Neuroscientist最新文献

The brain has the powerful ability to transform experiences into anatomic maps and continuously integrate massive amounts of information to form new memories. The manner in which the brain performs these processes has been investigated extensively for decades. Emerging reports suggest that dendritic spines are the structural basis of information storage. The complex orchestration of functional and structural dynamics of dendritic spines is associated with learning and memory. Owing to advancements in techniques, more precise observations and manipulation enable the investigation of dendritic spines and provide clues to the challenging question of how memories reside in dendritic spines. In this review, we summarize the remarkable progress made in revealing the role of dendritic spines in fear memory and the techniques used in this field.

The cerebellum and its thalamic projections to the primary motor cortex (M1) are well known to play an essential role in executing daily actions. Anatomic investigations in animals and postmortem humans have established the reciprocal connections between these regions; however, how these pathways can shape cortical activity in behavioral contexts and help promote recovery in neuropathological conditions remains not well understood. The present review aims to provide a comprehensive description of these pathways in animals and humans and discuss how novel noninvasive brain stimulation (NIBS) methods can be used to gain a deeper understanding of the cerebellar-M1 connections. In the first section, we focus on recent animal literature that details how information sent from the cerebellum and thalamus is integrated into an broad network of cortical motor neurons. We then discuss how NIBS approaches in humans can be used to reliably assess the connectivity between the cerebellum and M1. Moreover, we provide the latest perspectives on using advanced NIBS approaches to investigate and modulate multiple cerebellar-cortical networks involved in movement behavior and plasticity. Finally, we discuss how these emerging methods have been used in translation research to produce long-lasting modifications of cerebellar-thalamic-M1 to restore cortical activity and motor function in neurologic patients.

The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and glial cells. During development, cortical neurons and glia acquire a precise cellular arrangement and architecture to support higher-order cognitive functioning. Decades of study using rodent models, naturally gyrencephalic animal models, human pathology specimens, and, recently, human cerebral organoids, reveal that rodents recapitulate some but not all the cellular and molecular features of human cortices. Whereas rodent cortices are smooth-surfaced or lissencephalic, larger mammals, including humans and nonhuman primates, have highly folded/gyrencephalic cortices that accommodate an expansion in neuronal mass and increase in surface area. Several genes have evolved to drive cortical gyrification, arising from gene duplications or de novo origins, or by alterations to the structure/function of ancestral genes or their gene regulatory regions. Primary cortical folds arise in stereotypical locations, prefigured by a molecular "blueprint" that is set up by several signaling pathways (e.g., Notch, Fgf, Wnt, PI3K, Shh) and influenced by the extracellular matrix. Mutations that affect neural progenitor cell proliferation and/or neurogenesis, predominantly of upper-layer neurons, perturb cortical gyrification. Below we review the molecular drivers of cortical folding and their roles in disease.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with onset in childhood. The molecular mechanisms underlying ASD have not yet been elucidated completely. Evidence has emerged to support a link between microglial dysfunction and the etiology of ASD. This review summarizes current research on microglial dysfunction in neuroinflammation and synaptic pruning, which are associated with altered transcriptomes and autophagy in ASD. Dysbiosis of gut microbiota in ASD and its correlation with microglial dysfunction are also addressed.

Empathy is an ability to fully understand and feel the mental states of others. We emphasize that empathy is elicited by the transmission of pain, fear, and sensory information. In clinical studies, impaired empathy has been observed in most psychiatric conditions. However, the precise impairment mechanism of the network systems on the pathogenesis of empathy impairment in psychiatric disorders is still unclear. Multiple lines of evidence suggest that disturbances in the excitatory/inhibitory balance in neurologic disorders are key to empathetic impairment in psychiatric disorders. Therefore, we here describe the roles played by the anterior cingulate cortex- and medial prefrontal cortex-dependent neural circuits and their impairments in psychiatric disorders, including anxiety, depression, and autism. In addition, we review recent studies on the role of microglia in neural network excitation/inhibition imbalance, which contributes to a better understanding of the neural network excitation/inhibition imbalance and may open up innovative psychiatric therapies.

