eNeuro最新文献

The "sign-tracking" and "goal-tracking" model of individual variation in associative learning permits the identification of rats with different cue reactivity and predisposition to addiction-like behaviors. Certainly, compared with "goal-trackers" (GTs), "sign-trackers" (STs) show more susceptibility traits such as increased cue-induced "relapse" of drugs of abuse. Different cue- and reward-evoked patterns of activity in the nucleus accumbens (NAc) have been a hallmark of the ST/GT phenotype. However, it is unknown whether differences in the intrinsic neuronal properties of NAc medium spiny neurons (MSNs) in the core and shell subregions are also a physiological correlate of these phenotypes. We performed whole-cell slice electrophysiology in outbred male rats and found that STs exhibited the lowest excitability in the NAc core, with lower number of action potentials and firing frequency as well as a blunted voltage/current relationship curve in response to hyperpolarized potentials in both the NAc core and shell. Although firing properties of shell MSNs did not differ between STs and GTs, intermediate responders that engage in both behaviors showed greater excitability compared with both STs and GTs. These findings suggest that intrinsic excitability in the NAc may contribute to individual differences in the attribution of incentive salience.

RNA localization to neuronal axons and dendrites provides spatiotemporal control over gene expression to support synapse function. Neuronal messenger RNAs (mRNAs) localize as ribonucleoprotein particles (RNPs), commonly known as RNA granules, the composition of which influences when and where proteins are made. High-throughput sequencing has revealed thousands of mRNAs that localize to the hippocampal neuropil. Whether these mRNAs are spatially organized into common RNA granules or distributed as independent mRNAs for proper delivery to synapses is debated. Here, using highly multiplexed single-molecule fluorescence in situ hybridization (HiPlex smFISH) and colocalization analyses, we investigate the subcellular spatial distribution of 15 synaptic neuropil localized mRNAs in the male and female rodent hippocampus. We observed that these mRNAs are present in the neuropil as heterogeneously sized fluorescent puncta with spatial colocalization patterns that generally scale by neuropil mRNA abundance. Indeed, differentially expressed mRNAs across cell types displayed colocalization patterns that scaled by abundance, as did simulations that reproduce cell-specific differences in abundance. Thus, the probability of these mRNAs colocalizing in the neuropil is best explained by stochastic interactions based on abundance, which places constraints on the mechanisms mediating efficient transport to synapses.

Across brain regions and species, the dynamics and balance of excitation and inhibition critically determine neuronal firing. The hippocampal dentate gyrus is a brain area thought to be strongly regulated by inhibition. In vivo, it exhibits remarkably sparse activity, a characteristic proposed to underlie computational tasks like pattern separation. Several populations of interneurons mediate strong feedforward as well as feedback inhibition onto granule cells. However, how the dynamics of inhibition controls granule cell activity in vivo is insufficiently studied. Using two-photon in vivo Ca²⁺ imaging in mice of either sex, we show that sensory stimulation activates only a small number of dentate gyrus granule cells, while inducing widespread inhibition across the remaining granule cell population. Dual-color imaging of both bulk medial perforant path activity and individual granule cell activity allowed us to probe input-output conversion in this pathway. To examine the interplay of MPP-evoked excitation and inhibition at the cellular level, we used in vivo whole-cell patch-clamp recordings, while simultaneously photo-activating MPP inputs. Our findings reveal that MPP-triggered inhibition is fast, significantly larger than excitation, and long-lasting. These results reveal specific properties of inhibition in the dentate gyrus inhibition that are likely crucial for its computational functions, in maintaining sparse activity with a high signal-to-noise ratio.

Mirror-invariance is the cognitive tendency to perceive mirror-image objects as identical. Mirrored letters, however, are distinct orthographic units, and must be identified as different; mirror-invariance must be 'broken' to enable efficient reading. Consistent with this phenomenon, a small, localized region in the ventral visual stream, the Visual Word Form Area (VWFA), exhibits repetition suppression to both identical and mirror pairs of objects but only to identical, not mirror, pairs of letters (Pegado et al., 2011), a phenomenon named mirror 'breaking". The ability of congenitally blind individuals to 'break' mirror invariance for pairs of mirrored Braille letters has been demonstrated behaviorally (de Heering et al., 2018, Korczyk et al., 2024). However, its neural underpinnings have not yet been investigated. Here, in an fMRI repetition suppression paradigm, congenitally blind individuals (8 males and 10 females) recognized pairs of everyday objects and Braille letters in identical ('p' & 'p'), mirror ('p' & 'q'), and different ('p' & 'z') orientations. We found repetition suppression for identical and mirror pairs of everyday objects in the parietal and ventral-lateral occipital cortex, indicating that mirror-invariant object recognition engages the ventral visual stream in tactile modality as well. However, repetition suppression for identical but not mirrored pairs of Braille letters was found not in the VWFA, but in broad areas of the left parietal cortex and the lateral occipital cortex. These results suggest that reading-related orthographic processes in blind individuals depend on different neural computations that those of the sighted.Significance Statement Mirror-invariance is a perceptual bias to recognize mirrored objects as identical. Letters constitute a unique category of object: for example, 'b' and 'd' share identical shape yet must be identified as distinct entities to enable efficient reading. In our study, we investigated the neural underpinnings of tactile mirror-invariance in congenitally blind individuals and whether it was affected by tactile reading acquisition. We showed engagement of the parietal, occipital, and ventral visual regions in mirror-invariant tactile object recognition, indicating that this perceptual bias extends beyond the visual modality. Moreover, we found that unlike in the sighted, it was the parietal and lateral occipital cortex that showed neural signatures of breaking mirror-invariance for Braille letters in congenitally blind individuals, demonstrating, how following congenital visual deprivation, neural computations can be repurposed to meet novel task requirements.

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.