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Background: Intracortical microstimulation (ICMS) is used to map neuronal circuitry in the brain and restore lost sensory function, including vision, hearing, and somatosensation. The temporal response of cortical neurons to single pulse ICMS is remarkably stereotyped and comprises short latency excitation followed by prolonged inhibition and, in some cases, rebound excitation. However, the neural origin of the different response components to ICMS are poorly understood, and the interactions between the three response components during trains of ICMS pulses remains unclear. Objective: We used computational modeling to determine the mechanisms contributing to the temporal response to ICMS in model cortical neurons. Methods: We implemented a biophysically based computational model of a cortical column comprising neurons with realistic morphology and synapses and quantified the temporal response of cortical neurons to different ICMS protocols. We characterized the temporal responses to single pulse ICMS across stimulation intensities and inhibitory (GABA-B/GABA-A) synaptic strengths. To probe interactions between response components, we quantified the response to paired pulse ICMS at different inter-pulse intervals and the response to short trains at different stimulation frequencies. Finally, we evaluated the performance of biomimetic ICMS trains in evoking sustained neural responses. Results: Single pulse ICMS evoked short latency excitation followed by a period of inhibition, but model neurons did not exhibit post-inhibitory excitation. The strength of short latency excitation increased and the duration of inhibition increased with increased stimulation amplitude. Prolonged inhibition resulted from both after-hyperpolarization currents and GABA-B synaptic transmission. During the paired pulse protocol, the strength of short latency excitation evoked by a test pulse decreased marginally compared to those evoked by a single pulse for interpulse intervals (IPI) 50 m s, the duration of inhibition evoked by the test pulse was comparable to those evoked by a single pulse. Short ICMS trains evoked repetitive excitatory responses against a background of inhibition. However, the strength of the repetitive excitatory response declined during ICMS at higher frequencies. Further, the duration of inhibition at the cessation of ICMS at higher frequencies was prolonged compared to the duration following a single pulse. Biomimetic pulse trains evoked comparable neural response between the onset and offset phases despite the presence of stimulation induced inhibition. Conclusions: The cortical column model replicated the short latency excitation and long-lasting inhibitory components of the stereotyped neural response documented in experimental studies of ICMS. Both cellular and synaptic mechanisms influenced the response components generated by ICMS. The non-linear interactions between response components resulted in dynamic ICMS-evoked neural activity and may play an important role in mediating the ICMS-induced precepts.

Intracortical microstimulation (ICMS) is used to map neuronal circuitry in the brain and restore lost sensory function, including vision, hearing, and somatosensation. The temporal response of cortical neurons to single pulse ICMS is remarkably stereotyped and comprises short latency excitation followed by prolonged inhibition and, in some cases, rebound excitation. However, the neural origin of the different response components to ICMS are poorly understood, and the interactions between the three response components during trains of ICMS pulses remains unclear. We used computational modeling to determine the mechanisms contributing to the temporal response to ICMS in model cortical neurons. We implemented a biophysically based computational model of a cortical column comprising neurons with realistic morphology and synapses and quantified the temporal response of cortical neurons to different ICMS protocols. We characterized the temporal responses to single pulse ICMS across stimulation intensities and inhibitory (GABA-B/GABA-A) synaptic strengths. To probe interactions between response components, we quantified the response to paired pulse ICMS at different inter-pulse intervals and the response to short trains at different stimulation frequencies. Finally, we evaluated the performance of biomimetic ICMS trains in evoking sustained neural responses. Single pulse ICMS evoked short latency excitation followed by a period of inhibition, but model neurons did not exhibit post-inhibitory excitation. The strength of short latency excitation increased and the duration of inhibition increased with increased stimulation amplitude. Prolonged inhibition resulted from both after-hyperpolarization currents and GABA-B synaptic transmission. During the paired pulse protocol, the strength of short latency excitation evoked by a test pulse decreased marginally compared to those evoked by a single pulse for interpulse intervals (IPI) < 100 m s. Further, the duration of inhibition evoked by the test pulse was prolonged compared to single pulse for IPIs <50 m s and was not predicted by linear superposition of individual inhibitory responses. For IPIs>50 m s, the duration of inhibition evoked by the test pulse was comparable to those evoked by a single pulse. Short ICMS trains evoked repetitive excitatory responses against a background of inhibition. However, the strength of the repetitive excitatory response declined during ICMS at higher frequencies. Further, the duration of inhibition at the cessation of ICMS at higher frequencies was prolonged compared to the duration following a single pulse. Biomimetic pulse trains evoked comparable neural response between the onset and offset phases despite the presence of stimulation induced inhibition. The cortical column model replicated the short latency excitation and long-lasting inhibitory components of the stereotyped neural response documented in experimental studies of ICMS. Both cellular and synaptic mechanisms influenced the response components generated by ICMS. The non-linear interactions between response components resulted in dynamic ICMS-evoked neural activity and may play an important role in mediating the ICMS-induced precepts. • Implemented a biophysical model of the cortical column to study the temporal response of neurons to ICMS. • Neural response comprised short latency excitation followed by a prolonged inhibition but did not include rebound excitation. • Excitation was mediated by both antidromic and synaptic mechanisms and inhibition by both cellular and GABAergic mechanisms. • The temporal dynamics of the response to ICMS should be considered when designing paradigms for sensory prostheses. [ABSTRACT FROM AUTHOR]

Tissue engineering is a powerful tool with which to systematically identify the determinants of biological functions. Applied to the design and fabrication of biomimetic brains, tissue engineering serves to disentangle the complex anatomy of neural circuits and pathways by recapitulating structure-function relationships in simplified model systems. The complex neuroanatomy of the cerebral cortex, with its enigmatic columnar and stratified cytoarchitectonic organization, represents a major challenge toward isolating the minimal set of elements that are required to assemble neural tissues with cognitive functions. Whereas considerable efforts have highlighted important genetic and physical correlates of early cortical tissue patterning, no substantive attempt to identify the determinants of how the cortices acquire their relatively conserved, narrow range of numbered layers is evident in the literature. Similarly, it is not yet clear whether cortical columns and laminae are functionally relevant or epiphenomena of embryonic neurodevelopment. Here, we demonstrate that spatial frequencies (m−1) derived from the width-to-height ratios of cerebral cortical columns predict sinusoids with a narrow range of spatial cycles over the average cortical thickness. The resulting periodicities, denoted by theoretical wavenumbers, reflect the number of observed cortical layers among humans and across several other species as revealed by a comparative anatomy approach. We present a hypothesis that cortical columns and their periodic layers are emergent of the intrinsic spatial dimensions of neurons and their nested, self-similar aggregate structures including minicolumns. Finally, we discuss the implications of periodic tissue patterns in the context of neural tissue engineering.

