Generation Of Gamma Oscillations Research Articles

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role in feedforward and feedback synaptic inhibition, preventing run away excitation in neural networks. Hence, their dysfunction can lead to hyperexcitability and increased susceptibility to seizures. PV+ interneurons are also key players in generating gamma oscillations, which are synchronized neural oscillations associated with various cognitive functions. PV+ interneuron are particularly vulnerable to aging and their degeneration has been associated with cognitive decline and memory impairment in dementia and Alzheimer’s disease (AD). Overall, dysfunction of PV+ interneurons disrupts the normal excitatory/inhibitory balance within specific neurocircuits in the brain and thus has been linked to a wide range of neurodevelopmental and neuropsychiatric disorders. This review focuses on the role of dysfunctional PV+ inhibitory interneurons in the generation of epileptic seizures and cognitive impairment and their potential as targets in the design of future therapeutic strategies to treat these disorders. Recent research using cutting-edge optogenetic and chemogenetic technologies has demonstrated that they can be selectively manipulated to control seizures and restore the balance of neural activity in the brains of animal models. This suggests that PV+ interneurons could be important targets in developing future treatments for patients with epilepsy and comorbid disorders, such as AD, where seizures and cognitive decline are directly linked to specific PV+ interneuron deficits.

A mean-field model of gamma-frequency oscillations in networks of excitatory and inhibitory neurons.

Gamma oscillations are widely seen in the cerebral cortex in different states of the wake-sleep cycle and are thought to play a role in sensory processing and cognition. Here, we study the emergence of gamma oscillations at two levels, in networks of spiking neurons, and a mean-field model. At the network level, we consider two different mechanisms to generate gamma oscillations and show that they are best seen if one takes into account the synaptic delay between neurons. At the mean-field level, we show that, by introducing delays, the mean-field can also produce gamma oscillations. The mean-field matches the mean activity of excitatory and inhibitory populations of the spiking network, as well as their oscillation frequencies, for both mechanisms. This mean-field model of gamma oscillations should be a useful tool to investigate large-scale interactions through gamma oscillations in the brain.

Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction.

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35-45 Hz) power (n = 22, r = 0.613, P < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power (t13 = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.

Parvalbumin and parvalbumin chandelier interneurons in autism and other psychiatric disorders.

Parvalbumin (PV) is a calcium binding protein expressed by inhibitory fast-spiking interneurons in the cerebral cortex. By generating a fast stream of action potentials, PV+ interneurons provide a quick and stable inhibitory input to pyramidal neurons and contribute to the generation of gamma oscillations in the cortex. Their fast-firing rates, while advantageous for regulating cortical signaling, also leave them vulnerable to metabolic stress. Chandelier (Ch) cells are a type of PV+ interneuron that modulate the output of pyramidal neurons and synchronize spikes within neuron populations by directly innervating the pyramidal axon initial segment. Changes in the morphology and/or function of PV+ interneurons, mostly of Ch cells, are linked to neurological disorders. In ASD, the number of PV+ Ch cells is decreased across several cortical areas. Changes in the morphology and/or function of PV+ interneurons have also been linked to schizophrenia, epilepsy, and bipolar disorder. Herein, we review the role of PV and PV+ Ch cell alterations in ASD and other psychiatric disorders.

An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction.

