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Background: Information theory is an increasingly popular framework for studying how the brain encodes sensory information. Despite its widespread use for the analysis of spike trains of single neurons and of small neural populations, its application to the analysis of other types of neurophysiological signals (EEGs, LFPs, BOLD) has remained relatively limited so far. This is due to the limited-sampling bias which affects calculation of information, to the complexity of the techniques to eliminate the bias, and to the lack of publicly available fast routines for the information analysis of multi-dimensional responses.Results: Here we introduce a new C- and Matlab-based information theoretic toolbox, specifically developed for neuroscience data. This toolbox implements a novel computationally-optimized algorithm for estimating many of the main information theoretic quantities and bias correction techniques used in neuroscience applications. We illustrate and test the toolbox in several ways. First, we verify that these algorithms provide accurate and unbiased estimates of the information carried by analog brain signals (i.e. LFPs, EEGs, or BOLD) even when using limited amounts of experimental data. This test is important since existing algorithms were so far tested primarily on spike trains. Second, we apply the toolbox to the analysis of EEGs recorded from a subject watching natural movies, and we characterize the electrodes locations, frequencies and signal features carrying the most visual information. Third, we explain how the toolbox can be used to break down the information carried by different features of the neural signal into distinct components reflecting different ways in which correlations between parts of the neural signal contribute to coding. We illustrate this breakdown by analyzing LFPs recorded from primary visual cortex during presentation of naturalistic movies.Conclusion: The new toolbox presented here implements fast and data-robust computations of the most relevant quantities used in information theoretic analysis of neural data. The toolbox can be easily used within Matlab, the environment used by most neuroscience laboratories for the acquisition, preprocessing and plotting of neural data. It can therefore significantly enlarge the domain of application of information theory to neuroscience, and lead to new discoveries about the neural code. [ABSTRACT FROM AUTHOR]

The acoustic startle reflex (ASR) and prepulse inhibition of the ASR (PPI) assess the efficiency of salience processing, a fundamental brain function that is impaired in many psychiatric conditions. Both ASR and PPI depend on noradrenergic transmission, yet the modulatory role of the locus coeruleus (LC) remains controversial. Clonidine (0.05 mg/kg, i.p.), an alpha2-adrenoreceptor agonist, strongly reduced the ASR amplitude. In contrast, chemogenetic LC inhibition only mildly suppressed the ASR and did affect the PPI in virus-transduced rats. The canine adenovirus type 2 (CAV2)-based vector carrying a gene cassette for the expression of inhibitory receptors (hM4Di) and noradrenergic cell-specific promoter (PRSx8) had high cell-type specificity (94.4 ± 3.1%) but resulted in heterogeneous virus transduction of DbH-positive LC neurons (range: 9.2-94.4%). Clozapine-N-oxide (CNO; 1 mg/kg, i.p.), a hM4Di actuator, caused the firing cessation of hM4Di-expressing LC neurons, yet complete inhibition of the entire population of LC neurons was not achieved. Case-based immunohistochemistry revealed that virus injections distal (> 150 μm) to the LC core resulted in partial LC transduction, while proximal (< 50 μm) injections caused neuronal loss due to virus neurotoxicity. Neither the ASR nor PPI differed between the intact and virus-transduced rats. Our results suggest that a residual activity of virus-non-transduced LC neurons might have been sufficient for mediating an unaltered ASR and PPI. Our study highlights the importance of a case-based assessment of the virus efficiency, specificity, and neurotoxicity for targeted cell populations and of considering these factors when interpreting behavioral effects in experiments employing chemogenetic modulation., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The critical brain hypothesis states that the brain can benefit from operating close to a second-order phase transition. While it has been shown that several computational aspects of sensory processing (e.g., sensitivity to input) can be optimal in this regime, it is still unclear whether these computational benefits of criticality can be leveraged by neural systems performing behaviorally relevant computations. To address this question, we investigate signatures of criticality in networks optimized to perform efficient coding. We consider a spike-coding network of leaky integrate-and-fire neurons with synaptic transmission delays. Previously, it was shown that the performance of such networks varies nonmonotonically with the noise amplitude. Interestingly, we find that in the vicinity of the optimal noise level for efficient coding, the network dynamics exhibit some signatures of criticality, namely, scale-free dynamics of the spiking and the presence of crackling noise relation. Our work suggests that two influential, and previously disparate theories of neural processing optimization (efficient coding and criticality) may be intimately related., Competing Interests: Competing interests statement:The authors declare no competing interest.

Brightness illusions are a powerful tool in studying vision, yet their neural correlates are poorly understood. Based on a human paradigm, we presented illusory drifting gratings to mice. Primary visual cortex (V1) neurons responded to illusory gratings, matching their direction selectivity for real gratings, and they tracked the spatial phase offset between illusory and real gratings. Illusion responses were delayed compared to real gratings, in line with the theory that processing illusions requires feedback from higher visual areas (HVAs). We provide support for this theory by showing a reduced V1 response to illusions, but not real gratings, following HVAs optogenetic inhibition. Finally, we used the pupil response (PR) as an indirect perceptual report and showed that the mouse PR matches the human PR to perceived luminance changes. Our findings resolve debates over whether V1 neurons are involved in processing illusions and highlight the involvement of feedback from HVAs., (© 2024. The Author(s).)

Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) of cortical layers relies on the hemodynamic response and is biased toward large veins on the cortical surface. Functional changes in the cerebral metabolic rate of oxygen (ΔCMRO 2 ) may reflect neural cortical function better than BOLD fMRI, but it is unknown whether the calibrated BOLD model for functional CMRO 2 measurement remains valid at high resolution. Here, we measure laminar ΔCMRO 2 elicited by visual stimulation in macaque primary visual cortex (V1) and find that ΔCMRO 2 peaks in the middle of the cortex, in agreement with autoradiographic measures of metabolism. ΔCMRO 2 values in gray matter are similar as found previously. Reductions in CMRO 2 are associated with veins at the cortical surface, suggesting that techniques for vein removal may improve the accuracy of the model at very high resolution. However, our results show feasibility of laminar ΔCMRO 2 measurement, providing a physiologically meaningful metric of laminar functional metabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Transient phenomena play a key role in coordinating brain activity at multiple scales, however their underlying mechanisms remain largely unknown. A key challenge for neural data science is thus to characterize the network interactions at play during these events. Methods: Using the formalism of Structural Causal Models and their graphical representation, we investigate the theoretical and empirical properties of Information Theory based causal strength measures in the context of recurring spontaneous transient events. Results: After showing the limitations of Transfer Entropy and Dynamic Causal Strength in this setting, we introduce a novel measure, relative Dynamic Causal Strength, and provide theoretical and empirical support for its benefits. Discussion: These methods are applied to simulated and experimentally recorded neural time series and provide results in agreement with our current understanding of the underlying brain circuits., Competing Interests: The author NL declared that he was an editorial board member of Frontiers, at the time of submission. The remaining 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 Shao, Logothetis and Besserve.)