Introduction: The visual cortex is a key region in the mouse brain, responsible for processing visual information. Comprised of six distinct layers, each with unique neuronal types and connections, the visual cortex exhibits diverse decoding properties across its layers. This study aimed to investigate the relationship between visual stimulus decoding properties and the cortical layers of the visual cortex while considering howthis relationship varies across different decoders and brain regions. Methods: This study reached the above conclusions by analyzing two publicly available datasets obtained through two-photon microscopy of visual cortex neuronal responses. Various types of decoders were tested for visual cortex decoding. Results: Our findings indicate that the decoding accuracy of neuronal populations with consistent sizes varies among visual cortical layers for visual stimuli such as drift gratings and natural images. In particular, layer 4 neurons in VISp exhibited significantly higher decoding accuracy for visual stimulus identity compared to other layers. However, in VISm, the decoding accuracy of neuronal populations with the same size in layer 2/3 was higher than that in layer 4, despite the overall accuracy being lower than that in VISp and VISl. Furthermore, SVM surpassed other decoders in terms of accuracy, with the variation in decoding performance across layers being consistent among decoders. Additionally, we found that the difference in decoding accuracy across different imaging depths was not associated with the mean orientation selectivity index (OSI) and the mean direction selectivity index (DSI) neurons, but showed a significant positive correlation with the mean reliability and mean signal-to-noise ratio (SNR) of each layer's neuron population. Discussion: These findings lend new insights into the decoding properties of the visual cortex, highlighting the role of different cortical layers and decoders in determining decoding accuracy. The correlations identified between decoding accuracy and factors such as reliability and SNR pave the way for more nuanced understandings of visual cortex functioning. [ABSTRACT FROM AUTHOR]

Tissue engineering is a powerful tool with which to systematically identify the determinants of biological functions. Applied to the design and fabrication of biomimetic brains, tissue engineering serves to disentangle the complex anatomy of neural circuits and pathways by recapitulating structure-function relationships in simplified model systems. The complex neuroanatomy of the cerebral cortex, with its enigmatic columnar and stratified cytoarchitectonic organization, represents a major challenge toward isolating the minimal set of elements that are required to assemble neural tissues with cognitive functions. Whereas considerable efforts have highlighted important genetic and physical correlates of early cortical tissue patterning, no substantive attempt to identify the determinants of how the cortices acquire their relatively conserved, narrow range of numbered layers is evident in the literature. Similarly, it is not yet clear whether cortical columns and laminae are functionally relevant or epiphenomena of embryonic neurodevelopment. Here, we demonstrate that spatial frequencies (m−1) derived from the width-to-height ratios of cerebral cortical columns predict sinusoids with a narrow range of spatial cycles over the average cortical thickness. The resulting periodicities, denoted by theoretical wavenumbers, reflect the number of observed cortical layers among humans and across several other species as revealed by a comparative anatomy approach. We present a hypothesis that cortical columns and their periodic layers are emergent of the intrinsic spatial dimensions of neurons and their nested, self-similar aggregate structures including minicolumns. Finally, we discuss the implications of periodic tissue patterns in the context of neural tissue engineering. [ABSTRACT FROM AUTHOR]

Recent work in the philosophy of scientific concepts has seen the simultaneous revival of operationalism and development of patchwork approaches to scientific concepts. We argue that these two approaches are natural allies. Both recognize an important role for measurement techniques in giving meaning to scientific terms. The association of multiple techniques with a single term, however, raises the threat of proliferating concepts (Hempel, 1966). While contemporary operationalists have developed some resources to address this challenge, these resources are inadequate to account for the full range of complex behaviors of scientific concepts. We adopt show how the patchwork approach’s repertoire of inter-patch relations can expand the resources available to the operationalist. We focus on one especially important type of inter-patch relation: sharing a general reasoning strategy. General reasoning strategies serve two important functions: (1) they bind together distinct patches of scientific concepts, and (2) they provide normative guidance for extending concepts to new domains. [ABSTRACT FROM AUTHOR]

Network features found in the brain may help implement more efficient and robust neural networks. Spiking neural networks (SNNs) process spikes in the spatiotemporal domain and can offer better energy efficiency than deep neural networks. However, most SNN implementations rely on simple point neurons that neglect the rich neuronal and dendritic dynamics. Herein, a bio‐inspired columnar learning network (CLN) structure that employs feedforward, lateral, and feedback connections to make robust classification with sparse data is proposed. CLN is inspired by the mammalian neocortex, comprising cortical columns each containing multiple minicolumns formed by interacting pyramidal neurons. A column continuously processes spatiotemporal signals from its sensor, while learning spatial and temporal correlations between features in different regions of an object along with the sensor's movement through sensorimotor interaction. CLN can be implemented using memristor crossbars with a local learning rule, spiking timing‐dependent plasticity (STDP), which can be natively obtained in second‐order memristors. CLN allows inputs from multiple sensors to be simultaneously processed by different columns, resulting in higher classification accuracy and better noise tolerance. Analysis of networks implemented on memristor crossbars shows that the system can operate at very low power and high throughput, with high accuracy and robustness to noise. [ABSTRACT FROM AUTHOR]

Network features found in the brain may help implement more efficient and robust neural networks. Spiking neural networks (SNNs) process spikes in the spatiotemporal domain and can offer better energy efficiency than deep neural networks. However, most SNN implementations rely on simple point neurons that neglect the rich neuronal and dendritic dynamics. Herein, a bio‐inspired columnar learning network (CLN) structure that employs feedforward, lateral, and feedback connections to make robust classification with sparse data is proposed. CLN is inspired by the mammalian neocortex, comprising cortical columns each containing multiple minicolumns formed by interacting pyramidal neurons. A column continuously processes spatiotemporal signals from its sensor, while learning spatial and temporal correlations between features in different regions of an object along with the sensor's movement through sensorimotor interaction. CLN can be implemented using memristor crossbars with a local learning rule, spiking timing‐dependent plasticity (STDP), which can be natively obtained in second‐order memristors. CLN allows inputs from multiple sensors to be simultaneously processed by different columns, resulting in higher classification accuracy and better noise tolerance. Analysis of networks implemented on memristor crossbars shows that the system can operate at very low power and high throughput, with high accuracy and robustness to noise.

