Parvalbumin-expressing Inhibitory Interneurons Research Articles

Whole-brain mapping of long-range inputs to the VIP-expressing inhibitory neurons in the primary motor cortex.

The primary motor cortex (MOp) is an important site for motor skill learning. Interestingly, neurons in MOp possess reward-related activity, presumably to facilitate reward-based motor learning. While pyramidal neurons (PNs) and different subtypes of GABAergic inhibitory interneurons (INs) in MOp all undergo cell-type specific plastic changes during motor learning, the vasoactive intestinal peptide-expressing inhibitory interneurons (VIP-INs) in MOp have been shown to preferentially respond to reward and play a critical role in the early phases of motor learning by triggering local circuit plasticity. To understand how VIP-INs might integrate various streams of information, such as sensory, pre-motor, and reward-related inputs, to regulate local plasticity in MOp, we performed monosynaptic rabies tracing experiments and employed an automated cell counting pipeline to generate a comprehensive map of brain-wide inputs to VIP-INs in MOp. We then compared this input profile to the brain-wide inputs to somatostatin-expressing inhibitory interneurons (SST-INs) and parvalbumin-expressing inhibitory interneurons (PV-INs) in MOp. We found that while all cell types received major inputs from sensory, motor, and prefrontal cortical regions, as well as from various thalamic nuclei, VIP-INs received more inputs from the orbital frontal cortex (ORB) - a region associated with reinforcement learning and value predictions. Our findings provide insight on how the brain leverages microcircuit motifs by both integrating and partitioning different streams of long-range input to modulate local circuit activity and plasticity.

The contribution of gamma bursting to spontaneous gamma activity in schizophrenia.

Increased spontaneous gamma (30-100 Hz) activity (SGA) has been reported in the auditory cortex in schizophrenia. This phenomenon has been correlated with psychotic symptoms such as auditory hallucinations and could reflect the dysfunction of NMDA receptors on parvalbumin-expressing inhibitory interneurons. Previous findings are from time-averaged spectra, so it is unknown whether increased spontaneous gamma occurs at a constant level, or rather in bursts. To better understand the dynamical nature of spontaneous gamma activity in schizophrenia, here we examined the contribution of gamma bursting and the slope of the EEG spectrum to this phenomenon. The main results from this data set were previously reported. Participants were 24 healthy control participants (HC) and 24 matched participants with schizophrenia (SZ). The data were from EEG recordings during auditory steady-state stimulation, which were localized to bilateral pairs of dipoles in auditory cortex. Time-frequency analysis was performed using Morlet wavelets. Oscillation bursts in the gamma range were defined as periods during which power exceeded 2 standard deviations above the trial-wide average value for at least one cycle. We extracted the burst parameters power, count, and area, as well as non-burst trial power and spectral slope. Gamma burst power and non-burst trial power were greater in SZ than HC, but burst count and area did not differ. Spectral slope was less negative in SZ than HC. Regression modeling found that gamma burst power alone best predicted SGA for both HC and SZ (> = 90% of variance), while spectral slope made a small contribution and non-burst trial power did not influence SGA. Increased SGA in the auditory cortex in schizophrenia is accounted for by increased power within gamma bursts, rather than a tonic increase in gamma-range activity, or a shift in spectral slope. Further research will be necessary to determine if these measures reflect different network mechanisms. We propose that increased gamma burst power is the main component of increased SGA in SZ and could reflect abnormally increased plasticity in cortical circuits due to enhanced plasticity of synapses on parvalbumin-expressing inhibitory interneurons. Thus, increased gamma burst power may be involved in producing psychotic symptoms and cognitive dysfunction.

Pairing with Enriched Sound Exposure Restores Auditory Processing Degraded by an Antidepressant.

Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.

Perinatal Penicillin Exposure Affects Cortical Development and Sensory Processing