Access of sensory information to consciousness has been linked to the ignition of content-specific representations in association cortices. How does ignition interact with intrinsic cortical state fluctuations to give rise to conscious perception? We addressed this question in the prefrontal cortex (PFC) by combining multi-electrode recordings with a binocular rivalry (BR) paradigm inducing spontaneously driven changes in the content of consciousness, inferred from the reflexive optokinetic nystagmus (OKN) pattern. We find that fluctuations between low-frequency (LF, 1-9 Hz) and beta (∼20-40 Hz) local field potentials (LFPs) reflect competition between spontaneous updates and stability of conscious contents, respectively. Both LF and beta events were locally modulated. The phase of the former locked differentially to the competing populations just before a spontaneous transition while the latter synchronized the neuronal ensemble coding the consciously perceived content. These results suggest that prefrontal state fluctuations gate conscious perception by mediating internal states that facilitate perceptual update and stability., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite the considerable progress of in vivo neural recording techniques, inferring the biophysical mechanisms underlying large scale coordination of brain activity from neural data remains challenging. One obstacle is the difficulty to link high dimensional functional connectivity measures to mechanistic models of network activity. We address this issue by investigating spike-field coupling (SFC) measurements, which quantify the synchronization between, on the one hand, the action potentials produced by neurons, and on the other hand mesoscopic "field" signals, reflecting subthreshold activities at possibly multiple recording sites. As the number of recording sites gets large, the amount of pairwise SFC measurements becomes overwhelmingly challenging to interpret. We develop Generalized Phase Locking Analysis (GPLA) as an interpretable dimensionality reduction of this multivariate SFC. GPLA describes the dominant coupling between field activity and neural ensembles across space and frequencies. We show that GPLA features are biophysically interpretable when used in conjunction with appropriate network models, such that we can identify the influence of underlying circuit properties on these features. We demonstrate the statistical benefits and interpretability of this approach in various computational models and Utah array recordings. The results suggest that GPLA, used jointly with biophysical modeling, can help uncover the contribution of recurrent microcircuits to the spatio-temporal dynamics observed in multi-channel experimental recordings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Safavi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The therapeutic use of noradrenergic drugs makes the evaluation of their effects on cognition of high priority. Norepinephrine (NE) is an important neuromodulator for a variety of cognitive processes and may importantly contribute to sleep-mediated memory consolidation. The NE transmission fluctuates with the behavioral and/or brain state and influences associated neural activity. Here, we assessed the effects of altered NE transmission after learning of a hippocampal-dependent task on neural activity and spatial memory in adult male rats. We administered clonidine (0.05 mg/kg, i.p.; n = 12 rats) or propranolol (10 mg/kg, i.p.; n = 11) after each of seven daily learning sessions on an 8-arm radial maze. Compared to the saline group (n = 9), the drug-treated rats showed lower learning rates. To assess the effects of drugs on cortical and hippocampal activity, we recorded prefrontal EEG and local field potentials from the CA1 subfield of the dorsal hippocampus for 2 h after each learning session or drug administration. Both drugs significantly reduced the number of hippocampal ripples for at least 2 h. An EEG-based sleep scoring revealed that clonidine made the sleep onset faster while prolonging quiet wakefulness. Propranolol increased active wakefulness at the expense of non-rapid eye movement (NREM) sleep. Clonidine reduced the occurrence of slow oscillations (SO) and sleep spindles during NREM sleep and altered the temporal coupling between SO and sleep spindles. Thus, pharmacological alteration of NE transmission produced a suboptimal brain state for memory consolidation. Our results suggest that the post-learning NE contributes to the efficiency of hippocampal-cortical communication underlying memory consolidation., (© 2023. The Author(s).)

The locus coeruleus norepinephrine (LC-NE) system modulates many visceral and cognitive functions, while LC-NE dysfunction leads to neurological and neurodegenerative conditions such as sleep disorders, depression, ADHD, or Alzheimer's disease. Innovative viral-vector and gene-engineering technology combined with the availability of cell-specific promoters enabled regional targeting and selective control over phenotypically specific populations of neurons. We transduced the LC-NE neurons in adult male rats by delivering the canine adenovirus type 2-based vector carrying the NE-specific promoter PRSx8 and a light-sensitive channelrhodopsin-2 receptor (ChR2) directly in the LC or retrogradely from the LC targets. The highest ChR2 expression level was achieved when the virus was delivered medially to the trigeminal pathway and ~100 μm lateral to the LC. The injections close or directly in the LC compromised the tissue integrity and NE cell phenotype. Retrograde labeling was more optimal given the transduction of projection-selective subpopulations. Our results highlight a limited inference of ChR2 expression from representative cases to the entire population of targeted cells. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. The actual fraction of manipulated neurons appears most essential for an adequate interpretation of the study outcome. Thus, besides the cell-type specificity and the transduction efficiency, the between-subject variability in the proportion of the remaining viral-transduced targeted cell population must be considered in any functional connectivity study.

The noradrenergic locus coeruleus (LC) is a controller of brain and behavioral states. Activating LC neurons en masse by electrical or optogenetic stimulation promotes a stereotypical “activated” cortical state of high-frequency oscillations. However, it has been recently reported that spontaneous activity of LC cell pairs has sparse yet structured time-averaged cross-correlations, which is unlike the highly synchronous neuronal activity evoked by stimulation. Therefore, LC population activity could consist of distinct multicell ensembles each with unique temporal evolution of activity. We used nonnegative matrix factorization (NMF) to analyze large populations of simultaneously recorded LC single units in the rat LC. NMF identified ensembles of spontaneously coactive LC neurons and their activation time courses. Since LC neurons selectively project to specific forebrain regions, we hypothesized that distinct ensembles activate during different cortical states. To test this hypothesis, we calculated band-limited power and spectrograms of local field potentials in cortical area 24a aligned to spontaneous activations of distinct LC ensembles. A diversity of state modulations occurred around activation of different LC ensembles, including a typical activated state with increased high-frequency power as well as other states including decreased high-frequency power. Thus—in contrast to the stereotypical activated brain state evoked by en masse LC stimulation—spontaneous activation of distinct LC ensembles is associated with a multitude of cortical states.