Recent developments in high-density neurophysiological tools now make it possible to record from hundreds of single neurons within local, highly interconnected neural networks. Among the many advantages of such recordings is that they dramatically increase the quantity of identifiable, functional interactions between neurons thereby providing an unprecedented view of local circuits. Using high-density, Neuropixels recordings from single neocortical columns of primary visual cortex in nonhuman primates, we identified 1000s of functionally interacting neuronal pairs using established crosscorrelation approaches. Our results reveal clear and systematic variations in the synchrony and strength of functional interactions within single cortical columns. Despite neurons residing within the same column, both measures of interactions depended heavily on the vertical distance separating neuronal pairs, as well as on the similarity of stimulus tuning. In addition, we leveraged the statistical power afforded by the large numbers of functionally interacting pairs to categorize interactions between neurons based on their crosscorrelation functions. These analyses identified distinct, putative classes of functional interactions within the full population. These classes of functional interactions were corroborated by their unique distributions across defined laminar compartments and were consistent with known properties of V1 cortical circuitry, such as the lead-lag relationship between simple and complex cells. Our results provide a clear proof-of-principle for the use of high-density neurophysiological recordings to assess circuit-level interactions within local neuronal networks.

The neocortex, and with it the mammalian brain, achieves a level of computational efficiency like no other existing computational engine. A deeper understanding of its building blocks (cortical microcircuits), and their underlying computational principles is thus of paramount interest. To this end, we need reproducible computational models that can be analyzed, modified, extended and quantitatively compared. In this study, we further that aim by providing a replication of a seminal cortical column model. This model consists of noisy Hodgkin-Huxley neurons connected by dynamic synapses, whose connectivity scheme is based on empirical findings from intracellular recordings. Our analysis confirms the key original finding that the specific, data-based connectivity structure enhances the computational performance compared to a variety of alternatively structured control circuits. For this comparison, we use tasks based on spike patterns and rates that require the systems not only to have simple classification capabilities, but also to retain information over time and to be able to compute nonlinear functions. Going beyond the scope of the original study, we demonstrate that this finding is independent of the complexity of the neuron model, which further strengthens the argument that it is the connectivity which is crucial. Finally, a detailed analysis of the memory capabilities of the circuits reveals a stereotypical memory profile common across all circuit variants. Notably, the circuit with laminar structure does not retain stimulus any longer than any other circuit type. We therefore conclude that the model's computational advantage lies in a sharper representation of the stimuli.

Our perception of the environment relies on the efficient propagation of neural signals across cortical networks. During the time course of a day, neural responses fluctuate dramatically as the state of the brain changes to possibly influence how electrical signals propagate across neural circuits. Despite the importance of this issue, how patterns of spiking activity propagate within neuronal circuits in different brain states remains unknown. Here, we used multielectrode laminar arrays to reveal that brain state strongly modulates the propagation of neural activity across the layers of early visual cortex (V1). We optogenetically induced synchronized state transitions within a group of neurons and examined how far electrical signals travel during wakefulness and rest. Although optogenetic stimulation elicits stronger neural responses during wakefulness relative to rest, signals propagate only weakly across the cortical column during wakefulness, and the extent of spread is inversely related to arousal level. In contrast, the light-induced population activity vigorously propagates throughout the entire cortical column during rest, even when neurons are in a desynchronized wake-like state prior to light stimulation. Mechanistically, the influence of global brain state on the propagation of spiking activity across laminar circuits can be explained by state-dependent changes in the coupling between neurons. Our results impose constraints on the conclusions of causal manipulation studies attempting to influence neural function and behavior, as well as on previous computational models of perception assuming robust signal propagation across cortical layers and areas. [ABSTRACT FROM AUTHOR]

Organization of horizontal axons in the inferior temporal cortex and primary visual cortex of the macaque monkey. Keywords: axon collaterals; cortical column; diversity; horizontal connections; like-to-like; pyramidal cells; recurrent EN axon collaterals cortical column diversity horizontal connections like-to-like pyramidal cells recurrent 1 6 6 06/07/22 20220603 NES 220603 Introduction In both sensory and non-sensory cortical areas, pyramidal neurons typically have horizontal collaterals spatially extending in a 1.0-3.0 mm radius from the cell body; and in primates and cats, these often have a patchy or discontinuous conformation (aka "daisy", Douglas and Martin, [17]). Axon topography of layer 6 spiny cells to orientation map in the primary visual cortex of the cat (area 18). The architectural significance of this mixed linear-and-clustered geometry is unclear; but, intriguingly in the context of cortical organization, something similar has been observed for some feedback axons (e.g., V4 to V1, figure 12 in Rockland et al., [53]) and for some pulvinocortical axons in V2 (figures 8, 17 in Rockland et al., [50]). [Extracted from the article]

Electrocorticography (ECoG) methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. To address this gap, we recorded from rat auditory cortex using customized lECoG, and simulated cortical surface electrical potentials with a full-scale, biophysically detailed cortical column model. Experimentally, lECoG-derived auditory representations were tonotopically organized and signals were anisotropically localized to less than or equal to 6200 lm, that is, a single cortical column. Biophysical simulations reproduce experimental findings and indicate that neurons in cortical layers V and VI contribute; 85% of evoked high-gamma signal recorded at the surface. Cell number and synchrony were the primary biophysical properties determining laminar contributions to evoked lECoG signals, whereas distance was only a minimal factor. Thus, evoked lECoG signals primarily originate from neurons in the infragranular layers of a single cortical column. [ABSTRACT FROM AUTHOR]

The influence of sensory experience on cortical feedforward and feedback interactions has rarely been studied in the auditory cortex. Previous work has documented a dystrophic effect of deafness in deep cortical layers, and a reduction of interareal couplings between primary and secondary auditory areas in congenital deafness which was particularly pronounced in the top-down direction (from the secondary to the primary area). In the present study, we directly quantified the functional interaction between superficial (supragranular, I to III) and deep (infragranular, V and VI) layers of feline's primary auditory cortex A1, and also between superficial/deep layers of A1 and a secondary auditory cortex, namely the posterior auditory field (PAF). We compared adult hearing cats under acoustic stimulation and cochlear implant (CI) stimulation to adult congenitally deaf cats (CDC) under CI stimulation. Neuronal activity was recorded from auditory fields A1 and PAF simultaneously with two NeuroNexus electrode arrays. We quantified the spike field coherence (i.e., the statistical dependence of spike trains at one electrode with local field potentials on another electrode) using pairwise phase consistency (PPC). Both the magnitude as well as the preferred phase of synchronization was analyzed. The magnitude of PPC was significantly smaller in CDCs than in controls. Furthermore, controls showed no significant difference between the preferred phase of synchronization between supragranular and infragranular layers, both in acoustic and electric stimulation. In CDCs, however, there was a large difference in the preferred phase between supragranular and infragranular layers. These results demonstrate a loss of synchrony and for the first time directly document a functional decoupling of the interaction between supragranular and infragranular layers of the primary auditory cortex in congenital deafness. Since these are key for the influence of top-down to bottom-up computations, the results suggest a loss of recurrent cortical processing in congenital deafness and explain the outcomes of previous studies by deficits in intracolumnar microcircuitry. [ABSTRACT FROM AUTHOR]

