What and Where: Location-Dependent Feature Sensitivity as a Canonical Organizing Principle of the Visual System.

Traditionally, functional representations in early visual areas are conceived as retinotopic maps preserving ego-centric spatial location information while ensuring that other stimulus features are uniformly represented for all locations in space. Recent results challenge this framework of relatively independent encoding of location and features in the early visual system, emphasizing location-dependent feature sensitivities that reflect specialization of cortical circuits for different locations in visual space. Here we review the evidence for such location-specific encoding including: (1) systematic variation of functional properties within conventional retinotopic maps in the cortex; (2) novel periodic retinotopic transforms that dramatically illustrate the tight linkage of feature sensitivity, spatial location, and cortical circuitry; and (3) retinotopic biases in cortical areas, and groups of areas, that have been defined by their functional specializations. We propose that location-dependent feature sensitivity is a fundamental organizing principle of the visual system that achieves efficient representation of positional regularities in visual experience, and reflects the evolutionary selection of sensory and motor circuits to optimally represent behaviorally relevant information. Future studies are necessary to discover mechanisms underlying joint encoding of location and functional information, how this relates to behavior, emerges during development, and varies across species.

DeBruyn and Casagrande manuscripts on tree shrew retinal ganglion cells as a basis for cross-species retina research.

The purpose of this brief communication is to make publicly available three unpublished manuscripts on the organization of retinal ganglion cells in the tree shrew. The manuscripts were authored in 1986 by Dr. Edward DeBruyn, a PhD student in the laboratory of the late Dr. Vivien Casagrande at Vanderbilt University. As diurnal animals closely related to primates, tree shrews are ideally suited for comparative analyses of visual structures including the retina. We hope that providing this basic information in a citable form inspires other groups to pursue further characterization of the tree shrew retina using modern techniques.

A sinusoidal transformation of the visual field is the basis for periodic maps in area V2.

Retinotopic maps of many visual areas are thought to follow the fundamental principles described for the primary visual cortex (V1), where nearby points on the retina map to nearby points on the surface of V1, and orthogonal axes of the retinal surface are represented along orthogonal axes of the cortical surface. Here we demonstrate a striking departure from this mapping in the secondary visual area (V2) of the tree shrew best described as a sinusoidal transformation of the visual field. This sinusoidal topography is ideal for achieving uniform coverage in an elongated area like V2, as predicted by mathematical models designed for wiring minimization, and provides a novel explanation for periodic banded patterns of intra-cortical connections and functional response properties in V2 of tree shrews as well as several other species. Our findings suggest that cortical circuits flexibly implement solutions to sensory surface representation, with dramatic consequences for large-scale cortical organization.

A bright future for the tree shrew in neuroscience research: Summary from the inaugural Tree Shrew Users Meeting.

Tree shrews (Tupaia spp.) have been used in neuroscience research since the 1960s due to their evolutionary proximity to primates. The use and interest in this animal model have recently increased, in part due to the adaptation of modern neuroscience tools in this species. These tools include quantitative behavioral assays, calcium imaging, optogenetics and transgenics. To facilitate the exchange and development of these new technologies and associated research findings, we organized the inaugural "Tree Shrew Users Meeting" which was held online due to the COVID-19 pandemic. Here, we review this meeting and discuss the history of tree shrews as an animal model in neuroscience research and summarize the current themes being investigated using this animal, as well as future directions.

Thalamocortical synapses in the cat visual system in vivo are weak and unreliable.

The thalamocortical synapse of the visual system has been central to our understanding of sensory computations in the cortex. Although we have a fair understanding of the functional properties of the pre and post-synaptic populations, little is known about their synaptic properties, particularly in vivo. We used simultaneous recordings in LGN and V1 in cat in vivo to characterize the dynamic properties of thalamocortical synaptic transmission in monosynaptically connected LGN-V1 neurons. We found that thalamocortical synapses in vivo are unreliable, highly variable and exhibit short-term plasticity. Using biologically constrained models, we found that variable and unreliable synapses serve to increase cortical firing by means of increasing membrane fluctuations, similar to high conductance states. Thus, synaptic variability and unreliability, rather than acting as system noise, do serve a computational function. Our characterization of LGN-V1 synaptic properties constrains existing mathematical models, and mechanistic hypotheses, of a fundamental circuit in computational neuroscience.

