Neuroscientist最新文献

Ketamine is a unique anesthetic agent that induces dissociative anesthesia, characterized by perceptual detachment, analgesia, and altered states of consciousness. Beyond its widespread use in anesthesia, subhypnotic ketamine dosing has emerged as a rapid-acting antidepressant and a valuable model for probing the neural mechanisms underlying consciousness and neuropsychiatric disorders. At the core of its effects are actions on cortical circuits, primarily through NMDA receptor and HCN1 channel antagonism, disinhibition of pyramidal neurons, and altered thalamocortical connectivity. This review brings together emerging findings from ketamine pharmacology, cell type-resolved and region-specific in vivo imaging, and systems neuroscience to define how ketamine alters cortical circuit dynamics to drive dissociation. We further explore the intriguing possibility that ketamine freely diffuses into and concentrates within intracellular compartments and, in doing so, modulates neuronal excitability, intracellular signaling, and an epigenetic state, even following a single dose. A deeper mechanistic understanding of these cortical and cellular processes will not only advance our knowledge of ketamine's complex pharmacology but may also inform new therapeutic strategies for treatment-resistant depression and facilitate the study of diverse states of consciousness.

Invertebrate and vertebrate experimental models, each providing unique advantages for addressing specific questions, offer a multifaceted and multiscale view of plasticity. Integration of the obtained knowledge is crucial for understanding general principles and specific mechanisms of synaptic plasticity. However, this process is hindered by field-specific discrepancies in terminology and concepts. A profound case of such discrepancy is heterosynaptic plasticity, which refers to distinct experimental phenomena and mechanisms and serves different functional roles in invertebrate and vertebrate nervous systems. In Aplysia research, heterosynaptic facilitation originally referred to several phenomena and mechanisms of synaptic plasticity that mediate simple forms of learning. In vertebrate research, heterosynaptic plasticity originally referred to changes at synapses that were not activated during the induction of long-term potentiation in the hippocampus. Ironically, most of the difference between the wordings comes from the meaning attributed to their common part, the heterosynaptic. Here, we consider these differences and discuss how the phenomena and concepts behind the field-specific terminologies are related and can be compared.

Kv4.2 channels, principal mediators of the neuronal A-type K+ current, are emerging as multifunctional regulators of excitability, plasticity, and synaptic signaling. Beyond their canonical role in shaping backpropagating action potentials, Kv4.2 channels integrate diverse signaling modalities through interactions with calcium channels, scaffolding and auxiliary proteins (DPP6, KChIPs), and posttranslational regulators such as Pin1 and UBE3A. These interactions create a context-dependent network that allows Kv4.2 to function as a molecular break, stabilizing excitability under resting conditions and facilitating plasticity and learning when modulated. Recent advances in molecular and genetic tools are transforming how Kv4.2 can be studied. Next-generation genetically encoded inhibitors, for instance membrane-tethered toxins, offer cell-specific modulation of the channel. Complementary genetically encoded potassium indicators provide important steps toward real-time optical monitoring of potassium dynamics, although improvements remain necessary. After a period of diminished attention, the Kv4.2 channel is reemerging as a significant focus of scientific investigation. Recent breakthroughs, coupled with next-generation technologies, are bound to unravel the complex and multifaceted roles of Kv4.2.

Neural activity in the beta band is increasingly recognized to occur not as sustained oscillations but as transient burst-like events. These beta bursts are diverse in shape, timing, and spatial distribution, but their precise functional significance remains unclear. Here, we review emerging evidence on beta burst properties, functional roles, and developmental trajectories and propose a new framework in which beta bursts are not homogeneous events but reflect distinct patterns of synaptic input from different brain regions targeting different cortical layers. We argue that burst waveform shape carries mechanistic and computational significance, offering a window into the dynamic integration of specific combinations of cortical and subcortical signals. This perspective repositions beta bursts as transient computational primitives, rather than generic inhibitory signals or averaged rhythms. We conclude by outlining key open questions and research priorities, including the need for improved detection methods, investigation into developmental and clinical biomarkers, and translational applications in neuromodulation and brain-computer interfaces.

