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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 -
Trends in Cognitive Sciences Jun 2021The prefrontal cortex (PFC) supports decision-making, goal tracking, and planning. Spatial navigation is a behavior that taxes these cognitive processes, yet the role of... (Review)
Review
The prefrontal cortex (PFC) supports decision-making, goal tracking, and planning. Spatial navigation is a behavior that taxes these cognitive processes, yet the role of the PFC in models of navigation has been largely overlooked. In humans, activity in dorsolateral PFC (dlPFC) and ventrolateral PFC (vlPFC) during detours, reveal a role in inhibition and replanning. Dorsal anterior cingulate cortex (dACC) is implicated in planning and spontaneous internally-generated changes of route. Orbitofrontal cortex (OFC) integrates representations of the environment with the value of actions, providing a 'map' of possible decisions. In rodents, medial frontal areas interact with hippocampus during spatial decisions and switching between navigation strategies. In reviewing these advances, we provide a framework for how different prefrontal regions may contribute to different stages of navigation.
Topics: Gyrus Cinguli; Hippocampus; Prefrontal Cortex; Spatial Navigation
PubMed: 33752958
DOI: 10.1016/j.tics.2021.02.010 -
Neuroscience and Biobehavioral Reviews Dec 2020Two thalamic sites are of especial significance for understanding hippocampal - diencephalic interactions: the anterior thalamic nuclei and nucleus reuniens. Both nuclei... (Review)
Review
Two thalamic sites are of especial significance for understanding hippocampal - diencephalic interactions: the anterior thalamic nuclei and nucleus reuniens. Both nuclei have dense, direct interconnections with the hippocampal formation, and both are directly connected with many of the same cortical and subcortical areas. These two thalamic sites also contain neurons responsive to spatial stimuli while lesions within these two same areas can disrupt spatial learning tasks that are hippocampal dependent. Despite these many similarities, closer analysis reveals important differences in the details of their connectivity and the behavioural impact of lesions in these two thalamic sites. These nuclei play qualitatively different roles that largely reflect the contrasting relative importance of their medial frontal cortex interactions (nucleus reuniens) compared with their retrosplenial, cingulate, and mammillary body interactions (anterior thalamic nuclei). While the anterior thalamic nuclei are critical for multiple aspects of hippocampal spatial encoding and performance, nucleus reuniens contributes, as required, to aid cognitive control and help select correct from competing memories.
Topics: Anterior Thalamic Nuclei; Hippocampus; Humans; Mammillary Bodies; Midline Thalamic Nuclei; Neural Pathways; Neurons
PubMed: 33069688
DOI: 10.1016/j.neubiorev.2020.10.006 -
Current Opinion in Neurobiology Dec 2021A comparison of the vertebrate motor systems of the oldest group of now living vertebrates (lamprey) with that of mammals shows that there are striking similarities not... (Review)
Review
A comparison of the vertebrate motor systems of the oldest group of now living vertebrates (lamprey) with that of mammals shows that there are striking similarities not only in the basic organization but also with regard to synaptic properties, transmitters and neuronal properties. The lamprey dorsal pallium (cortex) has a motor, a visual and a somatosensory area, and the basal ganglia, including the dopamine system, are organized in a virtually identical way in the lamprey and rodents. This also applies to the midbrain, brainstem and spinal cord. However, during evolution additional capabilities such as systems for the control of foreleg/arms, hands and fingers have evolved. The findings suggest that when the evolutionary lineages of mammals and lamprey became separate around 500 million years ago, the blueprint of the vertebrate motor system had already evolved.
