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1.
Nature ; 622(7984): 802-809, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37853123

ABSTRACT

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.


Subject(s)
Antidepressive Agents , Depression , Habenula , Ketamine , Receptors, N-Methyl-D-Aspartate , Animals , Mice , Antidepressive Agents/administration & dosage , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/pharmacology , Depression/drug therapy , Depression/metabolism , Habenula/drug effects , Habenula/metabolism , Half-Life , Ketamine/administration & dosage , Ketamine/metabolism , Ketamine/pharmacokinetics , Ketamine/pharmacology , Neurons/physiology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Time Factors , Protein Binding
2.
Nat Rev Neurosci ; 21(5): 277-295, 2020 05.
Article in English | MEDLINE | ID: mdl-32269316

ABSTRACT

The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating negatively motivated behaviour and its implication in major depression. The LHb, sometimes referred to as the brain's 'antireward centre', receives inputs from diverse limbic forebrain and basal ganglia structures, and targets essentially all midbrain neuromodulatory systems, including the noradrenergic, serotonergic and dopaminergic systems. Its unique anatomical position enables the LHb to act as a hub that integrates value-based, sensory and experience-dependent information to regulate various motivational, cognitive and motor processes. Dysfunction of the LHb may contribute to the pathophysiology of several psychiatric disorders, especially major depression. Recently, exciting progress has been made in identifying the molecular and cellular mechanisms in the LHb that underlie negative emotional state in animal models of drug withdrawal and major depression. A future challenge is to translate these advances into effective clinical treatments.


Subject(s)
Basal Ganglia/physiology , Basal Ganglia/physiopathology , Habenula/physiology , Habenula/physiopathology , Limbic System/physiology , Limbic System/physiopathology , Mesencephalon/physiology , Mesencephalon/physiopathology , Animals , Health , Humans , Mental Disorders/physiopathology , Neural Pathways/physiology , Neural Pathways/physiopathology
3.
Nature ; 554(7692): 317-322, 2018 02 14.
Article in English | MEDLINE | ID: mdl-29446381

ABSTRACT

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.


Subject(s)
Action Potentials/drug effects , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Depression/drug therapy , Habenula/drug effects , Habenula/metabolism , Ketamine/pharmacology , Ketamine/therapeutic use , Affect/drug effects , Anhedonia/drug effects , Animals , Antidepressive Agents/administration & dosage , Calcium Channel Blockers/pharmacology , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Disease Models, Animal , Habenula/pathology , Habenula/radiation effects , Ketamine/administration & dosage , Male , Mice , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Reward , Theta Rhythm/drug effects
4.
Nature ; 554(7692): 323-327, 2018 02 14.
Article in English | MEDLINE | ID: mdl-29446379

ABSTRACT

Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia-neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.


Subject(s)
Astrocytes/metabolism , Depression/metabolism , Habenula/metabolism , Neurons/metabolism , Potassium Channels, Inwardly Rectifying/metabolism , Action Potentials/drug effects , Animals , Astrocytes/drug effects , Depression/drug therapy , Depression/pathology , Habenula/drug effects , Habenula/pathology , Male , Molecular Targeted Therapy , Potassium Channels, Inwardly Rectifying/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Reward
6.
Plant Cell Physiol ; 64(8): 866-879, 2023 Aug 17.
Article in English | MEDLINE | ID: mdl-37225421

ABSTRACT

In land plants, sexual dimorphism can develop in both diploid sporophytes and haploid gametophytes. While developmental processes of sexual dimorphism have been extensively studied in the sporophytic reproductive organs of model flowering plants such as stamens and carpels of Arabidopsis thaliana, those occurring in gametophyte generation are less well characterized due to the lack of amenable model systems. In this study, we performed three-dimensional morphological analyses of gametophytic sexual branch differentiation in the liverwort Marchantia polymorpha, using high-depth confocal imaging and a computational cell segmentation technique. Our analysis revealed that the specification of germline precursors initiates in a very early stage of sexual branch development, where incipient branch primordia are barely recognizable in the apical notch region. Moreover, spatial distribution patterns of germline precursors differ between males and females from the initial stage of primordium development in a manner dependent on the master sexual differentiation regulator MpFGMYB. At later stages, distribution patterns of germline precursors predict the sex-specific gametangia arrangement and receptacle morphologies seen in mature sexual branches. Taken together, our data suggest a tightly coupled progression of germline segregation and sexual dimorphism development in M. polymorpha.


