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Neuroscience in numbers

The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.

Articles

by Yongtaek Oh, Christine Chesebrough, Brian Erickson, Fengqing Zhang, John Kounios in NeuroImage

A new neuroimaging study points to an answer of what may have driven the evolutionary development of creativity

Problem-solving by insight and analysis recruit different brain activity.

Reward sensitivity modulates brain activity during problem solving.

Insights evoke a neural reward signal in people high in reward sensitivity.

The insight reward signal is too quick to be conscious, post-solution appraisal.

This reward signal implies that creative cognition is intrinsically motivating.

Log EEG power values at electrodes nearest to peak voxels for significant correlations between insight-minus-analytic (I–A) differences and Reward Responsiveness Scale (RRS) scores. Power values from right parietal electrode P6 (left) and right anterior frontal electrode AF4 (right) are shown averaged over the time and frequency windows of interest. Upper row: I-A EEG power values from electrode P6 (left) showed a significant negative correlation with RRS scores, while electrode AF4 (right) showed a positive correlation. Both graphs include best-fit regression lines. Lower row: EEG power values are shown separately for I and A trials, separately for high-RRS and low-RRS groups. Error bars show standard errors. The topographic maps at the middle of the figure show the spatial and temporal extent of these effects.

Moments of insight, a phenomenon of creative cognition in which an idea suddenly emerges into awareness as an “Aha!” are often reported to be affectively positive experiences. Researchers tested the hypothesis that problem-solving by insight is accompanied by neural reward processing. They recorded high-density EEGs while participants solved a series of anagrams. For each solution, they reported whether the answer had occurred to them as a sudden insight or whether they had derived it deliberately and incrementally (i.e., “analytically’). Afterwards, they filled out a questionnaire that measures general dispositional reward sensitivity. They computed the time-frequency representations of the EEGs for trials with insight (I) solutions and trials with analytic (A) solutions and subtracted them to obtain an I-A time-frequency representation for each electrode. Statistical Parametric Mapping (SPM) analyses tested for significant I-A and reward-sensitivity effects. SPM revealed the time, frequency, and scalp locations of several I ​> ​A effects. No A ​> ​I effect was observed. The primary neural correlate of insight was a burst of (I ​> ​A) gamma-band oscillatory activity over prefrontal cortex approximately 500 ​ms before participants pressed a button to indicate that they had solved the problem. Scientists correlated the I-A time-frequency representation with reward sensitivity to discover insight-related effects that were modulated by reward sensitivity. This revealed a separate anterior prefrontal burst of gamma-band activity, approximately 100 ​ms after the primary I-A insight effect, which they interpreted to be an insight-related reward signal. This interpretation was supported by source reconstruction showing that this signal was generated in part by orbitofrontal cortex, a region associated with reward learning and hedonically pleasurable experiences such as food, positive social experiences, addictive drugs, and orgasm. These findings support the notion that for many people insight is rewarding. Additionally, these results may explain why many people choose to engage in insight-generating recreational and vocational activities such as solving puzzles, reading murder mysteries, creating inventions, or doing research. This insight-related reward signal may be a manifestation of an evolutionarily adaptive mechanism for the reinforcement of exploration, problem solving, and creative cognition.

Correlation between Insight-minus-Analytic (I–A) effect power and reward-related interaction power at the moment of insight. For I-A at approximately −500 ​ms, the right middle frontal gyrus and left inferior temporal gyrus were identified as the sources. For the positive I-A correlation with reward sensitivity at approximately -400 ms, the right anterior orbital gyrus was identified as the main source of interest. Source power values were averaged within time and frequency windows from the scalp domain results. The correlation between the power at I-A effect and reward-related effect revealed a significant relationship between the left inferior temporal gyrus and right anterior orbital gyrus, but no significant relationship between right middle frontal gyrus and right anterior orbital gyrus.

by Thackery I. Brown, Stephanie A. Gagnon, Anthony D. Wagner in Current Biology

New research from Stanford University has found that stress can hinder our ability to develop informed plans by preventing us from being able to make decisions based on memory.