Olfactory information is relayed and processed in the olfactory bulb (OB). Mitral cells, the principal output excitatory neurons of the OB, are controlled by multiple types of interneurons. However, mechanisms that regulate the activity of OB interneurons are not well understood. We provide evidence that the transmembrane tyrosine kinase ErbB4 is selectively expressed in subsets of OB inhibitory neurons in both male and female mice. ErbB4-positive (ErbB4+) neurons are mainly located in the glomerular layer (GL) and granule cell layer (GCL) and do not express previously defined markers. Optogenetic activation of GL-ErbB4+ neurons promotes theta oscillation, whereas activation of those in the GCL generates γ oscillations. Stimulation of OB slices with NRG1, a ligand that activates ErbB4, increases GABA transmission onto mitral cells, suggesting a role of OB NRG1-ErbB4 signaling in olfaction. In accord, ErbB4 mutant mice or acute inhibition of ErbB4 by a chemical genetic approach diminishes GABA transmission, reduces bulbar local field potential power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Together, these results identified a bulbar inhibitory network of ErbB4+ neurons for olfaction. Considering that both Nrg1 and Erbb4 are susceptibility genes for neuropsychiatric disorders, our study provides insight into pathologic mechanisms of olfactory malfunctions in these disorders.SIGNIFICANCE STATEMENT This study demonstrates that ErbB4+ neurons are a new subset of olfactory bulb inhibitory neurons in the glomerular layer and granule cell layer that innervate mitral cells and ErbB4- cells. They regulate olfaction by controlling local synchrony and distinct oscillations. ErbB4 inhibition diminishes GABA transmission, reduces bulbar local field potential power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Our results provide insight into pathophysiological mechanism of olfaction deficits in brain disorders associated with Nrg1 or Erbb4 mutations.

Mechanism of carbachol-induced 40 Hz gamma oscillations and the effects of NMDA activation on oscillatory dynamics in a model of the CA3 subfield of the hippocampus

Gamma oscillations are a prominent feature of various neural systems, including the CA3 subfield of the hippocampus. In CA3, in vitro carbachol application induces ∼40 Hz gamma oscillations in the network of glutamatergic excitatory pyramidal neurons (PNs) and local GABAergic inhibitory neurons (INs). Activation of NMDA receptors within CA3 leads to an increase in the frequency of carbachol-induced oscillations to ∼60 Hz, a broadening of the distribution of individual oscillation cycle frequencies, and a decrease in the time lag between PN and IN spike bursts. In this work, we develop a biophysical integrate-and-fire model of the CA3 subfield, we show that the dynamics of our model are in concordance with physiological observations, and we provide computational support for the hypothesis that the ‘E-I’ mechanism is responsible for the emergence of ∼40 Hz gamma oscillations in the absence of NMDA activation. We then incorporate NMDA receptors into our CA3 model, and we show that our model exhibits the increase in gamma oscillation frequency, broadening of the cycle frequency distribution, and decrease in the time lag between PN and IN spike bursts observed experimentally. Remarkably, we find an inverse relationship in our model between the net NMDA current delivered to PNs and INs in an oscillation cycle and cycle frequency. Furthermore, we find a disparate effect of NMDA receptors on PNs versus INs – we show that NMDA receptors on INs tend to increase oscillation frequency, while NMDA receptors on PNs tend to slightly decrease or not affect oscillation frequency. We find that these observations can be explained if NMDA activity above a threshold level causes a shift in the mechanism underlying gamma oscillations; in the absence of NMDA receptors, the ‘E-I’ mechanism is primarily responsible for the generation of gamma oscillations (at 40 Hz), while when NMDA receptors are active, the mechanism of gamma oscillations shifts to the ‘I-I’ mechanism, and we argue that within the ‘I-I’ regime (which displays a higher baseline oscillation frequency of ∼60 Hz), slight changes in the level of NMDA activity are inversely related to cycle frequency.

