Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Mol Psychiatry ; 27(2): 865-872, 2022 02.
Article in English | MEDLINE | ID: mdl-34650202

ABSTRACT

The triple-network model of psychopathology is a framework to explain the functional and structural neuroimaging phenotypes of psychiatric and neurological disorders. It describes the interactions within and between three distributed networks: the salience, default-mode, and central executive networks. These have been associated with brain disorder traits in patients. Homologous networks have been proposed in animal models, but their integration into a triple-network organization has not yet been determined. Using resting-state datasets, we demonstrate conserved spatio-temporal properties between triple-network elements in human, macaque, and mouse. The model predictions were also shown to apply in a mouse model for depression. To validate spatial homologies, we developed a data-driven approach to convert mouse brain maps into human standard coordinates. Finally, using high-resolution viral tracers in the mouse, we refined an anatomical model for these networks and validated this using optogenetics in mice and tractography in humans. Unexpectedly, we find serotonin involvement within the salience rather than the default-mode network. Our results support the existence of a triple-network system in the mouse that shares properties with that of humans along several dimensions, including a disease condition. Finally, we demonstrate a method to humanize mouse brain networks that opens doors to fully data-driven trans-species comparisons.


Subject(s)
Magnetic Resonance Imaging , Nerve Net , Animals , Brain , Brain Mapping/methods , Humans , Magnetic Resonance Imaging/methods , Mice , Neural Pathways
2.
Am J Pathol ; 186(3): 478-88, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26724386

ABSTRACT

Midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta and ventral tegmental area regulate extrapyramidal movement and important cognitive functions, including motivation, reward associations, and habit learning. Dysfunctions in DA neuron circuitry have been implicated in several neuropsychiatric disorders, including addiction and schizophrenia, whereas selective degeneration of DA neurons in substantia nigra pars compacta is a key neuropathological feature in Parkinson disease. Efforts to understand these disorders have focused on dissecting the underlying causes, as well as developing therapeutic strategies to replenish dopamine deficiency. In particular, the promise of cell replacement therapies for clinical intervention has led to extensive research in the identification of mechanisms involved in DA neuron development. It is hoped that a comprehensive understanding of these mechanisms will lead to therapeutic strategies that improve the efficiency of DA neuron production, engraftment, and function. This review provides a comprehensive discussion on how Wnt/ß-catenin and sonic hedgehog-Smoothened signaling mechanisms control the specification and expansion of DA progenitors and the differentiation of DA neurons. We also discuss how mechanisms involving transforming growth factor-ß and transcriptional cofactor homeodomain interacting protein kinase 2 regulate the survival and maturation of DA neurons in early postnatal life. These results not only reveal fundamental mechanisms regulating DA neuron development, but also provide important insights to their potential contributions to neuropsychiatric and neurodegenerative diseases.


Subject(s)
Dopamine/metabolism , Dopaminergic Neurons/physiology , Neurogenesis , Parkinson Disease/physiopathology , Wnt Signaling Pathway , Cell Differentiation , Hedgehog Proteins/metabolism , Humans , Models, Biological , Motivation , Reward , Substantia Nigra/cytology , Substantia Nigra/physiology , Ventral Tegmental Area/physiology
3.
Article in English | MEDLINE | ID: mdl-35969548

ABSTRACT

Gaze behavior in dyadic conversations can indicate active listening and attention. However, gaze behavior that is different from the engagement expected during neurotypical social interaction cues may be interpreted as uninterested or inattentive, which can be problematic in both personal and professional situations. Neurodivergent individuals, such as those with autism spectrum conditions, often exhibit social communication differences broadly including via gaze behavior. This project aims to support situational social gaze practice through a virtual reality (VR) mock job interview practice using the HTC Vive Pro Eye VR headset. We show how gaze behavior varies in the mock job interview between neurodivergent and neurotypical participants. We also investigate the social modulation of gaze behavior based on conversational role (speaking and listening). Our three main contributions are: (i) a system for fully-automatic analysis of social modulation of gaze behavior using a portable VR headset with a novel realistic mock job interview, (ii) a signal processing pipeline, which employs Kalman filtering and spatial-temporal density-based clustering techniques, that can improve the accuracy of the headset's built-in eye-tracker, and (iii) being the first to investigate social modulation of gaze behavior among neurotypical/divergent individuals in the realm of immersive VR.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Virtual Reality , Attention , Fixation, Ocular , Humans
4.
J Neurosci ; 30(27): 9280-91, 2010 Jul 07.
Article in English | MEDLINE | ID: mdl-20610763

