An automated, low-latency environment for studying the neural basis of behavior in freely moving rats.

BACKGROUND: Behavior consists of the interaction between an organism and its environment, and is controlled by the brain. Brain activity varies at sub-second time scales, but behavioral measures are usually coarse (often consisting of only binary trial outcomes). RESULTS: To overcome this mismatch, we developed the Rat Interactive Foraging Facility (RIFF): a programmable interactive arena for freely moving rats with multiple feeding areas, multiple sound sources, high-resolution behavioral tracking, and simultaneous electrophysiological recordings. The paper provides detailed information about the construction of the RIFF and the software used to control it. To illustrate the flexibility of the RIFF, we describe two complex tasks implemented in the RIFF, a foraging task and a sound localization task. Rats quickly learned to obtain rewards in both tasks. Neurons in the auditory cortex as well as neurons in the auditory field in the posterior insula had sound-driven activity during behavior. Remarkably, neurons in both structures also showed sensitivity to non-auditory parameters such as location in the arena and head-to-body angle. CONCLUSIONS: The RIFF provides insights into the cognitive capabilities and learning mechanisms of rats and opens the way to a better understanding of how brains control behavior. The ability to do so depends crucially on the combination of wireless electrophysiology and detailed behavioral documentation available in the RIFF.

Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks.

The medial septum/diagonal band of Broca complex (MSDB) is a key structure that modulates hippocampal rhythmogenesis. Cholinergic neurons of the MSDB play a central role in generating and pacing theta-band oscillations in the hippocampal formation during exploration, novelty detection, and memory encoding. How precisely cholinergic neurons affect hippocampal network dynamics in vivo, however, has remained elusive. In this study, we show that stimulation of cholinergic MSDB neurons in urethane-anesthetized mice acts on hippocampal networks via two distinct pathways. A direct septo-hippocampal cholinergic projection causes increased firing of hippocampal inhibitory interneurons with concomitantly decreased firing of principal cells. In addition, cholinergic neurons recruit noncholinergic neurons within the MSDB. This indirect pathway is required for hippocampal theta synchronization. Activation of both pathways causes a reduction in pyramidal neuron firing and a more precise coupling to the theta oscillatory phase. These two anatomically and functionally distinct pathways are likely relevant for cholinergic control of encoding versus retrieval modes in the hippocampus.

How coupled slow oscillations, spindles and ripples coordinate neuronal processing and communication during human sleep.

Learning and plasticity rely on fine-tuned regulation of neuronal circuits during offline periods. An unresolved puzzle is how the sleeping brain, in the absence of external stimulation or conscious effort, coordinates neuronal firing rates (FRs) and communication within and across circuits to support synaptic and systems consolidation. Using intracranial electroencephalography combined with multiunit activity recordings from the human hippocampus and surrounding medial temporal lobe (MTL) areas, we show that, governed by slow oscillation (SO) up-states, sleep spindles set a timeframe for ripples to occur. This sequential coupling leads to a stepwise increase in (1) neuronal FRs, (2) short-latency cross-correlations among local neuronal assemblies and (3) cross-regional MTL interactions. Triggered by SOs and spindles, ripples thus establish optimal conditions for spike-timing-dependent plasticity and systems consolidation. These results unveil how the sequential coupling of specific sleep rhythms orchestrates neuronal processing and communication during human sleep.

Concept neurons in the human medial temporal lobe flexibly represent abstract relations between concepts.

Concept neurons in the medial temporal lobe respond to semantic features of presented stimuli. Analyzing 61 concept neurons recorded from twelve patients who underwent surgery to treat epilepsy, we show that firing patterns of concept neurons encode relations between concepts during a picture comparison task. Thirty-three of these responded to non-preferred stimuli with a delayed but well-defined onset whenever the task required a comparison to a response-eliciting concept, but not otherwise. Supporting recent theories of working memory, concept neurons increased firing whenever attention was directed towards this concept and could be reactivated after complete activity silence. Population cross-correlations of pairs of concept neurons exhibited order-dependent asymmetric peaks specifically when their response-eliciting concepts were to be compared. Our data are consistent with synaptic mechanisms that support reinstatement of concepts and their relations after activity silence, flexibly induced through task-specific sequential activation. This way arbitrary contents of experience could become interconnected in both working and long-term memory.