Subject(s)
Arabidopsis , Marchantia , Marchantia/genetics , Sex Characteristics , Germ Cells, Plant
7.
Mol Psychiatry ; 27(12): 5154-5166, 2022 12.
Article in English | MEDLINE | ID: mdl-36131044

ABSTRACT

Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Δ3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Δ3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs' Wnt/ß-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Δ3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Δ3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease.


Subject(s)
Oligodendrocyte Precursor Cells , Schizophrenia , Animals , Humans , Mice , Brain/metabolism , Brain/pathology , Myelin Sheath/metabolism , Nerve Tissue Proteins/genetics , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Precursor Cells/pathology , Oligodendroglia/metabolism , Schizophrenia/metabolism , Schizophrenia/pathology , Disease Models, Animal
8.
J Physiol ; 593(13): 2833-49, 2015 Jul 01.
Article in English | MEDLINE | ID: mdl-25873197

ABSTRACT

KEY POINTS: Although learning can arise from few or even a single trial, synaptic plasticity is commonly assessed under prolonged activation. Here, we explored the existence of rapid responsiveness of synaptic plasticity at corticostriatal synapses in a major synaptic learning rule, spike-timing-dependent plasticity (STDP). We found that spike-timing-dependent depression (tLTD) progressively disappears when the number of paired stimulations (below 50 pairings) is decreased whereas spike-timing-dependent potentiation (tLTP) displays a biphasic profile: tLTP is observed for 75-100 pairings, is absent for 25-50 pairings and re-emerges for 5-10 pairings. This tLTP induced by low numbers of pairings (5-10) depends on activation of the endocannabinoid system, type-1 cannabinoid receptor and the transient receptor potential vanilloid type-1. Endocannabinoid-tLTP may represent a physiological mechanism operating during the rapid learning of new associative memories and behavioural rules characterizing the flexible behaviour of mammals or during the initial stages of habit learning. ABSTRACT: Synaptic plasticity, a main substrate for learning and memory, is commonly assessed with prolonged stimulations. Since learning can arise from few or even a single trial, synaptic strength is expected to adapt rapidly. However, whether synaptic plasticity occurs in response to limited event occurrences remains elusive. To answer this question, we investigated whether a low number of paired stimulations can induce plasticity in a major synaptic learning rule, spike-timing-dependent plasticity (STDP). It is known that 100 pairings induce bidirectional STDP, i.e. spike-timing-dependent potentiation (tLTP) and depression (tLTD) at most central synapses. In rodent striatum, we found that tLTD progressively disappears when the number of paired stimulations is decreased (below 50 pairings) whereas tLTP displays a biphasic profile: tLTP is observed for 75-100 pairings, absent for 25-50 pairings and re-emerges for 5-10 pairings. This tLTP, induced by very few pairings (∼5-10) depends on the endocannabinoid (eCB) system. This eCB-dependent tLTP (eCB-tLTP) involves postsynaptic endocannabinoid synthesis, requires paired activity (post- and presynaptic) and the activation of type-1 cannabinoid receptor (CB1R) and transient receptor potential vanilloid type-1 (TRPV1). eCB-tLTP occurs in both striatopallidal and striatonigral medium-sized spiny neurons (MSNs) and is dopamine dependent. Lastly, we show that eCB-LTP and eCB-LTD can be induced sequentially in the same neuron, depending on the cellular conditioning protocol. Thus, while endocannabinoids are usually thought simply to depress synaptic function, they also constitute a versatile system underlying bidirectional plasticity. Our results reveal a novel form of synaptic plasticity, eCB-tLTP, which may underlie rapid learning capabilities characterizing behavioural flexibility.


Subject(s)
Endocannabinoids/pharmacology , Long-Term Potentiation , Long-Term Synaptic Depression , Animals , Corpus Striatum/cytology , Corpus Striatum/metabolism , Corpus Striatum/physiology , Female , Male , Mice , Mice, Inbred C57BL , Neurons/drug effects , Neurons/metabolism , Neurons/physiology , Rats , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Synapses/drug effects , Synapses/metabolism , Synapses/physiology , TRPV Cation Channels/metabolism
9.
J Zhejiang Univ Sci B ; : 1-11, 2024 Apr 07.
Article in English, Zh | MEDLINE | ID: mdl-38616136

ABSTRACT

Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.

