Correction: Spatiotemporal network coding of physiological mossy fiber inputs by the cerebellar granular layer.

[This corrects the article DOI: 10.1371/journal.pcbi.1005754.].

Spatiotemporal network coding of physiological mossy fiber inputs by the cerebellar granular layer.

The granular layer, which mainly consists of granule and Golgi cells, is the first stage of the cerebellar cortex and processes spatiotemporal information transmitted by mossy fiber inputs with a wide variety of firing patterns. To study its dynamics at multiple time scales in response to inputs approximating real spatiotemporal patterns, we constructed a large-scale 3D network model of the granular layer. Patterned mossy fiber activity induces rhythmic Golgi cell activity that is synchronized by shared parallel fiber input and by gap junctions. This leads to long distance synchrony of Golgi cells along the transverse axis, powerfully regulating granule cell firing by imposing inhibition during a specific time window. The essential network mechanisms, including tunable Golgi cell oscillations, on-beam inhibition and NMDA receptors causing first winner keeps winning of granule cells, illustrate how fundamental properties of the granule layer operate in tandem to produce (1) well timed and spatially bound output, (2) a wide dynamic range of granule cell firing and (3) transient and coherent gating oscillations. These results substantially enrich our understanding of granule cell layer processing, which seems to promote spatial group selection of granule cell activity as a function of timing of mossy fiber input.

Cerebellar Nuclear Neurons Use Time and Rate Coding to Transmit Purkinje Neuron Pauses.

Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it.

Are GABAergic drugs beneficial in providing neuroprotection after traumatic brain injuries? A comprehensive literature review of preclinical studies.

Traumatic brain injuries (TBI) caused by physical impact to the brain can adversely impact the welfare and well-being of the affected individuals. One of the leading causes of mortality and dysfunction in the world, TBI is a major public health problem facing the human community. Drugs that target GABAergic neurotransmission are commonly used for sedation in clinical TBI yet their potential to cause neuroprotection is unclear. In this paper, I have performed a rigorous literature review of the neuroprotective effects of drugs that increase GABAergic currents based on the results reported in preclinical literature. The drugs covered in this review include the following: propofol, benzodiazepines, barbiturates, isoflurane, and other drugs that are agonists of GABAA receptors. A careful review of numerous preclinical studies reveals that these drugs fail to produce any neuroprotection after a primary impact to the brain. In numerous circumstances, they could be detrimental to neuroprotection by increasing the size of the contusional brain tissue and by severely interfering with behavioral and functional recovery. Therefore, anesthetic agents that work by enhancing the effect of neurotransmitter GABA should be administered with caution of TBI patients until a clear and concrete picture of their neuroprotective efficacy emerges in the clinical literature.

Prevalence of comorbidities post mild traumatic brain injuries: a traumatic brain injury model systems study.

Traumatic brain injury (TBI) is associated with an increased risk of long-lasting health-related complications. Survivors of brain trauma often experience comorbidities which could further dampen functional recovery and severely interfere with their day-to-day functioning after injury. Of the three TBI severity types, mild TBI constitutes a significant proportion of total TBI cases, yet a comprehensive study on medical and psychiatric complications experienced by mild TBI subjects at a particular time point is missing in the field. In this study, we aim to quantify the prevalence of psychiatric and medical comorbidities post mild TBI and understand how these comorbidities are influenced by demographic factors (age, and sex) through secondary analysis of patient data from the TBI Model Systems (TBIMS) national database. Utilizing self-reported information from National Health and Nutrition Examination Survey (NHANES), we have performed this analysis on subjects who received inpatient rehabilitation at 5 years post mild TBI. Our analysis revealed that psychiatric comorbidities (anxiety, depression, and post-traumatic stress disorder (PTSD)), chronic pain, and cardiovascular comorbidities were common among survivors with mild TBI. Furthermore, depression exhibits an increased prevalence in the younger compared to an older cohort of subjects whereas the prevalence of rheumatologic, ophthalmological, and cardiovascular comorbidities was higher in the older cohort. Lastly, female survivors of mild TBI demonstrated increased odds of developing PTSD compared to male subjects. The findings of this study would motivate additional analysis and research in the field and could have broader implications for the management of comorbidities after mild TBI.

Thalamus and claustrum control parallel layer 1 circuits in retrosplenial cortex.

The granular retrosplenial cortex (RSG) is critical for both spatial and non-spatial behaviors, but the underlying neural codes remain poorly understood. Here, we use optogenetic circuit mapping in mice to reveal a double dissociation that allows parallel circuits in superficial RSG to process disparate inputs. The anterior thalamus and dorsal subiculum, sources of spatial information, strongly and selectively recruit small low-rheobase (LR) pyramidal cells in RSG. In contrast, neighboring regular-spiking (RS) cells are preferentially controlled by claustral and anterior cingulate inputs, sources of mostly non-spatial information. Precise sublaminar axonal and dendritic arborization within RSG layer 1, in particular, permits this parallel processing. Observed thalamocortical synaptic dynamics enable computational models of LR neurons to compute the speed of head rotation, despite receiving head direction inputs that do not explicitly encode speed. Thus, parallel input streams identify a distinct principal neuronal subtype ideally positioned to support spatial orientation computations in the RSG.

