eNeuro最新文献

Dopamine release in the nucleus accumbens is classically linked to associative learning, signaling relationships between predictive cues and outcomes. Yet, dopamine is also strongly modulated by novelty, a nonassociative factor that has received comparatively little attention. Here, we used optical dopamine sensors in awake, behaving male and female mice to define how novelty alters the temporal dynamics of dopamine release during aversive learning. We manipulated novelty in three ways: (1) omitting expected footshocks, (2) introducing novel neutral cues concurrently with shock-predictive stimuli, and (3) presenting novel stimuli in an unpaired fashion within a context. Across all conditions, manipulations robustly increased dopamine release and in some cases altered the directionality of cue-evoked dopamine responses. Notably, these effects extended beyond the immediate stimulus window, altering subsequent responses to both conditioned cues and footshocks. Together, these findings demonstrate that changes in the environment that extend beyond prediction-based learning can exert a powerful and sustained influence on dopamine signaling, reshaping how aversive cues and outcomes are represented in the brain.

Recent work showed unexpectedly large, daily modulation of intracellular chloride concentration ([Cl^-]_in) in cortical pyramidal cells, with consequences for GABAergic function and network excitability ( Alfonsa et al., 2023; Pracucci et al., 2023). One explanation for this [Cl^-]_in modulation is that it arises from variation in presynaptic drive. In that case, neuronal classes with similar synaptic inputs should show correlated changes in activity-dependent ionic redistribution. To examine this prediction, we performed in vivo, LSSm-ClopHensor imaging to measure [Cl^-]_in and pH_in in populations of parvalbumin- (PV) and somatostatin (SST)-expressing interneurons in neocortical Layer 2/3 of male and female adult mice. Imaging was performed at zeitgeber time (ZT)5 and ZT17, when pyramidal cell [Cl^-]_in shows maximal divergence ( Pracucci et al., 2023). Interestingly, PV interneurons also showed large physiological [Cl^-]_in modulation between these times but out-of-phase with that in pyramidal cells, being raised at ZT5 and lower at ZT17, and with a far higher mean [Cl^-]_in SST interneurons showed less modulation, with higher variance, and with a temporal dynamic resembling the pyramidal cell pattern. Notably, in vitro experimental assays of inhibition, involving these two classes of interneuron, differed markedly at ZT5 and ZT17. The persistence of these time-of-day effects in vitro and the difference in [Cl^-]_in dynamics between pyramidal cells and PV interneurons in vivo both point toward cell-intrinsic regulation being more important than activity-dependent effects in setting these slow, daily, physiological, ionic redistribution patterns. We discuss what other possible factors may influence variations in brain state through the day.

The medial habenula (MHb) and its main projection target, the interpeduncular nucleus (IPN), play an important role in mood/affect, anxiety, and the aversive experience associated with nicotine withdrawal. Given that MHb axons release glutamate onto IPN neurons, we investigated the expression and functional responses of ionotropic glutamate receptors (iGluRs) in neurons of the rostral IPN (IPR) in male rats. After confirming mRNA expression of Gria1 and Grin1 iGluR subunits in IPR, we employed glutamate uncaging coupled with two-photon imaging and patch-clamp electrophysiology. IPR dendrites, which often contained spine-like protrusions suggestive of synaptic contacts, featured a variety of response profiles following localized glutamate uncaging. Pharmacology experiments confirmed functional α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-d-aspartate iGluR responses in IPR neuronal somata. Rats were trained to self-administer nicotine or saline during 10 fixed ratio 1 sessions and seven intermittent access sessions. In rats with a history of nicotine self-administration, perisomatic IPR iGluR responses are reduced. Acute nicotine application to slices from drug-naive rats recapitulated the effect of nicotine self-administration. These results identify a mechanism, whereby nicotine, even acute nicotine, may reduce IPR neuron sensitivity to glutamate from MHb axons, which could play a role in the aversive response to nicotine withdrawal.

Signaling at nicotinic acetylcholine receptors (nAChRs) is vital for normal development of cerebral cortical circuits. These developing circuits are also shaped by fast-spiking (FS) inhibitory cortical neurons. While nicotinic dysfunction in FS neurons is implicated in a number of psychiatric and neurodevelopmental disorders, FS neurons are thought to not have nicotinic responses in adults. Here, we establish a timeline of FS neuron response to nicotine pre- and postsynaptically in primary somatosensory cortex in male and female rats. We found that nicotine increases the frequency of spontaneous synaptic inputs to FS neurons during the second postnatal week, and this effect persisted through development. In contrast, FS neurons in S1 had no postsynaptic responses to nicotine from as early as they can be reliably identified. This was not attributable to receptor desensitization, and we further revealed that FS neurons express abundant mRNA for several nAChR subunits, beginning early in development. To determine why FS neurons do not respond to nicotine despite expressing these receptors, we probed for the expression of lynx1, a negative nicotinic modulator. Lynx1 mRNA was expressed in FS neurons from early development, with expression increasing dramatically during the second postnatal week.