INSP-05. Development of fast cortical rhythms in health and mental disease

Synchronization of neuronal activity in fast oscillatory rhythms is a commonly observed feature in the adult cerebral cortex. While its exact functions are still a matter of debate, oscillatory activity in gamma frequency range (20-100 Hz) has been proposed to organize neuronal ensembles and to shape information processing in cortical networks. Gamma activity emerges from reciprocal interactions between excitatory and inhibitory neurons. A fine-tuned balance between excitatory drive and inhibitory feedback is mandatory for circuit function underlying cognitive performance, whereas imbalance between excitation and inhibition and resulting gamma disruption have been proposed to cause cognitive disabilities in psychiatric disorders. Despite extensive investigation of gamma activity in adult brain, its development and function early in life are still poorly understood. The talk will highlight recent experimental findings that uncover the mechanisms and role of fast oscillatory activity throughout development. We will uncover how different neuronal populations interact to generate gamma oscillations. Moreover, we will show that these early oscillations are necessary for the adult cognitive abilities. On the flip side, poorer mnemonic and social abilities that have been characterized in several psychiatric disorders, such as schizophrenia and autism, might result from developmental miswiring of the brain. Our data support this hypothesis by demonstrating that weaker fast oscillatory rhythms, sparser connectivity and lower communication are present in the core circuit of cognitive processing, including the prefrontal cortex, hippocampus and entorhinal cortex, in mouse models of these disorders. Together, these findings highlight the relevance of fast cortical rhythms early in life for the adult brain function.

Transforming Discoveries About Cortical Microcircuits and Gamma Oscillations Into New Treatments for Cognitive Deficits in Schizophrenia.

The major cause of disability in schizophrenia is cognitive impairment, which remains largely refractory to existing treatments. This reflects the fact that antipsychotics and other therapies have not been designed to address specific brain abnormalities that cause cognitive impairment. This overview proposes that understanding how specific cellular and synaptic loci within cortical microcircuits contribute to cortical gamma oscillations may reveal treatments for cognitive impairment. Gamma oscillations are rhythmic patterns of high frequency (∼30-100 Hz) neuronal activity that are synchronized within and across brain regions, generated by a class of inhibitory interneurons that express parvalbumin, and recruited during a variety of cognitive tasks. In schizophrenia, both parvalbumin interneuron function and task-evoked gamma oscillations are deficient. While it has long been controversial whether gamma oscillations are merely a biomarker of circuit function or actually contribute to information processing by neuronal networks, recent neurobiological studies in mice have shown that disrupting or enhancing synchronized gamma oscillations can reproduce or ameliorate cognitive deficits resembling those seen in schizophrenia. In fact, transiently enhancing the synchrony of parvalbumin interneuron-generated gamma oscillations can lead to long-lasting improvements in cognition in mice that model aspects of schizophrenia. Gamma oscillations emerge from specific patterns of connections between a variety of cell types within cortical microcircuits. Thus, a critical next step is to understand how specific cell types and synapses generate gamma oscillations, mediate the effects of gamma oscillations on information processing, and/or undergo plasticity following the induction of gamma oscillations. Modulating these circuit loci, potentially in combination with other approaches such as cognitive training and brain stimulation, may yield potent and selective interventions for enhancing cognition in schizophrenia.

Bidirectionally Regulating Gamma Oscillations in Wilson-Cowan Model by Self-Feedback Loops: A Computational Study.

The Wilson-Cowan model can emulate gamma oscillations, and thus is extensively used to research the generation of gamma oscillations closely related to cognitive functions. Previous studies have revealed that excitatory and inhibitory inputs to the model can modulate its gamma oscillations. Inhibitory and excitatory self-feedback loops are important structural features of the model, however, its functional role in the regulation of gamma oscillations in the model is still unclear. In the present study, bifurcation analysis and spectrum analysis are employed to elucidate the regulating mechanism of gamma oscillations underlined by the inhibitory and excitatory self-feedback loops, especially how the two self-feedback loops cooperate to generate the gamma oscillations and regulate the oscillation frequency. The present results reveal that, on one hand, the inhibitory self-feedback loop is not conducive to the generation of gamma oscillations, and increased inhibitory self-feedback strength facilitates the enhancement of the oscillation frequency. On the other hand, the excitatory self-feedback loop promotes the generation of gamma oscillations, and increased excitatory self-feedback strength leads to the decrease of oscillation frequency. Finally, theoretical analysis is conducted to provide explain on how the two self-feedback loops play a crucial role in the generation and regulation of neural oscillations in the model. To sum up, Inhibitory and excitatory self-feedback loops play a complementary role in generating and regulating the gamma oscillation in Wilson-Cowan model, and cooperate to bidirectionally regulate the gamma-oscillation frequency in a more flexible manner. These results might provide testable hypotheses for future experimental research.

