eNeuro最新文献

Recent findings have shifted the view of cholecystokinin (CCK) from being a cellular neuronal marker to being recognized as a crucial neuropeptide pivotal in synaptic plasticity and memory processes. Despite its now appreciated importance in various brain regions and abundance in the basal ganglia, its role in the striatum, which is vital for motor control, remains unclear. This study sought to fill this gap by performing a comprehensive investigation of the role of CCK in modulating striatal medium spiny neurons (MSN) membrane properties, as well as the secondary somatosensory cortex S2 to MSN synaptic transmission and plasticity in rodents. Using in-vivo optopatch-clamp recording in mice on identified medium spiny neurons (MSNs), we showed that the application of CCK receptor type 2 (CCK2R) antagonists decreases corticostriatal transmission in both direct and indirect pathway MSNs. Moving to an ex vivo rat preparation to maximize experimental access, we showed that CCK2R inhibition impacts MSN membrane properties by reducing spike threshold and rheobase, suggesting an excitability increase. Moreover, CCK modulates corticostriatal transmission mainly via CCK2R, and CCK2R blockage shifted spike-timing-dependent plasticity (STDP) from long-term potentiation to long-term depression. Our study advances the understanding of CCK's importance in modulating corticostriatal transmission. By showing how CCK2R blockade influences synaptic function and plasticity, we provide new insights into the mechanisms underlying striatal functions, opening new paths for exploring its potential relevance to neurological disorders involving basal ganglia related behaviors.Significance Statement Cholecystokinin (CCK) plays a critical role in synaptic plasticity and memory but completely unexplored in corticostriatal synapses and motor control. This study shows that blocking the CCK2 receptor (CCK2R) reduces postsynaptic potentials (EPSPs) and excitatory postsynaptic currents (EPSCs) in the motor striatum (in vivo and ex vivo) and disrupts corticostriatal spike-timing-dependent plasticity (STDP), shifting it from long-term potentiation (LTP) to long-term depression (LTD). These findings reveal CCK signaling as a key modulator of corticostriatal communication, capable of reversing the direction of synaptic plasticity. The results position CCK as a crucial regulator of synaptic and motor functions, with implications for understanding corticostriatal mechanisms.

The amygdala is believed to make invaluable contributions to visual emotion processing. Yet how this subcortical body contributes to emotion perception across time is contended. Here, we measured differences in the perceptual processing of emotional stimuli after unilateral temporal lobe and amygdala resection (TLR) in humans, using EEG. Through mass univariate analysis of brain activity, we compared responses to fearful and neutral faces (left TLR N = 8, right TLR N = 8, control N = 8), and fearful and neutral bodies (left TLR N = 9, right TLR N = 9, control N = 9). We found that TLR impaired the early-stage perceptual processing of emotional stimuli seen in the control group. Indeed, in controls a heightened responses to fearful faces was found in the 140-170 ms time window, over temporoparietal electrodes. This effect was also present in the left TLR group but disappeared in the right TLR group. For emotional bodies, brain activity was differentially sensitive to fearful stimuli at 90-120 ms in the control group, but this effect was eliminated in both TLR groups. Collectively, these results reveal the amygdala contributes to the early stages of perceptual processing that discriminate emotional stimuli from neutral stimuli. Further, they emphasize the unique role of the right medial temporal structures such as the amygdala in emotional face perception.

The behavioral interactions between adults and newborns are decisive for the fitness and the survival of offspring across the animal kingdom. In laboratory mice, while virgin females display caregiving behaviors, virgin males are rather neglectful or aggressive toward pups. Despite the importance of these behavioral variations, the underlying neural mechanisms remain poorly understood. Brain regions encoding these behaviors may exhibit sex-dependent functional differences at the baseline. Additionally, these structures might undergo sex-specific plasticity after adults interact with the offspring. Emerging evidence suggests sex-based differences in input connectivity, genetics, and receptor expression of the epithalamic lateral habenula (LHb). Moreover, LHb neuronal activity is instrumental for adult-newborn interactions. However, whether LHb neuronal function varies between sexes and/or undergoes adaptations following interactions with pups has not been fully investigated. In this study, we used in vivo and ex vivo single-cell electrophysiology to examine the basal LHb neuronal activity of virgin female and male mice. In a second set of experiments, we exposed mice to pups and recapitulated sex-based divergent behaviors. Recordings in acute slices showed no alterations in LHb firing properties, regardless of sex or pup exposure. These findings suggest that, although the LHb participates in adult behaviors toward pups, this is not mediated by sex-dependent functional differences or adaptations in the neuronal firing properties. Thus, this study provides new insights into the neural basis of sex-specific adult-newborn behaviors and the role of the LHb in these processes.

