Current Opinion in Neurobiology最新文献

A significant source of risk for neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorder (ASD), lies in genes located on the X chromosome. Males can be particularly vulnerable to X-linked variation because of hemizygosity, and male-specific segregation in pedigrees has guided earlier gene discovery for X-linked recessive conditions. More recently, X-linked disorders disproportionally affecting females, with complex inheritance patterns and/or presenting with sex differences, have surfaced. Here, we discuss the genetics and neurobiology of X-linked genes that are paradigmatic to understand NDDs in females. Integrating genetic, clinical, and functional data will be key to understand how X-linked variation contributes to the risk architecture of NDDs.

Jellyfish comprise a diverse clade of free-swimming predators that arose prior to the Cambrian explosion. They play major roles in ocean ecosystems via a suite of complex foraging, reproductive, and defensive behaviors. These behaviors arise from decentralized, regenerative nervous systems composed of body parts that generate the appropriate part-specific behaviors autonomously following excision. Here, we discuss the organization of jellyfish nervous systems and opportunities afforded by the recent development of a genetically tractable jellyfish model for systems and evolutionary neuroscience.

Nicotine use is driven by pleasurable effects, but following chronic exposure, nicotine use becomes largely driven by the desire need to avoid withdrawal symptoms. Current cessation strategies focusing on alleviating withdrawal, but current cessation interventions are less effective for women than men. Also, hormone fluctuations across the menstrual cycle appear to impact use patterns, withdrawal severity, and treatment efficacy. This raises important questions regarding optimal quit dates and the application of hormone interventions to alleviate withdrawal in women. This review surveys the existing literature assessing the impact of ovarian hormones on nicotine withdrawal severity. This is an important issue because women seeking cessation treatments may be using hormone-based contraceptives or hormone replacement post-menopause. Hormone interventions may also offer a novel treatment avenue that is more effective than current cessation approaches. Future work in this area is important for reducing health disparities produced by excessive nicotine use in women.

Stress-related and substance use disorders are both characterized by disruptions in reward-related behaviors, and these disorders are often comorbid with one another. Recent investigations have identified a novel mechanism of inhibitory plasticity induced by both stress and substance use within the ventral tegmental area (VTA), a key region in reward processing. This mechanism involves the neuron-specific potassium chloride cotransporter isoform 2 (KCC2), which is essential in modulating inhibitory signaling through the regulation of intracellular chloride (Cl⁻) in VTA GABA neurons. Experiences, such as exposure to stress or substance use, diminish KCC2 expression in VTA GABA neurons, leading to abnormal reward-related behaviors. Here, we review literature suggesting that KCC2 downregulation contributes to irregular dopamine (DA) transmission, impacting multiple reward circuits and promoting maladaptive behaviors. Activating KCC2 restores canonical GABA functioning and reduces behavioral deficits in preclinical models, leading us to advocate for KCC2 as a target for therapies aimed at alleviating and mitigating various stress-related and substance use disorders.

Emerging therapies for Angelman syndrome, a severe neurodevelopmental disorder, are focused on restoring UBE3A gene expression in the brain. Further therapeutic opportunities may arise from a better understanding of how UBE3A gene products—both long and short isoforms of the ubiquitin ligase E3A (UBE3A)—function in neurons. Great strides have been made recently toward identifying ubiquitin substrates of UBE3A in vitro and in heterologous expression systems. From this work, a particularly close relationship between UBE3A and subunits of the 19S regulatory particle of the proteasome has become evident. We propose that further research cognizant of isoform-specific UBE3A functional roles will be instrumental in elucidating key UBE3A/substrate relationships within distinct neuronal compartments, lending to the discovery of novel therapeutic targets and valuable clinical biomarkers for the treatment of Angelman syndrome.

Misuse and accidental overdoses attributed to stimulants are escalating rapidly. These stimulants include methamphetamine, cocaine, amphetamine, ecstasy-type drugs, and prescription stimulants such as methylphenidate. Unlike opioids and alcohol, there are no therapies approved by the US Food and Drug Administration (FDA) to treat stimulant-use disorder. The high rate of relapse among this population highlights the insufficiency of current treatment options, which are limited to abstinence support programs and behavioral modification therapies. Here, we briefly outline recent regulatory actions taken by FDA to help support the development of new stimulant use disorder treatments and highlight several new therapeutics in the clinical development pipeline.

Mosquito behaviors have been the subject of extensive research for over a century due to their role in the spread of human disease. However, these behaviors are also beginning to be appreciated as excellent models for neurobiological research in their own right. Many of the same behaviors and sensory abilities that help mosquitoes survive and reproduce alongside humans represent striking examples of generalizable phenomena of longstanding neurobiological interest. In this review, we highlight four prominent examples that promise new insight into (1) precise circadian tuning of sensory systems, (2) processing of complex natural odors, (3) multisensory integration, and (4) modulation of behavior by internal states.

G protein-coupled receptors (GPCRs) are the largest group of membrane receptors in the central nervous system and one of the key proteins for signal transduction between cells. Currently, many drugs available on the market act via GPCRs and these receptors remain attractive targets for the treatment of brain disorders, including alcohol use disorder (AUD). Here, we describe the most recent literature, with a primary focus on the past 5 years, on GPCR targets with the potential for reducing behaviours associated with excessive alcohol intake. Specifically, we focus on preclinical evidence of compounds with attractive pharmacological profiles and potential for future clinical investigation for the treatment of AUD.

The integrated stress response (ISR) is a highly conserved biochemical pathway that regulates protein synthesis. The ISR is activated in response to diverse stressors to restore cellular homeostasis. As such, the ISR is implicated in a wide range of diseases, including brain disorders. However, in the brain, the ISR also has potent influence on processes beyond proteostasis, namely synaptic plasticity, learning and memory. Thus, in the setting of brain diseases, ISR activity may have dual effects on proteostasis and synaptic function. In this review, we consider the ISR's contribution to brain disorders through the lens of its potential effects on synaptic plasticity. From these examples, we illustrate that at times ISR activity may be a “double-edged sword”. We also highlight its potential as a therapeutic target to improve circuit function in brain diseases independent of its role in disease pathogenesis.

Animals of all kinds evolved to deal with anticipated and unanticipated changes in a variety of features in their environments. Consequently, all environmental perturbations, adaptations, and acclimation involve a myriad of factors that, together, contribute to environmental resilience. New work highlights the importance of neuromodulation in the control of environmental resilience, and illustrates that different components of the nervous system may be differentially resilient to environmental perturbations. Climate change is today pushing animals to deal with previously unanticipated environmental challenges, and therefore understanding the complex biology of adaptation and acclimation to various environmental conditions takes on new urgency.