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Environmental Pollution (Barking, Essex... Nov 2023The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in...
The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in pluripotent cell-derived organoid systems open up novel avenues for human development, disease and toxicity modeling. Here, we have established a forebrain organoid system and recapitulated early human cortical development spatiotemporally including neuroepithelium induction, apical-basal axis formation, neural progenitor proliferation and maintenance, neuronal differentiation and layer/region patterning. To explore whether this forebrain organoid system is suitable for neurotoxicity modeling, we subjected the organoids to bisphenol A (BPA), a common environmental toxicant of global presence and high epidemic significance. BPA exposure caused substantial abnormalities in key cortical developmental events, inhibited progenitor cell proliferation and promoted precocious neuronal differentiation, leading premature progenitor cell depletion and aberrant cortical layer patterning and structural organization. Consistent with an antagonistic mechanism between thyroid hormone and BPA, T3 supplementation attenuated BPA-mediated cortical developmental abnormalities. Altogether, our in vitro recapitulation of cortical development with forebrain organoids provides a paradigm for efficient neural development and toxicity modeling and related remedy testing/screening.
Topics: Humans; Neurogenesis; Prosencephalon; Stem Cells; Organoids
PubMed: 37757934
DOI: 10.1016/j.envpol.2023.122624 -
Cell Reports Oct 2023Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates...
Chronic pain is a complex experience with multifaceted behavioral manifestations, often leading to pain avoidance at the expense of reward approach. How pain facilitates avoidance in situations with mixed outcomes is unknown. The anterior cingulate cortex (ACC) plays a key role in pain processing and in value-based decision-making. Distinct ACC inputs inform about the sensory and emotional quality of pain. However, whether specific ACC circuits underlie pathological conflict assessment in pain remains underexplored. Here, we demonstrate that mice with chronic pain favor cold avoidance rather than reward approach in a conflicting task. This occurs along with selective strengthening of basolateral amygdala inputs onto ACC layer 2/3 pyramidal neurons. The amygdala-cingulate projection is necessary and sufficient for the conflicting cold avoidance. Further, low-frequency stimulation of this pathway restores AMPA receptor function and reduces avoidance in pain mice. Our findings provide insights into the circuits and mechanisms underlying cognitive aspects of pain and offer potential targets for treatment.
Topics: Mice; Animals; Gyrus Cinguli; Chronic Pain; Amygdala; Basolateral Nuclear Complex; Emotions
PubMed: 37733589
DOI: 10.1016/j.celrep.2023.113125 -
The Journal of Comparative Neurology Dec 2023Retrosplenial cortex (RSC) has unique problems for human neuroimaging studies as its divisions are small, at the lower end of functional scanner spatial resolution, and...
Retrosplenial cortex (RSC) has unique problems for human neuroimaging studies as its divisions are small, at the lower end of functional scanner spatial resolution, and it is buried in the callosal sulcus. The present study sought to define the cytoarchitecture of RSC in human and monkey brains along its entire anteroposterior extent. The results show anterior extensions, a newly defined dichotomy of area 30, a new area p30, and an area p29v in monkey that differentiates into three divisions in human. Accordingly, anterior (a), intermediate (i), and posterior (p) divisions of areas 29l, 29m, 30l, and 30m were identified. Posterior area 29 has higher neuron packing in the granular layer than anterior and intermediate divisions of area 29. A newly detected dysgranular area p30 has larger neurons in layers II-IIIab than a30 and i30 and with substantially higher NFP expression in layer IIIab of posterior areas than areas a30 and i30. Medial area 30 has larger pyramids and higher NFP expression in all layers than area 30l. The new area p30 was seen between areas p29m and p30I in both species. Finally, a ventral area p29v is present in monkeys. This latter area appears to differentiate into three divisions in human with the most extensive granular layer adjacent to layer I in p29vm and p29vl. Functional imaging has identified pRSC as part of a cognitive map which is engaged in spatial navigation and localization of personally relevant objects.
Topics: Humans; Gyrus Cinguli; Neocortex; Neurons; Pyramidal Tracts; Cerebral Cortex
PubMed: 38062543
DOI: 10.1002/cne.25561 -
ENeuro Oct 2023Lysosomes are acidic organelles that traffic throughout neurons delivering catabolic enzymes to distal regions of the cell and maintaining degradative demands. Loss of...
Lysosomes are acidic organelles that traffic throughout neurons delivering catabolic enzymes to distal regions of the cell and maintaining degradative demands. Loss of function mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher's disease (GD) and are the most common genetic risk factor for synucleinopathies like Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GCase degrades the membrane lipid glucosylceramide (GlcCer) and mutations in , or inhibiting its activity, results in the accumulation of GlcCer and disturbs the composition of the lysosomal membrane. The lysosomal membrane serves as the platform to which intracellular trafficking complexes are recruited and activated. Here, we investigated whether lysosomal trafficking in axons was altered by inhibition of GCase with the pharmacological agent Conduritol B Epoxide (CBE). Using live cell imaging in human male induced pluripotent human stem cell (iPSC)-derived forebrain neurons, we demonstrated that lysosomal transport was similar in both control and CBE-treated neurons. Furthermore, we tested whether lysosomal rupture, a process implicated in various neurodegenerative disorders, was affected by inhibition of GCase. Using L-leucyl-L-leucine methyl ester (LLoME) to induce lysosomal membrane damage and immunocytochemical staining for markers of lysosomal rupture, we found no difference in susceptibility to rupture between control and CBE-treated neurons. These results suggest the loss of GCase activity does not contribute to neurodegenerative disease by disrupting either lysosomal transport or rupture.