Axons in the mammalian brain show significant diversity in myelination motifs, displaying spatial heterogeneity in sheathing along individual axons and across brain regions. However, its impact on neural signaling and susceptibility to injury remains poorly understood. To address this, we leveraged cable theory and developed model axons replicating the myelin sheath distributions observed experimentally in different regions of the mouse central nervous system. We examined how the spatial arrangement of myelin affects propagation and predisposition to conduction failure in axons with cortical versus callosal myelination motifs. Our results indicate that regional differences in myelination significantly influence conduction timing and signaling reliability. Sensitivity of action potential propagation to the specific positioning, lengths, and ordering of myelinated and exposed segments reveals non-linear and path-dependent conduction. Furthermore, myelination motifs impact signaling vulnerability to demyelination, with callosal motifs being particularly sensitive to myelin changes. These findings highlight the crucial role of myelinating glia in brain function and disease.

The striatum is the primary input nucleus of the basal ganglia, integrating a dense plexus of inputs from the cerebral cortex and thalamus to regulate action selection and learning. Neuroanatomical mapping of the striatum and its sub compartments has been carried out extensively in rats and mice, non-human primates, and cats allowing comparative neuroanatomy studies to derive heuristics about striatal composition and function. Here, we systematically map corticostriatal topography from motor, somatosensory, auditory, and visual cortices as well as thalamostriatal parafascicular (PfN) inputs in the Mongolian Gerbil. We also map a pathway reported in mice from medial vestibular nucleus to the PfN that could convey vestibular information to the striatum. Our findings align with those of similar studies in other rodents, indicating homologous neuroanatomical connectivity patterns within the corticostriatal projectome across rodentia. We observed corticostriatal peaks of dense labeling for each input with a diffuse projection throughout striatal subregions from each cortical region, suggesting a global integration of all cortical information by the striatum. Thalamostriatal projections from PfN covered most of the striatum with a peak of PfN specific compartmentalized labeling similar to other sensory and motor systems. We also confirm the connection from the medial vestibular nucleus to PfN thalamus, indicating that vestibular information may be widely integrated throughout the striatum. The findings build upon our body of knowledge on striatal connectivity across mammalian species and provide a foundation for striatal research focusing on vestibulothalamostriatal circuits in rodentia.Significance statement In this study, systematic mapping of the projections to striatum from motor, somatosensory, auditory, and visual cortices in Mongolian gerbil reveal commonalities with rodents. Principally, while some areas receive compartmentalized innervation from specific modalities, there also exists a global interspersed plexus of integrating inputs from each cortical area to each striatal subregion. Additionally, we also demonstrate a clear thalamostriatal innervation from parafascicular thalamus (PfN), that is homologous to other rodents and primates. Finally, we confirm a pathway from the medial vestibular nucleus to PfN thalamus that could broadly convey vestibular information across the striatum. Our results reveal common principles in neuroanatomical connectivity across another mammalian species and provide an anatomical map to guide future vestibular striatal studies in gerbils and other animal models.

In models of visual spatial attention control, it is commonly held that top-down control signals originate in the dorsal attention network, propagating to the visual cortex to modulate baseline neural activity and bias sensory processing. However, the precise distribution of these top-down influences across different levels of the visual hierarchy is debated. In addition, it is unclear whether these changes in baseline neural activity directly translate into improved performance. We analyzed attention-related baseline activity during the anticipatory period of a trial-by-trial voluntary spatial attention task, using two independent fMRI datasets, and two different analytic approaches. First, as in prior studies, univariate analysis showed that covert attention significantly enhanced baseline neural activity in higher-order visual areas contralateral to the attended visual hemifield, while effects in lower-order visual areas (e.g., V1) were weaker and more variable. Second, in contrast, multivariate pattern analysis (MVPA) revealed significant decoding of attention conditions across all visual cortical areas, with lower-order visual areas exhibiting higher decoding accuracies than higher-order areas. Third, decoding accuracy, rather than the magnitude of univariate activation, was a better predictor of a subject's stimulus discrimination performance. Finally, the MVPA results were replicated across two experimental conditions, where the direction of spatial attention was either externally instructed by a cue or based on the participants free choice decision about where to attend. Together, these findings offer new insights into the extent of attentional biases in the visual hierarchy under top-down control, and how these biases influence both sensory processing and behavioral performance.Significance Statement Attention can be deployed in advance of stimulus processing. Understanding how top-down control of attention facilitates the processing of the attended stimuli and enhances task performance has remained a longstanding question in attention research. Here, applying multivariate pattern analysis (MVPA) to fMRI data, we showed that throughout the entire visual hierarchy including the primary visual cortex, there exist distinct neural representations for different attended information in anticipatory visual spatial attention, and the distinctiveness of these neural representations is positively associated with behavioral performance. Importantly, the MVPA findings were consistent across two experimental conditions where the direction of spatial attention was driven either by external instructions or from purely internal decisions.