A major debate about the neural correlates of conscious perception concerns its cortical organization, namely, whether it includes the prefrontal cortex (PFC), which mediates executive functions, or it is constrained within posterior cortices. It has been suggested that PFC activity during paradigms investigating conscious perception is conflated with post-perceptual processes associated with reporting the contents of consciousness or feedforward signals originating from exogenous stimulus manipulations and relayed via posterior cortical areas. We addressed this debate by simultaneously probing neuronal populations in the rhesus macaque (Macaca mulatta) PFC during a no-report paradigm, capable of instigating internally generated transitions in conscious perception, without changes in visual stimulation. We find that feature-selective prefrontal neurons are modulated concomitantly with subjective perception and perceptual suppression of their preferred stimulus during both externally induced and internally generated changes in conscious perception. Importantly, this enables reliable single-trial, population decoding of conscious contents. Control experiments confirm significant decoding of stimulus contents, even when oculomotor responses, used for inferring perception, are suppressed. These findings suggest that internally generated changes in the contents of conscious visual perception are reliably reflected within the activity of prefrontal populations in the absence of volitional reports or changes in sensory input., (© 2022. The Author(s).)

In the adult visual system, topographic reorganization of the primary visual cortex (V1) after retinal lesions has been extensively investigated. In contrast, the plasticity of higher order extrastriate areas following retinal lesions is less well studied. Here, we used fMRI to study reorganization of visual areas V2/V3 following the induction of permanent, binocular, homonymous retinal lesions in 4 adult macaque monkeys. We found that the great majority of voxels that did not show visual modulation on the day of the lesion in the V2/V3 lesion projection zone (LPZ) demonstrated significant visual modulations 2 weeks later, and the mean modulation strength remained approximately stable thereafter for the duration of our observations (4-5 months). The distribution of eccentricities of visually modulated voxels inside the V2/V3 LPZ spanned a wider range post-lesion than pre-lesion, suggesting that neurons inside the LPZ reorganize by receiving input either from the foveal or the peripheral border of the LPZ, depending on proximity. Overall, we conclude that area V2/V3 of adult rhesus macaques displays a significant capacity for topographic reorganization following retinal lesions markedly exceeding the corresponding capacity of area V1., 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 © 2022 Keliris, Shao, Schmid, Augath, Logothetis and Smirnakis.)

Water restriction is commonly used to motivate rodents to perform behavioral tasks; however, its effects on hydration and stress hormone levels are unknown. Here, we report daily body weight and bi-weekly packed red blood cell volume and corticosterone (CORT) in adult male rats across 80 days for three commonly used water restriction schedules. We also assessed renal adaptation to water restriction using postmortem histologic evaluation of renal medulla. A control group received ad libitum water. After one week of water restriction, rats on all restriction schedules resumed similar levels of growth relative to the control group. Normal hydration was observed, and water restriction did not drive renal adaptation. An intermittent restriction schedule was associated with an increase in CORT relative to the control group. However, intermittent restriction evokes a stress response which could affect behavioral and neurobiological results. Our results also suggest that stable motivation in behavioral tasks may only be achieved after one week of restriction., (Copyright © 2021 Vasilev et al.)

Digitized neuroanatomical atlases that can be overlaid onto functional data are crucial for localizing brain structures and analyzing functional networks identified by neuroimaging techniques. To aid in functional and structural data analysis, we have created a comprehensive parcellation of the rhesus macaque subcortex using a high-resolution ex vivo structural imaging scan. This anatomical scan and its parcellation were warped to the updated NIMH Macaque Template (NMT v2), an in vivo population template, where the parcellation was refined to produce the Subcortical Atlas of the Rhesus Macaque (SARM) with 210 primary regions-of-interest (ROIs). The subcortical parcellation and nomenclature reflect those of the 4 th edition of the Rhesus Monkey Brain in Stereotaxic Coordinates (Paxinos et al., in preparation), rather than proposing yet another novel atlas. The primary ROIs are organized across six spatial hierarchical scales from small, fine-grained ROIs to broader composites of multiple ROIs, making the SARM suitable for analysis at different resolutions and allowing broader labeling of functional signals when more accurate localization is not possible. As an example application of this atlas, we have included a functional localizer for the dorsal lateral geniculate (DLG) nucleus in three macaques using a visual flickering checkerboard stimulus, identifying and quantifying significant fMRI activation in this atlas region. The SARM has been made openly available to the neuroimaging community and can easily be used with common MRI data processing software, such as AFNI, where the atlas has been embedded into the software alongside cortical macaque atlases., Competing Interests: Declaration of Competing Interest The authors report no competing interest., (Copyright © 2021. Published by Elsevier Inc.)

Time series data sets often contain heterogeneous signals, composed of both continuously changing quantities and discretely occurring events. The coupling between these measurements may provide insights into key underlying mechanisms of the systems under study. To better extract this information, we investigate the asymptotic statistical properties of coupling measures between continuous signals and point processes. We first introduce martingale stochastic integration theory as a mathematical model for a family of statistical quantities that include the phase locking value, a classical coupling measure to characterize complex dynamics. Based on the martingale central limit theorem, we can then derive the asymptotic gaussian distribution of estimates of such coupling measure that can be exploited for statistical testing. Second, based on multivariate extensions of this result and random matrix theory, we establish a principled way to analyze the low-rank coupling between a large number of point processes and continuous signals. For a null hypothesis of no coupling, we establish sufficient conditions for the empirical distribution of squared singular values of the matrix to converge, as the number of measured signals increases, to the well-known Marchenko-Pastur (MP) law, and the largest squared singular value converges to the upper end of the MP support. This justifies a simple thresholding approach to assess the significance of multivariate coupling. Finally, we illustrate with simulations the relevance of our univariate and multivariate results in the context of neural time series, addressing how to reliably quantify the interplay between multichannel local field potential signals and the spiking activity of a large population of neurons., (© 2021 Massachusetts Institute of Technology.)

Functional magnetic resonance imaging (fMRI) is an extensively used method for the investigation of normal and pathological brain function. In particular, fMRI has been used to characterize spatiotemporal hemodynamic response to pharmacological challenges as a non-invasive readout of neuronal activity. However, the mechanisms underlying regional signal changes are yet unclear. In this study, we use a meta-analytic approach to converge data from microdialysis experiments with relative cerebral blood volume (rCBV) changes following acute administration of neuropsychiatric drugs in adult male rats. At whole-brain level, the functional response patterns show very weak correlation with neurochemical alterations, while for numerous brain areas a strong positive correlation with noradrenaline release exists. At a local scale of individual brain regions, the rCBV response to neurotransmitters is anatomically heterogeneous and, importantly, based on a complex interplay of different neurotransmitters that often exert opposing effects, thus providing a mechanism for regulating and fine tuning hemodynamic responses in specific regions.