Seizure Onset Zone Lateralization Using a Non-linear Analysis of Micro vs. Macro Electroencephalographic Recordings During Seizure-Free Stages of the Sleep-Wake Cycle From Epilepsy Patients.

The application of non-linear signal analysis techniques to biomedical data is key to improve our knowledge about complex physiological and pathological processes. In particular, the use of non-linear techniques to study electroencephalographic (EEG) recordings can provide an advanced characterization of brain dynamics. In epilepsy these dynamics are altered at different spatial scales of neuronal organization. We therefore apply non-linear signal analysis to EEG recordings from epilepsy patients derived with intracranial hybrid electrodes, which are composed of classical macro contacts and micro wires. Thereby, these electrodes record EEG at two different spatial scales. Our aim is to test the degree to which the analysis of the EEG recorded at these different scales allows us to characterize the neuronal dynamics affected by epilepsy. For this purpose, we retrospectively analyzed long-term recordings performed during five nights in three patients during which no seizures took place. As a benchmark we used the accuracy with which this analysis allows determining the hemisphere that contains the seizure onset zone, which is the brain area where clinical seizures originate. We applied the surrogate-corrected non-linear predictability score (ψ), a non-linear signal analysis technique which was shown previously to be useful for the lateralization of the seizure onset zone from classical intracranial EEG macro contact recordings. Higher values of ψ were found predominantly for signals recorded from the hemisphere containing the seizure onset zone as compared to signals recorded from the opposite hemisphere. These differences were found not only for the EEG signals recorded with macro contacts, but also for those recorded with micro wires. In conclusion, the information obtained from the analysis of classical macro EEG contacts can be complemented by the one of micro wire EEG recordings. This combined approach may therefore help to further improve the degree to which quantitative EEG analysis can contribute to the diagnostics in epilepsy patients.

Recollection in the human hippocampal-entorhinal cell circuitry.

Imagine how flicking through your photo album and seeing a picture of a beach sunset brings back fond memories of a tasty cocktail you had that night. Computational models suggest that upon receiving a partial memory cue ('beach'), neurons in the hippocampus coordinate reinstatement of associated memories ('cocktail') in cortical target sites. Here, using human single neuron recordings, we show that hippocampal firing rates are elevated from ~ 500-1500 ms after cue onset during successful associative retrieval. Concurrently, the retrieved target object can be decoded from population spike patterns in adjacent entorhinal cortex (EC), with hippocampal firing preceding EC spikes and predicting the fidelity of EC object reinstatement. Prior to orchestrating reinstatement, a separate population of hippocampal neurons distinguishes different scene cues (buildings vs. landscapes). These results elucidate the hippocampal-entorhinal circuit dynamics for memory recall and reconcile disparate views on the role of the hippocampus in scene processing vs. associative memory.

Single-Neuron Correlates of Conscious Perception in the Human Medial Temporal Lobe.