10.
Transl Psychiatry ; 14(1): 335, 2024 Aug 21.
Article in English | MEDLINE | ID: mdl-39168993

ABSTRACT

Long-term synaptic plasticity is critical for adaptive function of the brain, but presynaptic mechanisms of functional plasticity remain poorly understood. Here, we show that changes in synaptic efficacy induced by activation of the cannabinoid type-1 receptor (CB1R), one of the most widespread G-protein coupled receptors in the brain, requires contractility of the neuronal actomyosin cytoskeleton. Specifically, using a synaptophysin-pHluorin probe (sypH2), we show that inhibitors of non-muscle myosin II (NMII) ATPase as well as one of its upstream effectors Rho-associated kinase (ROCK) prevent the reduction of synaptic vesicle release induced by CB1R activation. Using 3D STORM super-resolution microscopy, we find that activation of CB1R induces a redistribution of synaptic vesicles within presynaptic boutons in an actomyosin dependent manner, leading to vesicle clustering within the bouton and depletion of synaptic vesicles from the active zone. We further show, using sypH2, that inhibitors of NMII and ROCK specifically restore the release of the readily releasable pool of synaptic vesicles from the inhibition induced by CB1R activation. Finally, using slice electrophysiology, we find that activation of both NMII and ROCK is necessary for the long-term, but not the short-term, form of CB1R induced synaptic plasticity at excitatory cortico-striatal synapses. We thus propose a novel mechanism underlying CB1R-induced plasticity, whereby CB1R activation leads to a contraction of the actomyosin cytoskeleton inducing a reorganization of the functional presynaptic vesicle pool, preventing vesicle release and inducing long-term depression.


Subject(s)
Actomyosin , Neuronal Plasticity , Presynaptic Terminals , Receptor, Cannabinoid, CB1 , Synaptic Vesicles , rho-Associated Kinases , Animals , Synaptic Vesicles/metabolism , Synaptic Vesicles/drug effects , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Actomyosin/metabolism , rho-Associated Kinases/metabolism , Neuronal Plasticity/physiology , Neuronal Plasticity/drug effects , Presynaptic Terminals/metabolism , Presynaptic Terminals/drug effects , Mice , Rats , Male , Myosin Type II/metabolism
11.
Cell Rep ; 43(9): 114717, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39264811

ABSTRACT

Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei. Here, we present mice lacking dopaminergic histamine H2 receptor (H2R) in the ventral tegmental area (VTA) that exhibit a behavioral phenotype mirroring some of the symptoms of mania, including increased locomotor activity and reduced anxiety- and depression-like behavior. These behavioral deficits can be reversed by the mood stabilizers lithium and valproate. H2R deletion in dopaminergic neurons significantly enhances neuronal activity, concurrent with a decrease in the γ-aminobutyric acid (GABA) type A receptor (GABAAR) membrane presence and inhibitory transmission. Conversely, either overexpression of H2R in VTA dopaminergic neurons or treatment of H2R agonist amthamine within the VTA counteracts amphetamine-induced hyperactivity. Together, our results demonstrate the engagement of H2R in reducing VTA dopaminergic activity, shedding light on the role of H2R as a potential target for mania therapy.

12.
PLoS Comput Biol ; 8(4): e1002493, 2012.
Article in English | MEDLINE | ID: mdl-22536151

ABSTRACT

Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development.


Subject(s)
Action Potentials/physiology , Calcium/metabolism , Corpus Striatum/metabolism , Models, Neurological , N-Methylaspartate/metabolism , Neuronal Plasticity/physiology , Neurons/physiology , Animals , Computer Simulation , Humans , Models, Chemical , N-Methylaspartate/chemistry , Protein Subunits , Structure-Activity Relationship
13.
Neuron ; 111(23): 3703-3705, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38061329

ABSTRACT

Repeated reward intake decreases its subjective pleasantness, which is a common phenomenon called reward devaluation. In this issue of Neuron, Yuan et al.1 unravel that blunted inhibitory response of anterior cingulate cortex (ACC) encodes this process, whose hypersensitization leads to anhedonia.


Subject(s)
Anhedonia , Prefrontal Cortex , Humans , Prefrontal Cortex/physiology , Anhedonia/physiology , Emotions , Neurons/physiology , Reward , Gyrus Cinguli/physiology , Magnetic Resonance Imaging
14.
Biol Psychiatry ; 94(3): 262-277, 2023 08 01.
Article in English | MEDLINE | ID: mdl-36842495

ABSTRACT

BACKGROUND: The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive. METHODS: We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval. RESULTS: We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors. CONCLUSIONS: Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation.


