Input-output specific orchestration of aversive valence in lateral habenula during stress dynamics. / åŽ‹åŠ›åŠ¨æ€è¿‡ç¨‹ä¸­è´Ÿæ€§æƒ ç»ªåœ¨å¤–ä¾§ç¼°æ ¸çš„"è¾“å ¥-输出"特异性整合.

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.

Dynamic prefrontal inhibition code mediates reward devaluation.

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.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

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.

Three-Dimensional Morphological Analysis Revealed the Cell Patterning Bases for the Sexual Dimorphism Development in the Liverwort Marchantia polymorpha.

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.

NMDA Receptor-Dependent Synaptic Potentiation via APPL1 Signaling Is Required for the Accessibility of a Prefrontal Neuronal Assembly in Retrieving Fear Extinction.

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.

Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model.

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.

Striatum expresses region-specific plasticity consistent with distinct memory abilities.

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.

Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset.

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.

Intracellular Properties of Deep-Layer Pyramidal Neurons in Frontal Eye Field of Macaque Monkeys.

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.

Deep evolutionary origin of gamete-directed zygote activation by KNOX/BELL transcription factors in green plants.

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.

Lights on Endocannabinoid-Mediated Synaptic Potentiation.

The endocannabinoid (eCB) system is a lipid-based neurotransmitter complex that plays crucial roles in the neural control of learning and memory. The current model of eCB-mediated retrograde signaling is that eCBs released from postsynaptic elements travel retrogradely to presynaptic axon terminals, where they activate cannabinoid type-1 receptors (CB1Rs) and ultimately decrease neurotransmitter release on a short- or long-term scale. An increasing body of evidence has enlarged this view and shows that eCBs, besides depressing synaptic transmission, are also able to increase neurotransmitter release at multiple synapses of the brain. This indicates that eCBs act as bidirectional regulators of synaptic transmission and plasticity. Recently, studies unveiled links between the expression of eCB-mediated long-term potentiation (eCB-LTP) and learning, and between its dysregulation and several pathologies. In this review article, we first distinguish the various forms of eCB-LTP based on their mechanisms, resulting from homosynaptically or heterosynaptically-mediated processes. Next, we consider the neuromodulation of eCB-LTP, its behavioral impact on learning and memory, and finally, eCB-LTP disruptions in various pathologies and its potential as a therapeutic target in disorders such as stress coping, addiction, Alzheimer's and Parkinson's disease, and pain. Cannabis is gaining popularity as a recreational substance as well as a medicine, and multiple eCB-based drugs are under development. In this context, it is critical to understand eCB-mediated signaling in its multi-faceted complexity. Indeed, the bidirectional nature of eCB-based neuromodulation may offer an important key to interpret the functions of the eCB system and how it is impacted by cannabis and other drugs.

Circuits and functions of the lateral habenula in health and in disease.

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.

Lateral Habenular Burst Firing as a Target of the Rapid Antidepressant Effects of Ketamine.

The revolutionary discovery of the rapid antidepressant ketamine has been a milestone in psychiatry field in the last half century. Unlike conventional antidepressants that often take weeks to months to show efficacy, ketamine causes rapid antidepressant effects, emerging as early as within 1h after administration. However, how ketamine improves mood symptoms so quickly has remained elusive. Here, we first introduce the historical background of ketamine as a rapid antidepressant. We then discuss current hypotheses underlying ketamine's rapid antidepressant effects, with a focus on our latest discovery that ketamine silences NMDAR-dependent burst firing in the 'anti-reward center', the lateral habenula. While ketamine may act on many brain regions, we argue that its rapid antidepressant effects are critically dependent on ketamine's action in the lateral habenula, with this brain region acting as a primary site of action (or one among a few primary nodes). This molecular-, cellular-, and circuit-based mechanism advances our understanding of the etiology of depression and suggests a new conceptual framework for the rapid antidepressant effects of ketamine.

Dopamine-endocannabinoid interactions mediate spike-timing-dependent potentiation in the striatum.