The prevalent use of antibiotics in pregnant women and neonates raises concerns about long-term risks for children’s health, but their effects on the central nervous system is not well understood. We studied the effects of perinatal penicillin exposure (PPE) on brain structure and function in mice with a therapeutically relevant regimen. We used a battery of behavioral tests to evaluate anxiety, working memory, and sensory processing, and immunohistochemistry to quantify changes in parvalbumin-expressing inhibitory interneurons (PV+ INs), perineuronal nets (PNNs), as well as microglia density and morphology. In addition, we performed mesoscale calcium imaging to study neural activity and functional connectivity across cortical regions, and two-photon imaging to monitor dendritic spine and microglial dynamics. We found that adolescent PPE mice have abnormal sensory processing, including impaired texture discrimination and altered prepulse inhibition. Such behavioral changes are associated with increased spontaneous neural activities in various cortical regions, and delayed maturation of PV+ INs in the somatosensory cortex. Furthermore, adolescent PPE mice have elevated elimination of dendritic spines on the apical dendrites of layer 5 pyramidal neurons, as well as increased ramifications and spatial coverage of cortical microglia. Finally, while synaptic defects are transient during adolescence, behavioral abnormalities persist into adulthood. Our study demonstrates that early-life exposure to antibiotics affects cortical development, leaving a lasting effect on brain functions.

Extinction of Cocaine Memory Depends on a Feed-Forward Inhibition Circuit Within the Medial Prefrontal Cortex

BackgroundCocaine-associated environments (i.e., contexts) evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users. From a therapeutic perspective, enhancing inhibitory control over cocaine-conditioned responses is of pivotal importance but requires a more detailed understanding of the neural circuitry that can suppress context-evoked cocaine memories, e.g., through extinction learning. The ventral medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (dmPFC) are thought to bidirectionally regulate responding to cocaine cues through their projections to other brain regions. However, whether these mPFC subregions interact to enable adaptive responding to cocaine-associated contextual stimuli has remained elusive. MethodsWe used antero- and retrograde tracing combined with chemogenetic intervention to examine the role of vmPFC-to-dmPFC projections in extinction of cocaine-induced place preference in mice. In addition, electrophysiological recordings and optogenetics were used to determine whether parvalbumin-expressing inhibitory interneurons and pyramidal neurons in the dmPFC are innervated by vmPFC projections. ResultsWe found that vmPFC-to-dmPFC projecting neurons are activated during unreinforced re-exposure to a cocaine-associated context, and selective suppression of these cells impairs extinction learning. Parvalbumin-expressing inhibitory interneurons in the dmPFC receive stronger monosynaptic excitatory input from vmPFC projections than local dmPFC pyramidal neurons, consequently resulting in disynaptic inhibition of pyramidal neurons. In line with this, we show that chemogenetic suppression of dmPFC parvalbumin-expressing inhibitory interneurons impairs extinction learning. ConclusionsOur data reveal that vmPFC projections mediate extinction of a cocaine-associated contextual memory through recruitment of feed-forward inhibition in the dmPFC, thereby providing a novel neuronal substrate that promotes extinction-induced inhibitory control.

Cortico-Cortical Feedback in Mouse S1 Regulates Motor Coordination Via Inhibitory Interneurons

The primary somatosensory cortex (S1) is important for the control of movement as it encodes sensory input from the body periphery and external environment during ongoing movements. Mouse S1 consists of several distinct sensorimotor subnetworks that receive topographically organized cortico-cortical inputs from distant sensorimotor areas, including the secondary somatosensory cortex (S2) and primary motor cortex (M1). The role of the vibrissal S1 area and associated cortical connections during active sensing is well documented, but whether (and if so, how) non-whisker S1 areas are involved in movement control remains relatively unexplored. Here, we demonstrate that unilateral silencing of the non-whisker S1 area disrupts the balance of hindlimb movements during locomotion. S2 and M1 provide major feedback input to this S1 area, and they both synapse onto parvalbumin-expressing inhibitory interneurons in M1. Ablating parvalbumin interneurons in S1 or specifically silencing S2 feedback projections impairs motor coordination. We conclude that the S2–S1 cortical interaction mediated by parvalbumin interneurons is critical for the control of movement.

Maternal Experience-Dependent Cortical Plasticity in Mice Is Circuit- and Stimulus-Specific and Requires MECP2.

The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2 Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het ) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in WT adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het , suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically relevant behavior.SIGNIFICANCE STATEMENT Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in nonmutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.