Topics: Animals; Biological Evolution; Lampreys; Mammals; Prosencephalon; Spinal Cord; Vertebrates
PubMed: 34450468
DOI: 10.1016/j.conb.2021.07.016 -
Philosophical Transactions of the Royal... Jan 2020Vocalization is an ancient vertebrate trait essential to many forms of communication, ranging from courtship calls to free verse. Vocalizations may be entirely innate... (Review)
Review
Vocalization is an ancient vertebrate trait essential to many forms of communication, ranging from courtship calls to free verse. Vocalizations may be entirely innate and evoked by sexual cues or emotional state, as with many types of calls made in primates, rodents and birds; volitional, as with innate calls that, following extensive training, can be evoked by arbitrary sensory cues in non-human primates and corvid songbirds; or learned, acoustically flexible and complex, as with human speech and the courtship songs of oscine songbirds. This review compares and contrasts the neural mechanisms underlying innate, volitional and learned vocalizations, with an emphasis on functional studies in primates, rodents and songbirds. This comparison reveals both highly conserved and convergent mechanisms of vocal production in these different groups, despite their often vast phylogenetic separation. This similarity of central mechanisms for different forms of vocal production presents experimentalists with useful avenues for gaining detailed mechanistic insight into how vocalizations are employed for social and sexual signalling, and how they can be modified through experience to yield new vocal repertoires customized to the individual's social group. This article is part of the theme issue 'What can animal communication teach us about human language?'
Topics: Animals; Birds; Brain Mapping; Emotions; Female; Humans; Language; Learning; Male; Mammals; Motor Cortex; Neurobiology; Neurons; Phylogeny; Primates; Prosencephalon; Songbirds; Vocalization, Animal; Volition
PubMed: 31735150
DOI: 10.1098/rstb.2019.0054 -
International Journal of Molecular... Jun 2023Neuroinflammation is one of the postulated mechanisms for Pb neurotoxicity. However, the exact molecular mechanisms responsible for its pro-inflammatory effect are not...
Neuroinflammation is one of the postulated mechanisms for Pb neurotoxicity. However, the exact molecular mechanisms responsible for its pro-inflammatory effect are not fully elucidated. In this study, we examined the role of glial cells in neuroinflammation induced by Pb exposure. We investigated how microglia, a type of glial cell, responded to the changes caused by perinatal exposure to Pb by measuring the expression of Iba1 at the mRNA and protein levels. To assess the state of microglia, we analyzed the mRNA levels of specific markers associated with the cytotoxic M1 phenotype ( and ) and the cytoprotective M2 phenotype ( and ). Additionally, we measured the concentration of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). To assess the reactivity and functionality status of astrocytes, we analyzed the GFAP (mRNA expression and protein concentration) as well as glutamine synthase (GS) protein level and activity. Using an electron microscope, we assessed ultrastructural abnormalities in the examined brain structures (forebrain cortex, cerebellum, and hippocampus). In addition, we measured the mRNA levels of and , and their receptor, . Our data showed that perinatal exposure to Pb at low doses affected both microglia and astrocyte cells' status (their mobilization, activation, function, and changes in gene expression profile) in a brain-structure-specific manner. The results suggest that both microglia and astrocytes represent a potential target for Pb neurotoxicity, thus being key mediators of neuroinflammation and further neuropathology evoked by Pb poisoning during perinatal brain development.
Topics: Pregnancy; Female; Humans; Astrocytes; Microglia; Lead; Neuroinflammatory Diseases; Cytokines; Prosencephalon; RNA, Messenger
PubMed: 37373050
DOI: 10.3390/ijms24129903 -
Developmental Dynamics : An Official... Aug 2019Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and... (Review)
Review
Evolutionary conservation and experimental tractability have made animal model systems invaluable tools in our quest to understand human embryogenesis, both normal and abnormal. Standard genetic approaches, particularly useful in understanding monogenic diseases, are no longer sufficient as research attention shifts toward multifactorial outcomes. Here, we examine this progression through the lens of holoprosencephaly (HPE), a common human malformation involving incomplete forebrain division, and a classic example of an etiologically complex outcome. We relate the basic underpinning of HPE pathogenesis to critical cell-cell interactions and signaling molecules discovered through embryological and genetic approaches in multiple model organisms, and discuss the role of the mouse model in functional examination of HPE-linked genes. We then outline the most critical remaining gaps to understanding human HPE, including the conundrum of incomplete penetrance/expressivity and the role of gene-environment interactions. To tackle these challenges, we outline a strategy that leverages new and emerging technologies in multiple model systems to solve the puzzle of HPE.