Topics: Male; Humans; Glucosylceramidase; Neurodegenerative Diseases; Axonal Transport; Induced Pluripotent Stem Cells; Neurons; Prosencephalon; Lysosomes; alpha-Synuclein
PubMed: 37816595
DOI: 10.1523/ENEURO.0079-23.2023 -
The Journal of Neuroscience : the... Nov 2023In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is...
In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABA and GABA receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing. We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.
Topics: Male; Female; Rats; Animals; Insular Cortex; Thalamus; Ventral Thalamic Nuclei; Neurons; gamma-Aminobutyric Acid; Cerebral Cortex
PubMed: 37704374
DOI: 10.1523/JNEUROSCI.2255-22.2023 -
NeuroImage Jul 2023Humans adjust their behavioral strategies based on feedback, a process that may depend on intrinsic preferences and contextual factors such as visual salience. In this...
Humans adjust their behavioral strategies based on feedback, a process that may depend on intrinsic preferences and contextual factors such as visual salience. In this study, we hypothesized that decision-making based on visual salience is influenced by habitual and goal-directed processes, which can be evidenced by changes in attention and subjective valuation systems. To test this hypothesis, we conducted a series of studies to investigate the behavioral and neural mechanisms underlying visual salience-driven decision-making. We first established the baseline behavioral strategy without salience in Experiment 1 (n = 21). We then highlighted the utility or performance dimension of the chosen outcome using colors in Experiment 2 (n = 30). We demonstrated that the difference in staying frequency increased along the salient dimension, confirming a salience effect. Furthermore, the salience effect was abolished when directional information was removed in Experiment 3 (n = 28), suggesting that the salience effect is feedback-specific. To generalize our findings, we replicated the feedback-specific salience effects using eye-tracking and text emphasis. The fixation differences between the chosen and unchosen values were enhanced along the feedback-specific salient dimension in Experiment 4 (n = 48) but unchanged after removing feedback-specific information in Experiment 5 (n = 32). Moreover, the staying frequency was correlated with fixation properties, confirming that salience guides attention deployment. Lastly, our neuroimaging study (Experiment 6, n = 25) showed that the striatum subregions encoded salience-based outcome evaluation, while the vmPFC encoded salience-based behavioral adjustments. The connectivity of the vmPFC-ventral striatum accounted for individual differences in utility-driven, whereas the vmPFC-dmPFC for performance-driven behavioral adjustments. Together, our results provide a neurocognitive account of how task-irrelevant visual salience drives decision-making by involving attention and the frontal-striatal valuation systems. PUBLIC SIGNIFICANCE STATEMENT: Humans may use the current outcome to make behavior adjustments. How this occurs may depend on stable individual preferences and contextual factors, such as visual salience. Under the hypothesis that visual salience determines attention and subsequently modulates subjective valuation, we investigated the underlying behavioral and neural bases of visual-context-guided outcome evaluation and behavioral adjustments. Our findings suggest that the reward system is orchestrated by visual context and highlight the critical role of attention and the frontal-striatal neural circuit in visual-context-guided decision-making that may involve habitual and goal-directed processes.
Topics: Humans; Decision Making; Attention; Ventral Striatum; Neostriatum; Cognition; Reward
PubMed: 37192677
DOI: 10.1016/j.neuroimage.2023.120170 -
European Psychiatry : the Journal of... Oct 2023Observations from different fields of research coincide in indicating that a defective gamma-aminobutyric acid (GABA) interneuron system may be among the primary factors...
BACKGROUND
Observations from different fields of research coincide in indicating that a defective gamma-aminobutyric acid (GABA) interneuron system may be among the primary factors accounting for the varied clinical expression of schizophrenia. GABA interneuron deficiency is locally expressed in the form of neural activity desynchronization. We mapped the functional anatomy of local synchrony in the cerebral cortex in schizophrenia using functional connectivity MRI.
METHODS
Data from 86 patients with schizophrenia and 137 control subjects were obtained from publicly available repositories. Resting-state functional connectivity maps based on Iso-Distant Average Correlation measures across three distances were estimated detailing the local functional structure of the cerebral cortex.
RESULTS
Patients with schizophrenia showed weaker local functional connectivity (i.e., lower MRI signal synchrony) in (i) prefrontal lobe areas, (ii) somatosensory, auditory, visual, and motor cortices, (iii) paralimbic system at the anterior insula and anterior cingulate cortex, and (iv) hippocampus. The distribution of the defect in cortical area synchrony largely coincided with the synchronization effect of the GABA agonist alprazolam previously observed using identical functional connectivity measures. There was also a notable resemblance between the anatomy of our findings and cortical areas showing higher density of parvalbumin (prefrontal lobe and sensory cortices) and somatostatin (anterior insula and anterior cingulate cortex) GABA interneurons in humans.