Shape analysis of gamma rhythm supports a superlinear inhibitory regime in an inhibition-stabilized network.

Visual inspection of stimulus-induced gamma oscillations (30-70 Hz) often reveals a non-sinusoidal shape. Such distortions are a hallmark of non-linear systems and are also observed in mean-field models of gamma oscillations. A thorough characterization of the shape of the gamma cycle can therefore provide additional constraints on the operating regime of such models. However, the gamma waveform has not been quantitatively characterized, partially because the first harmonic of gamma, which arises because of the non-sinusoidal nature of the signal, is typically weak and gets masked due to a broadband increase in power related to spiking. To address this, we recorded local field potential (LFP) from the primary visual cortex (V1) of two awake female macaques while presenting full-field gratings or iso-luminant chromatic hues that produced huge gamma oscillations with prominent peaks at harmonic frequencies in the power spectra. We found that gamma and its first harmonic always maintained a specific phase relationship, resulting in a distinctive shape with a sharp trough and a shallow peak. Interestingly, a Wilson-Cowan (WC) model operating in an inhibition stabilized mode could replicate this shape, but only when the inhibitory population operated in the super-linear regime, as predicted recently. However, another recently developed model of gamma that operates in a linear regime driven by stochastic noise failed to produce salient harmonics or the observed shape. Our results impose additional constraints on models that generate gamma oscillations and their operating regimes.

Top-Down Control of Inhibitory Granule Cells in the Main Olfactory Bulb Reshapes Neural Dynamics Giving Rise to a Diversity of Computations.

Growing evidence shows that top-down projections from excitatory neurons in piriform cortex selectively synapse onto local inhibitory granule cells in the main olfactory bulb, effectively gating their own inputs by controlling inhibition. An open question in olfaction is the role this feedback plays in shaping the dynamics of local circuits, and the resultant computational benefits it provides. Using rate models of neuronal firing in a network consisting of excitatory mitral and tufted cells, inhibitory granule cells and top-down piriform cortical neurons, we found that changes in the weight of feedback to inhibitory neurons generated diverse network dynamics and complex transitions between these dynamics. Changes in the weight of top-down feedback supported a number of computations, including both pattern separation and oscillatory synchrony. Additionally, the network could generate gamma oscillations though a mechanism we termed Top-down control of Inhibitory Neuron Gamma (TING). Collectively, these functions arose from a codimension-2 bifurcation in the dynamical system. Our results highlight a key role for this top-down feedback, gating inhibition to facilitate often diametrically different computations.

Critical period regulation across multiple timescales

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

Synchronicity of excitatory inputs drives hippocampal networks to distinct oscillatory patterns.

The rodent hippocampus expresses a variety of neuronal network oscillations depending on the behavioral state of the animal. Locomotion and active exploration are accompanied by theta-nested gamma oscillations while resting states and slow-wave sleep are dominated by intermittent sharp wave-ripple complexes. It is believed that gamma rhythms create a framework for efficient acquisition of information whereas sharp wave-ripples are thought to be involved in consolidation and retrieval of memory. While not strictly mutually exclusive, one of the two patterns usually dominates in a given behavioral state. Here we explore how different input patterns induce either of the two network states, using an optogenetic stimulation approach in hippocampal brain slices of mice. We report that the pattern of the evoked oscillation depends strongly on the initial synchrony of activation of excitatory cells within CA3. Short, synchronous activation favors the emergence of sharp wave-ripple complexes while persistent but less synchronous activity-as typical for sensory input during exploratory behavior-supports the generation of gamma oscillations. This dichotomy is reflected by different degrees of synchrony of excitatory and inhibitory synaptic currents within these two states. Importantly, the induction of these two fundamental network patterns does not depend on the presence of any neuromodulatory transmitter like acetylcholine, but is merely based on a different synchrony in the initial activation pattern.

