV and SST INs could both initiate and inhibit 4-AP-induced epileptiform activity in L5 PYRs. VIP INs did not contribute significantly to eliciting or inhibiting epileptiform discharges. These results suggest that subclasses of INs contribute differently to the initiation and modulation of epileptiform discharges in cortical networks.

Disinhibitory Circuitry Gates Associative Synaptic Plasticity in Olfactory Cortex.

Inhibitory microcircuits play an essential role in regulating cortical responses to sensory stimuli. Interneurons that inhibit dendritic or somatic integration act as gatekeepers for neural activity, synaptic plasticity, and the formation of sensory representations. Conversely, interneurons that selectively inhibit other interneurons can open gates through disinhibition. In the anterior piriform cortex, relief of inhibition permits associative LTP of excitatory synapses between pyramidal neurons. However, the interneurons and circuits mediating disinhibition have not been elucidated. In this study, we use an optogenetic approach in mice of both sexes to identify the inhibitory interneurons and disinhibitory circuits that regulate LTP. We focused on three prominent interneuron classes: somatostatin (SST), parvalbumin (PV), and vasoactive intestinal polypeptide (VIP) interneurons. We find that LTP is gated by the inactivation SST or PV interneurons and by the activation of VIP interneurons. Further, VIP interneurons strongly inhibit putative SST cells during LTP induction but only weakly inhibit PV interneurons. Together, these findings suggest that VIP interneurons mediate a disinhibitory circuit that gates synaptic plasticity during the formation of olfactory representations.SIGNIFICANCE STATEMENT Inhibitory interneurons stabilize neural activity during sensory processing. However, inhibition must also be modulated to allow sensory experience shape neural responses. In olfactory cortex, inhibition regulates activity-dependent increases in excitatory synaptic strength that accompany odor learning. We identify two inhibitory interneuron classes that act as gatekeepers preventing excitatory enhancement. We demonstrate that driving a third class of interneurons inhibits the gatekeepers and opens the gate for excitatory enhancement. All three inhibitory neuron classes comprise disinhibitory microcircuit motifs found throughout the cortex. Our findings suggest that a common disinhibitory microcircuit promotes changes in synaptic strength during sensory processing and learning.

Cholinergic modulation of hierarchical inhibitory control over cortical resting state dynamics: Local circuit modeling of schizophrenia-related hypofrontality

Nicotinic acetylcholine receptors (nAChRs) modulate the cholinergic drive to a hierarchy of inhibitory neurons in the superficial layers of the PFC, critical to cognitive processes. It has been shown that genetic deletions of the various types of nAChRs impact the properties of ultra-slow transitions between high and low PFC activity states in mice during quiet wakefulness. The impact characteristics depend on specific interneuron populations expressing the manipulated receptor subtype. In addition, recent data indicate that a genetic mutation of the α5 nAChR subunit, located on vasoactive intestinal polypeptide (VIP) inhibitory neurons, the rs16969968 single nucleotide polymorphism (α5 SNP), plays a key role in the hypofrontality observed in schizophrenia patients carrying the SNP. Data also indicate that chronic nicotine application to α5 SNP mice relieves the hypofrontality. We developed a computational model to show that the activity patterns recorded in the genetically modified mice can be explained by changes in the dynamics of the local PFC circuit. Notably, our model shows that these altered PFC circuit dynamics are due to changes in the stability structure of the activity states. We identify how this stability structure is differentially modulated by cholinergic inputs to the parvalbumin (PV), somatostatin (SOM) or the VIP inhibitory populations. Our model uncovers that a change in amplitude, but not duration of the high activity states can account for the lowered pyramidal (PYR) population firing rates recorded in α5 SNP mice. We demonstrate how nicotine-induced desensitization and upregulation of the β2 nAChRs located on SOM interneurons, as opposed to the activation of α5 nAChRs located on VIP interneurons, is sufficient to explain the nicotine-induced activity normalization in α5 SNP mice. The model further implies that subsequent nicotine withdrawal may exacerbate the hypofrontality over and beyond one caused by the SNP mutation.