ABSTRACT

Signaling mechanisms involving Wnt/beta-catenin and sonic hedgehog (Shh) are known to regulate the development of ventral midbrain (vMB) dopamine neurons. However, the interactions between these two mechanisms and how such interactions can be targeted to promote a maximal production of dopamine neurons are not fully understood. Here we show that conditional mouse mutants with region-specific activation of beta-catenin signaling in vMB using the Shh-Cre mice show a marked expansion of Sox2-, Ngn2-, and Otx2-positive progenitors but perturbs their cell cycle exit and reduces the generation of dopamine neurons. Furthermore, activation of beta-catenin in vMB also results in a progressive loss of Shh expression and Shh target genes. Such antagonistic effects between the activation of Wnt/beta-catenin and Shh can be recapitulated in vMB progenitors and in mouse embryonic stem cell cultures. Notwithstanding these antagonistic interactions, cell-type-specific activation of beta-catenin in the midline progenitors using the tyrosine hydroxylase-internal ribosomal entry site-Cre (Th-IRES-Cre) mice leads to increased dopaminergic neurogenesis. Together, these results indicate the presence of a delicate balance between Wnt/beta-catenin and Shh signaling mechanisms in the progression from progenitors to dopamine neurons. Persistent activation of beta-catenin in early progenitors perturbs their cell cycle progression and antagonizes Shh expression, whereas activation of beta-catenin in midline progenitors promotes the generation of dopamine neurons.


Subject(s)
Dopamine/metabolism , Hedgehog Proteins/metabolism , Mesencephalon/cytology , Neurogenesis/physiology , Neurons/physiology , Signal Transduction/physiology , Wnt1 Protein/metabolism , beta Catenin/metabolism , Age Factors , Animals , Animals, Newborn , Bromodeoxyuridine/metabolism , Cell Count/methods , Cell Differentiation/genetics , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Embryo, Mammalian , Enzyme Inhibitors/pharmacology , Gene Expression Regulation, Developmental/genetics , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hedgehog Proteins/genetics , Intercellular Signaling Peptides and Proteins/pharmacology , Mesencephalon/embryology , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurogenesis/drug effects , Pyridines/pharmacology , Pyrimidines/pharmacology , Signal Transduction/drug effects , Stem Cells/drug effects , Stem Cells/physiology , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism , Wnt1 Protein/genetics , beta Catenin/genetics
5.
Nat Neurosci ; 24(8): 1132-1141, 2021 08.
Article in English | MEDLINE | ID: mdl-34168339

ABSTRACT

Despite notable genetic influences, obesity mainly results from the overconsumption of food, which arises from the interplay of physiological, cognitive and environmental factors. In patients with obesity, eating is determined more by external cues than by internal physiological needs. However, how environmental context drives non-homeostatic feeding is elusive. Here, we identify a population of somatostatin (TNSST) neurons in the mouse hypothalamic tuberal nucleus that are preferentially activated by palatable food. Activation of TNSST neurons enabled a context to drive non-homeostatic feeding in sated mice and required inputs from the subiculum. Pairing a context with palatable food greatly potentiated synaptic transmission between the subiculum and TNSST neurons and drove non-homeostatic feeding that could be selectively suppressed by inhibiting TNSST neurons or the subiculum but not other major orexigenic neurons. These results reveal how palatable food, through a specific hypothalamic circuit, empowers environmental context to drive non-homeostatic feeding.


