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The hippocampus has a major role in encoding and consolidating long-term memories, and undergoes plastic changes during sleep1. These changes require precise homeostatic control by subcortical neuromodulatory structures2. 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.

Reports advances in the scientific study of visual perception. Examples derived from the painting 'Old Age, Adolescence, Infancy,' by Salvador Dali; Discussion of consciousness as a concept; Implications of ambiguous visual stimuli; Insight gleaned from studies of neural activity in animals; Details of the anatomy of the eye and the visual centers of the brain; Call for more research into brain activity and its relationship to visual perception. INSETS: How to Experience Binocular Rivalry;Keeping Moneys (and Experimenters) Honest.

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 GdIIIcomplexes 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 (LnL3) 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 17O NMR and 1H 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–1s–1(300 MHz and 37 °C). The apparent affinity constants range from Ka= 35 for γ-aminobutyric acid (GABA) to 80 M–1for glycine and glutamate, and there is no selectivity with respect to hydrogen carbonate (Ka= 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 GdIII-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 NdL3and YbL3, characteristic NIR emissions of NdIIIand YbIIIwere observed because of 4F3/2→ 4IJ(J= 9/2–13/2) and 2F5/2→ 2F7/2transitions, respectively, indicating that this chromophore is a suitable antenna. Despite these promising results, luminescence titrations of NdIIIand YbIIIcomplexes 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 NdIIIand EuIII.

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 (ΔCMRO2) may reflect neural cortical function better than BOLD fMRI, but it is unknown whether the calibrated BOLD model for functional CMRO2measurement remains valid at high resolution. Here, we measure laminar ΔCMRO2elicited by visual stimulation in macaque primary visual cortex (V1) and find that ΔCMRO2peaks in the middle of the cortex, in agreement with autoradiographic measures of metabolism. ΔCMRO2values in gray matter are similar as found previously. Reductions in CMRO2are 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 ΔCMRO2measurement, providing a physiologically meaningful metric of laminar functional metabolism.

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.

Experience-induced replay of neuronal ensembles occurs during hippocampal high-frequency oscillations, or ripples. Post-learning increase in ripple rate is predictive of memory recall, while ripple disruption impairs learning. Ripples may thus present a fundamental component of a neurophysiological mechanism of memory consolidation. In addition to system-level local and cross-regional interactions, a consolidation mechanism involves stabilization of memory representations at the synaptic level. Synaptic plasticity within experience-activated neuronal networks is facilitated by noradrenaline release from the axon terminals of the locus coeruleus (LC). Here, to better understand interactions between the system and synaptic mechanisms underlying “off-line” consolidation, we examined the effects of ripple-associated LC activation on hippocampal and cortical activity and on spatial memory. Rats were trained on a radial maze; after each daily learning session neural activity was monitored for 1 h via implanted electrode arrays. Immediately following “on-line” detection of ripple, a brief train of electrical pulses (0.05 mA) was applied to LC. Low-frequency (20 Hz) stimulation had no effect on spatial learning, while higher-frequency (100 Hz) trains transiently blocked generation of ripple-associated cortical spindles and caused a reference memory deficit. Suppression of synchronous ripple/spindle events appears to interfere with hippocampal-cortical communication, thereby reducing the efficiency of “off-line” memory consolidation.

Natural and behaviorally relevant sounds are characterized by temporal modulations of their waveforms, which carry important cues for sound segmentation and communication. Still, there is little consensus as to how this temporal information is represented in auditory cortex. Here, by using functional magnetic resonance imaging (fMRI) optimized for studying the auditory system, we report the existence of a topographically ordered spatial representation of temporal sound modulation rates in human auditory cortex. We found a topographically organized sensitivity within auditory cortex to sounds with varying modulation rates, with enhanced responses to lower modulation rates (2 and 4 Hz) on lateral parts of Heschl's gyrus (HG) and faster modulation rates (16 and 32 Hz) on medial HG. The representation of temporal modulation rates was distinct from the representation of sound frequencies (tonotopy) that was orientated roughly orthogonal. Moreover, the combination of probabilistic anatomical maps with a previously proposed functional delineation of auditory fields revealed that the distinct maps of temporal and spectral sound features both prevail within two presumed primary auditory fields hA1 and hR. Our results reveal a topographically ordered representation of temporal sound cues in human primary auditory cortex that is complementary to maps of spectral cues. They thereby enhance our understanding of the functional parcellation and organization of auditory cortical processing.

Functional Magnetic Resonance Imaging (fMRI) has quickly grown into one of the most important tools for studying brain function, especially in humans. Despite its prevalence, we still do not have a clear picture of what exactly the blood oxygenation level dependent (BOLD) signal represents or how it compares to the signals obtained with other methods (e.g., electrophysiology). We particularly refer to single neuron recordings and electroencephalography when we mention ‘electrophysiological methods’, given that these methods have been used for more than 50 years, and have formed the basis of much of our current understanding of brain function. Brain function involves the coordinated activity of many different areas and many different cell types that can participate in an enormous variety of processes (neural firing, inhibitory and excitatory synaptic activity, neuromodulation, oscillatory activity, etc.). Of these cells and processes, only a subset is sampled with electrophysiological techniques, and their contribution to the recorded signals is not exactly known. Functional imaging signals are driven by the metabolic needs of the active cells, and are most likely also biased toward certain cell types and certain neural processes, although we know even less about which processes actually drive the hemodynamic response. This article discusses the current status on the interpretation of the BOLD signal and how it relates to neural activity measured with electrophysiological techniques. WIREs Cogn Sci2012, 3:75–86. doi: 10.1002/wcs.153

The synthesis of two gadolinium(III) complexes that exhibit an increase in proton relaxivity in the presence of added Ca2+or Zn2+ions is reported. The complexes increase their hydration state from zero to one following metal‐ion binding, confirmed by spectral measurements on the corresponding EuIIIcomplexes. At a field of 1.4 T and 310 K, modulation of relaxivity of the order of 30–40 % was observed in mouse serum in each case. The dissociation constants for Ca2+and Zn2+binding were sensitive to the presence of added bicarbonate, and were 450 μM(Ca2+) and 200 μM(Zn2+) in serum. Such systems may, therefore, be considered for use as magnetic resonance imaging (MRI) contrast agents to track the restoration of changes in metal‐ion concentration in the cerebrospinal fluid of the brain, following neural stimulation.