Spatiotemporal evolution of focal epileptiform activity from surface and laminar field recordings in cat neocortex.

New devices that use targeted electrical stimulation to treat refractory localization-related epilepsy have shown great promise, although it is not well known which targets most effectively prevent the initiation and spread of seizures. To better understand how the brain transitions from healthy to seizing on a local scale, we induced focal epileptiform activity in the visual cortex of five anesthetized cats with local application of the GABAA blocker picrotoxin while simultaneously recording local field potentials on a high-resolution electrocorticography array and laminar depth probes. Epileptiform activity appeared in the form of isolated events, revealing a consistent temporal pattern of ictogenesis across animals with interictal events consistently preceding the appearance of seizures. Based on the number of spikes per event, there was a natural separation between seizures and shorter interictal events. Two distinct spatial regions were seen: an epileptic focus that grew in size as activity progressed, and an inhibitory surround that exhibited a distinct relationship with the focus both on the surface and in the depth of the cortex. Epileptiform activity in the cortical laminae was seen concomitant with activity on the surface. Focus spikes appeared earlier on electrodes deeper in the cortex, suggesting that deep cortical layers may be integral to recruiting healthy tissue into the epileptic network and could be a promising target for interventional devices. Our study may inform more effective therapies to prevent seizure generation and spread in localization-related epilepsies. NEW & NOTEWORTHY We induced local epileptiform activity and recorded continuous, high-resolution local field potentials from the surface and depth of the visual cortex in anesthetized cats. Our results reveal a consistent pattern of ictogenesis, characterize the spatial spread of the epileptic focus and its relationship with the inhibitory surround, and show that focus activity within events appears earliest in deeper cortical layers. These findings have potential implications for the monitoring and treatment of refractory epilepsy.

Inhibition in Simple Cell Receptive Fields Is Broad and OFF-Subregion Biased.

Inhibition in thalamorecipient layer 4 simple cells of primary visual cortex is believed to play important roles in establishing visual response properties and integrating visual inputs across their receptive fields (RFs). Simple cell RFs are characterized by nonoverlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the firing rate of the cell, depending on contrast. Inhibition is believed to be triggered exclusively from visual stimulation of individual RF subregions. However, this view is at odds with the known anatomy of layer 4 interneurons in visual cortex and differs from recent findings in mouse visual cortex. Here we show with in vivo intracellular recordings in cats that while excitation is restricted to RF subregions, inhibition spans the width of simple cell RFs. Consequently, excitatory stimuli within a subregion concomitantly drive excitation and inhibition. Furthermore, we found that the distribution of inhibition across the RF is stronger toward OFF subregions. This inhibitory OFF-subregion bias has a functional consequence on spatial integration of inputs across the RF. A model based on the known anatomy of layer 4 demonstrates that the known proportion and connectivity of inhibitory neurons in layer 4 of primary visual cortex is sufficient to explain broad inhibition with an OFF-subregion bias while generating a variety of phase relations, including antiphase, between excitation and inhibition in response to drifting gratings.SIGNIFICANCE STATEMENT The wiring of excitatory and inhibitory neurons in cortical circuits is key to determining the response properties in sensory cortex. In the visual cortex, the first cells that receive visual input are simple cells in layer 4. The underlying circuitry responsible for the response properties of simple cells is not yet known. In this study, we challenge a long-held view concerning the pattern of inhibitory input and provide results that agree with current known anatomy. We show here that inhibition is evoked broadly across the receptive fields of simple cells, and we identify a surprising bias in inhibition within the receptive field. Our findings represent a step toward a unified view of inhibition across different species and sensory systems.

Intracellular, In Vivo, Dynamics of Thalamocortical Synapses in Visual Cortex.