Humans and non-humans alike often make choices to gain information, even when the information cannot be used to change the outcome. Prior research has shown the anterior cingulate cortex (ACC) is important for evaluating options involving reward-predictive information. Here we studied the role of ACC in information choices using optical inhibition to evaluate the contribution of this region during specific epochs of decision making. Rats could choose between an uninformative option followed by a cue that predicted reward 50% of the time vs. a fully informative option that signaled outcomes with certainty, but was rewarded only 20% of the time. Reward seeking during the informative S+ cue decreased following ACC inhibition, indicating a causal contribution of this region in supporting reward expectation to a cue signaling reward with certainty. Separately in a positive control experiment and in support of a known role for this region in sustaining high-effort behavior for preferred rewards, we observed reduced lever presses and lower breakpoints in effort choices following ACC inhibition. The lack of changes in reward latencies in both types of decisions indicate the motivational value of rewards remained intact, revealing instead a common role for ACC in maintaining persistence toward certain and valuable rewards.Significance Statement We often make choices to gain information, even when the information cannot be used to change the outcome. Here we investigated the precise timing of the role of the anterior cingulate cortex (ACC) in decisions that involve seeking certain versus uncertain rewards. By optically inhibiting ACC neurons, we demonstrate that this region is crucial for maintaining persistence toward rewards signaled with certainty, without altering the motivational value of the reward itself. In a positive control experiment, we also confirm that ACC is important in effort-based choice. The findings reveal a common role for ACC in maintaining persistence toward certain and valuable rewards, necessary for making optimal decisions. These results have implications for understanding psychiatric disorders involving maladaptive reward-seeking behavior.

Facial paralysis is characterized by an injury to the facial nerve, causing the loss of the functions of the structures that it innervates, as well as changes in the motor cortex. Current models have some limitations for the study of facial paralysis, such as movement restriction, the absence of studying awake animals in behavioral contexts, and the lack of a model that fully evaluates facial movements. The development of an algorithm capable of automatically inferring facial paralysis and overcoming the existing limitations is proposed in this work. In C57/BL6J mice, we produced both irreversible and reversible facial paralysis. Video recordings were made of the faces of paralyzed mice to develop the algorithm for detecting facial paralysis applied to mice, which allows us to predict the presence of reversible and irreversible facial paralysis automatically. At the same time, the algorithm was used to track facial movement during gustatory stimulation, and extracellular electrophysiological recordings in the anterolateral motor cortex. In the basal state, mice can make facial expressions, whereas the algorithm can detect this movement. Simultaneously, such movement is correlated with the activation in the anterolateral motor cortex. In the presence of facial paralysis, the algorithm cannot detect movement. Furthermore, it predicts that the condition exists, and the neuronal activity in the cortex is affected with respect to the evolution of facial paralysis. This way, we conclude that the facial paralysis algorithm applied to mice allows for inferring the presence of experimental facial paralysis and its neuronal correlates for further studies.Significance Statement Recording the faces of mice can help predict facial paralysis unbiasedly and identify the presence of a reduction in facial movement associated with injury to the facial nerve. It can also be used to study facial movements, like facial expressions, and their neural correlates in cortical and subcortical strata. This will not only allow a deep understanding of the magnitude of the effects that facial paralysis can produce at the peripheral and central nervous system levels but also inspire further research and the search for potential treatments.