Two DO3Abased ligands appended with the propylphosphonate side arm and their Ln3+complexes were investigated. Proton relaxometric in vitro studies at 20 MHz and 60 MHz and 37 °C of the Gd3+complex containing free acid exhibited relative changes of up to 56  in r1relaxivity when the pH of the medium was changed from 4 to 7. This change is explained by the decrease in the number of coordinated water molecules from two to one. Temperaturedependent relaxivity and NMRD profiles of Gd3+complexes showed a fast water exchange and a slightly increased rotational correlation time, which is characteristic of phosphonatecontaining compounds. Thermodynamic and kinetic studies of the Gd3+and Eu3+complexes were performed by means of potentiometry and luminescence spectroscopy. The results indicate that the thermodynamic stability and kinetic inertness of these complexes are sufficient for their in vivo application. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

The article discusses the role of visual perception in consciousness. Visual ambiguities are discussed. The processing of vision in the brain, including processing in the areas of the lateral geniculate nuclei, the primary visual cortex, and the inferior temporal cortex, is discussed. The authors describe experiments they conducted that studied how consciousness arises from neuronal activity. Binocular rivalry and visual discrimination are discussed.

Magnetic resonance imaging (MRI) has rapidly become an important tool in clinical medicine and biological research. Its functional variant (functional magnetic resonance imaging; fMRI) is currently the most widely used method for brain mapping and studying the neural basis of human cognition. While the method is widespread, there is insufficient knowledge of the physiological basis of the fMRI signal to interpret the data confidently with respect to neural activity. This paper reviews the basic principles of MRI and fMRI, and subsequently discusses in some detail the relationship between the blood–oxygen–level–dependent (BOLD) fMRI signal and the neural activity elicited during sensory stimulation. To examine this relationship, we conducted the first simultaneous intracortical recordings of neural signals and BOLD responses. Depending on the temporal characteristics of the stimulus, a moderate to strong correlation was found between the neural activity measured with microelectrodes and the BOLD signal averaged over a small area around the microelectrode tips. However, the BOLD signal had significantly higher variability than the neural activity, indicating that human fMRI combined with traditional statistical methods underestimates the reliability of the neuronal activity. To understand the relative contribution of several types of neuronal signals to the haemodynamic response, we compared local field potentials (LFPs), single– and multi–unit activity (MUA) with high spatio–temporal fMRI responses recorded simultaneously in monkey visual cortex. At recording sites characterized by transient responses, only the LFP signal was significantly correlated with the haemodynamic response. Furthermore, the LFPs had the largest magnitude signal and linear systems analysis showed that the LFPs were better than the MUAs at predicting the fMRI responses. These findings, together with an analysis of the neural signals, indicate that the BOLD signal primarily measures the input and processing of neuronal information within a region and not the output signal transmitted to other brain regions.

Consciousness is a difficult concept to define, much less to study. Neuroscientists have made impressive progress toward understanding the complex patterns of activity that occur in nerve cells, or neurons, in the brain. As Nobel laureate Francis Crick of the Salk Institute for Biological Studies and Christof Koch of the California Institute of Technology have argued, the problem of consciousness can be broken down into several separate questions, some of which can be subjected to scientific inquiry. Perceptual ambiguity is not a whimsical behavior specific to the organization of the visual system. Rather it tells us something about the organization of the entire brain and its way of making us aware of all sensory information. We investigate ambiguities that result when two different visual patterns are presented simultaneously to each eye, a phenomenon called binocular rivalry. A critic might object that the changing perceptions that monkeys report during binocular rivalry could be caused by the brain suppressing visual information at the start of the visual pathway, first from one eye and then from the other, so that the brain perceives a single image at any given time. These findings reveal several things about visual awareness. They show that we are unaware of a great deal of activity in our brains. INSETS: HOW TO EXPERIENCE BINOCULAR RIVALRY;KEEPING MONKEYS (AND EXPERIMENTERS) HONEST.

Abstract:  Saccadic eye movements in primates continually shift the location at which a given stimulus strikes the retina. Even during periods of steady fixation, microsaccades frequently jerk the center of gaze by small but resolvable distances, yet perception remains stable and continuous, uninterrupted by sudden jumps or shifts. The effect of such fixational eye movements on the activity of single neurons was examined in several regions of the visual cortex in macaque monkeys. We found that the firing of many neurons in striate and extrastriate cortex is profoundly influenced by saccades much smaller than the neurons’ receptive fields. In striate cortex (V1) many cells showed a transient decrease in their firing shortly following a saccade. In sharp contrast, cells in the extrastriate areas V2 and V4 showed strong excitatory responses that closely coincided in time with the striate depression. No appreciable activity change was observed in the inferotemporal cortex (IT) following saccades. This activity pattern is consistent with the notion that topographic extrastriate areas receive extraretinal input associated with saccadic events. Such signals may be necessary for the stable perception of objects and scenes during eye movements, mediating the mapping between central object representations and the constantly changing retinotopic input.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03068-9.

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