Human participants engaged in a VR prospective navigational planning task

Psychological stress was manipulated post-learning during novel route planning

Cortical memory replay signals dynamically tracked prospective route planning

Stress disrupted memory and control circuitry and route neural replay and behavior

The ability to anticipate and flexibly plan for the future is critical for achieving goal-directed outcomes. Extant data suggest that neural and cognitive stress mechanisms may disrupt memory retrieval and restrict prospective planning, with deleterious impacts on behavior. Researchers examined whether and how acute psychological stress influences goal-directed navigational planning and efficient, flexible behavior. Their methods combined fMRI, neuroendocrinology, and machine learning with a virtual navigation planning task. Human participants were trained to navigate familiar paths in virtual environments and then (concurrent with fMRI) performed a planning and navigation task that could be most efficiently solved by taking novel shortcut paths. Strikingly, relative to non-stressed control participants, participants who performed the planning task under experimentally induced acute psychological stress demonstrated (1) disrupted neural activity critical for mnemonic retrieval and mental simulation and (2) reduced traversal of shortcuts and greater reliance on familiar paths. These neural and behavioral changes under psychological stress were tied to evidence for disrupted neural replay of memory for future locations in the spatial environment, providing mechanistic insight into why and how stress can alter planning and foster inefficient behavior.

(A) Regions showing a group 3 probe round interaction were more active during novel than repeated probe planning in the control group, but there was greater activity during repeated than novel probe planning in the stress group.

(B) Recovery in the stress group (probe 2 > probe 1) underlying interaction in (A). Frontoparietal control regions (particularly anterior PFC and lateral intraparietal sulcus [IPS]) and the hippocampal tail were notable a priori loci of this recovery on the basis of our predictions.

( C) Visualization of a priori cortical ROIs: cognitive control network (CCN), frontopolar cortex (FPC), angular gyrus (ANG), and retrosplenial cortex (RSC). p < 0.01, voxel-wise threshold; cluster-corrected p < 0.05.

by Peipei Li, Elizabeth Ensink, Sean Lang, Lee Marshall, Meghan Schilthuis, Jared Lamp, Irving Vega, Viviane Labrie in Genome Biology

Scientists may have solved one of the most puzzling and persistent mysteries in neuroscience: why some people are ‘right-brained’ while others are ‘left-brained.’ The answer lies in how certain genes on each side of the brain are switched ‘on’ and ‘off’ through a process called epigenetic regulation. The findings may explain why Parkinson’s disease and other neurological disorders frequently affect one side of the body first, a revelation that has far-reaching implications for development of potential future treatments.

Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson’s disease (PD), but its molecular determinants are unknown. Researchers identify divergent epigenetic patterns involved in hemispheric asymmetry by profiling DNA methylation in isolated prefrontal cortex neurons from control and PD brain hemispheres. DNA methylation is fine-mapped at enhancers and promoters, genome-wide, by targeted bisulfite sequencing in two independent sample cohorts.

They find that neurons of the human prefrontal cortex exhibit hemispheric differences in DNA methylation. Hemispheric asymmetry in neuronal DNA methylation patterns is largely mediated by differential CpH methylation, and chromatin conformation analysis finds that it targets thousands of genes. With aging, there is a loss of hemispheric asymmetry in neuronal epigenomes, such that hemispheres epigenetically converge in late life. In neurons of PD patients, hemispheric asymmetry in DNA methylation is greater than in controls and involves many PD risk genes. Epigenetic, transcriptomic, and proteomic differences between PD hemispheres correspond to the lateralization of PD symptoms, with abnormalities being most prevalent in the hemisphere matched to side of symptom predominance. Hemispheric asymmetry and symptom lateralization in PD is linked to genes affecting neurodevelopment, immune activation, and synaptic transmission. PD patients with a long disease course have greater hemispheric asymmetry in neuronal epigenomes than those with a short disease course. Hemispheric differences in DNA methylation patterns are prevalent in neurons and may affect the progression and symptoms of PD.

by Crhistian Luis Bender, Xingxing Sun, Muhammad Farooq, Qian Yang, Caroline Davison, Matthieu Maroteaux, Yi-shuian Huang, Yoshihiro Ishikawa, Siqiong June Liu in The Journal of Neuroscience

Research has shown how stress changes the structure of the brain and reveals a potential therapeutic target to the prevent or reverse it.

