Neuronal activity in the brain gives rise to transmembrane currents that can be measured in the extracellular medium. Although the major contributor of the extracellular signal is the synaptic transmembrane current, other sources — including Na+ and Ca2+ spikes, ionic fluxes through voltage- and ligand-gated channels, and intrinsic membrane oscillations — can substantially shape the extracellular field. High-density recordings of field activity in animals and subdural grid recordings in humans, combined with recently developed data processing tools and computational modelling, can provide insight into the cooperative behaviour of neurons, their average synaptic input and their spiking output, and can increase our understanding of how these processes contribute to the extracellular signal.

/pdf/the-origin-of-extracellular-fields-and-currents-eeg-ecog-lfp-2e79zygxj0.pdf

The origin of extracellular fields and currents — EEG, ECoG, LFP and spikes

The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.

http://www2.neuroscience.umn.edu/eanwebsite/PDF%20GJClub/Science%20342%20373%202013.pdf

Sleep Drives Metabolite Clearance From the Adult Brain

Large-scale brain networks and psychopathology: a unifying triple network model

In order to understand the working brain as a network, it is essential to identify the mechanisms by which information is gated between regions. We here propose that information is gated by inhibiting task-irrelevant regions, thus routing information to task-relevant regions. The functional inhibition is reflected in oscillatory activity in the alpha band (8-13 Hz). From a physiological perspective the alpha activity provides pulsed inhibition reducing the processing capabilities of a given area. Active processing in the engaged areas is reflected by neuronal synchronization in the gamma band (30-100 Hz) accompanied by an alpha band decrease. According to this framework the brain should be studied as a network by investigating cross-frequency interactions between gamma and alpha activity. Specifically the framework predicts that optimal task performance will correlate with alpha activity in task-irrelevant areas. In this review we will discuss the empirical support for this framework. Given that alpha activity is by far the strongest signal recorded by EEG and MEG, we propose that a major part of the electrophysiological activity detected from the working brain reflects gating by inhibition.

/pdf/shaping-functional-architecture-by-oscillatory-alpha-3mqqf8zuk0.pdf

Shaping functional architecture by oscillatory alpha activity : gating by inhibition

https://www.cell.com/trends/cognitive-sciences/pdf/S1364-6613(12)00243-4.pdf

Alpha-band oscillations, attention, and controlled access to stored information

Synchronized oscillations and inhibitory interneurons have important and interconnected roles within cortical microcircuits. In particular, interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin have been suggested to be involved in gamma (30-80 Hz) oscillations, which are hypothesized to enhance information processing. However, because parvalbumin interneurons cannot be selectively controlled, definitive tests of their functional significance in gamma oscillations, and quantitative assessment of the impact of parvalbumin interneurons and gamma oscillations on cortical circuits, have been lacking despite potentially enormous significance (for example, abnormalities in parvalbumin interneurons may underlie altered gamma-frequency synchronization and cognition in schizophrenia and autism). Here we use a panel of optogenetic technologies in mice to selectively modulate multiple distinct circuit elements in neocortex, alone or in combination. We find that inhibiting parvalbumin interneurons suppresses gamma oscillations in vivo, whereas driving these interneurons (even by means of non-rhythmic principal cell activity) is sufficient to generate emergent gamma-frequency rhythmicity. Moreover, gamma-frequency modulation of excitatory input in turn was found to enhance signal transmission in neocortex by reducing circuit noise and amplifying circuit signals, including inputs to parvalbumin interneurons. As demonstrated here, optogenetics opens the door to a new kind of informational analysis of brain function, permitting quantitative delineation of the functional significance of individual elements in the emergent operation and function of intact neural circuitry.

https://web.stanford.edu/group/dlab/media/papers/Sohal%20Nature%202009.pdf

Parvalbumin neurons and gamma rhythms enhance cortical circuit performance

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30–80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms. One model for the cellular disturbances underlying social and emotional deficits in disorders such as autism and schizophrenia is an imbalance in excitatory and inhibitory activity in certain neural systems. This idea has not been directly testable so far, but testability comes a little closer with the development of two optogenetic tools that have different spectral and temporal characteristics, thereby allowing selective control of two intermingled populations of neurons. Use of these new opsins shows that increasing relative excitation in mouse prefrontal cortex impairs social and learning behaviours. This provides support for the elevated cellular excitatory/inhibitory balance hypothesis of certain neuropsychiatric symptoms.

/pdf/neocortical-excitation-inhibition-balance-in-information-3pftybn6ip.pdf

Neocortical excitation/inhibition balance in information processing and social dysfunction

Optogenetics in neural systems.

Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and summarize the application of various optogenetic tools in diverse model organisms.

/pdf/the-development-and-application-of-optogenetics-49rsxufk6s.pdf

The Development and Application of Optogenetics

Neural activity in the noradrenergic locus coeruleus correlates with periods of wakefulness and arousal. However, it is unclear whether tonic or phasic activity in these neurons is necessary or sufficient to induce transitions between behavioral states and to promote long-term arousal. Using optogenetic tools in mice, we found that there is a frequency-dependent, causal relationship among locus coeruleus firing, cortical activity, sleep-to-wake transitions and general locomotor arousal. We also found that sustained, high-frequency stimulation of the locus coeruleus at frequencies of 5 Hz and above caused reversible behavioral arrests. These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders.

/pdf/tuning-arousal-with-optogenetic-modulation-of-locus-12jv1ko7d8.pdf

Ofer Yizhar

Papers

Parvalbumin neurons and gamma rhythms enhance cortical circuit performance

Neocortical excitation/inhibition balance in information processing and social dysfunction

Optogenetics in neural systems.

The Development and Application of Optogenetics

Tuning arousal with optogenetic modulation of locus coeruleus neurons.