Seminal studies of the thalamocortical circuit in the visual system of the cat have been central to our understanding of sensory encoding. However, thalamocortical synaptic properties remain poorly understood. We used paired recordings, in the lateral geniculate nucleus (LGN) and primary visual cortex (V1), to provide the first in vivo characterization of sensory-driven thalamocortical potentials in V1. The amplitudes of EPSPs we characterized were smaller than those previously reported in vitro Consistent with prior findings, connected LGN-V1 pairs were only found when their receptive fields (RFs) overlapped, and the probability of connection increased steeply with degree of RF overlap and response similarity. However, surprisingly, we found no relationship between EPSP amplitudes and the similarity of RFs or responses, suggesting different connectivity models for intracortical and thalamocortical circuits. Putative excitatory regular-spiking (RS) and inhibitory fast-spiking (FS) V1 cells had similar EPSP characteristics, showing that in the visual system, feedforward excitation and inhibition are driven with equal strength by the thalamus. Similar to observations in the somatosensory cortex, FS V1 cells received less specific input from LGN. Finally, orientation tuning in V1 was not inherited from single presynaptic LGN cells, suggesting that it must emerge exclusively from the combined input of all presynaptic LGN cells. Our results help to decipher early visual encoding circuits and have immediate utility in providing physiological constraints to computational models of the visual system.SIGNIFICANCE STATEMENT To understand how the brain encodes the visual environment, we must understand the transfer of visual signals between various regions of the brain. Therefore, understanding synaptic dynamics is critical to our understanding of sensory encoding. This study provides the first characterization of visually evoked synaptic potentials between the visual thalamus and visual cortex in an intact animal. To record these potentials, we simultaneously recorded the extracellular potential of presynaptic thalamic cells and the intracellular potential of postsynaptic cortical cells in input layers of primary visual cortex. Our characterization of synaptic potentials in vivo disagreed with prior findings in vitro This study will increase our understanding of thalamocortical circuits and will improve computational models of visual encoding.

Seizures and brain regulatory systems: consciousness, sleep, and autonomic systems.

Research into the physiologic underpinnings of epilepsy has revealed reciprocal relationships between seizures and the activity of several regulatory systems in the brain. This review highlights recent progress in understanding and using the relationships between seizures and the arousal or consciousness system, the sleep-wake and associated circadian system, and the central autonomic network.

α2-Adrenergic stimulation of the ventrolateral preoptic nucleus destabilizes the anesthetic state.

The sleep-promoting ventrolateral preoptic nucleus (VLPO) shares reciprocal inhibitory inputs with wake-active neuronal nuclei, including the locus ceruleus. Electrophysiologically, sleep-promoting neurons in the VLPO are directly depolarized by the general anesthetic isoflurane and hyperpolarized by norepinephrine, a wake-promoting neurotransmitter. However, the integration of these competing influences on the VLPO, a sleep- and anesthetic-active structure, has yet to be evaluated in either brain slices in vitro or the intact organism. Single-cell multiplex RT-PCR conducted on both isoflurane-activated, putative sleep-promoting VLPO neurons and neighboring, state-indifferent VLPO neurons in mouse brain slices revealed widespread expression of α2A-, α2B- and α2C-adrenergic receptors in both populations. Indeed, both norepinephrine and the highly selective α2 agonist dexmedetomidine each reversed the VLPO depolarization induced by isoflurane in slices in vitro. When microinjected directly into the VLPO of a mouse lightly anesthetized with isoflurane, dexmedetomidine increased behavioral arousal and reduced the depressant effects of isoflurane on barrel cortex somatosensory-evoked potentials but failed to elicit spectral changes in spontaneous EEG. Based on these observations, we conclude that local modulation of α-adrenergic activity in the VLPO destabilizes, but does not fully antagonize, the anesthetic state, thus priming the brain for anesthetic emergence.

Rapid eye movement sleep and hippocampal theta oscillations precede seizure onset in the tetanus toxin model of temporal lobe epilepsy.