Stress alters brain function by modifying the structure and function of neurons and astrocytes. The fine processes of astrocytes are critical for the clearance of neurotransmitters during synaptic transmission. Thus, experience-dependent remodeling of glial processes is anticipated to alter the output of neural circuits. However, the molecular mechanism(s) that underlie glial structural plasticity are not known. Researchers show that a single exposure of male and female mice to an acute stress produced a long-lasting retraction of the lateral processes of cerebellar Bergmann glial cells. These cells express the GluA1 subunit of AMPA-type glutamate receptors and GluA1 knockdown is known to shorten the length of glial processes. They found that stress reduced the level of GluA1 protein and AMPA receptor-mediated currents in Bergmann glial cells and these effects were absent in mice devoid of CPEB3, a protein that binds to GluA1 mRNA and regulates GluA1 protein synthesis. Administration of a β-adrenergic receptor blocker attenuated the reduction in GluA1 and deletion of adenylate cyclase 5 prevented GluA1 suppression. Therefore, stress suppresses GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway, and reduces the length of astrocyte lateral processes. Researchers’ results identify a novel mechanism for GluA1 subunit plasticity in non-neuronal cells, and suggest a previously unappreciated role for AMPA receptors in stress-induced astrocytic remodeling.

Significance statement: Astrocytes play important roles in synaptic transmission by extending fine processes around synapses. In this study, researchers showed that a single exposure to an acute stress triggered a retraction of lateral/fine processes in mouse cerebellar astrocytes. These astrocytes express GluA1, a glutamate receptor subunit known to lengthen astrocyte processes. They showed that astrocytic structural changes are associated with a reduction of GluA1 protein levels. This requires activation of β-adrenergic receptors and is triggered by noradrenaline released during stress. Researchers identified adenylyl cyclase 5 as a downstream effector, an enzyme that elevates cAMP levels, and found that lowering GluA1 levels depends on CPEB3 proteins that bind to GluA1 mRNA. Therefore, stress regulates GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway in astrocytes and remodels their fine processes.

by Lu Xu, Wenze Li, Venkatakaushik Voleti, Dong-Jing Zou, Elizabeth M. C. Hillman, Stuart Firestein in Science

NIH BRAIN Initiative tool helps researchers watch neural activity in 3D

The mammalian nose is arguably the best chemical sensor on the planet, able to detect and discriminate among a large and diverse repertoire of mostly small, organic molecules. It accomplishes this, at least in part, through a large family of G protein–coupled receptors (GPCRs) expressed in specialized olfactory sensory neurons (OSNs) arrayed over an epithelium deep within the nasal cavity. Each neuron expresses only one of the ~1000 receptor genes. It is thought that the specific activation of subsets of these receptors by a particular odor translates into a code that can be read by higher brain centers to create a perception. However, we rarely encounter pure odors. Our daily life is a stream of encounters with rich blends of odors, from garbage to cologne. Even a simple cup of coffee has >800 volatile components. To study how the olfactory system encodes this much more complex information, researchers explored how neurons within the peripheral olfactory epithelium of a mouse’s nose responded to a series of odor mixtures. Their analysis was enabled by a new high-speed three-dimensional (3D) imaging method called SCAPE (Swept Confocally Aligned Planar Excitation) microscopy, which allows the responses of thousands of single neurons within the intact olfactory epithelium to be monitored in parallel during delivery of repeated odor combinations.

Previous studies using single, monomolecular odors suggested that the diverse expression of receptors in OSNs could provide unambiguous representations of individual odors. However, it is unclear how the brain might be able to decode signals when multiple odor components within a blend generate overlapping patterns. Moreover, when smelling a mixture of odors, it is common to perceive one odor dominating another. Psychophysical tests have revealed both suppressive and enhancing effects of particular odors within a blend. However, it has long been assumed that such odor-coding interactions occur at higher processing levels within the brain. Scientists studied whether combinatorial effects of odors affect neural representations at the peripheral sensory level.

Large-scale single-cell recording of OSNs reveals receptor-driven modulation effects. Volumetric imaging of GCaMP in intact olfactory epithelium using high-speed SCAPE microscopy enables analysis of responses to mixtures of different odor molecules. Single-neuron response time courses show that odor mixtures can enhance (red) or suppress (green) responses compared with individual odors. Heatmap shows assessment of >10,000 individual neurons across five mice.

