Multisensory Integration: Is Medial Prefrontal Cortex Signaling Relevant for the Treatment of Higher-Order Visual Dysfunctions?

In the mammalian brain, information processing in sensory modalities and global mechanisms of multisensory integration facilitate perception. Emerging experimental evidence suggests that the contribution of multisensory integration to sensory perception is far more complex than previously expected. Here we revise how associative areas such as the prefrontal cortex, which receive and integrate inputs from diverse sensory modalities, can affect information processing in unisensory systems via processes of down-stream signaling. We focus our attention on the influence of the medial prefrontal cortex on the processing of information in the visual system and whether this phenomenon can be clinically used to treat higher-order visual dysfunctions. We propose that non-invasive and multisensory stimulation strategies such as environmental enrichment and/or attention-related tasks could be of clinical relevance to fight cerebral visual impairment.

Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

Mammalian brain glycoproteins exhibit diminished glycan complexity compared to other tissues

Glycosylation is essential to brain development and function, but prior studies have often been limited to a single analytical technique and excluded region- and sex-specific analyses. Here, using several methodologies, we analyze Asn-linked and Ser/Thr/Tyr-linked protein glycosylation between brain regions and sexes in mice. Brain N-glycans are less complex in sequence and variety compared to other tissues, consisting predominantly of high-mannose and fucosylated/bisected structures. Most brain O-glycans are unbranched, sialylated O-GalNAc and O-mannose structures. A consistent pattern is observed between regions, and sex differences are minimal compared to those in plasma. Brain glycans correlate with RNA expression of their synthetic enzymes, and analysis of glycosylation genes in humans show a global downregulation in the brain compared to other tissues. We hypothesize that this restricted repertoire of protein glycans arises from their tight regulation in the brain. These results provide a roadmap for future studies of glycosylation in neurodevelopment and disease.

A theory of cortical map formation in the visual brain

The cerebral cortex receives multiple afferents from the thalamus that segregate by stimulus modality forming cortical maps for each sense. In vision, the primary visual cortex also maps the multiple dimensions of the stimulus in patterns that vary across species for reasons unknown. Here we introduce a general theory of cortical map formation, which proposes that map diversity emerges from variations in sampling density of sensory space across species. In the theory, increasing afferent sampling density enlarges the cortical domains representing the same visual point allowing the segregation of afferents and cortical targets by additional stimulus dimensions. We illustrate the theory with a computational model that accurately replicates the maps of different species through afferent segregation followed by thalamocortical convergence pruned by visual experience. Because thalamocortical pathways use similar mechanisms for axon sorting and pruning, the theory may extend to other sensory areas of the mammalian brain.

Hardware Architecture for Asynchronous Cellular Self-Organizing Maps

Nowadays, one of the main challenges in computer architectures is scalability; indeed, novel processor architectures can include thousands of processing elements on a single chip and using them efficiently remains a big issue. An interesting source of inspiration for handling scalability is the mammalian brain and different works on neuromorphic computation have attempted to address this question. The Self-configurable 3D Cellular Adaptive Platform (SCALP) has been designed with the goal of prototyping such types of systems and has led to the proposal of the Cellular Self-Organizing Maps (CSOM) algorithm. In this paper, we present a hardware architecture for CSOM in the form of interconnected neural units with the specific property of supporting an asynchronous deployment on a multi-FPGA 3D array. The Asynchronous CSOM (ACSOM) algorithm exploits the underlying Network-on-Chip structure to be provided by SCALP in order to overcome the multi-path propagation issue presented by a straightforward CSOM implementation. We explore its behaviour under different map topologies and scalar representations. The results suggest that a larger network size with low precision coding obtains an optimal ratio between algorithm accuracy and FPGA resources.

FASN-dependent de novo lipogenesis is required for brain development

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell–derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism.

Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals, they are mostly composed of the protein connexin36. Circuits of electrically coupled neurons are widespread in these animals. Plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations such as lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on the gap junction resistance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage and ligand gated channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here, we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

Testing the state-dependent model of time perception against experimental evidence

Coordinated movements, speech and other actions are impossible without precise timing. Realistic computational models of interval timing in the mammalian brain are expected to provide key insights into the underlying mechanisms of timing. Existing computational models of time perception have only been partially replicating experimental observations, such as the linear increase of time, the dopaminergic modulation of this increase, and the scalar property, i.e., the linear increase of the standard deviation of temporal estimates. In this work, we incorporate the state-dependent computational model, which encodes time in the dynamic evolution of network states without the need for a specific network structure into a biologically plausible prefrontal cortex (PFC) model based on in vivo and in vitro recordings of rodents. Specifically, we stimulated 1000 neurons in the beginning and in the end of a range of different time intervals, extracted states of neurons and trained the readout layer based on these states using least squares to predict the respective inter stimulus interval. We show that the naturally occurring heterogeneity in cellular and synaptic parameters in the PFC is sufficient to encode time over several hundreds of milliseconds. The readout faithfully represents the duration between two stimuli applied to the superficial layers of the network, thus fulfilling the requirement of a linear encoding of time. A simulated activation of the D2 dopamine receptor leads to an overestimation and an inactivation to an underestimation of time, in line with experimental results. Furthermore, we show that the scalar property holds true for intervals of several hundred milliseconds, and provide a mechanistic explanation for the origin of the scalar property as well as its deviations. We conclude that this model can represent durations up to 750 ms in a biophysically plausible setting, compatible with experimental findings in this regime.

Identification of potential astrocytes in the teleost brain

Astrocytes are abundant star-shaped glial cells in the mammalian brain, with essential roles in metabolism, development, homeostasis, response to injury, behavior, and learning. Surprisingly, most regions of the teleost brain are thought to lack astrocytes, based primarily on the use of GFAP (glial fibrillary acidic protein) as a marker. Here, drawing on recent evidence that astrocytes are molecularly heterogeneous, we propose that astrocytes exist in the teleost brain, albeit of the olig2 subtype. Highly branched cells are present throughout the zebrafish brain, as shown here in Tg(sox10:EGFP) fish and previously in Tg(olig2:GFP) fish. Transcriptome data indicates the presence of brain cells that are olig2 and sox10 positive, which also express the astrocyte markers sox9b, sparcl1 and slc1a2b but lack gfap and the oligodendrocyte marker mbp. In situ hybridization confirms that stellate sox10:EGFP cells express olig2 and sox9b, while immunofluorescence indicates that they lack HuC/D and GFAP. We suggest that these cells be classified as astrocytes as this may more accurately reflect their functions.

Scaffolding layered control architectures through constraint closure: insights into brain evolution and development

The functional organization of the mammalian brain can be considered to form a layered control architecture, but how this complex system has emerged through evolution and is constructed during development remains a puzzle. Here we consider brain organization through the framework of constraint closure, viewed as a general characteristic of living systems, that they are composed of multiple sub-systems that constrain each other at different timescales. We do so by developing a new formalism for constraint closure, inspired by a previous model showing how within-lifetime dynamics can constrain between-lifetime dynamics, and we demonstrate how this interaction can be generalized to multi-layered systems. Through this model, we consider brain organization in the context of two major examples of constraint closure—physiological regulation and visual orienting. Our analysis draws attention to the capacity of layered brain architectures to scaffold themselves across multiple timescales, including the ability of cortical processes to constrain the evolution of sub-cortical processes, and of the latter to constrain the space in which cortical systems self-organize and refine themselves. This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.