Faculty Bibliography

Whereas hippocampal activity is thought to be driven by precise conjunctions of sensory input, a recent study by Villette and Malvache et al. (Villette et al., 2015, in this issue of Neuron) reveals that neurons imaged in a static sensory environment organize into sequences endowed with intrinsic spatiotemporal properties.

Sequential activity of multineuronal spiking can be observed during theta and high-frequency ripple oscillations in the hippocampal CA1 region and is linked to experience, but the mechanisms underlying such sequences are unknown. We compared multineuronal spiking during theta oscillations, spontaneous ripples, and focal optically induced high-frequency oscillations ("synthetic" ripples) in freely moving mice. Firing rates and rate modulations of individual neurons, and multineuronal sequences of pyramidal cell and interneuron spiking, were correlated during theta oscillations, spontaneous ripples, and synthetic ripples. Interneuron spiking was crucial for sequence consistency. These results suggest that participation of single neurons and their sequential order in population events are not strictly determined by extrinsic inputs but also influenced by local-circuit properties, including synapses between local neurons and single-neuron biophysics.

Despite decades of extracellular action potential (EAP) recordings monitoring brain activity, the biophysical origin and inherent variability of these signals remains enigmatic. We performed whole-cell patch recordings of excitatory and inhibitory neurons in rat somatosensory cortex slice while positioning a silicon probe in their vicinity to concurrently record intra- and extracellular voltages for spike frequencies under 20 Hz. We characterize biophysical events and properties (intracellular spiking, extracellular resistivity, temporal jitter, etc.) related to EAP-recordings at the single-neuron level in a layer-specific manner. EAP-amplitude was found to decay as the inverse of distance between the soma and the recording electrode with similar (but not identical) resistivity across layers. Furthermore, we assessed a number of EAP-features and their variability with spike activity: amplitude (but not temporal) features varied substantially (approx. 30-50% compared to mean) and non-monotonically as a function of spike frequency and spike order. Such EAP-variation only partly reflects intracellular somatic spike variability and points to the plethora of processes contributing to the EAP. Also, we show that the shape of the EAP-waveform is qualitative similar to the negative of the temporal derivative to the intracellular somatic voltage - as expected from theory. Finally, we tested to what extent EAPs can impact the lowpass filtered part of extracellular recordings, the local field potential (LFP), typically associated with synaptic activity. We found that spiking of excitatory neurons can significantly impact the LFP at frequencies as low as 20 Hz. Our results question the common assertion that LFPs act as proxy for synaptic activity.

Brain-implanted devices are no longer a futuristic idea. Traditionally, therapies for most neurological disorders are adjusted based on changes in clinical symptoms and diagnostic measures observed over time. These therapies are commonly pharmacological or surgical, requiring continuous or irreversible treatment regimens that cannot respond rapidly to fluctuations of symptoms or isolated episodes of dysfunction. In contrast, closed-loop systems provide intervention only when needed by detecting abnormal neurological signals and modulating them with instantaneous feedback. Closed-loop systems have been applied to several neurological conditions (most notably epilepsy and movement disorders), but widespread use is limited by conceptual and technical challenges. Herein, we discuss how advances in experimental closed-loop systems hold promise for improved clinical benefit in patients with neurological disorders.

To understand how function arises from the interactions between neurons, it is necessary to use methods that allow the monitoring of brain activity at the single-neuron, single-spike level and the targeted manipulation of the diverse neuron types selectively in a closed-loop manner. Large-scale recordings of neuronal spiking combined with optogenetic perturbation of identified individual neurons has emerged as a suitable method for such tasks in behaving animals. To fully exploit the potential power of these methods, multiple steps of technical innovation are needed. We highlight the current state of the art in electrophysiological recording methods, combined with optogenetics, and discuss directions for progress. In addition, we point to areas where rapid development is in progress and discuss topics where near-term improvements are possible and needed.

Neural oscillations have been measured and interpreted in multitudinous ways, with a variety of hypothesized functions in physiology, information processing and cognition. Much attention has been paid in recent years to gamma-band (30-100 Hz) oscillations and synchrony, with an increasing interest in 'high gamma' (>100 Hz) signals as mesoscopic measures of inter-regional communication. The biophysical origins of the measured variables are often difficult to precisely identify, however, making their interpretation fraught with pitfalls. Here we discuss how measurements of inter-regional gamma coherence can be prone to misinterpretation and suggest strategies for deciphering the roles that synchronized oscillations across brain networks may play in neural function.