Improved understanding of the interaction between state of vigilance (SOV) and seizure onset has therapeutic potential. Six rats received injections of tetanus toxin (TeTX) in the ventral hippocampus that resulted in chronic spontaneous seizures. The distribution of SOV before 486 seizures was analyzed for a total of 19 d of recording. Rapid eye movement sleep (REM) and exploratory wake, both of which express prominent hippocampal theta rhythm, preceded 47 and 34%, for a total of 81%, of all seizures. Nonrapid eye movement sleep (NREM) and nonexploratory wake, neither of which expresses prominent theta, preceded 6.8 and 13% of seizures. We demonstrate that identification of SOV yields significant differentiation of seizure susceptibilities, with the instantaneous seizure rate during REM nearly 10 times higher than baseline and the rate for NREM less than half of baseline. Survival analysis indicated a shorter duration of preseizure REM bouts, with a maximum transition to seizure at ∼90 s after the onset of REM. This study provides the first analysis of a correlation between SOV and seizure onset in the TeTX model of temporal lobe epilepsy, as well as the first demonstration that hippocampal theta rhythms associated with natural behavioral states can serve a seizure-promoting role. Our findings are in contrast with previous studies suggesting that the correlations between SOV and seizures are primarily governed by circadian oscillations and the notion that hippocampal theta rhythms inhibit seizures. The documentation of significant SOV-dependent seizure susceptibilities indicates the potential utility of SOV and its time course in seizure prediction and control.

Reconstructing mammalian sleep dynamics with data assimilation.

Data assimilation is a valuable tool in the study of any complex system, where measurements are incomplete, uncertain, or both. It enables the user to take advantage of all available information including experimental measurements and short-term model forecasts of a system. Although data assimilation has been used to study other biological systems, the study of the sleep-wake regulatory network has yet to benefit from this toolset. We present a data assimilation framework based on the unscented Kalman filter (UKF) for combining sparse measurements together with a relatively high-dimensional nonlinear computational model to estimate the state of a model of the sleep-wake regulatory system. We demonstrate with simulation studies that a few noisy variables can be used to accurately reconstruct the remaining hidden variables. We introduce a metric for ranking relative partial observability of computational models, within the UKF framework, that allows us to choose the optimal variables for measurement and also provides a methodology for optimizing framework parameters such as UKF covariance inflation. In addition, we demonstrate a parameter estimation method that allows us to track non-stationary model parameters and accommodate slow dynamics not included in the UKF filter model. Finally, we show that we can even use observed discretized sleep-state, which is not one of the model variables, to reconstruct model state and estimate unknown parameters. Sleep is implicated in many neurological disorders from epilepsy to schizophrenia, but simultaneous observation of the many brain components that regulate this behavior is difficult. We anticipate that this data assimilation framework will enable better understanding of the detailed interactions governing sleep and wake behavior and provide for better, more targeted, therapies.

Data assimilation of glucose dynamics for use in the intensive care unit.

We know much about the glucose regulatory system, yet the application of this knowledge is limited because simultaneous measurements of insulin and glucose are difficult to obtain. We present a data assimilation framework for combining sparse measurements of the glucose regulatory system, available in the intensive care unit setting, with a nonlinear computational model to estimate unmeasured variables and unknown parameters. We also demonstrate a method for choosing the best variables for measurement. We anticipate that this framework will improve glucose maintenance therapies and shed light on the underlying biophysical process.

Analyzing large data sets acquired through telemetry from rats exposed to organophosphorous compounds: an EEG study.

The organophosphorous compound soman is an acetylcholinesterase inhibitor that causes damage to the brain. Exposure to soman causes neuropathology as a result of prolonged and recurrent seizures. In the present study, long-term recordings of cortical EEG were used to develop an unbiased means to quantify measures of seizure activity in a large data set while excluding other signal types. Rats were implanted with telemetry transmitters and exposed to soman followed by treatment with therapeutics similar to those administered in the field after nerve agent exposure. EEG, activity and temperature were recorded continuously for a minimum of 2 days pre-exposure and 15 days post-exposure. A set of automatic MATLAB algorithms have been developed to remove artifacts and measure the characteristics of long-term EEG recordings. The algorithms use short-time Fourier transforms to compute the power spectrum of the signal for 2-s intervals. The spectrum is then divided into the delta, theta, alpha, and beta frequency bands. A linear fit to the power spectrum is used to distinguish normal EEG activity from artifacts and high amplitude spike wave activity. Changes in time spent in seizure over a prolonged period are a powerful indicator of the effects of novel therapeutics against seizures. A graphical user interface has been created that simultaneously plots the raw EEG in the time domain, the power spectrum, and the wavelet transform. Motor activity and temperature are associated with EEG changes. The accuracy of this algorithm is also verified against visual inspection of video recordings up to 3 days after exposure.