The activity-regulated cytoskeletal-associated protein/activity regulated gene (Arc/Arg3.1) is crucial for long-term synaptic plasticity and memory formation. However, the neurophysiological substrates of memory deficits occurring in the absence of Arc/Arg3.1 are unknown. We compared hippocampal CA1 single-unit and local field potential (LFP) activity in Arc/Arg3.1 knockout and wild-type mice during track running and flanking sleep periods. Locomotor activity, basic firing and spatial coding properties of CA1 cells in knockout mice were not different from wild-type mice. During active behavior, however, knockout animals showed a significantly shifted balance in LFP power, with a relative loss in high-frequency (beta-2 and gamma) bands compared to low-frequency bands. Moreover, during track-running, knockout mice showed a decrease in phase locking of spiking activity to LFP oscillations in theta, beta and gamma bands. Sleep architecture in knockout mice was not grossly abnormal. Sharp-wave ripples, which have been associated with memory consolidation and replay, showed only minor differences in dynamics and amplitude. Altogether, these findings suggest that Arc/Arg3.1 effects on memory formation are not only manifested at the level of molecular pathways regulating synaptic plasticity, but also at the systems level. The disrupted power balance in theta, beta and gamma rhythmicity and concomitant loss of spike-field phase locking may affect memory encoding during initial storage and memory consolidation stages.

Spatial navigation and memory depend on the neural coding of an organism's location. Fine-grained coding of location is thought to depend on the hippocampus. Likewise, animals benefit from knowledge parsing their environment into larger spatial segments, which are relevant for task performance. Here we investigate how such knowledge may be coded, and whether this occurs in structures in the temporal lobe, supplying cortical inputs to the hippocampus. We found that neurons in the perirhinal cortex of rats generate sustained firing patterns that discriminate large segments of the task environment. This contrasted to transient firing in hippocampus and sensory neocortex. These spatially extended patterns were not explained by task variables or temporally discrete sensory stimuli. Previously it has been suggested that the perirhinal cortex is part of a pathway processing object, but not spatial information. Our results indicate a greater complexity of neural coding than captured by this dichotomy.

To study the heritability of different training stages of appetitive operant conditioning, we carried out behavioral screening of 5 standard inbred mouse strains, 28 recombinant-inbred (BxD) mouse lines and their progenitor strains C57BL/6J and DBA/2J. We also computed correlations between successive training stages to study whether learning deficits at an advanced stage of operant conditioning may be dissociated from normal performance in preceding phases of training. The training consisted of two phases: an operant nose poking (NP) phase, in which mice learned to collect a sucrose pellet from a food magazine by NP, and an operant lever press and NP phase, in which mice had to execute a sequence of these two actions to collect a food pellet. As a measure of magazine oriented exploration, we also studied the nose poke entries in the food magazine during the intertrial intervals at the beginning of the first session of the nose poke training phase. We found significantly heritable components in initial magazine checking behavior, operant NP and lever press-NP. Performance levels in these phases were positively correlated, but several individual strains were identified that showed poor lever press-NP while performing well in preceding training stages. Quantitative trait loci mapping revealed suggestive likelihood ratio statistic peaks for initial magazine checking behavior and lever press-NP. These findings indicate that consecutive stages toward more complex operant behavior show significant heritable components, as well as dissociability between stages in specific mouse strains. These heritable components may reside in different chromosomal areas.

Primary sensory areas constitute crucial nodes during perceptual decision making. However, it remains unclear to what extent they mainly constitute a feedforward processing step, or rather are continuously involved in a recurrent network together with higher-order areas. We found that the temporal window in which primary visual cortex is required for the detection of identical visual stimuli was extended when task demands were increased via an additional sensory modality that had to be monitored. Late-onset optogenetic inactivation preserved bottom-up, early-onset responses which faithfully encoded stimulus features, and was effective in impairing detection only if it preceded a late, report-related phase of the cortical response. Increasing task demands were marked by longer reaction times and the effect of late optogenetic inactivation scaled with reaction time. Thus, independently of visual stimulus complexity, multisensory task demands determine the temporal requirement for ongoing sensory-related activity in V1, which overlaps with report-related activity.