The brainstem noradrenergic locus coeruleus (LC) is reciprocally connected with the prefrontal cortex (PFC). Coupling between LC spiking and the depolarizing phase of slow (1-2 Hz) waves in PFC field potentials during sleep and anesthesia suggests that LC drives cortical state transition. Reciprocal LC-PFC connectivity should also allow interactions in the opposing (top-down) direction, but prior work has only studied prefrontal control over LC activity using electrical or optogenetic stimulation. Here, we describe the physiological characteristics of spontaneously occurring top-down LC-PFC interactions. We recorded LC multiunit activity (MUA) simultaneously with PFC single-unit and local field potential (LFP) activity in urethane-anesthetized rats. We observed cross-regional coupling between the phase of 5-Hz oscillations in LC-MUA and the power of PFC LFP 60-200 Hz high γ (hγ). Transient increases in PFC hγ power preceded peaks in the 5-Hz LC-MUA oscillation. Analysis of cross-regional transfer entropy demonstrated that the PFC hγ transients were predictive of a transient increase in LC-MUA. An ∼29 ms delay between these signals was consistent with the conduction velocity from the PFC to the LC. Finally, we showed that PFC hγ transients are associated with synchronized spiking of a subset (27%) of PFC single units. Our data suggest that PFC hγ transients may indicate the timing of the top-down excitatory input to LC, at least under conditions when LC neuronal population activity fluctuates rhythmically at 5 Hz. Synchronized PFC neuronal spiking that occurs during hγ transients may provide a previously unknown mode of top-down control over the LC. NEW & NOTEWORTHY The prefrontal cortex (PFC) is thought to control activity in the noradrenergic locus coeruleus (LC). Prior anatomical and prefrontal stimulation studies demonstrated the potential for PFC-LC interactions; however, it is unknown what types of PFC activity affect the LC. Here, we show that transient increases in PFC high γ power and associated changes in PFC unit-pair synchrony are a potential sign of top-down control over the LC.

Cortical slow rhythmic activity, a hallmark of deep sleep, is observed under urethane anesthesia. Synchronized fluctuations of the membrane excitability of a large neuronal population are reflected in the extracellular Local Field Potential (LFP), as high-amplitude slow (∼1 Hz) oscillations (SO). The SO-phase indicates the presence (Up) or absence (Down) of neuronal spiking. The cortical state is controlled by the input from thalamic and neuromodulatory centers, including the brainstem noradrenergic nucleus Locus Coeruleus (LC). The bidirectional modulation of neuronal excitability by noradrenaline (NA) is well known. We have previously shown that LC phasic activation caused transient excitability increase in the medial prefrontal cortex (mPFC). In the present study, we characterized the effect of LC phasic activation on the prefrontal population dynamics at a temporal scale of a single SO cycle. We applied short (0.2 s) trains of electric pulses (0.02-0.05 mA at 20-50 Hz) to the LC cell bodies and monitored a broadband (0.1 Hz-8 kHz) mPFC LFP in urethane-anesthetized rats. The direct electrical stimulation of LC (LC-DES), applied during the Up-phase, enhanced the firing probability in the mPFC by ∼20% and substantially prolonged Up-states in 56% of trials. The LC-DES applied during Down-phase caused a rapid Down-to-Up transition in 81.5% of trials. The LC-DES was more effective at a higher frequency, but not at a higher current. Our results suggest that transient NA release, coupled to SO, may promote synaptic plasticity and memory consolidation by sustaining a depolarized state in the mPFC neurons., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

An alerting sound elicits the Acoustic Startle Response (ASR) that is dependent on the sound volume and organisms' state, which is regulated by neuromodulatory centers. The locus coeruleus (LC) neurons respond to salient stimuli and noradrenaline release affects sensory processing, including auditory. The LC hyperactivity is detrimental for sensorimotor gating. We report here that priming microstimulation of the LC (100-ms at 20, 50, and 100 Hz) attenuated the ASR in rats. The ASR reduction scaled with frequency and 100 Hz-stimulation mimicked pre-exposure to a non-startling tone (prepulse). A rapid (~ 40 ms) EEG desynchronization following the LC stimulation suggested that the ASR reduction was due to elevated cortical arousal. The effects of LC stimulation on the ASR and EEG were consistent with systematic relationships between the ASR, awake/sleep state, and the cortical arousal level; for that matter, a lower ASR amplitude corresponded to a higher arousal level. Thus, the LC appears to modulate the ASR circuit via its diffuse ascending projections to the forebrain saliency network. The LC modulation directly in the brainstem and/or spinal cord may also play a role. Our findings suggest the LC as a part of the brain circuitry regulating the ASR, while underlying neurophysiological mechanisms require further investigation.

The hippocampus has a major role in encoding and consolidating long-term memories, and undergoes plastic changes during sleep 1 . These changes require precise homeostatic control by subcortical neuromodulatory structures 2 . The underlying mechanisms of this phenomenon, however, remain unknown. Here, using multi-structure recordings in macaque monkeys, we show that the brainstem transiently modulates hippocampal network events through phasic pontine waves known as pontogeniculooccipital waves (PGO waves). Two physiologically distinct types of PGO wave appear to occur sequentially, selectively influencing high-frequency ripples and low-frequency theta events, respectively. The two types of PGO wave are associated with opposite hippocampal spike-field coupling, prompting periods of high neural synchrony of neural populations during periods of ripple and theta instances. The coupling between PGO waves and ripples, classically associated with distinct sleep stages, supports the notion that a global coordination mechanism of hippocampal sleep dynamics by cholinergic pontine transients may promote systems and synaptic memory consolidation as well as synaptic homeostasis.