Using SCAPE microscopy to image calcium-sensitive fluorescent proteins in OSNs, they were able to simultaneously monitor the activity of cells within a large volume of the intact mouse olfactory epithelium with single-cell resolution. Analyzing the responses of thousands of single neurons to blends of up to three odors, they discovered a series of surprising interactions that distorted the representation of the odor mixture compared with a simple combinatorial sum of responses to individual odors. Among the eight chemically distinct odors tested, researchers observed that the presence of one odor could either enhance or suppress the response of a neuron to another odor, even if the modulating odor by itself did not elicit a response from the neuron. This means that an odorless molecule could alter the perception of another odor, and that a neuron’s response to an odor blend can be much larger or smaller than its response to components of the blend. Overall, they observed clear evidence of agonism, antagonism, partial agonism, and enhancement occurring at the receptor level, suggesting a richer repertoire of receptor modulation mechanisms than previously thought. Finally, they note that enhancement of responses may be evidence of an allosteric modulatory site, a rare finding in class A GPCRs that bind small molecules.

Although inhibition and enhancement are well established in sensory systems, they are only a feature of higher circuit processing. Scientists observed complex receptor modulation at the level of peripheral olfactory sensory receptors. They propose that these peripheral modulatory interactions are crucial for discriminating complex blends of odors with overlapping activation patterns because they prevent the saturation of receptors and allow each new component to alter the overall activation pattern, rendering it distinctive. This result suggests that higher brain regions may rely on pattern recognition rather than on reading an additive combinatorial code to build a perception. This work also demonstrates an exciting and versatile new paradigm for high-throughput characterization of single-cell responses in intact systems.

by Elke Ydens, Lukas Amann, Bob Asselbergh, Charlotte L. Scott, Liesbet Martens, Dorine Sichien, Omar Mossad, Thomas Blank, Sofie De Prijck, Donovan Low, Takahiro Masuda, Yvan Saeys, Vincent Timmerman, Ralf Stumm, Florent Ginhoux, Marco Prinz, Sophie Janssens & Martin Guilliams in Nature Neuroscience

The authors identify two subsets of peripheral nerve macrophages residing in the endoneurium and the epineurium and displaying a distinct transcriptome and response to injury. These cells lack the main microglia identity and have a distinct origin.

While CNS microglia have been extensively studied, relatively little is known about macrophages populating the peripheral nervous system. Here we performed ontogenic, transcriptomic and spatial characterization of sciatic nerve macrophages (snMacs). Using multiple fate-mapping systems, researchers show that snMacs do not derive from the early embryonic precursors colonizing the CNS, but originate primarily from late embryonic precursors and become replaced by bone-marrow-derived macrophages over time. Using single-cell transcriptomics, we identified a tissue-specific core signature of snMacs and two spatially separated snMacs: Relmα+Mgl1+ snMacs in the epineurium and Relmα–Mgl1– snMacs in the endoneurium. Globally, snMacs lack most of the core signature genes of microglia, with only the endoneurial subset expressing a restricted number of these genes. In response to nerve injury, the two resident snMac populations respond differently. Moreover, and unlike in the CNS, monocyte-derived macrophages that develop during injury can engraft efficiently in the pool of resident peripheral nervous system macrophages.

by Gunnar H. D. Poplawski, Riki Kawaguchi, Erna Van Niekerk, Paul Lu, Neil Mehta, Philip Canete, Richard Lie, Ioannis Dragatsis, Jessica M. Meves, Binhai Zheng, Giovanni Coppola & Mark H. Tuszynski in Nature

In corticospinal injuries using a mouse model, adult neurons begin a natural regeneration process by reverting back to an embryonic state and that regeneration is sustained by a surprising gene.