Cortical computations require coordination of neuronal activity within and across multiple areas. We characterized spiking relationships within and between areas by quantifying coupling of single neurons to population firing patterns. Single-neuron population coupling (SNPC) was investigated using ensemble recordings from hippocampal CA1 region and somatosensory, visual, and perirhinal cortices. Within-area coupling was heterogeneous across structures, with area CA1 showing higher levels than neocortical regions. In contrast to known anatomical connectivity, between-area coupling showed strong firing coherence of sensory neocortices with CA1, but less with perirhinal cortex. Cells in sensory neocortices and CA1 showed positive correlations between within- and between-area coupling; these were weaker for perirhinal cortex. All four areas harbored broadcasting cells, connecting to multiple external areas, which was uncorrelated to within-area coupling strength. When examining correlations between SNPC and spatial coding, we found that, if such correlations were significant, they were negative. This result was consistent with an overall preservation of SNPC across different brain states, suggesting a strong dependence on intrinsic network connectivity. Overall, SNPC offers an important window on cell-to-population synchronization in multi-area networks. Instead of pointing to specific information-coding functions, our results indicate a primary function of SNPC in dynamically organizing communication in systems composed of multiple, interconnected areas.

Neurons in primary visual cortex (V1) may not only signal current visual input but also relevant contextual information such as reward expectancy and the subject's spatial position. Such contextual representations need not be restricted to V1 but could participate in a coherent mapping throughout sensory cortices. Here, we show that spiking activity coherently represents a location-specific mapping across auditory cortex (AC) and lateral, secondary visual cortex (V2L) of freely moving rats engaged in a sensory detection task on a figure-8 maze. Single-unit activity of both areas showed extensive similarities in terms of spatial distribution, reliability, and position coding. Importantly, reconstructions of subject position based on spiking activity displayed decoding errors that were correlated between areas. Additionally, we found that head direction, but not locomotor speed or head angular velocity, was an important determinant of activity in AC and V2L. By contrast, variables related to the sensory task cues or to trial correctness and reward were not markedly encoded in AC and V2L. We conclude that sensory cortices participate in coherent, multimodal representations of the subject's sensory-specific location. These may provide a common reference frame for distributed cortical sensory and motor processes and may support crossmodal predictive processing.

The Human Brain Project (HBP) is a European flagship project with a 10-year horizon aiming to understand the human brain and to translate neuroscience knowledge into medicine and technology. To achieve such aims, the HBP explores the multilevel complexity of the brain in space and time; transfers the acquired knowledge to brain-derived applications in health, computing, and technology; and provides shared and open computing tools and data through the HBP European brain research infrastructure. We discuss how the HBP creates a transdisciplinary community of researchers united by the quest to understand the brain, with fascinating perspectives on societal benefits.

Beta and gamma rhythms have been hypothesized to be involved in global and local coordination of neuronal activity, respectively. Here, we investigated how cells in rodent area S1BF are entrained by rhythmic fluctuations at various frequencies within the local area and in connected areas, and how this depends on behavioral state and cell type. We performed simultaneous extracellular field and unit recordings in four connected areas of the freely moving rat (S1BF, V1M, perirhinal cortex, CA1). S1BF spiking activity was strongly entrained by both beta and gamma S1BF oscillations, which were associated with deactivations and activations, respectively. We identified multiple classes of fast spiking and excitatory cells in S1BF, which showed prominent differences in rhythmic entrainment and in the extent to which phase locking was modulated by behavioral state. Using an additional dataset acquired by whole-cell recordings in head-fixed mice, these cell classes could be compared with identified phenotypes showing gamma rhythmicity in their membrane potential. We next examined how S1BF cells were entrained by rhythmic fluctuations in connected brain areas. Gamma-synchronization was detected in all four areas, however we did not detect significant gamma coherence among these areas. Instead, we only found long-range coherence in the theta-beta range among these areas. In contrast to local S1BF synchronization, we found long-range S1BF-spike to CA1-LFP synchronization to be homogeneous across inhibitory and excitatory cell types. These findings suggest distinct, cell-type contributions of low and high-frequency synchronization to intra- and inter-areal neuronal interactions.

Previous studies have demonstrated the importance of the primary sensory cortex for the detection, discrimination, and awareness of visual stimuli, but it is unknown how neuronal populations in this area process detected and undetected stimuli differently. Critical differences may reside in the mean strength of responses to visual stimuli, as reflected in bulk signals detectable in functional magnetic resonance imaging, electro-encephalogram, or magnetoencephalography studies, or may be more subtly composed of differentiated activity of individual sensory neurons. Quantifying single-cell Ca(2+) responses to visual stimuli recorded with in vivo two-photon imaging, we found that visual detection correlates more strongly with population response heterogeneity rather than overall response strength. Moreover, neuronal populations showed consistencies in activation patterns across temporally spaced trials in association with hit responses, but not during nondetections. Contrary to models relying on temporally stable networks or bulk signaling, these results suggest that detection depends on transient differentiation in neuronal activity within cortical populations.