Topics: Animals; Gene-Environment Interaction; Holoprosencephaly; Humans; Mice; Models, Animal; Penetrance; Prosencephalon; Signal Transduction
PubMed: 30993762
DOI: 10.1002/dvdy.41 -
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 -
Journal of Equine Veterinary Science May 2022Holoprosencephaly is a central nervous system malformation, characterized by incomplete or total lack of division of prosencephalon hemispheres, which is commonly...
Holoprosencephaly is a central nervous system malformation, characterized by incomplete or total lack of division of prosencephalon hemispheres, which is commonly accompanied by craniofacial malformations. A 9-month-gestation aborted American Quarter Horse fetus was submitted for postmortem examination. The fetus lacked haircoat and had severe facial malformations including marked shortening/absence of the maxillary, incisive and nasal bones, bilateral anophthalmia, and pre-maxillary agenesis. The prosencephalon was small and nearly spherical, represented by a single lobe, with no visible separation between cerebral hemispheres. The olfactory bulbs, piriform lobes, and the optic chiasm were absent. At cross sectioning of the prosencephalon, the inner structures of the brain were completely absent, and replaced by a monoventricle lined by the remaining compressed cortex, and the thalami were fused. Since mutations in the sonic hedgehog (SHH) gene have been associated with human holoprosencephaly, the three coding SHH exons were sequenced using liver DNA of the aborted foal. The obtained SHH sequence was similar to the Equus caballus SHH mRNA sequence deposited in Genbank (XM_023640069.1); therefore, no polymorphism in the coding region of this gene justifying the phenotype was observed. This is the first report of alobar holoprosencephaly in horses.
Topics: Aborted Fetus; Animals; Fetus; Hedgehog Proteins; Holoprosencephaly; Horse Diseases; Horses; Prosencephalon
PubMed: 35150851
DOI: 10.1016/j.jevs.2022.103898 -
Translational Psychiatry Mar 2022Valproic acid (VPA) exposure as an environmental factor that confers risk of autism spectrum disorder (ASD), its functional mechanisms in the human brain remain unclear...
Valproic acid (VPA) exposure as an environmental factor that confers risk of autism spectrum disorder (ASD), its functional mechanisms in the human brain remain unclear since relevant studies are currently restricted to two-dimensional cell cultures and animal models. To identify mechanisms by which VPA contribute to ASD risk in human, here we used human forebrain organoids (hFOs), in vitro derived three-dimensional cell cultures that recapitulate key human brain developmental features. We identified that VPA exposure in hFOs affected the expression of genes enriched in neural development, synaptic transmission, oxytocin signaling, calcium, and potassium signaling pathways, which have been implicated in ASD. Genes (e.g., CAMK4, CLCN4, DPP10, GABRB3, KCNB1, PRKCB, SCN1A, and SLC24A2) that affected by VPA were significantly overlapped with those dysregulated in brains or organoids derived from ASD patients, and known ASD risk genes, as well as genes in ASD risk-associated gene coexpression modules. Single-cell RNA sequencing analysis showed that VPA exposure affected the expression of genes in choroid plexus, excitatory neuron, immature neuron, and medial ganglionic eminence cells annotated in hFOs. Microelectrode array further identified that VPA exposure in hFOs disrupted synaptic transmission. Taken together, this study connects VPA exposure to ASD pathogenesis using hFOs, which is valuable for illuminating the etiology of ASD and screening for potential therapeutic targets.
Topics: Animals; Autism Spectrum Disorder; Autistic Disorder; Chloride Channels; Disease Models, Animal; Humans; Organoids; Prenatal Exposure Delayed Effects; Prosencephalon; Valproic Acid
PubMed: 35351869
DOI: 10.1038/s41398-022-01898-x