-
Cell Reports Jan 2023Cerebellar-thalamo-striatal synaptic communication has been implicated in a wide range of behaviors, including goal-directed actions, and is altered in cerebellar...
Cerebellar-thalamo-striatal synaptic communication has been implicated in a wide range of behaviors, including goal-directed actions, and is altered in cerebellar dystonia. However, its detailed connectivity through the thalamus and its contribution to the execution of forelimb movements is unclear. Here, we use trans-synaptic and retrograde tracing, ex vivo slice recordings, and optogenetic inhibitions during the execution of unidirectional or sequential joystick displacements to demonstrate that the deep cerebellar nuclei (DCN) influence the dorsal striatum with a very high probability. We show that this mainly occurs through the centrolateral (CL), parafascicular (PF), and ventrolateral (VL) nuclei of the thalamus, observing that the DCN→VL and DCN→CL pathways contribute to the execution of unidirectional forelimb displacements while the DCN→PF and DCN→thalamo→striatal pathways contribute to the appropriate execution of forelimb reaching and sequential displacements. These findings highlight specific contributions of the different cerebellar-thalamo-striatal paths to the control of skilled forelimb movement.
Topics: Animals; Cerebellar Nuclei; Corpus Striatum; Thalamus; Cerebellum; Movement; Forelimb
PubMed: 36656714
DOI: 10.1016/j.celrep.2023.112000 -
The Neuroradiology Journal Jun 2015The classification of posterior fossa congenital anomalies has been a controversial topic. Advances in genetics and imaging have allowed a better understanding of the... (Review)
Review
The classification of posterior fossa congenital anomalies has been a controversial topic. Advances in genetics and imaging have allowed a better understanding of the embryologic development of these abnormalities. A new classification schema correlates the embryologic, morphologic, and genetic bases of these anomalies in order to better distinguish and describe them. Although they provide a better understanding of the clinical aspects and genetics of these disorders, it is crucial for the radiologist to be able to diagnose the congenital posterior fossa anomalies based on their morphology, since neuroimaging is usually the initial step when these disorders are suspected. We divide the most common posterior fossa congenital anomalies into two groups: 1) hindbrain malformations, including diseases with cerebellar or vermian agenesis, aplasia or hypoplasia and cystic posterior fossa anomalies; and 2) cranial vault malformations. In addition, we will review the embryologic development of the posterior fossa and, from the perspective of embryonic development, will describe the imaging appearance of congenital posterior fossa anomalies. Knowledge of the developmental bases of these malformations facilitates detection of the morphological changes identified on imaging, allowing accurate differentiation and diagnosis of congenital posterior fossa anomalies.
Topics: Abnormalities, Multiple; Arachnoid Cysts; Arnold-Chiari Malformation; Cerebellar Diseases; Cerebellum; Cranial Fossa, Posterior; Dandy-Walker Syndrome; Eye Abnormalities; Hamartoma Syndrome, Multiple; Humans; Kidney Diseases, Cystic; Mesencephalon; Retina; Rhombencephalon; Walker-Warburg Syndrome
PubMed: 26246090
DOI: 10.1177/1971400915576665 -
Peptides Nov 2020Estrogens modulate different physiological functions, including reproduction, inflammation, bone formation, energy expenditure, and food intake. In this review, we... (Review)
Review
Estrogens modulate different physiological functions, including reproduction, inflammation, bone formation, energy expenditure, and food intake. In this review, we highlight the effect of estrogens on food intake regulation and the latest literature on intracellular estrogen signaling. In addition, gut satiety hormones, such as cholecystokinin, glucagon-like peptide 1 and leptin are essential to regulate ingestive behaviors in the postprandial period. These peripheral signals are sensed by vagal afferent terminals in the gut wall and transmitted to the hindbrain axis. Here we 1. review the role of the vagus-hindbrain axis in response to gut satiety signals and 2. consider the potential synergistic effects of estrogens on gut satiety signals at the level of vagal afferent neurons and nuclei located in the hindbrain. Understanding the action of estrogens in gut-brain axis provides a potential strategy to develop estrogen-based therapies for metabolic diseases and emphasizes the importance of sex difference in the treatment of obesity.
Topics: Animals; Cholecystokinin; Eating; Energy Metabolism; Estrogens; Female; Gastrointestinal Hormones; Glucagon-Like Peptide 1; Humans; Leptin; Male; Neurons, Afferent; Receptors, Estrogen; Rhombencephalon; Satiety Response; Vagus Nerve
PubMed: 32860834
DOI: 10.1016/j.peptides.2020.170389 -
Neuron May 2023In this issue of Neuron, Xiao et al. reported that inhibitory and excitatory neurons in the pontine central gray encode and transmit opposite valences of sensory...