Cortical gamma activity (30-80 Hz) is believed to play important functions in neural computation and arises from the interplay of parvalbumin-expressing interneurons (PV) and pyramidal cells (PYRs). However, the subthreshold dynamics underlying its emergence in the cortex of awake animals remain unclear. Here, we characterized the intracellular dynamics of PVs and PYRs during spontaneous and visually evoked gamma activity in layers 2/3 of V1 of awake mice using targeted patch-clamp recordings and synchronous local field potentials (LFPs). Strong gamma activity patterned in short bouts (one to three cycles), occurred when PVs and PYRs were depolarizing and entrained their membrane potential dynamics regardless of the presence of visual stimulation. PV firing phase locked unconditionally to gamma activity. However, PYRs only phase locked to visually evoked gamma bouts. Taken together, our results indicate that gamma activity corresponds to short pulses of correlated background synaptic activity synchronizing the output of cortical neurons depending on external sensory drive.

We act upon stimuli in our surrounding environment by gathering the multisensory information they convey and by integrating this information to decide on a behavioral action. We hypothesized that the anterolateral secondary visual cortex (area AL) of the mouse brain may serve as a hub for sensorimotor transformation of audiovisual information. We imaged neuronal activity in primary visual cortex (V1) and AL of the mouse during a detection task using visual, auditory, and audiovisual stimuli. We found that AL neurons were more sensitive to weak uni- and multisensory stimuli compared to V1. Depending on contrast, different subsets of AL and V1 neurons showed cross-modal modulation of visual responses. During audiovisual stimulation, AL neurons showed stronger differentiation of behaviorally reported versus unreported stimuli compared to V1, whereas V1 showed this distinction during unisensory visual stimulation. Thus, neural population activity in area AL correlates more closely with multisensory detection behavior than V1.

Throughout the last decades, understanding the neural mechanisms of sensory processing has been a key objective for neuroscientists. Many studies focused on uncovering the microcircuit-level architecture of somatosensation using the rodent whisker system as a model. Although these studies have significantly advanced our understanding of tactile processing, the question remains to what extent the whisker system can provide results translatable to the human somatosensory system. To address this, we developed a restrained vibrotactile detection task involving the limb system in mice. A vibrotactile stimulus was delivered to the hindlimb of head-fixed mice, who were trained to perform a Go/No-go detection task. Mice were able to learn this task with satisfactory performance and with reasonably short training times. In addition, the task we developed is versatile, as it can be combined with diverse neuroscience methods. Thus, this study introduces a novel task to study the neuron-level mechanisms of tactile processing in a system other than the more commonly studied whisker system.

The brain's default mode network (DMN) is activated during internally-oriented tasks and shows strong coherence in spontaneous rest activity. Despite a surge of recent interest, the functional role of the DMN remains poorly understood. Interestingly, the DMN activates during retrieval of past events but deactivates during encoding of novel events into memory. One hypothesis is that these opposing effects reflect a difference between attentional orienting towards internal events, such as retrieved memories, vs. external events, such as to-be-encoded stimuli. Another hypothesis is that hippocampal regions are coupled with the DMN during retrieval but decoupled from the DMN during encoding. The present fMRI study investigated these two hypotheses by combining a resting-state coherence analysis with a task that measured the encoding and retrieval of both internally-generated and externally-presented events. Results revealed that the main DMN regions were activated during retrieval but deactivated during encoding. Counter to the internal orienting hypothesis, this pattern was not modulated by whether memory events were internal or external. Consistent with the hippocampal coupling hypothesis, the hippocampus behaved like other DMN regions during retrieval but not during encoding. Taken together, our findings clarify the relationship between the DMN and the neural correlates of memory retrieval and encoding.