CONCLUSIONS
Our results thus provide detail of the functional anatomy of synchrony changes in the cerebral cortex in schizophrenia and suggest which elements of the interneuron system are affected. Such information could ultimately be relevant in the search for specific treatments.
Topics: Humans; Schizophrenia; Cerebral Cortex; Prefrontal Cortex; Gyrus Cinguli; gamma-Aminobutyric Acid; Magnetic Resonance Imaging
PubMed: 37848404
DOI: 10.1192/j.eurpsy.2023.2463 -
The Journal of Comparative Neurology Mar 2024The brain is spatially organized into subdivisions, nuclei and areas, which often correspond to functional and developmental units. A segmentation of brain regions in...
The brain is spatially organized into subdivisions, nuclei and areas, which often correspond to functional and developmental units. A segmentation of brain regions in the form of a consensus atlas facilitates mechanistic studies and is a prerequisite for sharing information among neuroanatomists. Gene expression patterns objectively delineate boundaries between brain regions and provide information about their developmental and evolutionary histories. To generate a detailed molecular map of the larval zebrafish diencephalon, we took advantage of the Max Planck Zebrafish Brain (mapzebrain) atlas, which aligns hundreds of transcript and transgene expression patterns in a shared coordinate system. Inspection and co-visualization of close to 50 marker genes have allowed us to resolve the tripartite prosomeric scaffold of the diencephalon at unprecedented resolution. This approach clarified the genoarchitectonic partitioning of the alar diencephalon into pretectum (alar part of prosomere P1), thalamus (alar part of prosomere P2, with habenula and pineal complex), and prethalamus (alar part of prosomere P3). We further identified the region of the nucleus of the medial longitudinal fasciculus, as well as the posterior and anterior parts of the posterior tuberculum, as molecularly distinct basal parts of prosomeres 1, 2, and 3, respectively. Some of the markers examined allowed us to locate glutamatergic, GABAergic, dopaminergic, serotoninergic, and various neuropeptidergic domains in the larval zebrafish diencephalon. Our molecular neuroanatomical approach has thus (1) yielded an objective and internally consistent interpretation of the prosomere boundaries within the zebrafish forebrain; has (2) produced a list of markers, which in sparse combinations label the subdivisions of the diencephalon; and is (3) setting the stage for further functional and developmental studies in this vertebrate brain.
Topics: Animals; Zebrafish; Larva; Diencephalon; Thalamus; Prosencephalon
PubMed: 37983970
DOI: 10.1002/cne.25549 -
Nature Apr 2024The human nervous system is a highly complex but organized organ. The foundation of its complexity and organization is laid down during regional patterning of the neural...
The human nervous system is a highly complex but organized organ. The foundation of its complexity and organization is laid down during regional patterning of the neural tube, the embryonic precursor to the human nervous system. Historically, studies of neural tube patterning have relied on animal models to uncover underlying principles. Recently, models of neurodevelopment based on human pluripotent stem cells, including neural organoids and bioengineered neural tube development models, have emerged. However, such models fail to recapitulate neural patterning along both rostral-caudal and dorsal-ventral axes in a three-dimensional tubular geometry, a hallmark of neural tube development. Here we report a human pluripotent stem cell-based, microfluidic neural tube-like structure, the development of which recapitulates several crucial aspects of neural patterning in brain and spinal cord regions and along rostral-caudal and dorsal-ventral axes. This structure was utilized for studying neuronal lineage development, which revealed pre-patterning of axial identities of neural crest progenitors and functional roles of neuromesodermal progenitors and the caudal gene CDX2 in spinal cord and trunk neural crest development. We further developed dorsal-ventral patterned microfluidic forebrain-like structures with spatially segregated dorsal and ventral regions and layered apicobasal cellular organizations that mimic development of the human forebrain pallium and subpallium, respectively. Together, these microfluidics-based neurodevelopment models provide three-dimensional lumenal tissue architectures with in vivo-like spatiotemporal cell differentiation and organization, which will facilitate the study of human neurodevelopment and disease.
Topics: Humans; Body Patterning; Cell Culture Techniques, Three Dimensional; Cell Differentiation; Microfluidics; Neural Crest; Neural Tube; Pluripotent Stem Cells; Prosencephalon; Spinal Cord
PubMed: 38408487
DOI: 10.1038/s41586-024-07204-7 -
Trends in Neurosciences Oct 2023Crows, a group of corvid songbird species, show superb behavioral flexibility largely stemming from their advanced cognitive control functions. These functions mainly...
Crows, a group of corvid songbird species, show superb behavioral flexibility largely stemming from their advanced cognitive control functions. These functions mainly originate from the associative avian pallium that evolved independently from the mammalian cerebral cortex. This article presents a brief overview of cognitive control functions and their neuronal foundation in crows.
Topics: Animals; Crows; Telencephalon; Cognition; Cerebral Cortex; Neurons; Mammals
PubMed: 37524636
DOI: 10.1016/j.tins.2023.07.002