Remarkable progress has come from whole-brain models linking anatomy and function. Paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. Neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. Here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. We demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dMRI], functional magnetic resonance imaging [fMRI], and positron electron tomography [PET]) to explain the functional effects of specific serotoninergic receptor (5-HT 2A R) stimulation with psilocybin in healthy humans. This advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. Overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Extensive in vivo imaging studies investigate the hippocampal neural network function, mainly focusing on the dorsal CA1 region given its optical accessibility. Multi-modality fMRI with simultaneous hippocampal electrophysiological recording reveal broad cortical correlation patterns, but the detailed spatial hippocampal functional map remains lacking given the limited fMRI resolution. In particular, hemodynamic responses linked to specific neural activity are unclear at the single-vessel level across hippocampal vasculature, which hinders the deciphering of the hippocampal malfunction in animal models and the translation to critical neurovascular coupling (NVC) patterns for human fMRI. We simultaneously acquired optogenetically-driven neuronal Ca 2+ signals with single-vessel blood-oxygen-level-dependent (BOLD) and cerebral-blood-volume (CBV)-fMRI from individual venules and arterioles. Distinct spatiotemporal patterns of hippocampal hemodynamic responses were correlated to optogenetically evoked and spreading depression-like calcium events. The calcium event-related single-vessel hemodynamic modeling revealed significantly reduced NVC efficiency upon spreading depression-like (SDL) events, providing a direct measure of the NVC function at various hippocampal states.

Thanks to their versatile magnetic and luminescence features, lanthanide complexes have gained a central position in biomedical imaging as magnetic resonance imaging (MRI) contrast agents and optical imaging probes. In addition, appropriate chemical design allows modification of the magnetic relaxation properties of Gd III complexes and the optical properties of visible- or near-infrared (NIR)-emitting lanthanide chelates upon interaction with various biomarkers, which makes them ideal candidates for the creation of responsive agents. In this Forum Article, we demonstrate such design principles as well as the difficulties encountered in the context of neurotransmitter (NT) detection. Lanthanide(III) complexes of a macrocyclic ligand incorporating a benzophenone chromophore and a monoazacrown ether (Ln L 3 ) have been synthesized as responsive probes to monitor amino acid NTs either in MRI (Ln = Gd) or in NIR optical detection (Ln = Nd or Yb). The parameters characterizing the water exchange and rotational dynamics of the gadolinium(III) complex were assessed by 17 O NMR and 1 H NMRD. In the presence of zwitterionic NTs, the inner-sphere water molecule is replaced by the carboxylate function of the NTs in the gadolinium(III) complex, leading to a decrease of the longitudinal relaxivity from 6.7 to 2-2.5 mM -1 s -1 (300 MHz and 37 °C). The apparent affinity constants range from K a = 35 for γ-aminobutyric acid (GABA) to 80 M -1 for glycine and glutamate, and there is no selectivity with respect to hydrogen carbonate ( K a = 232; pH 7.4). The gadolinium(III) complex interacts with human serum albumin (HSA), resulting in a 60% increase in the relaxivity (20 MHz, 37 °C) in the absence of NTs. The HSA-bound complex, however, was revealed to be less responsive to NTs because of displacement of the Gd III -bound water by HSA, which was confirmed by the hydration number calculated from luminescence lifetimes of the HSA-bound europium(III) complex. The creation of an imaging agent suitable for NIR detection of NTs for an enhanced sensitivity in biological systems using the benzophenone (BP) moiety as the sensitizer of lanthanide luminescence was also attempted. Upon excitation at 300 nm of the BP chromophore in aqueous solutions of Nd L 3 and Yb L 3 , characteristic NIR emissions of Nd III and Yb III were observed because of 4 F 3/2 → 4 I J ( J = 9 / 2 - 13 / 2 ) and 2 F 5/2 → 2 F 7/2 transitions, respectively, indicating that this chromophore is a suitable antenna. Despite these promising results, luminescence titrations of Nd III and Yb III complexes with NTs were not conclusive because of chemical conversion of the ligand triggered by light, preventing quantitative analysis. The observed photochemical reaction of the ligand is strongly dependent on the nature of the lanthanide chelated; it is considerably slowed down in the presence of Nd III and Eu III .

Cerebral ischemia is one of the leading causes of mortality and disability in infants and adults and its timely diagnosis is essential for an efficient treatment. We present a methodology for fast detection and real-time monitoring of fluctuations of calcium ions associated with focal ischemia using a molecular functional MRI approach. We used a dinuclear paramagnetic gadolinium(III) complex chelate that changes MR image contrast through its reversible interaction with extracellular calcium ions, while applying a remote transient middle cerebral artery occlusion as a model for ischemic stroke. Our method sensitively recognizes the onset and follows the dynamics of the ischemic core and penumbra with submillimeter spatial and second-scale temporal resolution, thus paving the way for noninvasive monitoring and development of targeted treatment strategies for cerebral ischemia., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

A fundamental problem in systems neuroscience is how to force a transition from one brain state to another by external driven stimulation in, for example, wakefulness, sleep, coma, or neuropsychiatric diseases. This requires a quantitative and robust definition of a brain state, which has so far proven elusive. Here, we provide such a definition, which, together with whole-brain modeling, permits the systematic study in silico of how simulated brain stimulation can force transitions between different brain states in humans. Specifically, we use a unique neuroimaging dataset of human sleep to systematically investigate where to stimulate the brain to force an awakening of the human sleeping brain and vice versa. We show where this is possible using a definition of a brain state as an ensemble of "metastable substates," each with a probabilistic stability and occurrence frequency fitted by a generative whole-brain model, fine-tuned on the basis of the effective connectivity. Given the biophysical limitations of direct electrical stimulation (DES) of microcircuits, this opens exciting possibilities for discovering stimulation targets and selecting connectivity patterns that can ensure propagation of DES-induced neural excitation, potentially making it possible to create awakenings from complex cases of brain injury., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Sexual arousal is a dynamical, highly coordinated neurophysiological process that is often induced by visual stimuli. Numerous studies have proposed that the cognitive processing stage of responding to sexual stimuli is the first stage, in which sex differences occur, and the divergence between men and women has been attributed to differences in the concerted activity of neural networks. The present comprehensive metaanalysis challenges this hypothesis and provides robust quantitative evidence that the neuronal circuitries activated by visual sexual stimuli are independent of biological sex. Sixty-one functional magnetic resonance imaging studies (1,850 individuals) that presented erotic visual stimuli to men and women of different sexual orientation were identified. Coordinate-based activation likelihood estimation was used to conduct metaanalyses. Sensitivity and clustering analyses of averaged neuronal response patterns were performed to investigate robustness of the findings. In contrast to neutral stimuli, sexual pictures and videos induce significant activations in brain regions, including insula, middle occipital, anterior cingulate and fusiform gyrus, amygdala, striatum, pulvinar, and substantia nigra. Cluster analysis suggests stimulus type as the most, and biological sex as the least, predictor for classification. Contrast analysis further shows no significant sex-specific differences within groups. Systematic review of sex differences in gray matter volume of brain regions associated with sexual arousal (3,723 adults) did not show any causal relationship between structural features and functional response to visual sexual stimuli. The neural basis of sexual arousal in humans is associated with sexual orientation yet, contrary to the widely accepted view, is not different between women and men., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Sensory input is inherently ambiguous but our brains achieve remarkable perceptual stability. Prior experience and knowledge of the statistical properties of the world are thought to play a key role in the stabilization process. Individual differences in responses to ambiguous input and biases toward one or the other interpretation could modulate the decision mechanism for perception. However, the role of perceptual bias and its interaction with stimulus spatial properties such as regularity and element density remain to be understood. To this end, we developed novel bi-stable moving visual stimuli in which perception could be parametrically manipulated between two possible mutually exclusive interpretations: transparently or coherently moving. We probed perceptual stability across three composite stimulus element density levels with normal or degraded regularity using a factorial design. We found that increased density led to the amplification of individual biases and consequently to a stabilization of one interpretation over the alternative. This effect was reduced for degraded regularity, demonstrating an interaction between density and regularity. To understand how prior knowledge could be used by the brain in this task, we compared the data with simulations coming from four different hierarchical models of causal inference. These models made different assumptions about the use of prior information by including conditional priors that either facilitated or inhibited motion direction integration. An architecture that included a prior inhibiting motion direction integration consistently outperformed the others. Our results support the hypothesis that direction integration based on sensory likelihoods maybe the default processing mode with conditional priors inhibiting integration employed in order to help motion segmentation and transparency perception.