Remembering past events - or episodic retrieval - consists of several components. There is evidence that mental imagery plays an important role in retrieval and that the brain regions supporting imagery overlap with those supporting retrieval. An open issue is to what extent these regions support successful vs. unsuccessful imagery and retrieval processes. Previous studies that examined regional overlap between imagery and retrieval used uncontrolled memory conditions, such as autobiographical memory tasks, that cannot distinguish between successful and unsuccessful retrieval. A second issue is that fMRI studies that compared imagery and retrieval have used modality-aspecific cues that are likely to activate auditory and visual processing regions simultaneously. Thus, it is not clear to what extent identified brain regions support modality-specific or modality-independent imagery and retrieval processes. In the current fMRI study, we addressed this issue by comparing imagery to retrieval under controlled memory conditions in both auditory and visual modalities. We also obtained subjective measures of imagery quality allowing us to dissociate regions contributing to successful vs. unsuccessful imagery. Results indicated that auditory and visual regions contribute both to imagery and retrieval in a modality-specific fashion. In addition, we identified four sets of brain regions with distinct patterns of activity that contributed to imagery and retrieval in a modality-independent fashion. The first set of regions, including hippocampus, posterior cingulate cortex, medial prefrontal cortex and angular gyrus, showed a pattern common to imagery/retrieval and consistent with successful performance regardless of task. The second set of regions, including dorsal precuneus, anterior cingulate and dorsolateral prefrontal cortex, also showed a pattern common to imagery and retrieval, but consistent with unsuccessful performance during both tasks. Third, left ventrolateral prefrontal cortex showed an interaction between task and performance and was associated with successful imagery but unsuccessful retrieval. Finally, the fourth set of regions, including ventral precuneus, midcingulate cortex and supramarginal gyrus, showed the opposite interaction, supporting unsuccessful imagery, but successful retrieval performance. Results are discussed in relation to reconstructive, attentional, semantic memory, and working memory processes. This is the first study to separate the neural correlates of successful and unsuccessful performance for both imagery and retrieval and for both auditory and visual modalities.

Behavioral states affect neuronal responses throughout the cortex and influence visual processing. Quiet wakefulness (QW) is a behavioral state during which subjects are quiescent but awake and connected to the environment. Here, we examined the effects of pre-stimulus arousal variability on post-stimulus neural activity in the primary visual cortex and posterior parietal cortex in awake ferrets, using pupil diameter as an indicator of arousal. We observed that the power of stimuli-induced alpha (8-12 Hz) decreases when the arousal level increases. The peak of alpha power shifts depending on arousal. High arousal increases inter- and intra-areal coherence. Using a simplified model of laminar circuits, we show that this connectivity pattern is compatible with feedback signals targeting infragranular layers in area posterior parietal cortex and supragranular layers in V1. During high arousal, neurons in V1 displayed higher firing rates at their preferred orientations. Broad-spiking cells in V1 are entrained to high-frequency oscillations (>80 Hz), whereas narrow-spiking neurons are phase-locked to low- (12-18 Hz) and high-frequency (>80 Hz) rhythms. These results indicate that the variability and sensitivity of post-stimulus cortical responses and coherence depend on the pre-stimulus behavioral state and account for the neuronal response variability observed during repeated stimulation.

Some patients with severe brain injury show short-term neurological improvements, such as recovery of consciousness, motor function, or speech after administering zolpidem, a GABA receptor agonist. The working mechanism of this paradoxical phenomenon remains unknown. In this study, we used electroencephalography and magnetoencephalography to investigate a spectacular zolpidem-induced awakening, including the recovery of functional communication and the ability to walk in a patient with severe hypoxic-ischemic brain injury. We show that cognitive deficits, speech loss, and motor impairments after severe brain injury are associated with stronger beta band connectivity throughout the brain and suggest that neurological recovery after zolpidem occurs with the restoration of beta band connectivity. This exploratory work proposes an essential role for beta rhythms in goal-directed behavior and cognition. It advocates further fundamental and clinical research on the role of increased beta band connectivity in the development of neurological deficits after severe brain injury.