In this issue of Neuron, Xiao et al. reported that inhibitory and excitatory neurons in the pontine central gray encode and transmit opposite valences of sensory stimuli through parallel circuits to a distributed brain network.
Topics: Pons; Neurons; Pontine Tegmentum; Cerebellar Nuclei
PubMed: 37141860
DOI: 10.1016/j.neuron.2023.04.009 -
Nature Communications Mar 2024The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many...
The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many vital functions. Notable among them are the parabrachial nucleus, the Kölliker Fuse, the Barrington nucleus, the locus coeruleus, and the dorsal, laterodorsal, and ventral tegmental nuclei. In this study, we applied single-nucleus RNA-seq (snRNA-seq) to resolve neuronal subtypes based on their unique transcriptional profiles and then used multiplexed error robust fluorescence in situ hybridization (MERFISH) to map them spatially. We sampled ~1 million cells across the dPnTg and defined the spatial distribution of over 120 neuronal subtypes. Our analysis identified an unpredicted high transcriptional diversity in this region and pinpointed the unique marker genes of many neuronal subtypes. We also demonstrated that many neuronal subtypes are transcriptionally similar between humans and mice, enhancing this study's translational value. Finally, we developed a freely accessible, GPU and CPU-powered dashboard ( http://harvard.heavy.ai:6273/ ) that combines interactive visual analytics and hardware-accelerated SQL into a data science framework to allow the scientific community to query and gain insights into the data.
Topics: Humans; Animals; Mice; In Situ Hybridization, Fluorescence; Pontine Tegmentum; Brain Stem; Locus Coeruleus; Parabrachial Nucleus; Ascomycota
PubMed: 38438345
DOI: 10.1038/s41467-024-45907-7 -
Molecular Metabolism Dec 2022Pancreatic insulin was discovered a century ago, and this discovery led to the first lifesaving treatment for diabetes. While still controversial, nearly one hundred...
OBJECTIVE
Pancreatic insulin was discovered a century ago, and this discovery led to the first lifesaving treatment for diabetes. While still controversial, nearly one hundred published reports suggest that insulin is also produced in the brain, with most focusing on hypothalamic or cortical insulin-producing cells. However, specific function for insulin produced within the brain remains poorly understood. Here we identify insulin expression in the hindbrain's dorsal vagal complex (DVC), and determine the role of this source of insulin in feeding and metabolism, as well as its response to diet-induced obesity in mice.
METHODS
To determine the contribution of Ins2-producing neurons to feeding behavior in mice, we used the cross of transgenic RipHER-cre mouse and channelrhodopsin-2 expressing animals, which allowed us to optogenetically stimulate neurons expressing Ins2 in vivo. To confirm the presence of insulin expression in Rip-labeled DVC cells, in situ hybridization was used. To ascertain the specific role of insulin in effects discovered via optogenetic stimulation a selective, CNS applied, insulin receptor antagonist was used. To understand the physiological contribution of insulin made in the hindbrain a virogenetic knockdown strategy was used.
RESULTS
Insulin gene expression and presence of insulin-promoter driven fluorescence in rat insulin promoter (Rip)-transgenic mice were detected in the hypothalamus, but also in the DVC. Insulin mRNA was present in nearly all fluorescently labeled cells in DVC. Diet-induced obesity in mice altered brain insulin gene expression, in a neuroanatomically divergent manner; while in the hypothalamus the expected obesity-induced reduction was found, in the DVC diet-induced obesity resulted in increased expression of the insulin gene. This led us to hypothesize a potentially divergent energy balance role of insulin in these two brain areas. To determine the acute impact of activating insulin-producing neurons in the DVC, optic stimulation of light-sensitive channelrhodopsin 2 in Rip-transgenic mice was utilized. Optogenetic photoactivation induced hyperphagia after acute activation of the DVC insulin neurons. This hyperphagia was blocked by central application of the insulin receptor antagonist S961, suggesting the feeding response was driven by insulin. To determine whether DVC insulin has a necessary contribution to feeding and metabolism, virogenetic insulin gene knockdown (KD) strategy, which allows for site-specific reduction of insulin gene expression in adult mice, was used. While chow-fed mice failed to reveal any changes of feeding or thermogenesis in response to the KD, mice challenged with a high-fat diet consumed less food. No changes in body weight were identified, possibly resulting from compensatory reduction in thermogenesis.
CONCLUSIONS
Together, our data suggest an important role for hindbrain insulin and insulin-producing cells in energy homeostasis.
Topics: Animals; Mice; Rats; Channelrhodopsins; Feeding Behavior; Hyperphagia; Insulin; Mice, Transgenic; Obesity; Receptor, Insulin; Rhombencephalon
PubMed: 36244663
DOI: 10.1016/j.molmet.2022.101614 -
Molecular Metabolism Nov 2021The area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and...
