A novel brainstem nucleus orchestrating reward and aversion.

Reward processing is a critical brain function. Zichó and colleagues recently identified a previously unrecognized brainstem nucleus, the subventricular tegmental nucleus (SVTg), as a novel reward center that modulates dopamine release and regulates reward processing by balancing the lateral habenula (LHb)-ventral tegmental area (VTA) axis.

Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TC), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TC). We demonstrated that E-TC repurposes molecules traditionally associated with E-TC to regulate mitochondrial DNA expression in areas closely linked to synaptic activation.

Deconstructing the neural circuit underlying social hierarchy in mice.

Social competition determines hierarchical social status, which profoundly influences animals' behavior and health. The dorsomedial prefrontal cortex (dmPFC) plays a fundamental role in regulating social competitions, but it was unclear how the dmPFC orchestrates win- and lose-related behaviors through its downstream neural circuits. Here, through whole-brain c-Fos mapping, fiber photometry, and optogenetics- or chemogenetics-based manipulations, we identified anatomically segregated win- and lose-related neural pathways downstream of the dmPFC in mice.

How can ethology inform the neuroscience of fear, aggression and dominance?

The study of behaviour is dominated by two approaches. On the one hand, ethologists aim to understand how behaviour promotes adaptation to natural contexts. On the other, neuroscientists aim to understand the molecular, cellular, circuit and psychological origins of behaviour.

Brain region-specific action of ketamine as a rapid antidepressant.

Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the -methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons.

The -methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies.

Substantial clinical evidence has unravelled the superior antidepressant efficacy of ketamine: in comparison to traditional antidepressants targeting the monoamine systems, ketamine, as an -methyl-d-aspartate receptor (NMDAR) antagonist, acts much faster and more potently. Surrounding the antidepressant mechanisms of ketamine, there is ample evidence supporting an NMDAR-antagonism-based hypothesis. However, alternative arguments also exist, mostly derived from the controversial clinical results of other NMDAR inhibitors.

Icariin promotes bone marrow mesenchymal stem cells osteogenic differentiation via the mTOR/autophagy pathway to improve ketogenic diet-associated osteoporosis.

Background: Icariin, a traditional Chinese medicine, has demonstrated anti-osteoporotic properties in ovariectomized mice. However, its effectiveness in preventing bone loss induced by ketogenic diet (KD), which mimics osteoporosis in human, remains unexplored. This study aims to investigate icariin's impact on KD-induced bone loss in mice.

Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection.

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion.

CB1R dysfunction of inhibitory synapses in the ACC drives chronic social isolation stress-induced social impairments in male mice.

Social isolation is a risk factor for multiple mood disorders. Specifically, social isolation can remodel the brain, causing behavioral abnormalities, including sociability impairments. Here, we investigated social behavior impairment in mice following chronic social isolation stress (CSIS) and conducted a screening of susceptible brain regions using functional readouts.

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

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects. Although the elimination half-life of ketamine is only 13 min in mice, its antidepressant activities can last for at least 24 h. This large discrepancy poses an interesting basic biological question and has strong clinical implications.

[Corrigendum] Icaritin promotes the osteogenesis of bone marrow mesenchymal stem cells via the regulation of sclerostin expression.

Following the publication of the above article, the authors have contacted the Editorial Office to explain that they had assembled the cellular morphological images in Fig. 1A on p. 819 incorrectly; essentially, the cell morphology of 2 passages of hBMSCs (centre panel) should have been shown as the data panel for 3 passages of hBMSCs (right-hand panel), and likewise, the cell morphology of 3 passages of hBMSCs should have been shown as the data panel for 2 passages of hBMSCs.

Neural mechanism underlying depressive-like state associated with social status loss.

Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism remains elusive. Here, by forcing mice to lose against their subordinates in a non-violent social contest, we lower their social ranks stably and induce depressive-like behaviors. These rank-decline-associated depressive-like behaviors can be reversed by regaining social status.

Potassium channel K 4.1 regulates oligodendrocyte differentiation via intracellular pH regulation.

In humans, loss-of-function mutations of Kcnj10 in SeSAME/EAST syndrome, which encodes the inwardly rectifying K channel 4.1 (K 4.1), causes progressive neurological decline.

Rational designing of oscillatory rhythmicity for memory rescue in plasticity-impaired learning networks.

In the brain, oscillatory strength embedded in network rhythmicity is important for processing experiences, and this process is disrupted in certain psychiatric disorders. The use of rhythmic network stimuli can change these oscillations and has shown promise in terms of improving cognitive function, although the underlying mechanisms are poorly understood. Here, we combine a two-layer learning model, with experiments involving genetically modified mice, that provides precise control of experience-driven oscillations by manipulating long-term potentiation of excitatory synapses onto inhibitory interneurons (LTP).

Cav3.1-driven bursting firing in ventromedial hypothalamic neurons exerts dual control of anxiety-like behavior and energy expenditure.

The central nervous system has evolved to coordinate the regulation of both the behavior response to the external environment and homeostasis of energy expenditure. Recent studies have indicated the dorsomedial ventromedial hypothalamus (dmVMH) as an important hub that regulates both innate behavior and energy homeostasis for coping stress. However, how dmVMH neurons control neuronal firing pattern to regulate chronic stress-induced anxiety and energy expenditure remains poorly understood.

A Critical Role for γCaMKII in Decoding NMDA Signaling to Regulate AMPA Receptors in Putative Inhibitory Interneurons.

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP). However, the molecular mechanism underlying how γCaMKII mediates LTP remains unclear.

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.

Dynamics of a disinhibitory prefrontal microcircuit in controlling social competition.

Social competition plays a pivotal role in determining individuals' social status. While the dorsomedial prefrontal cortex (dmPFC) is essential in regulating social competition, it remains unclear how information is processed within its local networks. Here, by applying optogenetic and chemogenetic manipulations in a dominance tube test, we reveal that, in accordance with pyramidal (PYR) neuron activation, excitation of the vasoactive intestinal polypeptide (VIP) or inhibition of the parvalbumin (PV) interneurons induces winning.

Excitation-transcription coupling via synapto-nuclear signaling triggers autophagy for synaptic turnover and long-lasting synaptic depression.

For network rewiring and information storage in the brain, late phase long-term synaptic depression (L-LTD) requires the long-lasting reorganization of cellular resources. We found that activation of GRIN/NMDAR recruits transcription-dependent autophagy for synaptic turnover to support L-LTD. Activity-dependent CRTC1 synapto-nuclear translocation increases nuclear CRTC1 that competes with FXR for binding to CREB; this in turn enhances the direct binding between CRTC1-CREB and macroautophagy/autophagy gene promoters.

Neuronal activity recruits the CRTC1/CREB axis to drive transcription-dependent autophagy for maintaining late-phase LTD.

Cellular resources must be reorganized for long-term synaptic plasticity during brain information processing, in which coordinated gene transcription and protein turnover are required. However, the mechanism underlying this process remains elusive. Here, we report that activating N-methyl-d-aspartate receptors (NMDARs) induce transcription-dependent autophagy for synaptic turnover and late-phase long-term synaptic depression (L-LTD), which invokes cytoplasm-to-nucleus signaling mechanisms known to be required for late-phase long-term synaptic potentiation (L-LTP).