VIP Interneurons Contribute to Avoidance Behavior by Regulating Information Flow across Hippocampal-Prefrontal Networks

Inhibitory interneurons expressing vasoactive intestinal polypeptide (VIP) are known to disinhibit cortical neurons. However, it is unclear how disinhibition, occurring at the single-cell level, interacts with network-level patterns of activity to shape complex behaviors. To address this, we examined the role of prefrontal VIP interneurons in a widely studied mouse behavior: deciding whether to explore or avoid the open arms of an elevated plus maze. VIP interneuron activity increases in the open arms and disinhibits prefrontal responses to hippocampal inputs, which are known to transmit signals related to open arm avoidance. Indeed, inhibiting VIP interneurons disrupts network-level representations of the open arms and decreases open arm avoidance specifically when hippocampal-prefrontal theta synchrony is strong. Thus, VIP interneurons effectively gate the ability of hippocampal input to generate prefrontal representations, which drive avoidance behavior. This shows how VIP interneurons enable cortical circuits to integrate specific inputs into network-level representations that guide complex behaviors. VIDEO ABSTRACT.

Subcellular Targeting of VIP Boutons in Mouse Barrel Cortex is Layer-Dependent and not Restricted to Interneurons.

Neocortical vasoactive intestinal polypeptide (VIP) expressing cells are a diverse subpopulation of GABAergic interneurons issuing distinct axonal projections. They are known to inhibit other types of interneurons as well as excitatory principal neurons and possess a disinhibitory net effect in cortical circuits. In order to elucidate their targeting specificity, the output connectivity of VIP interneurons was studied at the subcellular level in barrel cortex of interneuron-specific Cre-driver mice, using pre- and postembedding electron microscopy. Systematically sampling VIP boutons across all layers, we found a substantial proportion of the innervated subcellular structures were dendrites (80%), with somata (13%), and spines (7%) being much less targeted. In layer VI, a high proportion of axosomatic synapses was found (39%). GABA-immunopositive ratio was quantified among the targets using statistically validated thresholds: only 37% of the dendrites, 7% of the spines, and 26% of the somata showed above-threshold immunogold labeling. For the main target structure “dendrite”, a higher proportion of GABAergic subcellular profiles existed in deep than in superficial layers. In conclusion, VIP interneurons innervate non-GABAergic excitatory neurons and interneurons at their subcellular domains with layer-dependent specificity. This suggests a diverse output of VIP interneurons, which predicts multiple functionality in cortical circuitry beyond disinhibition.

Diverse Ensembles of Inhibitory Interneurons

In this issue of Neuron, Karnani etal. (2016) show that ensembles of specific types of inhibitory interneurons generate coordinated activity in mouse visual cortex. They also describe chemical and electrical synaptic mechanisms that may enable diverse interneuron ensembles to function as distinct operational units.

Cortical interneurons that specialize in disinhibitory control

In the mammalian cerebral cortex, the diversity of interneuronal subtypes underlies a division of labor subserving distinct modes of inhibitory control1–7. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation8,9. Although several interneuron populations are known to target other interneurons to varying degrees10–15, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively3,6,16,17. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell-type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.

Immunohistochemical characterization of cholecystokinin containing neurons in the rat basolateral amygdala