Subject(s)
Feeding Behavior/physiology , Hypothalamus/physiology , Neural Pathways/physiology , Neurons/physiology , Animals , Cues , Male , Mice , Somatostatin/metabolism
6.
Science ; 361(6397): 76-81, 2018 07 06.
Article in English | MEDLINE | ID: mdl-29976824

ABSTRACT

The tuberal nucleus (TN) is a surprisingly understudied brain region. We found that somatostatin (SST) neurons in the TN, which is known to exhibit pathological or cytological changes in human neurodegenerative diseases, play a crucial role in regulating feeding in mice. GABAergic tuberal SST (TNSST) neurons were activated by hunger and by the hunger hormone, ghrelin. Activation of TNSST neurons promoted feeding, whereas inhibition reduced it via projections to the paraventricular nucleus and bed nucleus of the stria terminalis. Ablation of TNSST neurons reduced body weight gain and food intake. These findings reveal a previously unknown mechanism of feeding regulation that operates through orexigenic TNSST neurons, providing a new perspective for understanding appetite changes.


Subject(s)
Appetite Regulation/physiology , GABAergic Neurons/physiology , Somatostatin/physiology , Ventral Thalamic Nuclei/physiology , Animals , Ghrelin/physiology , Mice , Mice, Mutant Strains , Paraventricular Hypothalamic Nucleus/cytology , Paraventricular Hypothalamic Nucleus/physiology , Ventral Thalamic Nuclei/cytology
7.
Cell Rep ; 17(12): 3233-3245, 2016 12 20.
Article in English | MEDLINE | ID: mdl-28009292

ABSTRACT

Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor ß (TGF-ß) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-ß type II receptor in DA neurons also disrupts the balance in TGF-ß1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-ß signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-ß in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.


Subject(s)
Dopaminergic Neurons/metabolism , Protein Serine-Threonine Kinases/genetics , Receptors, Transforming Growth Factor beta/genetics , Reversal Learning/physiology , Transforming Growth Factor beta1/genetics , Animals , Dendrites/genetics , Dendrites/physiology , Dopaminergic Neurons/physiology , GABAergic Neurons/metabolism , GABAergic Neurons/physiology , Gene Expression Regulation , Humans , Mesencephalon/growth & development , Mesencephalon/metabolism , Mice , Receptor, Transforming Growth Factor-beta Type II , Signal Transduction/genetics , Synapses/genetics , Synapses/metabolism , Transforming Growth Factor beta1/metabolism
8.
Science ; 350(6256): 102-6, 2015 Oct 02.
Article in English | MEDLINE | ID: mdl-26430123

ABSTRACT

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.


Subject(s)
Aldehyde Dehydrogenase/metabolism , Binge Drinking , Dopaminergic Neurons/metabolism , Mesencephalon/metabolism , Reward , gamma-Aminobutyric Acid/biosynthesis , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase 1 Family , Animals , Binge Drinking/blood , Binge Drinking/enzymology , Binge Drinking/genetics , Dopaminergic Neurons/enzymology , Ethanol/blood , Ethanol/pharmacology , Evolution, Molecular , Female , Gene Knockdown Techniques , Male , Mesencephalon/cytology , Mesencephalon/enzymology , Metabolic Networks and Pathways , Mice , Retinal Dehydrogenase , Sequence Deletion
9.
Neural Dev ; 8: 8, 2013 Apr 26.
Article in English | MEDLINE | ID: mdl-23618354

