Neonatal Restriction of Tactile Inputs Leads to Long-Lasting Impairments of Cross-Modal Processing.

Optimal behavior relies on the combination of inputs from multiple senses through complex interactions within neocortical networks. The ontogeny of this multisensory interplay is still unknown. Here, we identify critical factors that control the development of visual-tactile processing by combining in vivo electrophysiology with anatomical/functional assessment of cortico-cortical communication and behavioral investigation of pigmented rats. We demonstrate that the transient reduction of unimodal (tactile) inputs during a short period of neonatal development prior to the first cross-modal experience affects feed-forward subcortico-cortical interactions by attenuating the cross-modal enhancement of evoked responses in the adult primary somatosensory cortex. Moreover, the neonatal manipulation alters cortico-cortical interactions by decreasing the cross-modal synchrony and directionality in line with the sparsification of direct projections between primary somatosensory and visual cortices. At the behavioral level, these functional and structural deficits resulted in lower cross-modal matching abilities. Thus, neonatal unimodal experience during defined developmental stages is necessary for setting up the neuronal networks of multisensory processing.

Visual-tactile processing in primary somatosensory cortex emerges before cross-modal experience.

The presumptive unisensory neocortical areas process multisensory information by oscillatory entrainment of neuronal networks via direct cortico-cortical projections. While neonatal unimodal experience has been identified as necessary for setting up the neuronal networks of multisensory processing, it is still unclear whether early cross-modal experience equally controls the ontogeny of multisensory processing. Here, we assess the development of visual-somatosensory interactions and their anatomical substrate by performing extracellular recordings of network activity in primary sensory cortices in vivo and assessing the cortico-cortical connectivity in pigmented rats. Similar to adult animals, juvenile rats with minimal cross-modal experience display supra-additive augmentation of evoked responses, time-dependent modulation of power and phase reset of network oscillations in response to cross-modal light and whisker stimulation. Moreover, the neuronal discharge of individual neurons is stronger coupled to theta and alpha network oscillations after visual-tactile stimuli. The adult-like multisensory processing of juvenile rats relies on abundant direct visual-somatosensory connections and thalamocortical feedforward interactions. Thus, cellular and network interactions ensuring multisensory processing emerge before cross-modal experience and refine during juvenile development.

Activity-regulated cytoskeletal-associated protein (Arc) in presynaptic terminals and extracellular vesicles in hippocampal synapses.

The activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) is a neuron-specific immediate early gene (IEG) product. The protein regulates synaptic strength through modulation of spine density and morphology, AMPA receptor endocytosis, and as being part of a retrovirus-like inter-cellular communication mechanism. However, little is known about the detailed subsynaptic localization of the protein, and especially its possible presynaptic localization. In the present study, we provide novel electron microscopical data of Arc localization at hippocampal Schaffer collateral synapses in the CA1 region. The protein was found in both pre-and postsynaptic cytoplasm in a majority of synapses, associated with small vesicles. We also observed multivesicular body-like structures positive for Arc. Furthermore, the protein was located over the presynaptic active zone and the postsynaptic density. The relative concentration of Arc was 25% higher in the postsynaptic spine than in the presynaptic terminal. Notably, small extracellular vesicles labeled for Arc were detected in the synaptic cleft or close to the synapse, supporting a possible transsynaptic transmission of the protein in the brain.

An information-theoretic quantification of the content of communication between brain regions.

Quantifying the amount, content and direction of communication between brain regions is key to understanding brain function. Traditional methods to analyze brain activity based on the Wiener-Granger causality principle quantify the overall information propagated by neural activity between simultaneously recorded brain regions, but do not reveal the information flow about specific features of interest (such as sensory stimuli). Here, we develop a new information theoretic measure termed Feature-specific Information Transfer (FIT), quantifying how much information about a specific feature flows between two regions. FIT merges the Wiener-Granger causality principle with information-content specificity. We first derive FIT and prove analytically its key properties. We then illustrate and test them with simulations of neural activity, demonstrating that FIT identifies, within the total information flowing between regions, the information that is transmitted about specific features. We then analyze three neural datasets obtained with different recording methods, magneto- and electro-encephalography, and spiking activity, to demonstrate the ability of FIT to uncover the content and direction of information flow between brain regions beyond what can be discerned with traditional anaytical methods. FIT can improve our understanding of how brain regions communicate by uncovering previously hidden feature-specific information flow.