Subject(s)
Extinction, Psychological , Fear , Mice , Animals , Extinction, Psychological/physiology , Fear/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Neurons/physiology , Signal Transduction , Prefrontal Cortex/metabolism , Mice, Transgenic
15.
Cell Rep ; 38(11): 110521, 2022 03 15.
Article in English | MEDLINE | ID: mdl-35294877

ABSTRACT

The striatum mediates two learning modalities: goal-directed behavior in dorsomedial (DMS) and habits in dorsolateral (DLS) striata. The synaptic bases of these learnings are still elusive. Indeed, while ample research has described DLS plasticity, little remains known about DMS plasticity and its involvement in procedural learning. Here, we find symmetric and asymmetric anti-Hebbian spike-timing-dependent plasticity (STDP) in DMS and DLS, respectively, with opposite plasticity dominance upon increasing corticostriatal activity. During motor-skill learning, plasticity is engaged in DMS and striatonigral DLS neurons only during early learning stages, whereas striatopallidal DLS neurons are mobilized only during late phases. With a mathematical modeling approach, we find that symmetric anti-Hebbian STDP favors memory flexibility, while asymmetric anti-Hebbian STDP favors memory maintenance, consistent with memory processes at play in procedural learning.


Subject(s)
Corpus Striatum , Neostriatum , Corpus Striatum/physiology , Learning/physiology , Motor Skills/physiology , Neurons/physiology
16.
Neuron ; 110(8): 1400-1415.e6, 2022 04 20.
Article in English | MEDLINE | ID: mdl-35114101

ABSTRACT

Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.


Subject(s)
Habenula , Animals , Depression/etiology , Habenula/physiology , Hypothalamic Area, Lateral , Hypothalamus , Mice , Synapses/physiology
17.
Elife ; 102021 09 28.
Article in English | MEDLINE | ID: mdl-34579806

ABSTRACT

KNOX and BELL transcription factors regulate distinct steps of diploid development in plants. In the green alga Chlamydomonas reinhardtii, KNOX and BELL proteins are inherited by gametes of the opposite mating types and heterodimerize in zygotes to activate diploid development. By contrast, in land plants such as Physcomitrium patens and Arabidopsis thaliana, KNOX and BELL proteins function in meristem maintenance and organogenesis during the later stages of diploid development. However, whether the contrasting functions of KNOX and BELL were acquired independently in algae and land plants is currently unknown. Here, we show that in the basal land plant species Marchantia polymorpha, gamete-expressed KNOX and BELL are required to initiate zygotic development by promoting nuclear fusion in a manner strikingly similar to that in C. reinhardtii. Our results indicate that zygote activation is the ancestral role of KNOX/BELL transcription factors, which shifted toward meristem maintenance as land plants evolved.


Subject(s)
Biological Evolution , Germ Cells/physiology , Plants/metabolism , Transcription Factors/metabolism , Diploidy
18.
Front Synaptic Neurosci ; 13: 725880, 2021.
Article in English | MEDLINE | ID: mdl-34621162

ABSTRACT

Although many details remain unknown, several positive statements can be made about the laminar distribution of primate frontal eye field (FEF) neurons with different physiological properties. Most certainly, pyramidal neurons in the deep layer of FEF that project to the brainstem carry movement and fixation signals but clear evidence also support that at least some deep-layer pyramidal neurons projecting to the superior colliculus carry visual responses. Thus, deep-layer neurons in FEF are functionally heterogeneous. Despite the useful functional distinctions between neuronal responses in vivo, the underlying existence of distinct cell types remain uncertain, mostly due to methodological limitations of extracellular recordings in awake behaving primates. To substantiate the functionally defined cell types encountered in the deep layer of FEF, we measured the biophysical properties of pyramidal neurons recorded intracellularly in brain slices issued from macaque monkey biopsies. Here, we found that biophysical properties recorded in vitro permit us to distinguish two main subtypes of regular-spiking neurons, with, respectively, low-resistance and low excitability vs. high-resistance and strong excitability. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that at least two distinct populations of deep-layer neurons exist.