The current paper provides an explanation of neurophysiological pain processing based the Dimensional Systems Model (DSM), a theory of higher cortical functions in which the cortical column is considered the binary digit for all cortical functions. Within the discussion, novel views on the roles of the basal ganglia, cerebellum, and cingulate cortex are presented. Additionally, an applied Clinical Biopsychological Model (CBM) based on the DSM will be discussed as related to psychological treatment with chronic pain patients. Three specific areas that have not been adequately addressed in the psychological treatment of chronic pain patients will be discussed based on the CBM. The treatment approaches have been effectively used in a clinical setting. Conclusions focus on a call for researchers and clinicians to fully evaluate the value of both the DSM and CBM.

The influence of sensory experience on cortical feedforward and feedback interactions has rarely been studied in the auditory cortex. Previous work has documented a dystrophic effect of deafness in deep cortical layers, and a reduction of interareal couplings between primary and secondary auditory areas in congenital deafness which was particularly pronounced in the top-down direction (from the secondary to the primary area). In the present study, we directly quantified the functional interaction between superficial (supragranular, I to III) and deep (infragranular, V and VI) layers of feline’s primary auditory cortex A1, and also between superficial/deep layers of A1 and a secondary auditory cortex, namely the posterior auditory field (PAF). We compared adult hearing cats under acoustic stimulation and cochlear implant (CI) stimulation to adult congenitally deaf cats (CDC) under CI stimulation. Neuronal activity was recorded from auditory fields A1 and PAF simultaneously with two NeuroNexus electrode arrays. We quantified the spike field coherence (i.e., the statistical dependence of spike trains at one electrode with local field potentials on another electrode) using pairwise phase consistency (PPC). Both the magnitude as well as the preferred phase of synchronization was analyzed. The magnitude of PPC was significantly smaller in CDCs than in controls. Furthermore, controls showed no significant difference between the preferred phase of synchronization between supragranular and infragranular layers, both in acoustic and electric stimulation. In CDCs, however, there was a large difference in the preferred phase between supragranular and infragranular layers. These results demonstrate a loss of synchrony and for the first time directly document a functional decoupling of the interaction between supragranular and infragranular layers of the primary auditory cortex in congenital deafness. Since these are key for the influence of top-down to bottom-up computations, the results suggest a loss of recurrent cortical processing in congenital deafness and explain the outcomes of previous studies by deficits in intracolumnar microcircuitry.

The classical view of sensory information mainly flowing into barrel cortex at layer IV, moving up for complex feature processing and lateral interactions in layers II and III, then down to layers V and VI for output and corticothalamic feedback is becoming increasingly undermined by new evidence. We review the neurophysiology of sensing and processing whisker deflections, emphasizing the general processing and organisational principles present along the entire sensory pathway--from the site of physical deflection at the whiskers to the encoding of deflections in the barrel cortex. Many of these principles support the classical view. However, we also highlight the growing number of exceptions to these general principles, which complexify the system and which investigators should be mindful of when interpreting their results. We identify gaps in the literature for experimentalists and theorists to investigate, not just to better understand whisker sensation but also to better understand sensory and cortical processing. [ABSTRACT FROM AUTHOR]

The current paper provides an explanation of neurophysiological pain processing based the Dimensional Systems Model (DSM), a theory of higher cortical functions in which the cortical column is considered the binary digit for all cortical functions. Within the discussion, novel views on the roles of the basal ganglia, cerebellum, and cingulate cortex are presented. Additionally, an applied Clinical Biopsychological Model (CBM) based on the DSM will be discussed as related to psychological treatment with chronic pain patients. Three specific areas that have not been adequately addressed in the psychological treatment of chronic pain patients will be discussed based on the CBM. The treatment approaches have been effectively used in a clinical setting. Conclusions focus on a call for researchers and clinicians to fully evaluate the value of both the DSM and CBM. [ABSTRACT FROM AUTHOR]

How the neocortex works is a mystery. In this paper we propose a novel framework for understanding its function. Grid cells are neurons in the entorhinal cortex that represent the location of an animal in its environment. Recent evidence suggests that grid cell-like neurons may also be present in the neocortex. We propose that grid cells exist throughout the neocortex, in every region and in every cortical column. They define a location-based framework for how the neocortex functions. Whereas grid cells in the entorhinal cortex represent the location of one thing, the body relative to its environment, we propose that cortical grid cells simultaneously represent the location of many things. Cortical columns in somatosensory cortex track the location of tactile features relative to the object being touched and cortical columns in visual cortex track the location of visual features relative to the object being viewed. We propose that mechanisms in the entorhinal cortex and hippocampus that evolved for learning the structure of environments are now used by the neocortex to learn the structure of objects. Having a representation of location in each cortical column suggests mechanisms for how the neocortex represents object compositionality and object behaviors. It leads to the hypothesis that every part of the neocortex learns complete models of objects and that there are many models of each object distributed throughout the neocortex. The similarity of circuitry observed in all cortical regions is strong evidence that even high-level cognitive tasks are learned and represented in a location-based framework.

The leading hypothesis concerning the "reuse" or "recycling" of neural circuits builds on the assumption that evolution might prefer the redeployment of established circuits over the development of new ones. What conception of cognitive architecture can survive the evidence for this hypothesis? In particular, what sorts of "modules" are compatible with this evidence? I argue that the only likely candidates will, in effect, be the columns which Vernon Mountcastle originally hypothesized some 60 years ago, and which form part of the well-known columnar hypothesis in neuroscience—systems that cannot handle gross cognitive functions (vision, olfaction, language, etc.) as distinct from strictly exiguous subfunctions (such as aspects of edge detection, depth discrimination, etc.). This is in stark contrast to the modules postulated by much of cognitive psychology, cognitive neuropsychology, and evolutionary psychology. And yet the fate of this revised notion is unclear. The main issue confronting it is the effect of the neural network context on local function. At some point the effects of context are so strong that the degree of specialization required for modularity is not able to be met. Still, despite indications from neuroimaging that peripheral and central systems deploy shared circuitry, some skills clearly do seem to display modularization and autonomy. This article: (1) provides an in-depth analytical and historical review of the fortunes of modular thinking in cognitive science; (2) offers a systematic calibration of brain regions in terms of degrees of functional specificity and robustness; and (3) suggests another way of accounting for the partially encapsulated character of expertise and other highly practiced skills without having to resort to domain-specific modules. [ABSTRACT FROM AUTHOR]