Changes in concentrations of NMDA receptor subunit GluN2B, Arc and syntaxin-1 in dorsal hippocampus Schaffer collateral synapses in a rat learned helplessness model of depression.

Major depressive disorder involves changes in synaptic structure and function, but the molecular underpinnings of these changes are still not established. In an initial pilot experiment, whole-brain synaptosome screening with quantitative western blotting was performed to identify synaptic proteins that may show concentration changes in a congenital rat learned helplessness model of depression. We found that the N-methyl-d-aspartate receptor (NMDAR) subunits GluN2A/GluN2B, activity-regulated cytoskeleton-associated protein (Arc) and syntaxin-1 showed significant concentration differences between congenitally learned helpless (LH) and nonlearned helpless (NLH) rats. Having identified these three proteins, we then performed more elaborate quantitative immunogold electron microscopic analyses of the proteins in a specific synapse type in the dorsal hippocampus: the Schaffer collateral synapse in the CA1 region. We expanded the setup to include also unstressed wild-type (WT) rats. The concentrations of the proteins in the LH and NLH groups were compared to WT animals. In this specific synapse, we found that the concentration of NMDARs was increased in postsynaptic spines in both LH and NLH rats. The concentration of Arc was significantly increased in postsynaptic densities in LH animals as well as in presynaptic cytoplasm of NLH rats. The concentration of syntaxin-1 was significantly increased in both presynaptic terminals and postsynaptic spines in LH animals, while pre- and postsynaptic syntaxin-1 concentrations were significantly decreased in NLH animals. These protein changes suggest pathways by which synaptic plasticity may be increased in dorsal hippocampal Schaffer collateral synapses during depression, corresponding to decreased synaptic stability.

Cross-Talk of Low-Level Sensory and High-Level Cognitive Processing: Development, Mechanisms, and Relevance for Cross-Modal Abilities of the Brain.

The emergence of cross-modal learning capabilities requires the interaction of neural areas accounting for sensory and cognitive processing. Convergence of multiple sensory inputs is observed in low-level sensory cortices including primary somatosensory (S1), visual (V1), and auditory cortex (A1), as well as in high-level areas such as prefrontal cortex (PFC). Evidence shows that local neural activity and functional connectivity between sensory cortices participate in cross-modal processing. However, little is known about the functional interplay between neural areas underlying sensory and cognitive processing required for cross-modal learning capabilities across life. Here we review our current knowledge on the interdependence of low- and high-level cortices for the emergence of cross-modal processing in rodents. First, we summarize the mechanisms underlying the integration of multiple senses and how cross-modal processing in primary sensory cortices might be modified by top-down modulation of the PFC. Second, we examine the critical factors and developmental mechanisms that account for the interaction between neuronal networks involved in sensory and cognitive processing. Finally, we discuss the applicability and relevance of cross-modal processing for brain-inspired intelligent robotics. An in-depth understanding of the factors and mechanisms controlling cross-modal processing might inspire the refinement of robotic systems by better mimicking neural computations.

Multisensory integration in rodent tactile but not visual thalamus.

Behavioural performance requires a coherent perception of environmental features that address multiple senses. These diverse sensory inputs are integrated in primary sensory cortices, yet it is still largely unknown whether their convergence occurs even earlier along the sensory tract. Here we investigate the role of putatively modality-specific first-order (FO) thalamic nuclei (ventral posteromedial nucleus (VPM), dorsal lateral geniculate nucleus (dLGN)) and their interactions with primary sensory cortices (S1, V1) for multisensory integration in pigmented rats in vivo. We show that bimodal stimulation (i.e. simultaneous light flash and whisker deflection) enhances sensory evoked activity in VPM, but not dLGN. Moreover, cross-modal stimuli reset the phase of thalamic network oscillations and strengthen the coupling efficiency between VPM and S1, but not between dLGN and V1. Finally, the information flow from VPM to S1 is enhanced. Thus, FO tactile, but not visual, thalamus processes and relays sensory inputs from multiple senses, revealing a functional difference between sensory thalamic nuclei during multisensory integration.