This study determined the association between the triglyceride-glucose (TyG) index-waist-to-hip ratio (TyG-WHR) and stroke. Data from the China Health and Retirement Longitudinal Study (CHARLS) were utilized from baseline in 2011 to the wave six follow-up in 2020. The CHARLS cohort was assembled using a multistage probability sampling technique. Participants were comprehensively assessed through standardized questionnaires with face-to-face interviews. A total of 4,911 patients with 2,338 males (47.6%) and 2,573 females (52.4%) were included in this analysis. A significant association between the TyG-WHR and the risk of stroke was identified utilizing a Cox proportional hazards regression model with cubic spline functions that were characterized by a nonlinear relationship. The analysis determined a threshold for the TyG-WHR at 4.635. The association between the TyG-WHR and stroke was not significant [hazard ratio (HR), 0.813; 95% CI, 0.662-0.999; p = 0.049] to the left of the threshold. The association was statistically significant (HR, 1.271; 95% CI, 1.131-1.429; p < 0.001) to the right of the threshold. The current study demonstrated a positive and nonlinear association between the TyG-WHR and stroke risk among middle-aged and elderly Chinese populations. When the TyG-WHR exceeded 4.635, there was a statistically significant positive correlation with the occurrence of stroke. Clinically, reducing the TyG-WHR, especially <4.635, may reduce the risk of stroke.

Structural changes in dendritic spines underlie long-term potentiation (LTP). While CaMKII has been considered as the primary driver of these changes, we show that transient, localized activation of Rac1 alone is sufficient to induce structural LTP in hippocampal slices prepared from rat pups of either sex. Using photoactivatable Rac1 (PA-Rac1), we demonstrated that Rac1 activation triggers spine enlargement and actin polymerization. This PA-Rac1-induced plasticity was blocked by Rac1 and Pak1 inhibitors but not by a CaMKII inhibitor. Our results identify Rac1 as an upstream of persistent signaling that stabilizes actin-based spine structural changes critical for synaptic memory encoding.

In natural, free-viewing settings, visual perception is driven by a series of saccades and fixations. Perceptual mechanisms are typically studied through averaged fixation-related potentials generated from simultaneous eye-tracking and EEG recordings. Lambda responses following fixation onsets signal the arrival of new visual input to the primary visual cortex. In our study, we investigate the use and preprocessing parameter dependence of independent component analysis (ICA) in separating the lambda response from other neural sources. In our experiment, 10 subjects (2 males and 8 females) viewed 80 art paintings in natural, free-viewing settings, during which EEG data were recorded. Our results show that unique lambda response components can be detected reliably and individual lambda waves can be extracted in a single-trial manner, without signal averaging. ICA decomposition is most sensitive to high-pass filtering producing best results with a minimum 1 Hz filtering. We also propose a method that automatically and accurately identifies the lambda component among other independent components for further lambda peak detection. These individual lambda waves can then be used to study saccade-related modulation effects without losing temporal and spatial resolution. The novelty of our method is the automatic detection of lambda components and extraction lambda waves, which is a new approach in saccade/fixation and visual perception research under naturalistic viewing conditions.

ArfGAP, with dual PH domain-containing protein 1/Centaurin-α1 (ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. CentA1 upregulation and association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest the role of this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 knock-out (KO) mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris water maze test showed significant impairment in J20 mice, which was rescued in J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anticorrelated with changes caused by APP overexpression (J20 vs wild type), consistent with rescue of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.

Ongoing efforts over the last 50 years have made data and methods more reproducible and transparent across the life sciences. This openness has led to transformative insights and vastly accelerated scientific progress (Gražulis et al., 2012; Munafó et al., 2017). For example, structural biology (Bruno and Groom, 2014) and genomics (Benson et al., 2013; Porter and Hajibabaei, 2018) have undertaken systematic collection and publication of protein sequences and structures over the past half century. These data, in turn, have led to scientific breakthroughs that were unthinkable when data collection first began (Jumper et al., 2021). We believe that neuroscience is poised to follow the same path, and that principles of open data and open science will transform our understanding of the nervous system in ways that are impossible to predict at the moment. New social structures supporting an active and open scientific community are essential (Saunders, 2022) to facilitate and expand the still limited adoption of open science practices in our field (Schottdorf et al., 2024). Unified by shared values of openness, we set out to organize a symposium for open data in neurophysiology (ODIN) to strengthen our community and facilitate transformative open neuroscience research at large. In this report, we synthesize insights from this first ODIN event. We also lay out plans for how to grow this movement, document emerging conversations, and propose a path toward a better and more transparent science of tomorrow.

A central mechanism of exposure-based cognitive behavioral therapy for anxiety and trauma-related disorders is fear extinction. However, the mechanisms underlying fear extinction are deficient in some individuals, leading to treatment resistance. Recent animal studies demonstrate that upon omission of the aversive, unconditioned stimulus (US) during fear extinction, dopamine (DA) neurons in the ventral tegmental area (VTA) produce a prediction error (PE)-like signal. However, whether this VTA-DA neuronal PE-like signal is altered in animals exhibiting deficient fear extinction has not been studied. Here, we used a mouse model of impaired fear extinction [129S1/SvImJ (S1) inbred mouse strain] to monitor and manipulate VTA-DA neurons during extinction. Male DAT-Cre mice backcrossed onto an S1 background (S1-DAT-Cre) exhibited impaired extinction but normal VTA-DA neuron number, as compared with BL6-DAT-Cre mice. In vivo fiber photometry showed that impaired extinction in male S1-DAT-Cre mice was associated with abnormally sustained US omission-related VTA-DA neuronal calcium activity during extinction training and retrieval. Neither in vivo optogenetic photoexcitation of VTA-DA neuronal cell bodies nor their axons in the infralimbic cortex was sufficient to rescue deficient extinction in male S1-DAT-Cre mice, at least within the optogenetic and behavioral parameters used. These data suggest that alterations in the activity of VTA-DA neurons during extinction learning and retrieval may be associated with deficient fear extinction in male S1 mice and could potentially contribute to extinction impairments in patient populations.