19.
J Neurosci ; 29(10): 3307-21, 2009 Mar 11.
Article in English | MEDLINE | ID: mdl-19279268

ABSTRACT

The anterior cingulate cortex (ACC) is implicated in the affective response to noxious stimuli. However, little is known about the molecular mechanisms involved. The present study demonstrated that extracellular signal-regulated kinase (ERK) activation in the ACC plays a crucial role in pain-related negative emotion. Intraplantar formalin injection produced a transient ERK activation in laminae V-VI and a persistent ERK activation in laminae II-III of the rostral ACC (rACC) bilaterally. Using formalin-induced conditioned place avoidance (F-CPA) in rats, which is believed to reflect the pain-related negative emotion, we found that blockade of ERK activation in the rACC with MEK inhibitors prevented the induction of F-CPA. Interestingly, this blockade did not affect formalin-induced two-phase spontaneous nociceptive responses and CPA acquisition induced by electric foot-shock or U69,593, an innocuous aversive agent. Upstream, NMDA receptor, adenylyl cyclase (AC) and phosphokinase A (PKA) activators activated ERK in rACC slices. Consistently, intra-rACC microinjection of AC or PKA inhibitors prevented F-CPA induction. Downstream, phosphorylation of cAMP response element binding protein (CREB) was induced in the rACC by formalin injection and by NMDA, AC and PKA activators in brain slices, which was suppressed by MEK inhibitors. Furthermore, ERK also contributed to the expression of pain-related negative emotion. Thus, when rats were re-exposed to the conditioning context for retrieval of pain experience, ERK and CREB were reactivated in the rACC, and inhibiting ERK activation blocked the expression of F-CPA. All together, our results demonstrate that ERK activation in the rACC is required for the induction and expression of pain-related negative affect.


Subject(s)
Affect/physiology , Cerebral Cortex/enzymology , Extracellular Signal-Regulated MAP Kinases/metabolism , Gyrus Cinguli/enzymology , Pain/enzymology , Pain/etiology , Animals , Enzyme Activation , Male , Pain Measurement/methods , Rats , Rats, Sprague-Dawley
20.
J Physiol ; 588(Pt 16): 3045-62, 2010 Aug 15.
Article in English | MEDLINE | ID: mdl-20603333

ABSTRACT

Corticostriatal projections constitute the main input to the basal ganglia, an ensemble of interconnected subcortical nuclei involved in procedural learning. Thus, long-term plasticity at corticostriatal synapses would provide a basic mechanism for the function of basal ganglia in learning and memory. We had previously reported the existence of a corticostriatal anti-Hebbian spike timing-dependent plasticity (STDP) at synapses onto striatal output neurons, the medium-sized spiny neurons. Here, we show that the blockade of GABAergic transmission reversed the time dependence of corticostriatal STDP. We explored the receptors and signalling mechanisms involved in the corticostriatal STDP. Although classical models for STDP propose NMDA receptors as the unique coincidence detector, the involvement of multiple coincidence detectors has also been demonstrated. Here, we show that corticostriatal STDP depends on distinct coincidence detectors. Specifically, long-term potentiation is dependent on NMDA receptor activation, while long-term depression requires distinct coincidence detectors: the phospholipase Cbeta (PLCbeta) and the inositol-trisphosphate receptor (IP3R)-gated calcium stores. Furthermore, we found that PLCbeta activation is controlled by group-I metabotropic glutamate receptors, type-1 muscarinic receptors and voltage-sensitive calcium channel activities. Activation of PLCbeta and IP3Rs leads to robust retrograde endocannabinoid signalling mediated by 2-arachidonoyl-glycerol and cannabinoid CB1 receptors. Interestingly, the same coincidence detectors govern the corticostriatal anti-Hebbian STDP and the Hebbian STDP reported at cortical synapses. Therefore, LTP and LTD induced by STDP at corticostriatal synapses are mediated by independent signalling mechanisms, each one being controlled by distinct coincidence detectors.


Subject(s)
Basal Ganglia/metabolism , Cerebral Cortex/metabolism , Neuronal Plasticity , Signal Transduction , Synapses/metabolism , Animals , Arachidonic Acids/metabolism , Basal Ganglia/cytology , Basal Ganglia/drug effects , Calcium Channels/metabolism , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Endocannabinoids , Enzyme Activation , Enzyme Inhibitors/pharmacology , Excitatory Postsynaptic Potentials , Glycerides/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Neural Pathways/metabolism , Neuronal Plasticity/drug effects , Neurotransmitter Agents/pharmacology , Phospholipase C beta/metabolism , Rats , Receptor, Cannabinoid, CB1/metabolism , Receptor, Muscarinic M1/metabolism , Receptors, Metabotropic Glutamate/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction/drug effects , Synapses/drug effects , Time Factors , gamma-Aminobutyric Acid/metabolism
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