The posterior midline region (PMR)-considered a core of the default mode network-is deactivated during successful performance in different cognitive tasks. The extent of PMR-deactivations is correlated with task-demands and associated with successful performance in various cognitive domains. In the domain of episodic memory, functional MRI (fMRI) studies found that PMR-deactivations reliably predict learning (successful encoding). Yet it is unclear what explains this relation. One intriguing possibility is that PMR-deactivations are partially mediated by respiratory artifacts. There is evidence that the fMRI signal in PMR is particularly prone to respiratory artifacts, because of its large surrounding blood vessels. As respiratory fluctuations have been shown to track changes in attention, it is critical for the general interpretation of fMRI results to clarify the relation between respiratory fluctuations, cognitive performance, and fMRI signal. Here, we investigated this issue by measuring respiration during word encoding, together with a breath-holding condition during fMRI-scanning. Stimulus-locked respiratory analyses showed that respiratory fluctuations predicted successful encoding via a respiratory phase-locking mechanism. At the same time, the fMRI analyses showed that PMR-deactivations associated with learning were reduced during breath-holding and correlated with individual differences in the respiratory phase-locking effect during normal breathing. A left frontal region--used as a control region--did not show these effects. These findings indicate that respiration is a critical factor in explaining the link between PMR-deactivation and successful cognitive performance. Further research is necessary to demonstrate whether our findings are restricted to episodic memory encoding, or also extend to other cognitive domains.

Neural circuits support behavioral adaptations by integrating sensory and motor information with reward and error-driven learning signals, but it remains poorly understood how these signals are distributed across different levels of the corticohippocampal hierarchy. We trained rats on a multisensory object-recognition task and compared visual and tactile responses of simultaneously recorded neuronal ensembles in somatosensory cortex, secondary visual cortex, perirhinal cortex, and hippocampus. The sensory regions primarily represented unisensory information, whereas hippocampus was modulated by both vision and touch. Surprisingly, the sensory cortices and the hippocampus coded object-specific information, whereas the perirhinal cortex did not. Instead, perirhinal cortical neurons signaled trial outcome upon reward-based feedback. A majority of outcome-related perirhinal cells responded to a negative outcome (reward omission), whereas a minority of other cells coded positive outcome (reward delivery). Our results highlight a distributed neural coding of multisensory variables in the cortico-hippocampal hierarchy. Notably, the perirhinal cortex emerges as a crucial region for conveying motivational outcomes, whereas distinct functions related to object identity are observed in the sensory cortices and hippocampus.

Anesthesia affects brain activity at the molecular, neuronal and network level, but it is not well-understood how tuning properties of sensory neurons and network connectivity change under its influence. Using in vivo two-photon calcium imaging we matched neuron identity across episodes of wakefulness and anesthesia in the same mouse and recorded spontaneous and visually evoked activity patterns of neuronal ensembles in these two states. Correlations in spontaneous patterns of calcium activity between pairs of neurons were increased under anesthesia. While orientation selectivity remained unaffected by anesthesia, this treatment reduced direction selectivity, which was attributable to an increased response to the null-direction. As compared to anesthesia, populations of V1 neurons coded more mutual information on opposite stimulus directions during wakefulness, whereas information on stimulus orientation differences was lower. Increases in correlations of calcium activity during visual stimulation were correlated with poorer population coding, which raised the hypothesis that the anesthesia-induced increase in correlations may be causal to degrading directional coding. Visual stimulation under anesthesia, however, decorrelated ongoing activity patterns to a level comparable to wakefulness. Because visual stimulation thus appears to 'break' the strength of pairwise correlations normally found in spontaneous activity under anesthesia, the changes in correlational structure cannot explain the awake-anesthesia difference in direction coding. The population-wide decrease in coding for stimulus direction thus occurs independently of anesthesia-induced increments in correlations of spontaneous activity.

Extinction of instrumental responses is an essential skill for adaptive behavior such as foraging. So far, only few studies have focused on extinction following appetitive conditioning in mice. We studied extinction of appetitive operant lever-press behavior in six standard inbred mouse strains (A/J, C3H/HeJ, C57BL/6J, DBA/2J, BALB/cByJ and NOD/Ltj) and eight recombinant inbred mouse lines. From the response rates at the end of operant and extinction training we computed an extinction index, with higher values indicating better capability to omit behavioral responding in absence of reward. This index varied highly across the mouse lines tested, and the variability was partially due to a significant heritable component of 12.6%. To further characterize the relationship between operant learning and extinction, we calculated the slope of the time course of extinction across sessions. While many strains showed a considerable capacity to omit responding when lever pressing was no longer rewarded, we found a few lines showing an abnormally high perseveration in lever press behavior, showing no decay in response scores over extinction sessions. No correlation was found between operant and extinction response scores, suggesting that appetitive operant learning and extinction learning are dissociable, a finding in line with previous studies indicating that these forms of learning are dependent on different brain areas. These data shed light on the heritable basis of extinction learning and may help develop animal models of addictive habits and other perseverative disorders, such as compulsive food seeking and eating.