Jessica A. Cardin

Driving fast-spiking cells induces gamma rhythm and controls sensory responses

Cortical gamma oscillations (20-80 Hz) predict increases in focused attention, and failure in gamma regulation is a hallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons at varied frequencies (8-200 Hz) selectively amplifies gamma oscillations. In contrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.

A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior

Synchronous recruitment of fast-spiking (FS) parvalbumin (PV) interneurons generates gamma oscillations, rhythms that emerge during performance of cognitive tasks. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists alters gamma rhythms, and can induce cognitive as well as psychosis-like symptoms in humans. The disruption of NMDA receptor (NMDAR) signaling specifically in FS PV interneurons is therefore hypothesized to give rise to neural network dysfunction that could underlie these symptoms. To address the connection between NMDAR activity, FS PV interneurons, gamma oscillations and behavior, we generated mice lacking NMDAR neurotransmission only in PV cells (PV-Cre/NR1f/f mice). Here, we show that mutant mice exhibit enhanced baseline cortical gamma rhythms, impaired gamma rhythm induction after optogenetic drive of PV interneurons and reduced sensitivity to the effects of NMDAR antagonists on gamma oscillations and stereotypies. Mutant mice show largely normal behaviors except for selective cognitive impairments, including deficits in habituation, working memory and associative learning. Our results provide evidence for the critical role of NMDAR in PV interneurons for expression of normal gamma rhythms and specific cognitive behaviors.

Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of Channelrhodopsin-2.

A major long-term goal of systems neuroscience is to identify the different roles of neural subtypes in brain circuit function. The ability to causally manipulate selective cell types is critical to meeting this goal. This protocol describes techniques for optically stimulating specific populations of excitatory neurons and inhibitory interneurons in vivo in combination with electrophysiology. Cell type selectivity is obtained using Cre-dependent expression of the light-activated channel Channelrhodopsin-2. We also describe approaches for minimizing optical interference with simultaneous extracellular and intracellular recording. These optogenetic techniques provide a spatially and temporally precise means of studying neural activity in the intact brain and allow a detailed examination of the effect of evoked activity on the surrounding local neural network. Injection of viral vectors requires 30–45 min, and in vivo electrophysiology with optogenetic stimulation requires 1–4 h.

Arousal and Locomotion Make Distinct Contributions to Cortical Activity Patterns and Visual Encoding

Spontaneous and sensory-evoked cortical activity is highly state-dependent, yet relatively little is known about transitions between distinct waking states. Patterns of activity in mouse V1 differ dramatically between quiescence and locomotion, but this difference could be explained by either motor feedback or a change in arousal levels. We recorded single cells and local field potentials from area V1 in mice head-fixed on a running wheel and monitored pupil diameter to assay arousal. Using naturally occurring and induced state transitions, we dissociated arousal and locomotion effects in V1. Arousal suppressed spontaneous firing and strongly altered the temporal patterning of population activity. Moreover, heightened arousal increased the signal-to-noise ratio of visual responses and reduced noise correlations. In contrast, increased firing in anticipation of and during movement was attributable to locomotion effects. Our findings suggest complementary roles of arousal and locomotion in promoting functional flexibility in cortical circuits.

Stimulus Feature Selectivity in Excitatory and Inhibitory Neurons in Primary Visual Cortex

Although several lines of evidence suggest that stimulus selectivity in somatosensory and visual cortices is critically dependent on unselective inhibition, particularly in the thalamorecipient layer 4, no comprehensive comparison of the responses of excitatory and inhibitory cells has been conducted. Here, we recorded intracellularly from a large population of regular spiking (RS; presumed excitatory) and fast spiking (FS; presumed inhibitory) cells in layers 2–6 of primary visual cortex. In layer 4, where selectivity for orientation and spatial frequency first emerges, we found no untuned FS cells. Instead, the tuning of the spike output of layer 4 FS cells was significantly but moderately broader than that of RS cells. However, the tuning of the underlying synaptic responses was not different, indicating that the difference in spike-output selectivity resulted from differences in the transformation of synaptic input into firing rate. Layer 4 FS cells exhibited significantly lower input resistance and faster time constants than layer 4 RS cells, leading to larger and faster membrane potential (Vm) fluctuations. FS cell Vm fluctuations were more broadly tuned than those of RS cells and matched spike-output tuning, suggesting that the broader spike tuning of these cells was driven by visually evoked synaptic noise. These differences were not observed outside of layer 4. Thus, cell type-specific differences in stimulus feature selectivity at the first level of cortical sensory processing may arise as a result of distinct biophysical properties that determine the dynamics of synaptic integration.