Specific neuronal populations in the basolateral amygdala (ABL) exhibit immunoreactivity for distinct neuropeptides and calcium-binding proteins. In the present study, immunohistochemical techniques were used to analyze neurons in the rat ABL that contain cholecystokinin (CCK). Some pyramidal projection neurons in the anterior subdivision of the basolateral nucleus exhibited low levels of CCK immunoreactivity in rats that received injections of colchicine to interrupt axonal transport; staining was concentrated in the axon initial segments of these cells. High levels of CCK immunoreactivity were observed in two subpopulations of nonpyramidal interneurons in all nuclei of the ABL: (1) type L neurons (characterized by large somata and thick dendrites), and (2) type S neurons (characterized by small somata and thin dendrites). Dual-labeling immunofluorescence studies using confocal laser scanning microscopy revealed that many (30–40%) type L CCK+ interneurons exhibited immunoreactivity for calbindin (CB), but not for parvalbumin (PV), calretinin (CR), or vasoactive intestinal polypeptide (VIP). In contrast, there was extensive colocalization of CR and VIP with CCK in type S neurons, but no significant colocalization with CB or PV. In addition, the majority of CR and VIP interneurons exhibited colocalization of both neurochemicals. Collectively, the results of this and previous studies indicate that there are at least four distinct interneuronal subpopulations in the ABL: (1) PV+ neurons (the great majority of which are CB+); (2) SOM+ neurons (many of which are CB+ and NPY+); (3) large CCK+ neurons (some of which are CB+); and (4) small bipolar/bitufted neurons that exhibit various amounts of colocalization of CCK, VIP, and CR.

Neuronal messengers as mediators of microvascular tone in the cerebral cortex

Changes in regional neuronal activity are accompanied by concurrent temporal and spatial changes in the cerebral blood flow and these form the basis of modern brain imaging techniques used to map the functional neuronal activity. This neurovascular coupling is achieved by several mechanisms that are still poorly understood but ionic, glial, metabolic, and neuronal factors have been involved. In the present investigation, we provide evidence that specific populations of cortical interneurons, which play a central role in integrating multiple incoming local and afferent synaptic and paracrine signals, could act as local integrators of the neuronal activity and cerebral blood flow. We suggest that different subpopulations of cortical γ-amino-butyric acid (GABA) interneurons, which colocalize specific vasoactive substances such as nitric oxide (NO), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY), could serve as a functional relay in the neurovascular coupling that accompanies the activation of basal forebrain acetylcholine (ACh) and brainstem raphe nucleus serotonin (5-HT)-neurons. Thus, in addition to direct changes in the microvascular tone induced by ACh and 5-HT fibers projecting to cortical microvessels, these neurons also send projections to NO, VIP and/or NPY interneurons which, via their direct neurovascular projections, could affect the microvascular tone and therein adapt changes in perfusion to the local changes in neuronal activity. The results suggest that specific populations of GABA interneurons constitute a functional unit with their respective neuronal and vascular effects.

Morphometrical and microdensitometrical studies on peptide- and tyrosine hydroxylase-like immunoreactivities in the forebrain of rats prenatally exposed to methylazoxymethanol acetate

Methylazoxymethanol acetate (MAM Ac) injected into pregnant rats at a dose of 25 mg/kg at gestational day 15 causes microcephaly due to an atrophy of various telencephalic areas, mainly neocortex, hippocampus and basal ganglia. Previous studies demonstrated alterations in various neurochemical markers of classical transmitter systems in these regions. The present paper deals with changes in peptide and tyrosine hydroxylase (TH)-containing neurons in MAM Ac-induced microcephaly using immunocytochemistry coupled with computer-assisted morphometry and microdensitometry. No change in the number of vasoactive intestinal polypeptide (VIP)-immunoreactive neurons in the neocortex and neuropeptide Y (NPY)-immunoreactive neurons in the nucleus caudatus-putamen was found whereas cholecystokinin (CCK)- and NPY-immunoreactive neurons in the neocortex and CCK- and VIP-immunoreactive neurons in the hippocampus were decreased. The reduction of the latter peptide containing neuronal populations led to a maintained density of cells in MAM Ac-exposed rats, due to the parallel reduction of the overall mass of these regions. TH immunoreactivity was found to be unchanged in the basal ganglia, and increased in the cerebral cortex in agreement with previous reports on noradrenaline cortical system after MAM Ac exposure. The present results show a heterogeneous vulnerability of different peptide immunoreactive neuronal populations to MAM Ac exposure. The sparing of VIP- and NPY-immunoreactive neurons may be due to their late development in the neocortex and striatum, respectively. The hypothesis is introduced that cortical VIP interneurons can develop independent of marked alterations in the intrinsic circuitry of the cortical region.