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1.
Nature ; 606(7915): 655-656, 2022 06.
Article in English | MEDLINE | ID: mdl-35705863
2.
Cell Rep ; 37(9): 110067, 2021 11 30.
Article in English | MEDLINE | ID: mdl-34852221

ABSTRACT

Glucose homeostasis is initially regulated by the pancreatic hormone insulin. Glucose-stimulated insulin secretion in ß-cells is composed of two cellular mechanisms: a high glucose concentration not only depolarizes the membrane potential of the ß-cells by ATP-sensitive K+ channels but also induces cell inflation, which is sufficient to release insulin granules. However, the molecular identity of the stretch-activated cation channel responsible for the latter pathway remains unknown. Here, we demonstrate that Tentonin 3/TMEM150C (TTN3), a mechanosensitive channel, contributes to glucose-stimulated insulin secretion by mediating cation influx. TTN3 is expressed specifically in ß-cells and mediates cation currents to glucose and hypotonic stimulations. The glucose-induced depolarization, firing activity, and Ca2+ influx of ß-cells were significantly lower in Ttn3-/- mice. More importantly, Ttn3-/- mice show impaired glucose tolerance with decreased insulin secretion in vivo. We propose that TTN3, as a stretch-activated cation channel, contributes to glucose-stimulated insulin secretion.


Subject(s)
Calcium/metabolism , Glucose Intolerance/pathology , Glucose/pharmacology , Insulin Secretion , Insulin-Secreting Cells/metabolism , Membrane Proteins/physiology , Animals , Glucose Intolerance/etiology , Glucose Intolerance/metabolism , Insulin-Secreting Cells/drug effects , Male , Membrane Potentials , Mice , Mice, Inbred C57BL , Mice, Knockout , Sweetening Agents/pharmacology
3.
Nat Neurosci ; 24(7): 907-912, 2021 07.
Article in English | MEDLINE | ID: mdl-33972802

ABSTRACT

Physiological need states direct decision-making toward re-establishing homeostasis. Using a two-alternative forced choice task for mice that models elements of human decisions, we found that varying hunger and thirst states caused need-inappropriate choices, such as food seeking when thirsty. These results show limits on interoceptive knowledge of hunger and thirst states to guide decision-making. Instead, need states were identified after food and water consumption by outcome evaluation, which depended on the medial prefrontal cortex.


Subject(s)
Decision Making/physiology , Hunger/physiology , Prefrontal Cortex/physiology , Thirst/physiology , Animals , Female , Interoception/physiology , Male , Mice
4.
Cell Rep ; 19(7): 1343-1350, 2017 05 16.
Article in English | MEDLINE | ID: mdl-28514655

ABSTRACT

Object motion sensitive (OMS) W3-retinal ganglion cells (W3-RGCs) in mice respond to local movements in a visual scene but remain silent during self-generated global image motion. The excitatory inputs that drive responses of W3-RGCs to local motion were recently characterized, but which inhibitory neurons suppress W3-RGCs' responses to global motion, how these neurons encode motion information, and how their connections are organized along the excitatory circuit axis remains unknown. Here, we find that a genetically identified amacrine cell (AC) type, TH2-AC, exhibits fast responses to global motion and slow responses to local motion. Optogenetic stimulation shows that TH2-ACs provide strong GABAA receptor-mediated input to W3-RGCs but only weak input to upstream excitatory neurons. Cell-type-specific silencing reveals that temporally coded inhibition from TH2-ACs cancels W3-RGC spike responses to global but not local motion stimuli and, thus, controls the feature selectivity of OMS signals sent to the brain.