Dynamic Recovery from Depression Enables Rate Encoding in Inhibitory Synapses.

SummaryParvalbumin-expressing fast-spiking interneurons (PV-INs) control network firing and the gain of cortical response to sensory stimulation. Crucial for these functions, PV-INs can sustain high-frequency firing with no accommodation. However, PV-INs also exhibit short-term depression (STD) during sustained activation, largely due to the depletion of synaptic resources (vesicles). In most synapses the rate of replenishment of depleted vesicles is constant, determining an inverse relationship between depression levels and the activation rate, which theoretically, severely limits rate-coding capabilities. We examined STD of the PV-IN to pyramidal cell synapse in the mouse visual cortex and found that in these synapses the recovery from depression is not constant but increases linearly with the frequency of use. By combining modeling, dynamic clamp, and optogenetics, we demonstrated that this recovery enables PV-INs to reduce pyramidal cell firing in a linear manner, which theoretically is crucial for controlling the gain of cortical visual responses.

Speech-in-noise understanding in older age: The role of inhibitory cortical responses.

Studies of central auditory processing underlying speech-in-noise (SIN) recognition in aging have mainly concerned the degrading neural representation of speech sound in the auditory brainstem and cortex. Less attention has been paid to the aging-related decline of inhibitory function, which reduces the ability to suppress distraction from irrelevant sensory input. In a response suppression paradigm, young and older adults listened to sequences of three short sounds during MEG recording. The amplitudes of the cortical P30 response and the 40-Hz transient gamma response were compared with age, hearing loss and SIN performance. Sensory gating, indicated by the P30 amplitude ratio between the last and the first responses, was reduced in older compared to young listeners. Sensory gating was correlated with age in the older adults but not with hearing loss nor with SIN understanding. The transient gamma response expressed less response suppression. However, the gamma amplitude increased with age and SIN loss. Comparisons of linear multi-variable modeling showed a stronger brain-behavior relationship between the gamma amplitude and SIN performance than between gamma and age or hearing loss. The findings support the hypothesis that aging-related changes in the balance between inhibitory and excitatory neural mechanisms modify the generation of gamma oscillations, which impacts on perceptual binding and consequently on SIN understanding abilities. In conclusion, SIN recognition in older age is less affected by central auditory processing at the level of sensation, indicated by sensory gating, but is strongly affected at the level of perceptual organization, indicated by the correlation with the gamma responses.

Altered Gamma Oscillations during Motor Control in Children with Autism Spectrum Disorder.

Autism is hypothesized to result in a cortical excitatory and inhibitory imbalance driven by inhibitory interneuron dysfunction, which is associated with the generation of gamma oscillations. On the other hand, impaired motor control has been widely reported in autism. However, no study has focused on the gamma oscillations during motor control in autism. In the present study, we investigated the motor-related gamma oscillations in autism using magnetoencephalography. Magnetoencephalographic signals were recorded from 14 right-handed human children with autism (5 female), aged 5–7 years, and age- and IQ-matched 15 typically developing children during a motor task using their right index finger. Consistent with previous studies, the autism group showed a significantly longer button response time and reduced amplitude of motor-evoked magnetic fields. We observed that the autism group exhibited a low peak frequency of motor-related gamma oscillations from the contralateral primary motor cortex, and these were associated with the severity of autism symptoms. The autism group showed a reduced power of motor-related gamma oscillations in the bilateral primary motor cortex. A linear discriminant analysis using the button response time and gamma oscillations showed a high classification performance (86.2% accuracy). The alterations of the gamma oscillations in autism might reflect the cortical excitatory and inhibitory imbalance. Our findings provide an important clue into the behavioral and neurophysiological alterations in autism and a potential biomarker for autism.SIGNIFICANCE STATEMENT Currently, the diagnosis of autism has been based on behavioral assessments, and a crucial issue in the diagnosis of autism is to identify objective and quantifiable clinical biomarkers. A key hypothesis of the neurophysiology of autism is an excitatory and inhibitory imbalance in the brain, which is associated with the generation of gamma oscillations. On the other hand, motor deficits have also been widely reported in autism. This is the first study to demonstrate low motor performance and altered motor-related gamma oscillations in autism, reflecting a brain excitatory and inhibitory imbalance. Using these behavioral and neurophysiological parameters, we classified autism and control group with good accuracy. This work provides important information on behavioral and neurophysiological alterations in patients with autism.