To reduce statistical redundancy of natural inputs and increase the sparseness of coding, neurons in primary visual cortex (VI) show tuning for stimulus size and surround suppression. This integration of spatial information is a fundamental, context-dependent neural operation involving extensive neural circuits that span across all cortical layers of a VI column, and reflects both feedforward and feedback processing. However, how spatial integration is dynamically coordinated across cortical layers remains poorly understood. We recorded single- and multiunit activity and local field potentials across V1 layers of awake mice (both sexes) while they viewed stimuli of varying size and used dynamic Bayesian model comparisons to identify when laminar activity and interlaminar functional interactions showed surround suppression, the hallmark of spatial integration. We found that surround suppression is strongest in layer 3 (L3) and L4 activity, where suppression is established within ~ 10 ms after response onset, and receptive fields dynamically sharpen while suppression strength increases. Importantly, we also found that specific directed functional connections were strongest for intermediate stimulus sizes and suppressed for larger ones, particularly for connections from L3 targeting L5 and L1. Together, the results shed light on the different functional roles of cortical layers in spatial integration and on how L3 dynamically coordinates activity across a cortical column depending on spatial context. [ABSTRACT FROM AUTHOR]

• A phased array system was designed for ultrasound neuromodulation. • A high-resolution region-specific ultrasound neuromodulation requires 200 um range accuracy. • A phased array system provides the accuracy with electronic focusing. • Ultrasound neuromodulation with phased array shows reproducible results in region specificity. Ultrasonic neuromodulation (UNMOD) provides a non-invasive brain stimulation. However, the high-resolution region-specificity of UNMOD with a single element transducer combined with a mechanical positioning system could have limits due to the intrinsic positioning error from mechanical systems. A phased array system could lead to highly selective neuromodulation with electronic control. A specialized phased-array system with a robotic arm is implemented for a rhesus monkey model. Various primary motor cortex areas related to tail, hand, and mouth were stimulated with a 200 μm step size. The ultrasonic parameters were I SPTA of 840 mW/cm2, pulse repetition frequency of 100 Hz, and a 5% duty factor at 600 kHz. The induced movement were recorded and analyzed. Separate digits, mouth, and tongue motions were successfully induced by electronically controlling the focus. The identical body part movement could be induced when the focus was moved back to the identical primary motor cortex with electronic control. Accordingly, the reproducibility of UNMOD could be partially validated with rhesus monkey model. A phased-array system appears to have a potential for the non-invasive and region-selective neuromodulation method. [ABSTRACT FROM AUTHOR]

Introduction: The visual cortex is a key region in the mouse brain, responsible for processing visual information. Comprised of six distinct layers, each with unique neuronal types and connections, the visual cortex exhibits diverse decoding properties across its layers. This study aimed to investigate the relationship between visual stimulus decoding properties and the cortical layers of the visual cortex while considering how this relationship varies across different decoders and brain regions., Methods: This study reached the above conclusions by analyzing two publicly available datasets obtained through two-photon microscopy of visual cortex neuronal responses. Various types of decoders were tested for visual cortex decoding., Results: Our findings indicate that the decoding accuracy of neuronal populations with consistent sizes varies among visual cortical layers for visual stimuli such as drift gratings and natural images. In particular, layer 4 neurons in VISp exhibited significantly higher decoding accuracy for visual stimulus identity compared to other layers. However, in VISm, the decoding accuracy of neuronal populations with the same size in layer 2/3 was higher than that in layer 4, despite the overall accuracy being lower than that in VISp and VISl. Furthermore, SVM surpassed other decoders in terms of accuracy, with the variation in decoding performance across layers being consistent among decoders. Additionally, we found that the difference in decoding accuracy across different imaging depths was not associated with the mean orientation selectivity index (OSI) and the mean direction selectivity index (DSI) neurons, but showed a significant positive correlation with the mean reliability and mean signal-to-noise ratio (SNR) of each layer's neuron population., Discussion: These findings lend new insights into the decoding properties of the visual cortex, highlighting the role of different cortical layers and decoders in determining decoding accuracy. The correlations identified between decoding accuracy and factors such as reliability and SNR pave the way for more nuanced understandings of visual cortex functioning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kong, Wang and Xiao.)

The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of the marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: "patchy" projections that formed many columns of submillimeter scale in nearby and distant regions and "diffuse" projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections' local and global distribution patterns. We also demonstrated column-scale precision of reciprocal corticocortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain. [Display omitted] • A whole-brain map of marmoset PFC projections has been created for open access • Two projection types (patchy and diffuse) were identified in cortex and striatum • Tightly reciprocal connections with column-scale precision were discovered • Interregional connectivity is topographically arranged both globally and locally In this article, Watakabe et al. perform extensive tracer mapping of the marmoset PFC, finding two types of projections (patchy and diffuse) to be topographically arranged in the cortex and striatum. Fine-grained analyses enabled by this new resource deepen our understanding of local and long-range connectivity of the primate PFC. [ABSTRACT FROM AUTHOR]

The role of gamma-band synchronization and NMDA receptors in cognitive functions and neuropsychiatric disorders has received increased attention over the past two decades, with significant controversy about their roles. The role of the cortical column as a basic unit in cortical processing has also been debated. The current paper presents the theoretical argument that the dynamically formed column is the binary unit (bit) involved in all cortical processing and memory, and that gamma-band synchronization is required for columnar formation. Moreover, the role of NMDA receptors is explained as allowing the consolidation of synchronized boundary minicolumns that serve as the bit, as well as strengthening the connections among the circuit of columns that are involved with any given memory. Following a discussion of the microcircuitry that may be involved, there is a brief discussion on how the serious neuropsychiatric disorders of schizophrenia, autism, and Alzheimer’s disease can be conceptualized as disorders of disrupted column formation. The arguments presented provide a theoretical basis for future research to determine the validity of this novel view.

Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological β-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical β-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aβ are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.