Testosterone stimulates perineuronal nets development around parvalbumin cells in the adult canary brain in parallel with song crystallization

Perineuronal nets (PNN) of the extracellular matrix are dense aggregations of chondroitin-sulfate proteoglycans that usually surround fast-spiking parvalbumin-expressing inhibitory interneurons (PV). The development of PNN around PV appears specifically at the end of sensitive periods of visual learning and limits the synaptic plasticity in the visual cortex of mammals. Seasonal songbirds display a high level of adult neuroplasticity associated with vocal learning, which is regulated by fluctuations of circulating testosterone concentrations. Seasonal changes in testosterone concentrations and in neuroplasticity are associated with vocal changes between the non-breeding and breeding seasons. Increases in blood testosterone concentrations in the spring lead to the annual crystallization of song so that song becomes more stereotyped. Here we explore whether testosterone also regulates PNN expression in the song control system of male and female canaries. We show that, in both males and females, testosterone increases the number of PNN and of PV neurons in the three main telencephalic song control nuclei HVC, RA (nucleus robustus arcopallialis) and Area X and increases the PNN localization around PV interneurons. Singing activity was recorded in males and quantitative analyses demonstrated that testosterone also increased male singing rate, song duration and song energy while decreasing song entropy. Together, these data suggest that the development of PNN could provide the synaptic stability required to maintain the stability of the testosterone-induced crystallized song. This provides the new evidence for a role of PNN in the regulation of adult seasonal plasticity in seasonal songbirds.

Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury.

Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro application of 2-DG decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3 to 5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated the loss of parvalbumin-expressing inhibitory interneurons. In summary, 2-DG may have therapeutic potential to restore network function following TBI.

Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception

In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.

Aggrecan Directs Extracellular Matrix-Mediated Neuronal Plasticity.

In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity. The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs), and the specific role of PNNs on neural plasticity remains elusive. Here, we genetically targeted the Acan gene encoding for aggrecan using a novel animal model. This allowed for conditional and targeted loss of aggrecan in vivo, which ablated the PNN structure and caused a shift in the population of parvalbumin-expressing inhibitory interneurons toward a high plasticity state. Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity, which was mechanistically identical to critical period plasticity. Brain-wide targeting improved object recognition memory.SIGNIFICANCE STATEMENT The study provides the first direct evidence of aggrecan as the main functional constituent and orchestrator of perineuronal nets (PNNs), and that loss of PNNs by aggrecan removal induces a permanent state of critical period-like plasticity. Loss of aggrecan ablates the PNN structure, resulting in invoked juvenile plasticity in the visual cortex and enhanced object recognition memory.

Selective activation of parvalbumin interneurons prevents stress-induced synapse loss and perceptual defects

Stress, a prevalent experience in modern society, is a major risk factor for many psychiatric disorders. Although sensorimotor abnormalities are often present in these disorders, little is known about how stress affects the sensory cortex. Combining behavioral analyses with in vivo synaptic imaging, we show that stressful experiences lead to progressive, clustered loss of dendritic spines along the apical dendrites of layer (L) 5 pyramidal neurons (PNs) in the mouse barrel cortex, and such spine loss closely associates with deteriorated performance in a whisker-dependent texture discrimination task. Furthermore, the activity of parvalbumin-expressing inhibitory interneurons (PV+ INs) decreases in the stressed mouse due to reduced excitability of these neurons. Importantly, both behavioral defects and structural changes of L5 PNs are prevented by selective pharmacogenetic activation of PV+INs in the barrel cortex during stress. Finally, stressed mice raised under environmental enrichment (EE) maintain normal activation of PV+ INs, normal texture discrimination, and L5 PN spine dynamics similar to unstressed EE mice. Our findings suggest that the PV+ inhibitory circuit is crucial for normal synaptic dynamics in the mouse barrel cortex and sensory function. Pharmacological, pharmacogenetic and environmental approaches to prevent stress-induced maladaptive behaviors and synaptic malfunctions converge on the regulation of PV+ IN activity, pointing to a potential therapeutic target for stress-related disorders.

Impaired fear extinction retention and increased anxiety-like behaviours induced by limited daily access to a high-fat/high-sugar diet in male rats: Implications for diet-induced prefrontal cortex dysregulation