Emerging evidence highlights the potential role of auditory stimulation in enhancing sleep-dependent memory consolidation. Pink noise appears to be an effective auditory stimulus for enhancing memory consolidation, likely due to its wide-range influence on brain oscillations. However, the specific underlying mechanisms by which pink noise enhances memory consolidation remain unclear. This perspective article presents a novel hypothesis exploring how pink noise, delivered through closed-loop auditory stimulation, may facilitate memory consolidation. Specifically, we suggest that pink noise may reach the hippocampus via the rapid auditory pathway, potentially increasing the likelihood of sharp-wave ripple (SW-R) generation. By increasing hippocampal ripple activity, the overall likelihood of synchronization with spindles and slow oscillations is also increased, enhancing hippocampal-cortical coupling. This suggests that pink noise might indirectly support slow oscillation-ripple-spindle coordination to promote systems-level consolidation and interregional information transfer. This, in turn, could enable long-term memory storage and support abstraction and generalization. Our hypothesis emphasizes a bottom-up mechanism originating from the hippocampus. Although this hypothesis currently lacks direct support from subcortical recordings, it builds on existing knowledge of sleep rhythms, hippocampal auditory pathways, and the known effects of SW-R modulation on memory formation. This perspective offers a framework for future work investigating the mechanisms by which pink noise stimulation can lead to memory enhancement.

Alzheimer's disease (AD) is increasingly understood as a disorder of network-state and plasticity-capacity, in which amyloid-β and tau pathologies disrupt the activity-dependent mechanisms that build and stabilize memory engrams. Here, I review how amyloid-β-driven neuronal hyperactivity contributes to plasticity and memory deficits in AD. I also discuss how various cellular pathologies reinforce one another, leading to a cellular environment that is impermissive to plasticity. I relate these cellular and circuit-level disturbances to failures in memory encoding, consolidation, and recall, emphasizing the role of interference arising from coexisting hyper- and hypoactive neuronal populations. Finally, I discuss the relevance and limitations of amyloid mouse models in understanding the cognitive decline in AD.

Neuropathic pain (NP) is a chronic pain condition caused by nerve damage. Current NP treatments have limited efficacy and significant side effects. Emerging evidence demonstrates that N-methyl-d-aspartate receptors (NMDARs) play a key role in the development of NP, especially in their pre- and postsynaptic functions. This review provides an overview of the mechanistic roles of NMDARs in NP, focusing on their subunit structures and involvement in pain transmission. The interactions between NMDARs and other neurotransmitter receptors are further discussed, emphasizing NMDARs as a promising therapeutic target. Finally, we discuss the pharmacologic mechanisms of NMDARs relevant to pain management and nonpharmacologic interventions, which have not been covered in previous reviews. This review aims to advance future research on NMDAR-mediated mechanisms in NP and promote the development of targeted, low-side effect therapeutic strategies.

In September 1887, the 28-year-old neuropathologist Carlo Martinotti, an assistant to Camillo Golgi, presented his discovery of a new cell type in the mammalian cerebral cortex at the 12th congress of the Italian Medical Association, held in Pavia. The actual papers were published between 1888 and 1890. This neuron received the eponym "Martinotti cell" by Albert Kölliker and Santiago Ramón y Cajal, while its axon was designated the "Martinotti fiber" by Ramón y Cajal and other pioneer neuroanatomists, including Constantin von Economo and Georg N. Koskinas. Martinotti cells were later found to be inhibitory interneurons scattered throughout cortical layers II to VI, having an axon that ascends and extends rich collaterals into the molecular layer. Based on modern experiments, Martinotti cells have been implicated in a broad spectrum of functions, including regulation of cortical activity, speed of information processing, cortical plasticity, audition, motor learning, sensorimotor integration, and sleep.