Congenital deafness leads to functional deficits in the auditory cortex for which early cochlear implantation can effectively compensate. Most of these deficits have been demonstrated functionally. Furthermore, the majority of previous studies on deafness have involved the primary auditory cortex; knowledge of higher-order areas is limited to effects of cross-modal reorganization. In this study, we compared the cortical cytoarchitecture of four cortical areas in adult hearing and congenitally deaf cats (CDCs): the primary auditory field A1, two secondary auditory fields, namely the dorsal zone and second auditory field (A2); and a reference visual association field (area 7) in the same section stained either using Nissl or SMI-32 antibodies. The general cytoarchitectonic pattern and the area-specific characteristics in the auditory cortex remained unchanged in animals with congenital deafness. Whereas area 7 did not differ between the groups investigated, all auditory fields were slightly thinner in CDCs, this being caused by reduced thickness of layers IV-VI. The study documents that, while the cytoarchitectonic patterns are in general independent of sensory experience, reduced layer thickness is observed in both primary and higher-order auditory fields in layer IV and infragranular layers. The study demonstrates differences in effects of congenital deafness between supragranular and other cortical layers, but similar dystrophic effects in all investigated auditory fields. [ABSTRACT FROM AUTHOR]

The processing sequence through primary auditory cortex (A1) is impaired by deafness as evidenced by reduced neuronal activation in A1 of cochlear-implanted deaf cats. Such a loss of neuronal excitation should be manifest as changes in excitatory synaptic number and/or size, for which the post-synaptic correlate is the dendritic spine. Therefore, the present study sought evidence for this functional disruption using Golgi-Cox/light microscopic techniques that examined spine-bearing neurons and their dendritic spine features across all laminae in A1 of early-deaf (ototoxic lesion <1 month; raised into adulthood >16 months) and hearing cats. Surprisingly, in the early-deaf significant increases in spine density and size were observed in the supragranular layers, while significant reductions in spine density were observed for spiny non-pyramidal, but not pyramidal, neurons in the granular layer. No changes in dendritic spine density consistent with loss of excitatory inputs were seen for infragranular neurons. These results indicate that long-term early-deafness induces plastic changes in the excitatory circuitry of A1 that are laminar and cell-specific. An additional finding was that, unlike the expected abundance of stellate neurons that characterize the granular layer of other primary sensory cortices, pyramidal neurons predominate within layer 4 of A1. Collectively, these observations are important for understanding how neuronal connectional configurations contribute to region-specific processing capabilities in normal brains as well as those with altered sensory experiences. [ABSTRACT FROM AUTHOR]

Whisker trimming causes substantial reorganization of neuronal response properties in barrel cortex. However, little is known about experience-dependent rerouting of sensory processing following sensory deprivation. To address this, we performed in vivo intracellular recordings from layers 2/3 (L2/3), layer 4 (L4), layer 5 regular-spiking (L5RS), and L5 intrinsically bursting (L5IB) neurons and measured their multiwhisker receptive field at the level of spiking activity, membrane potential, and synaptic conductance before and after sensory deprivation. We used Chernoff information to quantify the "sensory information" contained in the firing patterns of cells in response to spared and deprived whisker stimulation. In the control condition, information for flanking-row and same-row whiskers decreased in the order L4, L2/3, L5IB, L5RS. However, after whisker-row deprivation, spared flanking-row whisker information was reordered to L4, L5RS, L5IB, L2/3. Sensory information from the trimmed whiskers was reduced and delayed in L2/3 and L5IB neurons, whereas sensory information from spared whiskers was increased and advanced in L4 and L5RS neurons. Sensory information from spared whiskers was increased in L5IB neurons without a latency change. L5RS cells exhibited the largest changes in sensory information content through an atypical plasticity combining a significant decrease in spontaneous activity and an increase in a short-latency excitatory conductance. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the emergence and plasticity of representational discontinuities in the mammalian primary somatosensory cortical representation of the hand are investigated in a computational model. The model consists of an input lattice organized as a three-digit hand forward-connected to a lattice of cortical columns each of which contains a paired excitatory and inhibitory cell. Excitatory and inhibitory synaptic plasticity of feedforward and lateral connection weights is implemented as a simple covariance rule and competitive normalization. Receptive field properties are computed independently for excitatory and inhibitory cells and compared within and across columns. Within digit representational zones intracolumnar excitatory and inhibitory receptive field extents are concentric, single-digit, small, and unimodal. Exclusively in representational boundary-adjacent zones, intracolumnar excitatory and inhibitory receptive field properties diverge: excitatory cell receptive fields are single-digit, small, and unimodal; and the paired inhibitory cell receptive fields are bimodal, double-digit, and large. In simulated syndactyly (webbed fingers), boundary-adjacent intracolumnar receptive field properties reorganize to within-representation type; divergent properties are reacquired following syndactyly release. This study generates testable hypotheses for assessment of cortical laminar-dependent receptive field properties and plasticity within and between cortical representational zones. For computational studies, present results suggest that concurrent excitatory and inhibitory plasticity may underlie novel emergent properties.

In this work we reveal and explore a new class of attractor neural networks, based on inborn connections provided by model molecular markers, the molecular marker based attractor neural networks (MMBANN). Each set of markers has a metric, which is used to make connections between neurons containing the markers. We have explored conditions for the existence of attractor states, critical relations between their parameters and the spectrum of single neuron models, which can implement the MMBANN. Besides, we describe functional models (perceptron and SOM), which obtain significant advantages over the traditional implementation of these models, while using MMBANN. In particular, a perceptron, based on MMBANN, gets specificity gain in orders of error probabilities values, MMBANN SOM obtains real neurophysiological meaning, the number of possible grandma cells increases 1000-fold with MMBANN. MMBANN have sets of attractor states, which can serve as finite grids for representation of variables in computations. These grids may show dimensions of d = 0, 1, 2, ... We work with static and dynamic attractor neural networks of the dimensions d = 0 and d = 1. We also argue that the number of dimensions which can be represented by attractors of activities of neural networks with the number of elements N=104 does not exceed 8.

There are currently largescale efforts underway to understand the brain as connection machine. However, there has been little emphasis on understanding connection patterns between functionally specific cortical columns. Here, we review development and application of focal electrical and optical stimulation methods combined with optical imaging and fMRI mapping in the nonhuman primate. These new approaches, when applied systematically on a large scale, will elucidate functionally specific intra-areal and inter-areal network connection patterns. Such functionally specific network data can provide accurate views of brain network topology.