Anxiety disorders and obesity are both common in youth and young adults. Despite increasing evidence that over-consumption of palatable high-fat/high-sugar “junk” foods leads to adverse neurocognitive outcomes, little is known about the effects of palatable diets on emotional memories and fear regulation. In the present experiments we examined the effects of daily 2h consumption of a high-fat/high-sugar (HFHS) food across adolescence on fear inhibition and anxiety-like behaviour in young adult rats. Rats exposed to the HFHS diet exhibited impaired retention of fear extinction and increased anxiety-like behaviour in an emergence test compared to rats fed a standard diet. The HFHS-fed rats displayed diet-induced changes in prefrontal cortex (PFC) function which were detected by altered expression of GABAergic parvalbumin-expressing inhibitory interneurons and the stable transcription factor ΔFosB which accumulates in the PFC in response to chronic stimuli. Immunohistochemical analyses of the medial PFC revealed that animals fed the HFHS diet had fewer parvalbumin-expressing cells and increased levels of FosB/ΔFosB expression in the infralimbic cortex, a region implicated in the consolidation of fear extinction. There was a trend towards increased IBA-1 immunoreactivity, a marker of microglial activation, in the infralimbic cortex after HFHS diet exposure but expression of the extracellular glycoprotein reelin was unaffected. These findings demonstrate that a HFHS diet during adolescence is associated with reductions of prefrontal parvalbumin neurons and impaired fear inhibition in adulthood. Adverse effects of HFHS diets on the mechanisms of fear regulation may precipitate a vulnerability in obese individuals to the development of anxiety disorders.

A Mouse Model for Conditional Secretion of Specific Single-Chain Antibodies Provides Genetic Evidence for Regulation of Cortical Plasticity by a Non-cell Autonomous Homeoprotein Transcription Factor.

During postnatal life the cerebral cortex passes through critical periods of plasticity allowing its physiological adaptation to the environment. In the visual cortex, critical period onset and closure are influenced by the non-cell autonomous activity of the Otx2 homeoprotein transcription factor, which regulates the maturation of parvalbumin-expressing inhibitory interneurons (PV cells). In adult mice, the maintenance of a non-plastic adult state requires continuous Otx2 import by PV cells. An important source of extra-cortical Otx2 is the choroid plexus, which secretes Otx2 into the cerebrospinal fluid. Otx2 secretion and internalization requires two small peptidic domains that are part of the DNA-binding domain. Thus, mutating these “transfer” sequences also modifies cell autonomous transcription, precluding this approach to obtain a cell autonomous-only mouse. Here, we develop a mouse model with inducible secretion of an anti-Otx2 single-chain antibody to trap Otx2 in the extracellular milieu. Postnatal secretion of this single-chain antibody by PV cells delays PV maturation and reduces plasticity gene expression. Induced adult expression of this single-chain antibody in cerebrospinal fluid decreases Otx2 internalization by PV cells, strongly induces plasticity gene expression and reopens physiological plasticity. We provide the first mammalian genetic evidence for a signaling mechanism involving intercellular transfer of a homeoprotein transcription factor. Our single-chain antibody mouse model is a valid strategy for extracellular neutralization that could be applied to other homeoproteins and signaling molecules within and beyond the nervous system.

Effect of Contrast on Visual Spatial Summation in Different Cell Categories in Cat Primary Visual Cortex.

Multiple cell classes have been found in the primary visual cortex, but the relationship between cell types and spatial summation has seldom been studied. Parvalbumin-expressing inhibitory interneurons can be distinguished from pyramidal neurons based on their briefer action potential durations. In this study, we classified V1 cells into fast-spiking units (FSUs) and regular-spiking units (RSUs) and then examined spatial summation at high and low contrast. Our results revealed that the excitatory classical receptive field and the suppressive non-classical receptive field expanded at low contrast for both FSUs and RSUs, but the expansion was more marked for the RSUs than for the FSUs. For most V1 neurons, surround suppression varied as the contrast changed from high to low. However, FSUs exhibited no significant difference in the strength of suppression between high and low contrast, although the overall suppression decreased significantly at low contrast for the RSUs. Our results suggest that the modulation of spatial summation by stimulus contrast differs across populations of neurons in the cat primary visual cortex.

Spontaneous Gamma Activity in Schizophrenia.

A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30-100 Hz) gamma power was increased in patients with SZ compared with controls during steady-state stimulation (6.579 [3.783] vs 3.984 [1.843]; F1,46 = 9.128 [P = .004]; d = 0.87) but not during rest (0.006 [0.003] vs 0.005 [0.002]; F1,34 = 1.067 [P = .309]; d = 0.35). Induced gamma power in the left hemisphere of the patients with SZ during the 40-Hz stimulation was positively correlated with auditory hallucination symptoms (tangential, ρ = 0.587 [P = .031]; radial, ρ = 0.593 [P = .024]) and negatively correlated with the ASSR phase-locking factor (baseline: ρ = -0.572 [P = .024]; ASSR: ρ = -0.568 [P = .032]). Spontaneous gamma activity is increased during auditory steady-state stimulation in SZ, reflecting a disruption in the normal balance of excitation and inhibition. This phenomenon interacts with evoked oscillations, possibly contributing to the gamma ASSR deficit found in SZ. The similarity of increased spontaneous gamma power in SZ to the findings of increased spontaneous gamma power in animal models of NMDAR hypofunction suggests that spontaneous gamma power could serve as a biomarker for the integrity of NMDARs on parvalbumin-expressing inhibitory interneurons in humans and in animal models of neuropsychiatric disorders.