Auditory steady state response deficits are associated with symptom severity and poor functioning in patients with psychotic disorder

ObjectivesGamma oscillation is important for cortico-cortical coordination and the integration of information across neural networks. The 40 Hz auditory steady-state response (ASSR), which reflects neural synchrony in the gamma band (30–100 Hz), is abnormal in patients with schizophrenia (SZ). The present study used the ASSR at multiple frequencies to examine (1) gamma dysfunction in patients with SZ, schizoaffective (SA), and bipolar disorder (BD) compared with controls, (2) the relationship between ASSR measures and clinical symptom severity, and (3) the relationship between ASSR measures and real-life community functioning. MethodsEEG was recorded from 75 controls, 52 SZ, 55 SA, and 89 BD patients during 20–30-40-Hz binaural click trains. ANCOVA was used to compare ASSR measures between groups controlling for age, sex, and education. Associations between ASSR measures, symptom severity, and community functioning were examined using linear regression and Pearson partial correlations. ResultsASSR deficits at gamma frequency were observed in all patient groups. SA patients showed additional specific deficit in the 20 Hz ASSR. Severity of manic, depressive, and anxiety symptoms mediated ASSR deficits. Severity of hallucinatory symptom and community functioning, particularly independent living/meaningful activity, were significantly and independently associated with the 40 Hz ASSR. ConclusionsSZ, SA and BD patients are likely to share the same abnormalities in neural processes that generate gamma oscillations. 40 Hz ASSR are associated with community functioning across patients and may serve as a biomarker for predicting functional outcome.

Long-wavelength (reddish) hues induce unusually large gamma oscillations in the primate primary visual cortex

Gamma oscillations (∼30-80 Hz) are a prominent signature of electrophysiological signals, with a purported role in natural vision. Previous studies in the primary visual cortex (area V1) have shown that achromatic gratings or gabor stimuli generate salient gamma oscillations, whose strength and frequency depend on stimulus properties such as their size, contrast, and orientation. Surprisingly, although natural images are rarely achromatic, the effect of chromatic input on gamma has not been thoroughly investigated. Recording from primate V1, we show that gamma oscillations of extremely high magnitude (peak increase of ∼300-fold in some cases), far exceeding the gamma generated by optimally tuned achromatic gratings, are induced in the local field potentials by full-field color stimuli of different hues. Furthermore, gamma oscillations are sensitive to the hue of the chromatic input, with the strongest oscillations for long-wavelength (reddish) hues and another, smaller gamma response peak for hues in the short-wavelength (bluish) range, which lie approximately on the two cardinal chromatic response axes of the upstream lateral geniculate nucleus neurons. These oscillations depended critically on the purity of the hue, decreasing with hue desaturation, but remained robust for pure hue stimuli even at reduced luminance. Importantly, the magnitude of gamma oscillations was highly correlated with positive L-M cone contrast produced by the stimuli, suggesting that gamma could be a marker of the specific mechanisms underlying this computation. These findings provide insights into the generation of gamma oscillations, as well as the processing of color along the visual pathway.

3.1 ENHANCED PARVALBUMIN NETWORK ACTIVITY PROLONGS CRITICAL PERIOD PLASTICITY

BackgroundOscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.MethodsWe generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-α1 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity (loss of visual acuity, formation of preference behaviors) that are typically limited to a critical period early in life.ResultsPV-α1 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.DiscussionCortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset (see talk by P Uhlhaas).