Sitting in your car, about to drive home after a long day at work, you realize you have no idea which way to go: you recognize where you are right now, and you remember the name of the street your house is on, but you cannot figure out how to get there. This spatial disorientation happens to people with damage to a brain region called the retrosplenial cortex, whose role and inner workings remain poorly understood. Recent evidence has shown that this area contains 'low-rheobase' neurons which are not seen anywhere else in the brain, but what do these neurons do? Brennan, Jedrasiak-Cape, Kailasa et al. decided to explore the role of these neurons, focusing on the brain regions they are connected to. Experiments were conducted in mice using optogenetics, a technique that activates neurons using pulses of light. This revealed that brain areas involved in processing information about direction and position preferentially communicate with low-rheobase neurons rather than with nearby, more standard neurons in the retrosplenial cortex. The way these spatial signals are sent to the low-rheobase neurons allows these cells to 'calculate' how fast a mouse is turning its head using only information about which direction the mouse is facing. Essentially, this neuron can turn directional compass-like signals into a gyroscope signal that can track both direction and speed of head movement. These unique neurons may therefore be ideally suited to combine information about direction and space, suggesting that they may have evolved specifically to support spatial navigation. Individuals with Alzheimer's disease show exactly the same type of spatial disorientation as individuals with direct damage to the retrosplenial cortex. This region is also one of the first to show altered activity in Alzheimer's disease. Exploring whether these unique retrosplenial neurons and their communication patterns are altered in Alzheimer's disease models could help to understand and potentially treat this debilitating condition.

Hyperexcitable Neurons Enable Precise and Persistent Information Encoding in the Superficial Retrosplenial Cortex.

The retrosplenial cortex (RSC) is essential for memory and navigation, but the neural codes underlying these functions remain largely unknown. Here, we show that the most prominent cell type in layers 2/3 (L2/3) of the mouse granular RSC is a hyperexcitable, small pyramidal cell. These cells have a low rheobase (LR), high input resistance, lack of spike frequency adaptation, and spike widths intermediate to those of neighboring fast-spiking (FS) inhibitory neurons and regular-spiking (RS) excitatory neurons. LR cells are excitatory but rarely synapse onto neighboring neurons. Instead, L2/3 is a feedforward, not feedback, inhibition-dominated network with dense connectivity between FS cells and from FS to LR neurons. Biophysical models of LR but not RS cells precisely and continuously encode sustained input from afferent postsubicular head-direction cells. Thus, the distinct intrinsic properties of LR neurons can support both the precision and persistence necessary to encode information over multiple timescales in the RSC.

More Is More: Potential Benefits of Characterizing High-Frequency Activity Over Long Durations.

[Box: see text].

High-Frequency Activity During Stereotyped Low-Frequency Events Might Help to Identify the Seizure Onset Zone.

Stereotyped high-frequency oscillations discriminate seizure onset zones and critical functional cortex in focal epilepsy. Liu S, Gurses C, Sha Z, Quach MM, Sencer A, Bebek N, et al. Brain. 2018;141(3):713-730. doi:10.1093/brain/awx374. PMID: 29394328 . High-frequency oscillations in local field potentials recorded with intracranial electroencephalogram are putative biomarkers of seizure-onset zones in epileptic brain. However, localized 80- to 500-Hz oscillations can also be recorded from normal and nonepileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones that limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 patients with epilepsy and 5 control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent of the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step toward the translation of these signature events into valid clinical biomarkers.

Biophysical Modeling Suggests Optimal Drug Combinations for Improving the Efficacy of GABA Agonists after Traumatic Brain Injuries.

Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss caused by secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. These drugs not only fail to offer neuroprotection, but can also slow down functional recovery after TBI. Here, using computational modeling, we provide a biophysical hypothesis to explain these observations. We show that the accumulation of intracellular chloride ions caused by a transient upregulation of Na+-K+-2Cl- (NKCC1) co-transporters as observed following TBI, causes GABA receptor agonists to lead to excitation and depolarization block, rather than the expected hyperpolarization. The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method for identifying drug combinations for neuroprotection after TBI.

Quantitative simulation of extracellular single unit recording from the surface of cortex.

OBJECTIVE: Neural recording is important for a wide variety of clinical applications. Until recently, recording from the surface of the brain, even when using micro-electrocorticography (µECoG) arrays, was not thought to enable recording from individual neurons. Recent results suggest that when the surface electrode contact size is sufficiently small, it may be possible to record single neurons from the brain's surface. In this study, we use computational techniques to investigate the ability of surface electrodes to record the activity of single neurons. APPROACH: The computational model included the rat head, µECoG electrode, two existing multi-compartmental neuron models, and a novel multi-compartmental neuron model derived from patch clamp experiments in layer 1 of the cortex. MAIN RESULTS: Using these models, we reproduced single neuron recordings from µECoG arrays, and elucidated their possible source. The model resembles the experimental data when spikes originate from layer 1 neurons that are less than 60 µm from the cortical surface. We further used the model to explore the design space for surface electrodes. Although this model does not include biological or thermal noise, the results indicate the electrode contact area should be 100 µm2 or smaller to maintain a detectable waveform amplitude. Furthermore, the model shows the width of lateral insulation could be reduced, which may reduce scar formation, while retaining 95% of signal amplitude. SIGNIFICANCE: Overall, the model suggests single-unit surface recording is limited to neurons in layer 1 and further improvement in electrode design is needed.