Trends in Neurosciences最新文献

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.

The parabrachial nucleus (PBN) in the dorsal pons responds to bodily threats and transmits alarm signals to the forebrain. Parabrachial neuron activity is enhanced during chronic pain, and inactivation of PBN neurons in mice prevents the establishment of neuropathic, chronic pain symptoms. Chemogenetic or optogenetic activation of all glutamatergic neurons in the PBN, or just the subpopulation that expresses the Calca gene, is sufficient to establish pain phenotypes, including long-lasting tactile allodynia, that scale with the extent of stimulation, thereby promoting nociplastic pain, defined as diffuse pain without tissue inflammation or nerve injury. This review focuses on the role(s) of molecularly defined PBN neurons and the downstream nodes in the brain that contribute to establishing nociplastic pain.

Recent work by Giusti and colleagues showed that circTulp4 modulates excitatory synaptic strength. Knocking down circTulp4 disrupts the excitation-inhibition (E/I) balance in mice and leads to hypersensitivity toward aversive stimuli. These observations update our appreciation of the functions of circular (circ)RNA in the nervous system and their potential implication in neurodevelopmental and neuropsychiatric disorders.

Marked dysregulation of the human prefrontal cortex (PFC) and anterior cingulate cortex (ACC) characterises a variety of anxiety disorders, and its amelioration is a key feature of treatment success. Overall treatment response, however, is highly variable, and about a third of patients are resistant to treatment. In this review we hypothesise that a major contributor to this variation in treatment response are the multiple faces of anxiety induced by distinct forms of frontal cortex dysregulation. Comparison of findings from humans and non-human primates reveals marked similarity in the functional organisation of threat regulation across the frontal lobes. This organisation is discussed in relation to the 'predatory imminence continuum' model of threat and the differential engagement of executive functions at the core of both emotion generation and regulation strategies.

Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are characterized by neuronal loss accompanied by α-synuclein (α-syn) accumulation in the brain. While research conventionally focused on brain pathology, there is growing interest in peripheral alterations. Erythrocytes, which are rich in α-syn, have emerged as a compelling site for synucleinopathies-related alterations. Erythrocyte-derived extracellular vesicles (EVs), containing pathological α-syn species, can traverse the blood-brain barrier (BBB) under certain conditions and the gastrointestinal tract, where α-syn and gut microbiota interact extensively. This review explores the accumulating evidence of erythrocyte involvement in synucleinopathies, as well as their potential in disease pathogenesis and diagnosis. Given their unique properties, erythrocytes and erythrocyte-derived EVs may also serve as an ideal therapeutic platform for treating synucleinopathies and beyond.

The maturation of cerebral cortical networks during early life involves a major reorganization of long-range axonal connections. In a recent study, Bragg-Gonzalo, Aguilera, et al. discovered that in mice, the interhemispheric connections sent by S1L4 callosal projection neurons are pruned via the tight control of their ipsilateral synaptic integration, which relies on the early activity of specific interneurons.

Quiescence is a prolonged but reversible state of cell-cycle arrest that is an adaptive feature of most adult stem cell populations. In the brain, quiescence helps to protect adult neural stem cells from stress and supports lifelong neurogenesis. Unfortunately however, entry into a quiescent or a slow-cycling state is also a malignant feature of brain cancer stem cells. In glioblastoma, where the process has been best characterised, quiescent glioma stem cells preferentially survive chemoradiation, and after therapy, reactivate to regrow the tumour and drive recurrence. In this Review, we discuss the in vitro and in vivo models that have been developed for studying neural stem cell quiescence and how these tools may be used to deepen biological understanding and to develop novel therapies targeting quiescent glioma stem cells.

In the nervous system, G protein-coupled receptors (GPCRs) control neuronal excitability, synaptic transmission, synaptic plasticity, and, ultimately, behavior through spatiotemporally precise initiation of a variety of signaling pathways. However, despite their critical importance, there is incomplete understanding of how these receptors are regulated to tune their signaling to specific neurophysiological contexts. A deeper mechanistic picture of neuromodulatory GPCR function is needed to fully decipher their biological roles and effectively harness them for the treatment of neurological and psychiatric disorders. In this review, we highlight recent progress in identifying novel modes of regulation of neuromodulatory GPCRs, including G protein- and receptor-targeting mechanisms, receptor-receptor crosstalk, and unique features that emerge in the context of chemical synapses. These emerging principles of neuromodulatory GPCR tuning raise critical questions to be tackled at the molecular, cellular, synaptic, and neural circuit levels in the future.