Self-administration of addictive substances like heroin can couple the rewarding/euphoric effects of the drug with drug-associated cues, and opioid cue reactivity contributes to relapse vulnerability in abstinent individuals recovering from an opioid use disorder (OUD). Opioids are reported to alter the intrinsic excitability of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a key brain reward region linked to drug seeking, but how opioids alter NAc MSN neuronal excitability and the impact of altered MSN excitability on relapse-like opioid seeking remain unclear. Here we discovered that self-administered, but not experimenter-administered, heroin reduced NAc protein levels of the voltage-gated sodium channel auxiliary subunit, SCN1b in male and female rats. Viral-mediated reduction of NAc SCN1b increased the intrinsic excitability of MSNs, but without altering glutamatergic and GABAergic synaptic transmission. While reducing NAc SCN1b levels had no effect on acquisition of heroin self-administration or extinction learning, we observed a significant increase in cue-reinstated heroin seeking, suggesting that NAc SCN1b normally limits cue-reinstated heroin seeking. We also observed that NAc SCN1b protein levels returned to baseline following heroin self-administration, home-cage abstinence, and extinction training, suggesting that the noted reduction of NAc SCN1b during acquisition of heroin self-administration likely enhances MSN excitability and the strength of heroin-cue associations formed during active heroin use. As such, enhancing NAc SCN1b function might mitigate opioid cue reactivity and a return to active drug use in individuals suffering from OUD.Significance Statement Opioid use disorder (OUD) is a chronic, relapsing disease characterized by excessive craving. Here we found that repeated heroin self-administration reduced the expression of the sodium channel subunit, SCN1b, in the nucleus accumbens, a brain area important for reward signaling and addiction. We show here that reducing SCN1b increased excitability of NAc neurons and increased relapse-like drug seeking in a rodent model of opioid craving. The discovery of this novel mechanism of opioid action in the brain could help lead to future treatments for patients that suffer from OUD.

Neuroinflammation has been widely recognized as the primary pathophysiological mechanism underlying ischemic white matter lesions (IWML) in chronic cerebral hypoperfusion (CCH), with microglia serving as the principal effector cells. A2aR, an important adenosine receptor, exhibits a dual role in neuroinflammation by modulating both pro-inflammatory and anti-inflammatory responses, particularly through its regulation of microglial polarization. This study aimed to investigate the specific functions and mechanisms of A2aR in neuroinflammation. The findings revealed that A2aR initially exerted a pro-inflammatory role in the CCH model, transitioning to an anti-inflammatory role in later stages by regulating the phenotypic transformation of microglia. Further analyses using CoIP-MS, in situ proximity ligation assay, Alphafold protein structure prediction, [³⁵S]GTPγS Binding Assay and Nano-Bit technology demonstrated that A2aR formed heteromers with mGluR5 during the early stage of CCH under high glutamate conditions, promoting the polarization of microglia towards a pro-inflammatory phenotype. In contrast, during later stages characterized by low glutamate levels, A2aR predominantly existed as a monomer, facilitating microglial polarization towards an anti-inflammatory phenotype. Our findings indicate that elevated glutamate levels drive the formation of A2aR-mGluR5 heteromers, contributing to neuroinflammation by promoting pro-inflammatory microglial polarization in CCH white matter. Conversely, under low glutamate conditions, A2aR primarily functions in its monomeric form, favoring an anti-inflammatory microglial phenotype and exerting a protective effect. This study elucidates the mechanism by which A2aR mediates microglial phenotypic transformation and participates in neuroinflammation under CCH. It also identifies A2aR as a potential therapeutic target for the treatment of IWML.Significance Statement Neuroinflammation of white matter is widely recognized as the primary pathophysiological mechanism associated with vascular dementia (VaD) in middle-aged and elderly individuals.A2aR, a crucial adenosine receptor, exhibits a dual role in neuroinflammation by modulating both proinflammatory and anti-inflammatory responses, particularly in relation to microglia polarization. The objective of this study is to investigate the specific functions and mechanisms of A2aR in neuroinflammation. The results indicate that elevated glutamate levels facilitate the formation of A2aR-mGluR5 heteromers, thereby promoting the polarization of microglia towards a pro-inflammatory phenotype, which contributes to neuroinflammation in CCH white matter. Conversely, under conditions of low glutamate, A2aR predominantly exists in monomeric form, which favors the polarization of microglia towards an anti-inflammatory phenotype, thereby exerting a protective effect.