Perceptual Gap Detection Is Mediated by Gap Termination Responses in Auditory Cortex

Understanding speech in the presence of background noise often becomes increasingly difficult with age. These age-related speech processing deficits reflect impairments in temporal acuity. Gap detection is a model for temporal acuity in speech processing in which a gap inserted in white noise acts as a cue that attenuates subsequent startle responses. Lesion studies have shown that auditory cortex is necessary for the detection of brief gaps, and auditory cortical neurons respond to the end of the gap with a characteristic burst of spikes called the gap termination response (GTR). However, it remains unknown whether and how the GTR plays a causal role in gap detection. Wetested this by optogenetically suppressing the activity of somatostatin- or parvalbumin-expressing inhibitory interneurons, or CaMKII-expressing excitatory neurons, in auditory cortex of behaving mice during specific epochs of a gap detection protocol. Suppressing interneuron activity during the postgap interval enhanced gap detection. Suppressing excitatory cells during this interval attenuated gap detection. Suppressing activity preceding the gap had the opposite behavioral effects, whereas prolonged suppression across both intervals had no effect on gap detection. In addition to confirming cortical involvement, we demonstrate here for the first time a causal relationship between postgap neural activity and perceptual gap detection. Furthermore, our results suggest that gap detection involves an ongoing comparison of pre- and postgap spiking activity. Finally, we propose a simple yet biologically plausible neural circuit that reproduces each of these neural and behavioral results.

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.

Baseline gamma power during auditory steady-state stimulation in schizophrenia.

Several studies have reported deficits in γ oscillatory activity elicited by sensory stimulation or cognitive processes in schizophrenia patients (SZ) compared to healthy control subjects (HC). However, the evidence for cortical hyperexcitability and reduced function of N-methyl-D-aspartate receptors (NMDARs) on parvalbumin-expressing inhibitory interneurons in schizophrenia leads to the prediction that γ activity should rather be increased in SZ, but data supporting this hypothesis have been lacking. One possibility is that baseline induced γ power is increased, an effect that might have gone unnoticed in studies of stimulus-locked oscillations. Here we addressed this question by re-analyzing the data from a previously published study on the 40 Hz auditory steady-state response (ASSR) in schizophrenia in which dipole source localization was used to examine γ responses in the left and right auditory cortices. Subjects were 16 HC and 18 chronic SZ, who listened to trains of clicks presented at 40 Hz during electroencephalogram recording. Independent component analysis was used to remove ocular artifacts. Power spectra were computed for the pre-stimulus baseline period. We found that baseline power was higher in SZ than HC at 40 Hz in the left auditory cortex. Baseline 40 Hz power in the left auditory cortex was also correlated with ASSR evoked power in SZ. Thus, γ oscillation abnormalities in schizophrenia may include abnormal increases in baseline power as well as deficits in evoked oscillations. These baseline increases could be the sign of NMDAR hypofunction on parvalbumin-expressing inhibitory interneurons, which would be consistent with acute NMDAR antagonism and genetic ablation models of schizophrenia.

Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons

Epilepsy is a common and refractory neurological disorder, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear. Activity-dependent transcription of genes for neurotrophins such as brain-derived neurotrophic factor (BDNF) has been shown to promote epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counterbalancing mechanisms. Using rodent models, here we show that limbic seizure activity upregulated NRG1-ErbB4 signaling and that epileptogenesis was inhibited by infusing NRG1 intracerebrally but exacerbated by neutralizing endogenous NRG1 with soluble ErbB4 extracellular domain, by inhibiting ErbB4 activation or by deleting the Erbb4 gene. Furthermore, specific depletion of ErbB4 in parvalbumin-expressing interneurons abolished NRG1-mediated inhibition of epileptogenesis and promoted kindling progression, resulting in increased spontaneous seizures and exuberant mossy fiber sprouting. In contrast, depleting ErbB4 in CaMKIIα-positive pyramidal neurons had no effect. Thus, NRG1-induced activation of ErbB4 in parvalbumin-expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.