Grafts of spinal-cord-derived neural progenitor cells (NPCs) enable the robust regeneration of corticospinal axons and restore forelimb function after spinal cord injury; however, the molecular mechanisms that underlie this regeneration are unknown. Here we perform translational profiling specifically of corticospinal tract (CST) motor neurons in mice, to identify their ‘regenerative transcriptome’ after spinal cord injury and NPC grafting. Notably, both injury alone and injury combined with NPC grafts elicit virtually identical early transcriptomic responses in host CST neurons. However, in mice with injury alone this regenerative transcriptome is downregulated after two weeks, whereas in NPC-grafted mice this transcriptome is sustained. The regenerative transcriptome represents a reversion to an embryonic transcriptional state of the CST neuron. The huntingtin gene (Htt) is a central hub in the regeneration transcriptome; deletion of Htt significantly attenuates regeneration, which shows that Htt has a key role in neural plasticity after injury.

“Using the incredible tools of modern neuroscience, molecular genetics, virology and computational power, we were able for the first time to identify how the entire set of genes in an adult brain cell resets itself in order to regenerate. This gives us fundamental insight into how, at a transcriptional level, regeneration happens,” said senior author Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine. “While a lot of work has been done on trying to understand why Huntingtin mutations cause disease, far less is understood about the normal role of Huntingtin,” Tuszynski said. “Our work shows that Huntingtin is essential for promoting repair of brain neurons. Thus, mutations in this gene would be predicted to result in a loss of the adult neuron to repair itself. This, in turn, might result in the slow neuronal degeneration that results in Huntington’s disease.”

by Hwei-Ee Tan, Alexander C. Sisti, Hao Jin, Martin Vignovich, Miguel Villavicencio, Katherine S. Tsang, Yossef Goffer & Charles S. Zuker in Nature

Artificial sweeteners have never fully succeeded in impersonating sugar. Now, a Columbia study in mice has identified a brain mechanism that may explain why. Researchers have shown that the brain responds not only when sugar touches the tongue but also when it enters the gut.

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste. Researchers examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut–brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut–brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, they engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, scientists show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.

“When we drink diet soda, or use sweetener in coffee, it may taste similar but our brains can tell the difference,” said Hwei-Ee Tan, the paper’s co-first author who completed his doctoral research in the lab of Charles Zuker, PhD, at Columbia’s Zuckerman Institute. “The discovery of this specialized gut-brain circuit that responds to sugar — and sugar alone — could pave the way for sweeteners that don’t just trick our tongue but also our brain.”

by Larry A. Kramer , Khader M. Hasan, Michael B. Stenger, Ashot Sargsyan, Steven S. Laurie, Christian Otto, Robert J. Ploutz-Snyder, Karina Marshall-Goebel, Roy F. Riascos, Brandon R. Macias in Radiology

Extended periods in space have long been known to cause vision problems in astronauts. Now a new study in the journal Radiology suggests that the impact of long-duration space travel is more far-reaching, potentially causing brain volume changes and pituitary gland deformation. More than half of the crew members on the International Space Station (ISS) have reported changes to their vision following long-duration exposure to the microgravity of space. Postflight evaluation has revealed swelling of the optic nerve, retinal hemorrhage and other ocular structural changes.

Astronauts on long-duration spaceflight missions may develop changes in ocular structure and function, which can persist for years after the return to normal gravity. Chronic exposure to elevated intracranial pressure during spaceflight is hypothesized to be a contributing factor, however, the etiologic causes remain unknown. To investigate the intracranial effects of microgravity by measuring combined changes in intracranial volumetric parameters, pituitary morphologic structure, and aqueductal cerebrospinal fluid (CSF) hydrodynamics relative to spaceflight and to establish a comprehensive model of recovery after return to Earth. This prospective longitudinal MRI study enrolled astronauts with planned long-duration spaceflight. Measures were conducted before spaceflight followed by 1, 30, 90, 180, and 360 days after landing. Intracranial volumetry and aqueductal CSF hydrodynamics (CSF peak-to-peak velocity amplitude and aqueductal stroke volume) were quantified for each phase. Qualitative and quantitative changes in pre- to postflight (day 1) pituitary morphologic structure were determined. Statistical analysis included separate mixed-effects models per dependent variable with repeated observations over time.