Whenwe consider all of the methodswe employ to detect brain function, from electrophysiology to optical techniques to functional magnetic resonance imaging (fMRI), we do not really have a 'golden technique' that meets all of the needs for studying the brain. We have methods, each of which has significant limitations but provide often complimentary information. Clearly, there are many questions that need to be answered about fMRI, which unlike other methods, allows us to study the human brain. However, there are also extraordinary accomplishments or demonstration of the feasibility of reaching new and previously unexpected scales of function in the human brain. This article reviews some of the work we have pursued, often with extensive collaborations with other co-workers, towards understanding the underlying mechanisms of the methodology, defining its limitations, and developing solutions to advance it. No doubt, our knowledge of human brain function has vastly expanded since the introduction of fMRI. However, methods and instrumentation in this dynamic field have evolved to a state that discoveries about the human brain based on fMRI principles, together with information garnered at a much finer spatial and temporal scale through other methods, are poised to significantly accelerate in the next decade. [ABSTRACT FROM AUTHOR]

The concept of the cortical column refers to vertical cell bands with similar response properties, which were initially observed by Vernon Mountcastle's mapping of single cell recordings in the cat somatic cortex. It has subsequently guided over 50 years of neuroscientific research, in which fundamental questions about the modularity of the cortex and basic principles of sensory information processing were empirically investigated. Nevertheless, the status of the column remains controversial today, as skeptical commentators proclaim that the vertical cell bands are a functionally insignificant by-product of ontogenetic development. This paper inquires how the column came to be viewed as an elementary unit of the cortex from Mountcastle's discovery in 1955 until David Hubel and Torsten Wiesel's reception of the Nobel Prize in 1981. I first argue that Mountcastle's vertical electrode recordings served as criteria for applying the column concept to electrophysiological data. In contrast to previous authors, I claim that this move from electrophysiological data to the phenomenon of columnar responses was concept-laden, but not theory-laden. In the second part of the paper, I argue that Mountcastle's criteria provided Hubel Wiesel with a conceptual outlook, i.e. it allowed them to anticipate columnar patterns in the cat and macaque visual cortex. I argue that in the late 1970s, this outlook only briefly took a form that one could call a 'theory' of the cerebral cortex, before new experimental techniques started to diversify column research. I end by showing how this account of early column research fits into a larger project that follows the conceptual development of the column into the present. [ABSTRACT FROM AUTHOR]

Despite the hippocampus being extensively studied, controversy remains as to its role in cognitive processing. The current paper presents a theoretical argument that the hippocampus has only one purpose: the binding of parallel cortical circuits. The paper begins with a discussion of cortical columns as the common binary digit (bit) for all neocortical processing. This is followed by details on the Dimensional Systems Model and its explanation of cortical circuitry. As opposed to any independent function in cognitive processing, the hippocampal cells are viewed as serving a slave function to cortical circuits since they are activated as part of a cortical-hippocampal-thalamic-cortical circuit. As part of that circuit, the hippocampus serves the role of reactivating the cortical circuits involved in complex memories (i.e., involving multiple cortical circuits) to facilitate the consolidation of the involved cortical columns' interconnections. Next there is a brief discussion of prior theoretical views explaining hippocampal involvement in memory and spatial representations. To facilitate an appreciation of the unique aspects of the new model, it is contrasted against the extensively developed Component Process Model. Conclusions focus on how a complete model of cortical cognitive processing is necessary to adequately explain the purpose of the hippocampus, viewed as a complex structure with an elegantly simple function. [ABSTRACT FROM AUTHOR]

Gamma oscillations are a robust component of sensory responses but are also part of the background spontaneous activity of the brain. To determine whether the properties of gamma oscillations in cortex are specific to their mechanism of generation, we compared in mouse visual cortex in vivo the laminar geometry and single-neuron rhythmicity of oscillations produced during sensory representation with those occurring spontaneously in the absence of stimulation. In mouse visual cortex under anesthesia (isoflurane and xylazine), visual stimulation triggered oscillations mainly between 20 and 50 Hz, which, because of their similar functional significance to gamma oscillations in higher mammals, we define here as gamma range. Sensory representation in visual cortex specifically increased gamma oscillation amplitude in the supragranular (L2/3) and granular (L4) layers and strongly entrained putative excitatory and inhibitory neurons in infragranular layers, while spontaneous gamma oscillations were distributed evenly through the cortical depth and primarily entrained putative inhibitory neurons in the infragranular (L5/6) cortical layers. The difference in laminar distribution of gamma oscillations during the two different conditions may result from differences in the source of excitatory input to the cortex. In addition, modulation of superficial gamma oscillation amplitude did not result in a corresponding change in deep-layer oscillations, suggesting that superficial and deep layers of cortex may utilize independent but related networks for gamma generation. These results demonstrate that stimulus-driven gamma oscillations engage cortical circuitry in a manner distinct from spontaneous oscillations and suggest multiple networks for the generation of gamma oscillations in cortex. [ABSTRACT FROM AUTHOR]

ABSTRACT The isocortex of several primates and rodents shows a systematic increase in the number of neurons per unit of cortical surface area from its rostrolateral to caudomedial border. The steepness of the gradient in neuronal number and density is positively correlated with cortical volume. The relative duration of neurogenesis along the same rostrocaudal gradient predicts a substantial fraction of this variation in neuron number and laminar position, which is produced principally from layers II-IV neurons. However, virtually all of our quantitative knowledge about total and laminar variation in cortical neuron numbers and neurogenesis comes from rodents and primates, leaving whole taxonomic groups and many intermediate-sized brains unexplored. Thus, the ubiquity in mammals of the covariation of longer cortical neurogenesis and increased cortical neuron number deriving from cortical layers II-IV is undetermined. To begin to address this gap, we examined the isocortex of the manatee using the optical disector method in sectioned tissue, and also assembled partial data from published reports of the domestic cat brain. The manatee isocortex has relatively fewer neurons per total volume, and fewer II-IV neurons than primates with equivalently sized brains. The gradient in number of neurons from the rostral to the caudal pole is intermediate between primates and rodents, and, like those species, is observed only in the upper cortical layers. The cat isocortex ( Felis domesticus) shows a similar structure. Key species for further tests of the origin, ubiquity, and significance of this organizational feature are discussed. J. Comp. Neurol. 524:772-782, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this work we reveal and explore a new class of attractor neural networks, based on inborn connections provided by model molecular markers, the molecular marker based attractor neural networks (MMBANN). Each set of markers has a metric, which is used to make connections between neurons containing the markers. We have explored conditions for the existence of attractor states, critical relations between their parameters and the spectrum of single neuron models, which can implement the MMBANN. Besides, we describe functional models (perceptron and SOM), which obtain significant advantages over the traditional implementation of these models, while using MMBANN. In particular, a perceptron, based on MMBANN, gets specificity gain in orders of error probabilities values, MMBANN SOM obtains real neurophysiological meaning, the number of possible grandma cells increases 1000-fold with MMBANN. MMBANN have sets of attractor states, which can serve as finite grids for representation of variables in computations. These grids may show dimensions of d = 0, 1, 2,.... We work with static and dynamic attractor neural networks of the dimensions d = 0 and 1. We also argue that the number of dimensions which can be represented by attractors of activities of neural networks with the number of elements N = 104 does not exceed 8. [ABSTRACT FROM AUTHOR]