Optical Neural Interfaces

Genetically encoded optical actuators and indicators have changed the landscape of neuroscience, enabling targetable control and readout of specific components of intact neural circuits in behaving animals. Here, we review the development of optical neural interfaces, focusing on hardware designed for optical control of neural activity, integrated optical control and electrical readout, and optical readout of population and single-cell neural activity in freely moving mammals.

Noradrenergic Inputs Mediate State Dependence of Auditory Responses in the Avian Song System

Norepinephrine (NE) plays a complex role in the behavioral state-dependent regulation of sensory processing. However, the role of forebrain NE action in modulating high-order sensory activity has not been directly addressed. In this study, we take advantage of the discrete, feedforward organization of the avian song system to identify a site and mechanism of NE action underlying state-dependent modulation of sensory processing. We have developed an experimental paradigm in which brief arousal repeatedly suppresses song system auditory responsiveness. Using pharmacological manipulations in vivo, we show that infusion of α-adrenergic antagonists into the NIf (nucleus interfacialis of the nidopallium), an auditory forebrain area, blocks this state-dependent modulation. We also demonstrate dose-dependent enhancement and suppression of song system auditory response properties by NE and adrenergic agonists. Our results demonstrate that noradrenergic release in a single forebrain area is a mechanism underlying behavioral state-dependent regulation of auditory processing in a neural system specialized for vocal learning.

Neocortical Interneurons: From Diversity, Strength

Interneurons in the neocortex of the brain are small, locally projecting inhibitory GABAergic cells with a broad array of anatomical and physiological properties. The diversity of interneurons is believed to be crucial for regulating myriad operations in the neocortex. Here, we describe current theories about how interneuron diversity may support distinct neocortical processes that underlie perception.

Stimulus-Dependent γ (30 – 50 Hz) Oscillations in Simple and Complex Fast Rhythmic Bursting Cells in Primary Visual Cortex

Oscillatory activity is generated by many neural systems. γ band (∼40 Hz) oscillations in the thalamus and cortex occur spontaneously and in response to sensory stimuli. Fast rhythmic bursting (FRB) cells (also called chattering cells) comprise a unique class of cortical neurons that, during depolarization by current injection, intrinsically generate bursts of high-frequency action potentials with an interburst frequency between 30 and 50 Hz. In the present study, we show for the first time that FRB cells in the primary visual cortex can be either simple or complex and are distributed throughout all cortical layers. Strikingly, both simple and complex FRB cells generate spike bursts at γ frequencies in response to depolarizing current pulses, but only simple FRB cells exhibit a selective, stimulus feature-dependent increase in γ oscillations in response to visual stimulation. In addition, we find that hyperpolarization does not reduce the relative power of visually evoked γ oscillations in the Vm response of FRB cells. Our results thus indicate that visually evoked γ activity in individual simple and complex FRB cells is generated in large part by rhythmic synaptic input, rather than by depolarization-dependent activation of intrinsic properties. Finally, the presence of FRB cells in layer 6 suggests a role for corticothalamic feedback in potentiating thalamic oscillations and facilitating the generation of a corticothalamocortical oscillatory loop. We propose that rather than functioning as pacemakers, FRB cells amplify and distribute stimulus-driven γ oscillations in the neocortex.

Computational Modeling of Distinct Neocortical Oscillations Driven by Cell-Type Selective Optogenetic Drive: Separable Resonant Circuits Controlled by Low-Threshold Spiking and Fast-Spiking Interneurons

Selective optogenetic drive of fast-spiking (FS) interneurons (INs) leads to enhanced local field potential (LFP) power across the traditional “gamma” frequency band (20–80 Hz; Cardin et al., 2009). In contrast, drive to regular-spiking (RS) pyramidal cells enhances power at lower frequencies, with a peak at 8 Hz. The first result is consistent with previous computational studies emphasizing the role of FS and the time constant of GABAA synaptic inhibition in gamma rhythmicity. However, the same theoretical models do not typically predict low-frequency LFP enhancement with RS drive. To develop hypotheses as to how the same network can support these contrasting behaviors, we constructed a biophysically principled network model of primary somatosensory neocortex containing FS, RS, and low-threshold spiking (LTS) INs. Cells were modeled with detailed cell anatomy and physiology, multiple dendritic compartments, and included active somatic and dendritic ionic currents. Consistent with prior studies, the model demonstrated gamma resonance during FS drive, dependent on the time constant of GABAA inhibition induced by synchronous FS activity. Lower-frequency enhancement during RS drive was replicated only on inclusion of an inhibitory LTS population, whose activation was critically dependent on RS synchrony and evoked longer-lasting inhibition. Our results predict that differential recruitment of FS and LTS inhibitory populations is essential to the observed cortical dynamics and may provide a means for amplifying the natural expression of distinct oscillations in normal cortical processing.