The neuronal mechanisms giving rise to conscious perception remain largely elusive [1]. It is known that the strength of single-neuron activity correlates with conscious perception, especially in anterior regions of the ventral pathway in non-human primates [2-4] and in the human medial temporal lobe (MTL) [5, 6]. It is unclear, however, whether single-neuron correlates of conscious perception are characterized solely by the magnitude of neuronal responses, and whether the correlates of perception are equally prominent across different regions of the human MTL. While recording from 2,735 neurons in 21 neurosurgical patients during 40 experimental sessions, we created experimental conditions in which otherwise identical visual stimuli are sometimes seen and sometimes not detected at all by means of the attentional blink, i.e., the phenomenon that the second of two target stimuli in close succession often goes unnoticed to conscious perception [7]. Remarkably, responses to unseen versus seen stimuli were delayed and temporally more dispersed, in addition to being attenuated in firing rate. This finding suggests precise timing of neuronal responses as a novel candidate physiological marker of conscious perception. In addition, we found modulation of neuronal response timing and strength in response to seen versus unseen stimuli to increase along an anatomical gradient from the posterior to the anterior MTL. Our results thus map out the neuronal correlates of conscious perception in the human MTL both in time and in space.

Reliable Analysis of Single-Unit Recordings from the Human Brain under Noisy Conditions: Tracking Neurons over Hours.

Recording extracellulary from neurons in the brains of animals in vivo is among the most established experimental techniques in neuroscience, and has recently become feasible in humans. Many interesting scientific questions can be addressed only when extracellular recordings last several hours, and when individual neurons are tracked throughout the entire recording. Such questions regard, for example, neuronal mechanisms of learning and memory consolidation, and the generation of epileptic seizures. Several difficulties have so far limited the use of extracellular multi-hour recordings in neuroscience: Datasets become huge, and data are necessarily noisy in clinical recording environments. No methods for spike sorting of such recordings have been available. Spike sorting refers to the process of identifying the contributions of several neurons to the signal recorded in one electrode. To overcome these difficulties, we developed Combinato: a complete data-analysis framework for spike sorting in noisy recordings lasting twelve hours or more. Our framework includes software for artifact rejection, automatic spike sorting, manual optimization, and efficient visualization of results. Our completely automatic framework excels at two tasks: It outperforms existing methods when tested on simulated and real data, and it enables researchers to analyze multi-hour recordings. We evaluated our methods on both short and multi-hour simulated datasets. To evaluate the performance of our methods in an actual neuroscientific experiment, we used data from from neurosurgical patients, recorded in order to identify visually responsive neurons in the medial temporal lobe. These neurons responded to the semantic content, rather than to visual features, of a given stimulus. To test our methods with multi-hour recordings, we made use of neurons in the human medial temporal lobe that respond selectively to the same stimulus in the evening and next morning.

Burst firing of single neurons in the human medial temporal lobe changes before epileptic seizures.

OBJECTIVE: To better understand the mechanisms that lead to the sudden and unexpected occurrence of seizures, with the neuronal correlate being abnormally synchronous discharges that disrupt neuronal function. METHODS: To address this problem, we recorded single neuron activity in epilepsy patients during the transition to seizures to uncover specific changes of neuronal firing patterns. We focused particularly on neurons repeatedly firing discrete groups of high-frequency action potentials (so called bursters) that have been associated with ictogenesis. We analyzed a total of 459 single neurons and used the mean autocorrelation time as a quantitative measure of burstiness. To unravel the intricate roles of excitation and inhibition, we also examined differential contributions from putative principal cells and interneurons. RESULTS: During interictal recordings, burstiness was significantly higher in the seizure onset hemisphere, an effect found only for principal cells, but not for interneurons, and which disappeared before seizures. CONCLUSION: These findings deviate from conventional views of ictogenesis that propose slowly-increasing aggregates of bursting neurons which give rise to seizures once they reach a critical mass. SIGNIFICANCE: Instead our results are in line with recent hypotheses that bursting may represent a protective mechanism by preventing direct transmission of postsynaptic high-frequency oscillations.

Neurons in the human amygdala encode face identity, but not gaze direction.

The amygdala is important for face processing, and direction of eye gaze is one of the most socially salient facial signals. Recording from over 200 neurons in the amygdala of neurosurgical patients, we found robust encoding of the identity of neutral-expression faces, but not of their direction of gaze. Processing of gaze direction may rely on a predominantly cortical network rather than the amygdala.