Subject(s)
Motion , Neural Inhibition/physiology , Retina/physiology , Amacrine Cells/metabolism , Amino Acid Transport Systems, Acidic/metabolism , Animals , Brain/physiology , Gene Silencing , Mice , Optogenetics , Time Factors , Tyrosine 3-Monooxygenase/metabolism
5.
Cell Rep ; 15(7): 1369-1375, 2016 05 17.
Article in English | MEDLINE | ID: mdl-27160915

ABSTRACT

Neurons that release more than one transmitter exist throughout the CNS. Yet, how these neurons deploy multiple transmitters and shape the function of specific circuits is not well understood. VGluT3-expressing amacrine cells (VG3-ACs) provide glutamatergic input to ganglion cells activated by contrast and motion. Using optogenetics, we find that VG3-ACs provide selective glycinergic input to a retinal ganglion cell type suppressed by contrast and motion (SbC-RGCs). Firing of SbC-RGCs is suppressed at light ON and OFF over a broad range of stimulus sizes. Anatomical circuit reconstructions reveal that VG3-ACs form inhibitory synapses preferentially on processes that link ON and OFF arbors of SbC-RGC dendrites. Removal of VG3-ACs from mature circuits reduces inhibition and attenuates spike suppression of SbC-RGCs in a contrast- and size-selective manner, illustrating the modularity of retinal circuits. VG3-ACs thus use dual transmitters in a target-specific manner and shape suppressive contrast responses in the retina by glycinergic transmission.


Subject(s)
Amacrine Cells/metabolism , Amino Acid Transport Systems, Acidic/metabolism , Contrast Sensitivity , Glycine/metabolism , Synaptic Transmission , Action Potentials , Animals , Dendrites/metabolism , Mice, Transgenic , Retinal Ganglion Cells/metabolism , Synapses/metabolism
6.
Elife ; 42015 May 19.
Article in English | MEDLINE | ID: mdl-25988808

ABSTRACT

Retinal circuits detect salient features of the visual world and report them to the brain through spike trains of retinal ganglion cells. The most abundant ganglion cell type in mice, the so-called W3 ganglion cell, selectively responds to movements of small objects. Where and how object motion sensitivity arises in the retina is incompletely understood. In this study, we use 2-photon-guided patch-clamp recordings to characterize responses of vesicular glutamate transporter 3 (VGluT3)-expressing amacrine cells (ACs) to a broad set of visual stimuli. We find that these ACs are object motion sensitive and analyze the synaptic mechanisms underlying this computation. Anatomical circuit reconstructions suggest that VGluT3-expressing ACs form glutamatergic synapses with W3 ganglion cells, and targeted recordings show that the tuning of W3 ganglion cells' excitatory input matches that of VGluT3-expressing ACs' responses. Synaptic excitation of W3 ganglion cells is diminished, and responses to object motion are suppressed in mice lacking VGluT3. Object motion, thus, is first detected by VGluT3-expressing ACs, which provide feature-selective excitatory input to W3 ganglion cells.


Subject(s)
Amacrine Cells/physiology , Amino Acid Transport Systems, Acidic/metabolism , Motion Perception/physiology , Retina/cytology , Retinal Ganglion Cells/physiology , Amacrine Cells/metabolism , Animals , Mice , Patch-Clamp Techniques , Retina/physiology
7.
Nat Neurosci ; 15(7): 1015-21, 2012 May 27.
Article in English | MEDLINE | ID: mdl-22634729

ABSTRACT

Nociceptors are a subset of small primary afferent neurons that respond to noxious chemical, thermal and mechanical stimuli. Ion channels in nociceptors respond differently to noxious stimuli and generate electrical signals in different ways. Anoctamin 1 (ANO1 also known as TMEM16A) is a Ca(2+)-activated chloride channel that is essential for numerous physiological functions. We found that ANO1 was activated by temperatures over 44 °C with steep heat sensitivity. ANO1 was expressed in small sensory neurons and was highly colocalized with nociceptor markers, which suggests that it may be involved in nociception. Application of heat ramps to dorsal root ganglion (DRG) neurons elicited robust ANO1-dependent depolarization. Furthermore, knockdown or deletion of ANO1 in DRG neurons substantially reduced nociceptive behavior in thermal pain models. These results indicate that ANO1 is a heat sensor that detects nociceptive thermal stimuli in sensory neurons and possibly mediates nociception.


Subject(s)
Calcium/physiology , Chloride Channels/metabolism , Hot Temperature , Nociceptors/metabolism , Animals , Anoctamin-1 , Cells, Cultured , Chloride Channel Agonists , Chloride Channels/deficiency , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiology , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Neurological , Nociceptors/physiology , Pain Measurement/methods , Rats , Rats, Sprague-Dawley
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