Results:

Eleven astronauts (mean age, 45 years ± 5 [standard deviation]; 10 men) showed increased mean volumes in the brain (28 mL; P < .001), white matter (26 mL; P < .001), mean lateral ventricles (2.2 mL; P < .001), and mean summated brain and CSF (33 mL; P < .001) at postflight day 1 with corresponding increases in mean aqueductal stroke volume (14.6 μL; P = .045) and mean CSF peak-to-peak velocity magnitude (2.2 cm/sec; P = .01). Summated mean brain and CSF volumes remained increased at 360 days after spaceflight (28 mL; P < .001). Qualitatively, six of 11 (55%) astronauts developed or showed exacerbated pituitary dome depression compared with baseline. Average midline pituitary height decreased from 5.9 to 5.3 mm (P < .001).

Reconstructed sagittal 5-mm orthogonal midline images in the brain using the sagittal three-dimensional T1weighted data set. (a) Preflight baseline image and (b) matching postflight image (postflight day 1) in the same astronaut. The black arrowheads show upward expansion of the anterior, middle, and posterior superior margins of the lateral ventricle with associated narrowing of the marginal sulcus of the cingulate sulcus (white arrowhead). There is subtle expansion of the third ventricle (indicated by a 3), which has displaced the thalamus (T) from midline, making it less visible. There is thickening of the intermediate signal scalp soft tissues (arrows).

Long-duration spaceflight was associated with increased pituitary deformation, augmented aqueductal cerebrospinal fluid (CSF) hydrodynamics, and expansion of summated brain and CSF volumes. Summated brain and CSF volumetric expansion persisted up to 1 year into recovery, suggesting permanent alteration.

by Boglárka Barsy, Kinga Kocsis, Aletta Magyar, Ákos Babiczky, Mónika Szabó, Judit M. Veres, Dániel Hillier, István Ulbert, Ofer Yizhar & Ferenc Mátyás in Nature Neuroscience

The authors describe a thalamic population, innervated by multimodal brainstem inputs, that forms a CS–US association prior to the lateral amygdala. Its fast and plastic signal defines an amygdala activity pattern necessary for adaptive fear learning.

Decades of research support the idea that associations between a conditioned stimulus (CS) and an unconditioned stimulus (US) are encoded in the lateral amygdala (LA) during fear learning. However, direct proof for the sources of CS and US information is lacking. Definitive evidence of the LA as the primary site for cue association is also missing. Researchers show that calretinin (Calr)-expressing neurons of the lateral thalamus (Calr+LT neurons) convey the association of fast CS (tone) and US (foot shock) signals upstream from the LA in mice. Calr+LT input shapes a short-latency sensory-evoked activation pattern of the amygdala via both feedforward excitation and inhibition. Optogenetic silencing of Calr+LT input to the LA prevents auditory fear conditioning. Notably, fear conditioning drives plasticity in Calr+LT neurons, which is required for appropriate cue and contextual fear memory retrieval. Collectively, their results demonstrate that Calr+LT neurons provide integrated CS–US representations to the LA that support the formation of aversive memories.

by Yoonju Kim, You‐Na Jang, Ji‐Young Kim, Nari Kim, Seulgi Noh, Hyeyeon Kim, Bridget N. Queenan, Ryan Bellmore, Ji Young Mun, Hyungju Park et al. in FASEB Journal.

Unlocking the mysteries of memory: the research team discovered a new role for MAP2 in the synaptic potentiation process and expects to provide key insights into synaptic dysfunction in brain diseases.

Microtubule‐associated protein (MAP) 2 has been perceived as a static cytoskeletal protein enriched in neuronal dendritic shafts. Emerging evidence indicates dynamic functions for various MAPs in activity‐dependent synaptic plasticity. However, it is unclear how MAP2 is associated with synaptic plasticity mechanisms. Scientists demonstrate that specific silencing of high‐molecular‐weight MAP2 in vivo abolished induction of long‐term potentiation (LTP) in the Schaffer collateral pathway of CA1 pyramidal neurons and in vitro blocked LTP‐induced surface delivery of AMPA receptors and spine enlargement. In mature hippocampal neurons, they observed rapid translocation of a subpopulation of MAP2, present in dendritic shafts, to spines following LTP stimulation. Time‐lapse confocal imaging showed that spine translocation of MAP2 was coupled with LTP‐induced spine enlargement. Consistently, immunogold electron microscopy revealed that LTP stimulation of the Schaffer collateral pathway promoted MAP2 labeling in spine heads of CA1 neurons. This translocation depended on NMDA receptor activation and Ras‐MAPK signaling. Furthermore, LTP stimulation led to an increase in surface‐expressed AMPA receptors specifically in the neurons with MAP2 spine translocation. Altogether, this study indicates a novel role for MAP2 in LTP mechanisms and suggests that MAP2 participates in activity‐dependent synaptic plasticity in mature hippocampal networks.