OBJECTIVE
The area postrema (AP) and nucleus tractus solitarius (NTS) located in the hindbrain are key nuclei that sense and integrate peripheral nutritional signals and consequently regulate feeding behaviour. While single-cell transcriptomics have been used in mice to reveal the gene expression profile and heterogeneity of key hypothalamic populations, similar in-depth studies have not yet been performed in the hindbrain.
METHODS
Using single-nucleus RNA sequencing, we provide a detailed survey of 16,034 cells within the AP and NTS of mice in the fed and fasted states.
RESULTS
Of these, 8,910 were neurons that group into 30 clusters, with 4,289 from mice fed ad libitum and 4,621 from overnight fasted mice. A total of 7,124 nuclei were from non-neuronal cells, including oligodendrocytes, astrocytes, and microglia. Interestingly, we identified that the oligodendrocyte population was particularly transcriptionally sensitive to an overnight fast. The receptors GLP1R, GIPR, GFRAL, and CALCR, which bind GLP1, GIP, GDF15, and amylin, respectively, are all expressed in the hindbrain and are major targets for anti-obesity therapeutics. We characterise the transcriptomes of these four populations and show that their gene expression profiles are not dramatically altered by an overnight fast. Notably, we find that roughly half of cells that express GIPR are oligodendrocytes. Additionally, we profile POMC-expressing neurons within the hindbrain and demonstrate that 84% of POMC neurons express either PCSK1, PSCK2, or both, implying that melanocortin peptides are likely produced by these neurons.
CONCLUSION
We provide a detailed single-cell level characterisation of AP and NTS cells expressing receptors for key anti-obesity drugs that are either already approved for human use or in clinical trials. This resource will help delineate the mechanisms underlying the effectiveness of these compounds and also prove useful in the continued search for other novel therapeutic targets.
Topics: Animals; Area Postrema; Eating; Fasting; Feeding Behavior; Mice; Mice, Inbred C57BL; Neurons; Proprotein Convertase 1; Proprotein Convertase 2; Rhombencephalon; Sequence Analysis, RNA; Solitary Nucleus
PubMed: 33962048
DOI: 10.1016/j.molmet.2021.101240 -
Developmental Dynamics : An Official... Jul 2019The cerebellum coordinates vestibular input into the hindbrain to control balance and movement, and its anatomical complexity is increasingly viewed as a high-throughput... (Review)
Review
The cerebellum coordinates vestibular input into the hindbrain to control balance and movement, and its anatomical complexity is increasingly viewed as a high-throughput processing center for sensory and cognitive functions. Cerebellum development however is relatively simple, and arises from a specialized structure in the anterior hindbrain called the rhombic lip, which along with the ventricular zone of the rostral-most dorsal hindbrain region, give rise to the distinct cell types that constitute the cerebellum. Granule cells, being the most numerous cell types, arise from the rhombic lip and form a dense and distinct layer of the cerebellar cortex. In this short review, we describe the various strategies used by amniotes and anamniotes to generate and diversify granule cell types during cerebellar development.
Topics: Animals; Cell Differentiation; Cerebellum; Humans; Neocortex; Rhombencephalon
PubMed: 31131952
DOI: 10.1002/dvdy.64 -
Nature Neuroscience Aug 2023The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal...
The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal feedback to coordinate the kinematics of such fast movements is unclear. Here we unveil a unique nucleo-olivary loop in the cerebellum and its involvement in coordinating high-velocity movements. Activating the excitatory nucleo-olivary pathway induces well-timed internal feedback complex spike signals in Purkinje cells to shape cerebellar outputs. Anatomical tracing reveals extensive axonal collaterals from the excitatory nucleo-olivary neurons to downstream motor regions, supporting integration of motor output and internal feedback signals within the cerebellum. This pathway directly drives saccades and head movements with a converging direction, while curtailing their amplitude and velocity via the powerful internal feedback mechanism. Our finding challenges the long-standing dogma that the cerebellum inhibits the inferior olivary pathway and provides a new circuit mechanism for the cerebellar control of high-velocity movements.
Topics: Olivary Nucleus; Cerebellum; Neurons; Purkinje Cells; Axons
PubMed: 37474638
DOI: 10.1038/s41593-023-01387-4 -
Nature Communications Nov 2023Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to...
Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.
Topics: Mice; Animals; Cerebellar Nuclei; Conditioning, Eyelid; Conditioning, Classical; Cerebellum; Cerebellar Cortex; Blinking
PubMed: 37985778
DOI: 10.1038/s41467-023-43227-w