ABSTRACT

BACKGROUND: Several studies have indicated that Sonic hedgehog (Shh) regulates the expansion of dopaminergic (DA) progenitors and the subsequent generation of mature DA neurons. This prevailing view has been based primarily on in vitro culture results, and the exact in vivo function of Shh signaling in the patterning and neurogenesis of the ventral midbrain (vMB) remains unclear. METHODS: We characterized the transcriptional codes for the vMB progenitor domains, and correlated them with the expression patterns of Shh signaling effectors, including Shh, Smoothened, Patched, Gli1, Gli2 and Gli3. RESULTS: While Shh and its downstream effectors showed robust expression in the neurogenic niche for DA progenitors at embryonic day (E)8 to E8.5, their expression shifted to the lateral domains from E9.5 to E12.5. Consistent with this dynamic change, conditional mutants with region-specific removal of the Shh receptor Smoothened in the vMB progenitors (Shh-Cre;Smo(fl/fl)) showed a transient reduction in DA progenitors and DA neurons at E10.5, but had more profound defects in neurons derived from the more lateral domains, including those in the red nucleus, oculomotor nucleus, and raphe nuclei. Conversely, constitutive activation of Smoothened signaling in vMB (Shh-Cre;SmoM2) showed transient expansion of the same progenitor population. To further characterize the nature of Shh-Smoothened signaling in vMB, we examined the BAT-GAL reporter and the expression of Wnt1 in vMB, and found that the antagonistic effects of Shh and Wnt signaling critically regulate the development of DA progenitors and DA neurons. CONCLUSION: These results highlight previously unrecognized effects of Shh-Smoothened signaling in the region-specific neurogenesis within the vMB.


Subject(s)
Gene Expression Regulation, Developmental/physiology , Hedgehog Proteins/metabolism , Mesencephalon/embryology , Receptors, G-Protein-Coupled/metabolism , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , Cell Lineage/genetics , Dopaminergic Neurons/cytology , Dopaminergic Neurons/metabolism , Hedgehog Proteins/genetics , Mesencephalon/metabolism , Mice , Mice, Transgenic , Neurogenesis/physiology , Receptors, G-Protein-Coupled/genetics , Smoothened Receptor , Wnt Signaling Pathway/physiology
10.
Neural Dev ; 3: 35, 2008 Dec 15.
Article in English | MEDLINE | ID: mdl-19077309

ABSTRACT

BACKGROUND: Neurogenic placodes are focal thickenings of the embryonic ectoderm that form in the vertebrate head. It is within these structures that the precursors of the majority of the sensory neurons of the cranial ganglia are specified. The trigeminal placodes, the ophthalmic and maxillomandibular, form close to the midbrain-hindbrain boundary and many lines of evidence have shown that signals emanating from this level of the neuraxis are important for the development of the ophthalmic placode. RESULTS: Here, we provide the first evidence that both the ophthalmic and maxillomandibular placodes form under the influence of isthmic Wnt and FGF signals. Activated Wnt signals direct development of the Pax3 expressing ophthalmic placodal field and induce premature differentiation of both the ophthalmic and the maxillomandibular placodes. Similarly, overexpression of Fgf8 directs premature differentiation of the trigeminal placodes. Wnt signals require FGF receptor activity to initiate Pax3 expression and, subsequently, the expression of neural markers, such as Brn3a, within the cranial ectoderm. Furthermore, fibroblast growth factor signaling via the mitogen activated protein kinase pathway is required to maintain early neuronal differentiation within the trigeminal placodes. CONCLUSION: We demonstrate the identity of inductive signals that are necessary for trigeminal ganglion formation. This is the first report that describes how isthmic derived Wnt signals act in concert with fibroblast growth factor signaling. Together, both are necessary and sufficient for the establishment and differentiation of the ophthalmic and maxillomandibular placodes and, consequently, the trigeminal ganglion.


Subject(s)
Cell Differentiation/physiology , Fibroblast Growth Factor 8/metabolism , Neural Tube/embryology , Neural Tube/metabolism , Neurons/metabolism , Signal Transduction/physiology , Trigeminal Ganglion/physiology , Wnt Proteins/metabolism , Animals , Blotting, Western , Chick Embryo , Fibroblast Growth Factor 8/genetics , Gene Expression Regulation, Developmental , Immunohistochemistry , In Situ Hybridization , Neural Tube/cytology , Neurons/cytology , Receptors, Fibroblast Growth Factor/metabolism , Trigeminal Ganglion/embryology , Trigeminal Ganglion/growth & development , Trigeminal Ganglion/metabolism , Wnt Proteins/genetics
SELECTION OF CITATIONS
SEARCH DETAIL