Signaling pathways involved in MAP2 synaptic translocation

by Meghan E. Flanigan, Hossein Aleyasin, Long Li, C. Joseph Burnett, Kenny L. Chan, Katherine B. LeClair, Elizabeth K. Lucas, Bridget Matikainen-Ankney, Romain Durand-de Cuttoli, Aki Takahashi, et al. in Nature Neuroscience

Scientists show that activation of inhibitory neurons in the lateral habenula by the neuropeptide orexin (hypocretin) promotes both inter-male aggression and conditioned place preference for contexts associated with winning aggressive contests.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, researchers showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male–male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.

by Bin A. Wang (王斌), Lara Schlaffke and Burkhard Pleger in Journal of Neuroscience

Researchers have identified two brain regions that are important for decision making during learning and how expectation affects activity in these regions.

During learning, the brain is a prediction engine that continually makes theories about our environment and accurately registers whether an assumption is true or not. A team of neuroscientists from Ruhr-Universität Bochum has shown that expectation during these predictions affects the activity of various brain networks. Dr. Bin Wang, Dr. Lara Schlaffke and Associate Professor Dr. Burkhard Pleger from the Neurological Clinic of Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil report on the results in two articles that were published in the journals Cerebral Cortex and Journal of Neuroscience.

The neuroscientists identified two key regions in the brain: the thalamus plays a central role in decision-making. The insular cortex, on the other hand, is particularly active when it is clear whether the right or wrong decision has been made. “The expectation during learning then regulates specific connections in the brain and thus the prediction for learning-relevant sensory perception,” says Burkhard Pleger.

Abstract:

Awareness for surprising sensory events is shaped by their prior belief inferred from past experience. Researchers combined hierarchical Bayesian modeling with fMRI on an associative learning task in 28 male human participants to characterize the effect of the prior belief of tactile events on connections mediating the outcome of perceptual decisions. Activity in anterior insula (AIC), premotor cortex (PMd) and inferior parietal lobule (IPL) were modulated by prior belief on unexpected targets as compared to expected targets. On expected targets, prior belief decreased the connection strength from AIC to IPL, whereas it increased the connection strength from AIC to PMd when targets were unexpected. Individual differences in the modulatory strength of prior belief on insular projections correlated with the precision that increases the influence of prediction errors on belief updating. These results suggest complementary effects of prior belief on insular-frontoparietal projections mediating the precision of prediction during probabilistic tactile learning.

by Zhi-Xiang Xu, Gyu Hyun Kim, Ji-Wei Tan, Anna E. Riso, Ye Sun, Ethan Y. Xu, Guey-Ying Liao, Haifei Xu, Sang-Hoon Lee, Na-Young Do, Chan Hee Lee, Amy E. Clipperton-Allen, Soonwook Kwon, Damon T. Page, Kea Joo Lee & Baoji Xu in Nature Communications

Autism in males linked to defect in brain immune cells and microglia

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Researchers employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. They show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. Scientists propose that functional perturbation of male microglia is an important cause for sex-biased ASD.