Rate and Temporal Coding Convey Multisensory Information in Primary Sensory Cortices.

Optimal behavior and survival result from integration of information across sensory systems. Modulation of network activity at the level of primary sensory cortices has been identified as a mechanism of cross-modal integration, yet its cellular substrate is still poorly understood. Here, we uncover the mechanisms by which individual neurons in primary somatosensory (S1) and visual (V1) cortices encode visual-tactile stimuli. For this, simultaneous extracellular recordings were performed from all layers of the S1 barrel field and V1 in Brown Norway rats in vivo and units were clustered and assigned to pyramidal neurons (PYRs) and interneurons (INs). We show that visual-tactile stimulation modulates the firing rate of a relatively low fraction of neurons throughout all cortical layers. Generally, it augments the firing of INs and decreases the activity of PYRs. Moreover, bimodal stimulation shapes the timing of neuronal firing by strengthening the phase-coupling between neuronal discharge and theta-beta band network oscillations as well as by modulating spiking onset. Sparse direct axonal projections between neurons in S1 and V1 seem to time the spike trains between the two cortical areas and, thus, may act as a substrate of cross-modal modulation. These results indicate that few cortical neurons mediate multisensory effects in primary sensory areas by directly encoding cross-modal information by their rate and timing of firing.

Unraveling Cross-Modal Development in Animals: Neural Substrate, Functional Coding and Behavioral Readout.

The interaction of every living organism with its environment relies on sensory abilities. Hence, sensory systems need to develop rapidly and early in life to guarantee an individual's survival. Sensors have to emerge that are equipped with receptors that detect a variety of stimuli. These sensors have to be wired in basic interconnected networks that possess the ability to process the uni- as well as multisensory information encoded in the sensory input. Plastic changes to refine and optimize these circuits need to be effected quickly during periods of sensory experience so that uni- and multisensory systems can rapidly achieve the functional maturity needed to support the perceptual and behavioral functions reliant upon them. However, the requirement that sensory abilities mature quickly during periods of enhanced neuroplasticity is at odds with the complexity of sensory networks. Neuronal assemblies within sensory networks must be precisely wired so that processing and coding mechanisms can render relevant stimuli more salient and bind features together appropriately. Focusing on animal research, the first part of this review describes mechanisms of sensory processing that show a high degree of similarity within and between sensory systems and highlight the network complexity in relationship to the temporal and spatial precision that is needed for optimal coding and processing of sensory information. Given the resemblance of most adult intra- and intersensory coding mechanisms, it is likely that their developmental principles are similar. The second part of the review focuses on developmental aspects, summarizing the mechanisms underlying the emergence and refinement of precisely coordinated neuronal and multisensory functioning. For this purpose, we review animal research that elucidates the neural substrate of multisensory development applicable to, the less accessible, human development. Animal studies in this field have not only complemented human studies, but brought new ideas and numerous cutting edge conclusions leading to the discovery of common principles and mechanisms.

Visual short-term memory always requires general attention.

The role of attention in visual memory remains controversial; while some evidence has suggested that memory for binding between features demands no more attention than does memory for the same features, other evidence has indicated cognitive costs or mnemonic benefits for explicitly attending to bindings. We attempted to reconcile these findings by examining how memory for binding, for features, and for features during binding is affected by a concurrent attention-demanding task. We demonstrated that performing a concurrent task impairs memory for as few as two visual objects, regardless of whether each object includes one or more features. We argue that this pattern of results reflects an essential role for domain-general attention in visual memory, regardless of the simplicity of the to-be-remembered stimuli. We then discuss the implications of these findings for theories of visual working memory.