Chronic pain is highly prevalent and burdensome, affecting millions of people worldwide. Although it emerges at any point in life, it often manifests in adolescence. Given that adolescence is a unique developmental period, additional strains associated with persistent and often idiopathic pain lead to significant long-term consequences. While there is no singular cause for the chronification of pain, epigenetic modifications that lead to neural reorganization may underpin central sensitization and subsequent manifestation of pain hypersensitivity. Epigenetic processes are particularly active during the prenatal and early postnatal years. We demonstrate how exposure to various traumas, such as intimate partner violence while in utero or adverse childhood experiences, can significantly influence epigenetic regulation within the brain and in turn modify pain-related processes. We provide compelling evidence that the burden of chronic pain is likely initiated early in life, often being transmitted from mother to offspring. We also highlight two promising prophylactic strategies, oxytocin administration and probiotic use, that have the potential to attenuate the epigenetic consequences of early adversity. Overall, we advance understanding of the causal relationship between trauma and adolescent chronic pain by highlighting epigenetic mechanisms that underlie this transmission of risk, ultimately informing how to prevent this rising epidemic.

Traumatic brain injury is a common health problem affecting millions of people each year. BDNF has been investigated in the context of traumatic brain injury due to its crucial role in maintaining brain homeostasis. Val66Met is a functional single-nucleotide polymorphism that results in a valine-to-methionine amino acid substitution at codon 66 in the BDNF prodomain, which ultimately reduces secretion of BDNF. Here, we review experimental animal models as well as clinical studies investigating the role of the Val66Met single-nucleotide polymorphism in traumatic brain injury outcomes, including cognitive function, motor function, neuropsychiatric symptoms, and nociception. We also review studies investigating the role of BDNF on traumatic brain injury pathophysiology as well as circulating BDNF as a biomarker of traumatic brain injury.

High-level spinal cord injury (SCI) often results in cardiovascular dysfunction, especially the development of autonomic dysreflexia. This disorder, characterized as an episode of hypertension accompanied by bradycardia in response to visceral or somatic stimuli, causes substantial discomfort and potentially life-threatening symptoms. The neural mechanisms underlying this dysautonomia include a loss of supraspinal control to spinal sympathetic neurons, maladaptive plasticity of sensory inputs and propriospinal interneurons, and excessive discharge of sympathetic preganglionic neurons. While neural control of cardiovascular function is largely disrupted after SCI, the renin-angiotensin system (RAS), which mediates blood pressure through hormonal mechanisms, is up-regulated after injury. Whether the RAS engages in autonomic dysreflexia, however, is still controversial. Regarding therapeutics, transplantation of embryonic presympathetic neurons, collected from the brainstem or more specific raphe regions, into the injured spinal cord may reestablish supraspinal regulation of sympathetic activity for cardiovascular improvement. This treatment reduces the occurrence of spontaneous autonomic dysreflexia and the severity of artificially triggered dysreflexic responses in rodent SCI models. Though transplanting early-stage neurons improves neural regulation of blood pressure, hormonal regulation remains high and baroreflex dysfunction persists. Therefore, cell transplantation combined with selected RAS inhibition may enhance neuroendocrine homeostasis for cardiovascular recovery after SCI.

The neuronal endoplasmic reticulum (ER) consists of a dynamic, tubular network that extends all the way from the soma into dendrites, axons, and synapses. This morphology gives rise to an enormous membrane surface area that, through the presence of tethering proteins, lipid transfer proteins, and ion channels, plays critical roles in local calcium regulation, membrane dynamics, and the supply of ions and lipids to other organelles. Here, we summarize recent advances that highlight the various roles of the neuronal ER in axonal growth, repair, and presynaptic function. We review the variety of contact sites between the ER and other axonal organelles and describe their influence on neurodevelopment and neurotransmission.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain. A hallmark of both familial and sporadic PD is the presence of Lewy body inclusions composed mainly of aggregated α-synuclein (α-syn), a presynaptic protein encoded by the SNCA gene. The mechanisms driving the relationship between α-syn accumulation and neurodegeneration are not completely understood, although recent evidence indicates that multiple branches of the proteostasis pathway are simultaneously perturbed when α-syn aberrantly accumulates within neurons. Studies from patient-derived midbrain cultures that develop α-syn pathology through the endogenous expression of PD-causing mutations show that proteostasis disruption occurs at the level of synthesis/folding in the endoplasmic reticulum (ER), downstream ER-Golgi trafficking, and autophagic-lysosomal clearance. Here, we review the fundamentals of protein transport, highlighting the specific steps where α-syn accumulation may intervene and the downstream effects on proteostasis. Current therapeutic efforts are focused on targeting single pathways or proteins, but the multifaceted pathogenic role of α-syn throughout the proteostasis pathway suggests that manipulating several targets simultaneously will provide more effective disease-modifying therapies for PD and other synucleinopathies.