Dopamine modulates striatal synaptic plasticity, a key substrate for action selection and procedural learning. Thus, characterizing the repertoire of activity-dependent plasticity in striatum and its dependence on dopamine is of crucial importance. We recently unraveled a striatal spike-timing-dependent long-term potentiation (tLTP) mediated by endocannabinoids (eCBs) and induced with few spikes (~5-15). Whether this eCB-tLTP interacts with the dopaminergic system remains to be investigated. Here, we report that eCB-tLTP is impaired in a rodent model of Parkinson's disease and rescued by L-DOPA. Dopamine controls eCB-tLTP via dopamine type-2 receptors (D2R) located presynaptically in cortical terminals. Dopamine-endocannabinoid interactions via D2R are required for the emergence of tLTP in response to few coincident pre- and post-synaptic spikes and control eCB-plasticity by modulating the long-term potentiation (LTP)/depression (LTD) thresholds. While usually considered as a depressing synaptic function, our results show that eCBs in the presence of dopamine constitute a versatile system underlying bidirectional plasticity implicated in basal ganglia pathophysiology.

Endocannabinoid-LTP Mediated by CB1 and TRPV1 Receptors Encodes for Limited Occurrences of Coincident Activity in Neocortex.

Synaptic efficacy changes, long-term potentiation (LTP) and depression (LTD), underlie various forms of learning and memory. Synaptic plasticity is generally assessed under prolonged activation, whereas learning can emerge from few or even a single trial. Here, we investigated the existence of rapid responsiveness of synaptic plasticity in response to a few number of spikes, in neocortex in a synaptic Hebbian learning rule, the spike-timing-dependent plasticity (STDP). We investigated the effect of lowering the number of pairings from 100 to 50, and 10 on STDP expression, using whole-cell recordings from pyramidal cells in rodent somatosensory cortical brain slices. We found that a low number of paired stimulations induces LTP at neocortical layer 4-2/3 synapses. Besides the asymmetric Hebbian STDP reported in the neocortex induced by 100 pairings, we observed a symmetric anti-Hebbian LTD for 50 pairings and unveiled a unidirectional Hebbian spike-timing-dependent LTP (tLTP) induced by 10-15 pairings. This tLTP was not mediated by NMDA receptor activation but requires CB1 receptors and transient receptor potential vanilloid type-1 (TRPV1) activated by endocannabinoids (eCBs). eCBs have been widely described as mediating short- and long-term synaptic depression. Here, the eCB-tLTP reported at neocortical synapses could constitute a substrate operating in the online learning of new associative memories or during the initial stages of learning. In addition, these findings should provide useful insight into the mechanisms underlying eCB-plasticity occurring during marijuana intoxication.

Robustness of STDP to spike timing jitter.

In Hebbian plasticity, neural circuits adjust their synaptic weights depending on patterned firing. Spike-timing-dependent plasticity (STDP), a synaptic Hebbian learning rule, relies on the order and timing of the paired activities in pre- and postsynaptic neurons. Classically, in ex vivo experiments, STDP is assessed with deterministic (constant) spike timings and time intervals between successive pairings, thus exhibiting a regularity that differs from biological variability. Hence, STDP emergence from noisy inputs as occurring in in vivo-like firing remains unresolved. Here, we used noisy STDP pairings where the spike timing and/or interval between pairings were jittered. We explored with electrophysiology and mathematical modeling, the impact of jitter on three forms of STDP at corticostriatal synapses: NMDAR-LTP, endocannabinoid-LTD and endocannabinoid-LTP. We found that NMDAR-LTP was highly fragile to jitter, whereas endocannabinoid-plasticity appeared more resistant. When the frequency or number of pairings was increased, NMDAR-LTP became more robust and could be expressed despite strong jittering. Our results identify endocannabinoid-plasticity as a robust form of STDP, whereas the sensitivity to jitter of NMDAR-LTP varies with activity frequency. This provides new insights into the mechanisms at play during the different phases of learning and memory and the emergence of Hebbian plasticity in in vivo-like activity.

Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression.

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.

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression.

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.