Cognition fluctuates over relatively faster and slower timescales. This is enabled by dynamic interactions among cortical neurons over similarly diverse temporal and spatial scales. Fast and slow cognitive processes, such as reorienting to surprising stimuli or using experience to develop a behavioral strategy, are also sensitive to neuromodulation by the diffusely-projecting brainstem noradrenergic nucleus, Locus Coeruleus. However, while a dynamic, multi-scale cortical ensemble code influences cognition over multiple timescales, it is unknown to what extent LC neuronal activity operates in this regime. An ensemble code within the LC may permit an interface with cortical ensembles allowing noradrenergic modulation of fast and slow cognitive processes. Alternatively, given that LC neurons are thought to spike synchronously, there may be a mismatch between LC and cortical neuronal codes that constrains how the noradrenergic system can influence cognition. We review new evidence that clearly demonstrates cell type-specific ensemble activity within LC occurring over a range of behaviorally-relevant timescales. We also review recent studies demonstrating that sub-sets of LC neurons modulate specific forebrain targets to control behavior. A critical target for future research is to study the temporal dynamics of projection-specific LC ensembles, their interactions with cortical networks, and the relevance of multi-scale coerular-cortical dynamics to behaviors over various timescales., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Damage to the primary visual cortex (V1) leads to a visual field loss (scotoma) in the retinotopically corresponding part of the visual field. Nonetheless, a small amount of residual visual sensitivity persists within the blind field. This residual capacity has been linked to activity observed in the middle temporal area complex (V5/MT+). However, it remains unknown whether the organization of hV5/MT+ changes following early visual cortical lesions. We studied the organization of area hV5/MT+ of five patients with dense homonymous defects in a quadrant of the visual field as a result of partial V1+ or optic radiation lesions. To do so, we developed a new method, which models the boundaries of population receptive fields directly from the BOLD signal of each voxel in the visual cortex. We found responses in hV5/MT+ arising inside the scotoma for all patients and identified two possible sources of activation: 1) responses might originate from partially lesioned parts of area V1 corresponding to the scotoma, and 2) responses can also originate independent of area V1 input suggesting the existence of functional V1-bypassing pathways. Apparently, visually driven activity observed in hV5/MT+ is not sufficient to mediate conscious vision. More surprisingly, visually driven activity in corresponding regions of V1 and early extrastriate areas including hV5/MT+ did not guarantee visual perception in the group of patients with post-geniculate lesions that we examined. This suggests that the fine coordination of visual activity patterns across visual areas may be an important determinant of whether visual perception persists following visual cortical lesions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The noninvasive estimation of neuronal receptive field (RF) properties in vivo allows a detailed understanding of brain organization as well as its plasticity by longitudinal following of potential changes. Visual RFs measured invasively by electrophysiology in animal models have traditionally provided a great extent of our current knowledge about the visual brain and its disorders. Voxel-based estimates of population RF (pRF) by functional magnetic resonance imaging (fMRI) in humans revolutionized the field and have been used extensively in numerous studies. However, current methods cannot estimate single-neuron RF sizes as they reflect large populations of neurons with individual RF scatter. Here, we introduce an approach to estimate RF size using spatial frequency selectivity to checkerboard patterns. This method allowed us to obtain noninvasive, average single-neuron RF estimates over a large portion of human early visual cortex. These estimates were significantly smaller compared with prior pRF methods. Furthermore, fMRI and electrophysiology experiments in nonhuman primates demonstrated an exceptionally good match, validating the approach., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Discovering neural correlates of subjective perception and dissociating them from sensory input has fascinated neuroscientists for a long time. Bistable and multistable perception phenomena have exhibited great experimental potential to address this question. Here, we performed electrophysiological recordings from single neurons in lateral intraparietal area (LIP) of rhesus macaques during stimulus and perceptual transitions induced by binocular flash suppression (BFS). LIP neurons demonstrated transient bursts of activity after stimulus presentation and stimulus or perceptual switches but only a minority of cells demonstrated stimulus and perceptual selectivity. To enhance LIP neural selectivity, we performed a second experiment in which the competing stimuli were associated with asymmetric rewards. We found that transient and sustained activities substantially increased while the proportion of stimulus selective neurons remained approximately the same, albeit with increased selectivity magnitude. In addition, we observed mild increases in the proportion of perceptually selective neurons which also showed increase magnitude of selectivity. Importantly, the increased selectivity of cells after the reward manipulation was not directly reflecting the reward size per se but an enhancement in stimulus differentiation. Based on our results, we conjecture that LIP contributes to perceptual transitions and serves a modulatory role in perceptual selection taking into account the stimulus behavioral value.

Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal-prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus and the mPFC at different stages of information processing. Here, we characterized, in freely behaving Sprague Dawley male rats, the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal-cortical information transfer. Overall, the MD firing rate was transiently (0.76 ± 0.06 s) decreased around ripples, with the MD activity suppression preceding the ripple onset for 0.41 ± 0.04 s (range, 0.01-0.95 s). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal-cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During non-rapid eye movement sleep, MD firing rate decreased around spindle-uncoupled ripples, but increased around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamocortical and hippocampal-cortical networks supporting "on-line" and "off-line" information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay, as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments. SIGNIFICANCE STATEMENT Systems mechanisms of declarative memory consolidation beyond the hippocampal-prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extrahippocampal regions and with medial prefrontal cortex underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in "off-line" consolidation. We found that MD neural activity was transiently suppressed around hippocampal ripples, except for ripples co-occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay, as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer., (Copyright © 2019 the authors 0270-6474/19/390434-11$15.00/0.)

Cholinergic neuromodulation is involved in all aspects of sensory processing and is crucial for processes such as attention, learning and memory, etc. However, despite the known roles of acetylcholine (ACh), we still do not how to disentangle ACh contributions from sensory or task-evoked changes in functional magnetic resonance imaging (fMRI). Here, we investigated the effects of local injection of ACh on fMRI and neural signals in the primary visual cortex (V1) of anesthetized macaques by combining pharmaco-based MRI (phMRI) with electrophysiological recordings, using single electrodes and electrode arrays. We found that local injection of ACh elicited two distinct profiles of fMRI and neurophysiological activity, depending on the distance from the injector. Near the injection site, we observed an increase in the baseline blood oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) responses, while their visual modulation decreased. In contrast, further from the injection site, we observed an increase in the visually induced BOLD and CBF modulation without changes in baseline. Neurophysiological recordings suggest that the spatial correspondence between fMRI responses and neural activity does not change in the gamma, high-gamma, and multiunit activity (MUA) bands. The results near the injection site suggest increased inhibitory drive and decreased metabolism, contrasting to the far region. These changes are thought to reflect the kinetics of ACh and its metabolism to choline., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Hippocampal ripple oscillations likely support reactivation of memory traces that manifest themselves as temporally organized spiking of sparse neuronal ensembles. However, the network mechanisms concurring to achieve this function are largely unknown. We designed a multi-compartmental model of the CA3-CA1 subfields to generate biophysically realistic ripple dynamics from the cellular level to local field potentials. Simulations broadly parallel in vivo observations and support that ripples emerge from CA1 pyramidal spiking paced by recurrent inhibition. In addition to ripple oscillations, key coordination mechanisms involve concomitant aspects of network activity. Recurrent synaptic interactions in CA1 exhibit slow-gamma band coherence with CA3 input, thus offering a way to coordinate CA1 activities with CA3 inducers. Moreover, CA1 feedback inhibition controls the content of spontaneous replay during CA1 ripples, forming new mnemonic representations through plasticity. These insights are consistent with slow-gamma interactions and interneuronal circuit plasticity observed in vivo, suggesting a multifaceted ripple-related replay phenomenon., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The role of lateral prefrontal cortex (LPFC) in mediating conscious perception has been recently questioned due to potential confounds resulting from the parallel operation of task related processes. We have previously demonstrated encoding of contents of visual consciousness in LPFC neurons during a no-report task involving perceptual suppression. Here, we report a separate LPFC population that exhibits task-phase related activity during the same task. The activity profile of these neurons could be captured as canonical response patterns (CRPs), with their peak amplitudes sequentially distributed across different task phases. Perceptually suppressed visual input had a negligible impact on sequential firing and functional connectivity structure. Importantly, task-phase related neurons were functionally segregated from the neuronal population, which encoded conscious perception. These results suggest that neurons exhibiting task-phase related activity operate in the LPFC concurrently with, but segregated from neurons representing conscious content during a no-report task involving perceptual suppression., Competing Interests: The authors declare no competing interests.

Neuropsychiatric disorders are the third leading cause of global disease burden. Current pharmacological treatment for these disorders is inadequate, with often insufficient efficacy and undesirable side effects. One reason for this is that the links between molecular drug action and neurobehavioral drug effects are elusive. We use a big data approach from the neurotransmitter response patterns of 258 different neuropsychiatric drugs in rats to address this question. Data from experiments comprising 110,674 rats are presented in the Syphad database [ www.syphad.org ]. Chemoinformatics analyses of the neurotransmitter responses suggest a mismatch between the current classification of neuropsychiatric drugs and spatiotemporal neurostransmitter response patterns at the systems level. In contrast, predicted drug-target interactions reflect more appropriately brain region related neurotransmitter response. In conclusion the neurobiological mechanism of neuropsychiatric drugs are not well reflected by their current classification or their chemical similarity, but can be better captured by molecular drug-target interactions.

Understanding the underlying mechanisms of the human brain in health and disease will require models with necessary and sufficient details to explain how function emerges from the underlying anatomy and is shaped by neuromodulation. Here, we provide such a detailed causal explanation using a whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical data from diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) with neurotransmitter data obtained with positron emission tomography (PET) of the detailed serotonin 2A receptor (5-HT 2A R) density map. This allowed us to model the resting state (with and without concurrent music listening) and mechanistically explain the functional effects of 5-HT 2A R stimulation with lysergic acid diethylamide (LSD) on healthy participants. The whole-brain model used a dynamical mean-field quantitative description of populations of excitatory and inhibitory neurons as well as the associated synaptic dynamics, where the neuronal gain function of the model is modulated by the 5-HT 2A R density. The model identified the causative mechanisms for the non-linear interactions between the neuronal and neurotransmitter system, which are uniquely linked to (1) the underlying anatomical connectivity, (2) the modulation by the specific brainwide distribution of neurotransmitter receptor density, and (3) the non-linear interactions between the two. Taking neuromodulatory activity into account when modeling global brain dynamics will lead to novel insights into human brain function in health and disease and opens exciting possibilities for drug discovery and design in neuropsychiatric disorders., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Diffuse projections of locus coeruleus (LC) neurons and evidence of synchronous spiking have long been perceived as features of global neuromodulation. Recent studies demonstrated the possibility of targeted modulation by subsets of LC neurons. Non-global neuromodulation depends on target specificity and the differentiated spatiotemporal dynamics within LC. Here, we characterized interactions between 3,164 LC cell pairs in the rat LC under urethane anesthesia. Spike count correlations were near zero and only a small proportion of unit pairs had synchronized spontaneous (15%) or evoked (16%) discharge. We identified infra-slow (0.01-1 Hz) fluctuations of LC unit spike rate, which were also asynchronous across the population. Despite overall sparse population synchrony, we report the existence of LC ensembles and relate them to forebrain projection targets. We also show that spike waveform width was related to ensemble membership, propensity for synchronization, and interactions with cortex. Our findings suggest a partly differentiated and target-specific noradrenergic signal., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Correlated fluctuations of single neuron discharges, on a mesoscopic scale, decrease as a function of lateral distance in early sensory cortices, reflecting a rapid spatial decay of lateral connection probability and excitation. However, spatial periodicities in horizontal connectivity and associational input as well as an enhanced probability of lateral excitatory connections in the association cortex could theoretically result in nonmonotonic correlation structures. Here, we show such a spatially nonmonotonic correlation structure, characterized by significantly positive long-range correlations, in the inferior convexity of the macaque prefrontal cortex. This functional connectivity kernel was more pronounced during wakefulness than anesthesia and could be largely attributed to the spatial pattern of correlated variability between functionally similar neurons during structured visual stimulation. These results suggest that the spatial decay of lateral functional connectivity is not a common organizational principle of neocortical microcircuits. A nonmonotonic correlation structure could reflect a critical topological feature of prefrontal microcircuits, facilitating their role in integrative processes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

