Faculty Bibliography

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.

The head-direction (HD) system functions as a compass, with member neurons robustly increasing their firing rates when the animal's head points in a specific direction. HD neurons may be driven by peripheral sensors or, as computational models postulate, internally generated (attractor) mechanisms. We addressed the contributions of stimulus-driven and internally generated activity by recording ensembles of HD neurons in the antero-dorsal thalamic nucleus and the post-subiculum of mice by comparing their activity in various brain states. The temporal correlation structure of HD neurons was preserved during sleep, characterized by a 60 degrees -wide correlated neuronal firing (activity packet), both within and across these two brain structures. During rapid eye movement sleep, the spontaneous drift of the activity packet was similar to that observed during waking and accelerated tenfold during slow-wave sleep. These findings demonstrate that peripheral inputs impinge on an internally organized network, which provides amplification and enhanced precision of the HD signal.

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.

Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material-based, ultraconformable, biocompatible and scalable neural interface array (the 'NeuroGrid') that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 week's duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders.

Synaptic inhibition, brought about by a rich variety of interneuron types that target different domains of principal cells and other interneurons, counters excitation, modulates the gain, timing, tuning, bursting properties of principal cell firing, and exerts selective filtering of synaptic excitation. At the network level, it allows for coordinating transient interactions among the principal cells to form cooperative assemblies for efficient transmission of information and routing of excitatory activity across networks, typically in the form of brain oscillations. Targeted expression of neuronal activity modulators, such as optogenetics, allow physiological identification and perturbation of specific interneuron subtypes. Combined with large-scale recordings or imaging techniques, these approaches facilitate our understanding of the multiple roles of inhibitory interneurons in shaping circuit functions. This article is part of a Special Issue entitled 'GABAergic signaling'.

Theories of brain function have evolved through multiple stages. The first proposition was that brain networks support a set of reflex responses, with current sensory inputs producing immediate motor outputs. The behaviorist paradigm suggested that actions can always be explained as a response to immediate external cues. In response to these views, the cognitive paradigm argued that behavior cannot be understood simply as input-output functions because the hidden layers of brain generate unpredictability. The central processing was termed "cognition." Here we propose a neuroscience-based model of cognition. Our core hypothesis is that cognition depends on internal models of the animal and its world, where internally generated sequences can serve to perform "what if" scenarios and anticipate the possible consequences of alternative actions without actually testing them, and aid in the decisions of overt actions. We support our hypotheses by several examples of recent experimental findings and show how externally guided cell assembly sequences become internalized to support cognitive functions.

High-frequency ripple oscillations, observed most prominently in the hippocampal CA1 pyramidal layer, are associated with memory consolidation. The cellular and network mechanisms underlying the generation of the rhythm and the recruitment of spikes from pyramidal neurons are still poorly understood. Using intracellular, sharp electrode recordings in freely moving, drug-free mice, we observed consistent large depolarizations in CA1 pyramidal cells during sharp wave ripples, which are associated with ripple frequency fluctuation of the membrane potential ("intracellular ripple"). Despite consistent depolarization, often exceeding pre-ripple spike threshold values, current pulse-induced spikes were strongly suppressed, indicating that spiking was under the control of concurrent shunting inhibition. Ripple events were followed by a prominent afterhyperpolarization and spike suppression. Action potentials during and outside ripples were orthodromic, arguing against ectopic spike generation, which has been postulated by computational models of ripple generation. These findings indicate that dendritic excitation of pyramidal neurons during ripples is countered by shunting of the membrane and postripple silence is mediated by hyperpolarizing inhibition.

Advances in understanding the genetics and underlying pathology of the catastrophic childhood epilepsies are pointing toward treatments.