a Phagocytosis of FAM-Aβ(1–42) in cultured control and MG4E microglia. Male, n = 18 for control and n = 28 for MG4E; female, n = 14 for control and n = 13 for MG4E. **p = 0.0017 and n.s. not significant (p = 0.4919) by two-sided t-test. b, c Migration of microglia into FAM-Aβ(1–42) injection sites in 2-week-old male (b) and female ( C ) control and MG4E mice. Microglia clustering index is defined as (density of Iba1+ cells in the FAM-Aβ-covered area)/(density of Iba1+ cells in a contralateral site). Male, n = 6 control mice and 7 MG4E mice; female, n = 4 per genotype. Two-sided t-test: male mice, contralateral microglia density, **p = 0.0013; clustering index, **p = 0.0026, n.s. not significant. Scale bars, 100 μm. d Microglial surveillance in response to ATP treatment in male and female MG4E microglia at P14–P18. Microglial baseline motility was recorded for 5 min, then ATP was bath-applied to brain slices and recorded for another 10 min. Data was normalized to the mean process motility of first 5 min. Male, n = 15 microglia from 3 control mice and 20 microglia from 3 MG4E mice; female, n = 18 microglia from 3 control mice and 26 microglia from 3 MG4E mice. Male, two-way ANOVA for genotype during ATP treatment, F(1, 330) = 9.566, p = 0.002; female, two-way ANOVA for genotype during ATP treatment, F(1, 420) = 0.045, p = 0.831. Scale bar, 10 μm. e Engulfment of Homer1 by microglia. Upper panel shows confocal images of Homer1 and Iba1 double immunohistochemistry, and lower panel shows 3-D reconstruction of a microglial cell and Homer1 immunoreactivity. Arrowheads denote Homer1 inside the microglia. Male, 18 microglia from 6 control mice and 15 microglia from 5 MG4E mice; female, 15 microglia from 5 mice per genotype. *p = 0.0378 and n.s., not significant (p = 0.4891) by two-sided t-test. Scale bars, 5 μm. All data are shown as mean ± s.e.m.

Ashley E. Lepack, Craig T. Werner, Andrew F. Stewart, Sasha L. Fulton, Ping Zhong, Lorna A. Farrelly et al. in Science

Scientists have discovered a new role for the brain chemical dopamine that is independent of classic neurotransmission. The new role appears to be critical to changes in gene expression related to chronic exposure to, or abuse of, cocaine.

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. Researchers found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, they reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

“Our study provides the first evidence of how dopamine can directly impact drug-induced gene expression abnormalities and subsequent relapse behavior,” says Ian Maze, PhD, Associate Professor of Neuroscience, and Pharmacological Sciences, at the Icahn School of Medicine at Mount Sinai, and lead author of the study. “Beyond transmission of signals between neurons in the brain, we have found that dopamine can be chemically attached to histone proteins, which causes cells to switch different genes on and off, affecting regions of the brain that are involved in motivation and reward behavior. This biochemical process significantly affects cocaine vulnerability and relapse when perturbed by drugs of abuse.”

by Morten L. Kringelbach, Josephine Cruzat, Joana Cabral, Gitte Moos Knudsen, Robin Carhart-Harris, Peter C. Whybrow, Nikos K. Logothetis, and Gustavo Deco in Proceedings of the National Academy of Sciences

Computational simulations reveal the integration of both neuronal and neurotransmitter systems at a whole-brain level is vital to fully understand the effects of psilocybin on brain activity.

In a technical tour de force, researchers have created a framework demonstrating the underlying fundamental principles of bidirectional coupling of neuronal and neurotransmitter dynamical systems. Specifically, in the study, they combined multimodal neuroimaging data to causally explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. Longer term, this could provide a better understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction.

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. Scientists introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. They 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-HT2AR) 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.

Interest in research into the effects of psilocybin, a psychedelic drug, has increased significantly in recent years due to its promising therapeutic effects in neuropsychiatric disorders such as depression, anxiety and addiction.

by Jacqueline-Marie N. Ferland & Yasmin L. Hurd in Nature Neuroscience

The increasing use of cannabis has brought significant attention to cannabis use disorder (CUD) and its neurobiological underpinnings. In the recent paper published in Nature Neuroscience, scientists discuss risk factors related to the development of CUD its neurobiological characteristics.

There have been dramatic changes worldwide in the attitudes toward and consumption of recreational and medical cannabis. Cannabinoid receptors, which mediate the actions of cannabis, are abundantly expressed in brain regions known to mediate neural processes underlying reward, cognition, emotional regulation and stress responsivity relevant to addiction vulnerability. Despite debates regarding potential pathological consequences of cannabis use, cannabis use disorder is a clinical diagnosis with high prevalence in the general population and that often has its genesis in adolescence and in vulnerable individuals associated with psychiatric comorbidity, genetic and environmental factors. Integrated information from human and animal studies is beginning to expand insights regarding neurobiological systems associated with cannabis use disorder, which often share common neural characteristics with other substance use disorders, that could inform prevention and treatment strategies.

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