Sensory-evoked signal flow, at cellular and network levels, is primarily determined by the synaptic wiring of the underlying neuronal circuitry. Measurements of synaptic innervation, connection probabilities and subcellular organization of synaptic inputs are thus among the most active fields of research in contemporary neuroscience. Methods to measure these quantities range from electrophysiological recordings over reconstructions of dendrite-axon overlap at light-microscopic levels to dense circuit reconstructions of small volumes at electron-microscopic resolution. However, quantitative and complete measurements at subcellular resolution and mesoscopic scales to obtain all local and long-range synaptic in/outputs for any neuron within an entire brain region are beyond present methodological limits. Here, we present a novel concept, implemented within an interactive software environment called NeuroNet, which allows (i) integration of sparsely sampled (sub)cellular morphological data into an accurate anatomical reference frame of the brain region(s) of interest, (ii) up-scaling to generate an average dense model of the neuronal circuitry within the respective brain region(s) and (iii) statistical measurements of synaptic innervation between all neurons within the model. We illustrate our approach by generating a dense average model of the entire rat vibrissal cortex, providing the required anatomical data, and illustrate how to measure synaptic innervation statistically. Comparing our results with data from paired recordings in vitro and in vivo, as well as with reconstructions of synaptic contact sites at light- and electron-microscopic levels, we find that our in silico measurements are in line with previous results.

Cortical inhibitory interneurons (INs) are subdivided into a variety of morphologically and functionally specialized cell types. How the respective specific properties translate into mechanisms that regulate sensory-evoked responses of pyramidal neurons (PNs) remains unknown. Here, we investigated how INs located in cortical layer 1 (L1) of rat barrel cortex affect whisker-evoked responses of L2 PNs. To do so we combined in vivo electrophysiology and morphological reconstructions with computational modeling. We show that whisker-evoked membrane depolarization in L2 PNs arises from highly specialized spatiotemporal synaptic input patterns. Temporally L1 INs and L2--5 PNs provide near synchronous synaptic input. Spatially synaptic contacts from L1 INs target distal apical tuft dendrites, whereas PNs primarily innervate basal and proximal apical dendrites. Simulations of such constrained synaptic input patterns predicted that inactivation of L1 INs increases trial-to-trial variability of whisker-evoked responses in L2 PNs. The in silico predictions were confirmed in vivo by L1-specific pharmacological manipulations. We present a mechanism--consistent with the theory of distal dendritic shunting--that can regulate the robustness of sensory-evoked responses in PNs without affecting response amplitude or latency. [ABSTRACT FROM AUTHOR]

The mechanism of loss of consciousness (LOC) under anesthesia is unknown. Because consciousness depends on activity in the cortico-thalamic network, anesthetic actions on this network are likely critical for LOC. Competing theories stress the importance of anesthetic actions on bottom-up ‘core’ thalamo-cortical (TC) versus top-down cortico-cortical (CC) and matrix TC connections. We tested these models using laminar recordings in rat auditory cortex in-vivo and murine brain slices. We selectively activated bottom-up vs. top-down afferent pathways using sensory stimuli in vivo and electrical stimulation in brain slices, and compared effects of isoflurane on responses evoked via the two pathways. Auditory stimuli in vivo and core TC afferent stimulation in brain slices evoked short latency current sinks in middle layers, consistent with activation of core TC afferents. By contrast, visual stimuli in vivo and stimulation of CC and matrix TC afferents in brain slices evoked responses mainly in superficial and deep layers, consistent with projection patterns of top-down afferents that carry visual information to auditory cortex. Responses to auditory stimuli in vivo and core TC afferents in brain slices were significantly less affected by isoflurane compared to responses triggered by visual stimuli in vivo and CC/matrix TC afferents in slices. At a just-hypnotic dose in vivo, auditory responses were enhanced by isoflurane, whereas visual responses were dramatically reduced. At a comparable concentration in slices, isoflurane suppressed both core TC and CC/matrix TC responses, but the effect on the latter responses was far greater than on core TC responses, indicating that at least part of the differential effects observed in vivo were due to local actions of isoflurane in auditory cortex. These data support a model in which disruption of top-down connectivity contributes to anesthesia-induced LOC, and have implications for understanding the neural basis of consciousness.

Receptive fields of neurons in the forelimb region of areas 3b and 1 of primary somatosensory cortex, in cats and monkeys, were mapped using extracellular recordings obtained sequentially from nearly radial penetrations. Locations of the field centroids indicated the presence of a functional system, in which cortical homotypic representations of the limb surfaces are entwined in three-dimensional Mobius-strip-like patterns of synaptic connections. Boundaries of somatosensory receptive field in nested groups irregularly overlie the centroid order, and are interpreted as arising from the superposition of learned connections upon the embryonic order. Since the theory of embryonic synaptic self-organisation used to model these results was devised and earlier used to explain findings in primary visual cortex, the present findings suggest the theory may be of general application throughout cortex, and may reveal a modular functional synaptic system, which, only in some parts of the cortex, and in some species, is manifest as anatomical ordering into columns.

The state of the sensory cortical network can have a profound impact on neural responses and perception. In rodent auditory cortex, sensory responses are reported to occur in the context of network events, similar to brief UP states, that produce 'packets' of spikes and are associated with synchronized synaptic input (Bathellier et al., 2012; Hromadka et al., 2013; Luczak et al., 2013). However, traditional models based on data from visual and somatosensory cortex predict that ascending sensory thalamocortical (TC) pathways sequentially activate cells in layers 4 (L4), L2/3 and L5. The relationship between these two spatio-temporal activity patterns is unclear. Here, we used calcium imaging and electrophysiological recordings in murine auditory TC brain slices to investigate the laminar response pattern to stimulation of TC afferents. We show that although monosynaptically driven spiking in response to TC afferents occurs, the vast majority of spikes fired following TC stimulation occurs during brief UP states and outside the context of the L4>L2/3>L5 activation sequence. Specifically, monosynaptic subthreshold TC responses with similar latencies were observed throughout layers 2 - 6, presumably via synapses onto dendritic processes located in L3 & L4. However, monosynaptic spiking was rare, and occurred primarily in L4 and L5 non-pyramidal cells. By contrast, during brief, TC-induced UP states, spiking was dense and occurred primarily in pyramidal cells. These network events always involved infragranular layers, whereas involvement of supragranular layers was variable. During UP states, spike latencies were comparable between infragranular and supragranular cells. These data are consistent with a model in which activation of auditory cortex, especially supragranular layers, depends on internally generated network events that represent a nonlinear amplification process, are initiated by infragranular cells and tightly regulated by feed-forward inhibitory cells.