The locus coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory responses. The impact of phasic NE release on cortical activity and sensory processing is less explored. We previously reported that LC microstimulation caused a transient desynchronization of population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli. The LC receives nociceptive information from the medulla and therefore may mediate sensory signaling to its forebrain targets. Here we performed extracellular recordings in LC and mPFC while presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust phasic response in the LC and a transient change in the mPFC power spectrum, with the strongest modulation in the gamma (30-90 Hz) range. The LC phasic response preceded prefrontal gamma power increase, and cortical modulation was proportional to the LC excitation. We also quantitatively characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic injection of clonidine, an α 2 -adrenoreceptor agonist, completely eliminated sensory responses in the mPFC without shifting cortex to a less excitable state. Together, our results suggest that the LC phasic response induces gamma power increase in the PFC and is essential for mediating sensory information along an ascending noxious pathway. NEW & NOTEWORTHY Our study shows linear relationships between locus coeruleus phasic excitation and the amplitude of gamma oscillations in the prefrontal cortex. Results suggest that the locus coeruleus phasic response is essential for mediating sensory information along an ascending noxious pathway.

Spatial navigation depends on the hippocampal function, but also requires bidirectional interactions between the hippocampus (HPC) and the prefrontal cortex (PFC). The cross-regional communication is typically regulated by critical nodes of a distributed brain network. The thalamic nucleus reuniens (RE) is reciprocally connected to both HPC and PFC and may coordinate the information flow within the HPC-PFC pathway. Here we examined if RE activity contributes to the spatial memory consolidation. Rats were trained to find reward following a complex trajectory on a crossword-like maze. Immediately after each of the five daily learning sessions the RE was reversibly inactivated by local injection of muscimol. The post-training RE inactivation affected neither the spatial task acquisition nor the memory retention, which was tested after a 20-d "forgetting" period. In contrast, the RE inactivation in well-trained rats prior to the maze exposure impaired the task performance without affecting locomotion or appetitive motivation. Our results support the role of the RE in memory retrieval and/or "online" processing of spatial information, but do not provide evidence for its engagement in "off-line" processing, at least within a time window immediately following learning experience., (© 2018 Mei et al.; Published by Cold Spring Harbor Laboratory Press.)

Neural oscillations are ubiquitously observed in cortical activity, and are widely believed to be crucial for mediating transmission of information across the cortex. Yet, the neural phenomena contributing to each oscillation band, and their effect on information coding and transmission, are largely unknown. Here, we investigated whether individual frequency bands specifically reflect changes in the concentrations of dopamine, an important neuromodulator, and how dopamine affects oscillatory information processing. We recorded the local field potential (LFP) at different depths of primary visual cortex (V1) in anesthetized monkeys (Macaca mulatta) during spontaneous activity and during visual stimulation with Hollywood movie clips while pharmacologically mimicking dopaminergic neuromodulation by systemic injection of L-DOPA (a metabolic precursor of dopamine). We found that dopaminergic neuromodulation had marked effects on both spontaneous and movie-evoked neural activity. During spontaneous activity, dopaminergic neuromodulation increased the power of the LFP specifically in the [19-38 Hz] band, suggesting that the power of endogenous visual cortex oscillations in this band can be used as a robust marker of dopaminergic neuromodulation. Moreover, dopamine increased visual information encoding over all frequencies during movie stimulation. The information increase due to dopamine was prominent in the supragranular layers of cortex that project to higher cortical areas and in the gamma [50-100 Hz] band that has been previously implicated in mediating feedforward information transfer. These results thus individuate new neural mechanisms by which dopamine may promote the readout of relevant sensory information by strengthening the transmission of information from primary to higher areas., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Functional brain development is not well understood. In the visual system, neurophysiological studies in nonhuman primates show quite mature neuronal properties near birth although visual function is itself quite immature and continues to develop over many months or years after birth. Our goal was to assess the relative development of two main visual processing streams, dorsal and ventral, using BOLD fMRI in an attempt to understand the global mechanisms that support the maturation of visual behavior. Seven infant macaque monkeys (Macaca mulatta) were repeatedly scanned, while anesthetized, over an age range of 102 to 1431 days. Large rotating checkerboard stimuli induced BOLD activation in visual cortices at early ages. Additionally we used static and dynamic Glass pattern stimuli to probe BOLD responses in primary visual cortex and two extrastriate areas: V4 and MT-V5. The resulting activations were analyzed with standard GLM and multivoxel pattern analysis (MVPA) approaches. We analyzed three contrasts: Glass pattern present/absent, static/dynamic Glass pattern presentation, and structured/random Glass pattern form. For both GLM and MVPA approaches, robust coherent BOLD activation appeared relatively late in comparison to the maturation of known neuronal properties and the development of behavioral sensitivity to Glass patterns. Robust differential activity to Glass pattern present/absent and dynamic/static stimulus presentation appeared first in V1, followed by V4 and MT-V5 at older ages; there was no reliable distinction between the two extrastriate areas. A similar pattern of results was obtained with the two analysis methods, although MVPA analysis showed reliable differential responses emerging at later ages than GLM. Although BOLD responses to large visual stimuli are detectable, our results with more refined stimuli indicate that global BOLD activity changes as behavioral performance matures. This reflects an hierarchical development of the visual pathways. Since fMRI BOLD reflects neural activity on a population level, our results indicate that, although individual neurons might be adult-like, a longer maturation process takes place on a population level.