Journal of Neuroscience最新文献

Relief from psychological stress confers cardio-protection by altering brain activity and lowering blood pressure; however, the neuronal circuits orchestrating these effects are unknown. Here, we used male mice to discern neuronal circuits conferring stress relief and reduced blood pressure. We found that neurons residing in the central nucleus of the amygdala (CeA) expressing angiotensin type 2 receptors (AT₂R), deemed CeA^AT2R, innervate brain nuclei regulating stress responding. In vivo optogenetic excitation of CeA^AT2R lowered blood pressure and this effect was abrogated by systemic hexamethonium or antagonism of GABA receptors within the CeA. Intriguingly, in vivo optogenetic excitation of CeA^AT2R was also potently anxiolytic. Delivery of an AT₂R agonist into the CeA recapitulated the hypotensive and anxiolytic effects, but ablating AT₂R(s) from the CeA was anxiogenic. The results suggest that the excitation of CeA^AT2R couples lowered blood pressure with anxiolysis. The implication is that therapeutics targeting CeA^AT2R may provide stress relief and protection against cardiovascular disease.Significance statement There is increasing appreciation that brain-to-body communication promotes susceptibility or resiliency to cardiovascular disease. Here, we present preclinical research that discerns a neural circuit that orchestrates brain-to-body communication and provides relief from mental stress. We discover that neurons within the central nucleus of the amygdala that express angiotensin type 2 receptors (hereafter referred to as CeA^AT2R) are potent mediators of blood pressure and anxiolysis. The implication is that CeA^AT2R or their angiotensin type 2 receptors can be targeted to protect against stress-induced cardiovascular disease.

Reward-predictive cues can affect decision-making by enhancing instrumental responses toward the same (specific transfer) or similar (general transfer) rewards. The main theories on cue-guided decision-making consider specific transfer as driven by the activation of previously learned instrumental actions induced by cues sharing the sensory-specific properties of the reward they are associated with. However, to date, such theoretical assumption has never been directly investigated at the neural level. We hypothesize that such reactivation occurs within the premotor system and could be mapped by lateralized beta (12-30 Hz) desynchronization, a widely used marker of action selection and decision-making policy. To test this hypothesis, 42 participants (22 females) performed a pavlovian-to-instrumental transfer paradigm, while electroencephalographic activity was recorded. We anticipated increased beta desynchronization during the transfer phase when cues promoting specific transfer were presented, compared with cues predicting general transfer and neutral cues. The evidence collected confirmed our hypothesis, thus providing the first neural evidence in favor of the theorized reactivation of instrumental actions and corroborating the presence of two dissociable neural pathways underpinning specific and general transfer.

Cognitive control relies on neural representations that are inherently high-dimensional and distributed across multiple subregions in the prefrontal cortex (PFC). Traditional approaches tackle prefrontal representation by reducing it into a unidimensional measure (univariate amplitude) or using it to distinguish a limited number of alternatives (pattern classification). In contrast, representational similarity analysis (RSA) enables flexibly formulating various hypotheses about informational contents underlying the neural codes, explicitly comparing hypotheses, and examining the representational alignment between brain regions. Here, we used a multifaceted paradigm wherein the difficulty of cognitive control was manipulated separately for five cognitive tasks. We used RSA to unveil representational contents, measure the representational alignment between regions, and quantify representational generality versus specificity. We found a graded transition in the lateral PFC: The dorsocaudal PFC was tuned to task difficulty (indexed by reaction times), preferentially connected with the parietal cortex, and representationally generalizable across domains. The ventrorostral PFC was tuned to the abstract structure of tasks, preferentially connected with the temporal cortex, and representationally specific. The middle PFC (interposed between the dorsocaudal and ventrorostral PFC) was tuned to individual task sets and ranked in the middle in terms of connectivity and generalizability. Furthermore, whether a region was dimensionally rich or sparse covaried with its functional profile: Low dimensionality (only gist) in the dorsocaudal PFC dovetailed with better generality, whereas high dimensionality (gist plus details) in the ventrorostral PFC corresponded with better ability to encode subtleties. Our findings, collectively, demonstrate how cognitive control is decomposed into distinct facets that transition steadily along prefrontal subregions.

Chronic excessive alcohol (ethanol) consumption induces neuroadaptations in the brain's reward system, including biochemical and structural abnormalities in white matter that are implicated in addiction phenotypes. Here, we demonstrate that long-term (12-week) voluntary ethanol consumption enhances myelination in the nucleus accumbens (NAc) of female and male adult mice, as evidenced by molecular, ultrastructural, and cellular alterations. Specifically, transmission electron microscopy analysis showed increased myelin thickness in the NAc following long-term ethanol consumption, while axon diameter remained unaffected. These changes were paralleled by increased mRNA transcript levels of key transcription factors essential for oligodendrocyte differentiation, along with elevated expression of critical myelination-related genes. In addition, diffusion tensor imaging (DTI) revealed increased connectivity between the NAc and the prefrontal cortex (PFC), reflected by a higher number of tracts connecting these regions. We also observed ethanol-induced effects on oligodendrocyte (OL) lineage cells, with a reduction in the number of mature OLs (mOLs) after 3 weeks of ethanol consumption, followed by an increase after 6 weeks. These findings suggest that ethanol alters OL development prior to increasing myelination in the NAc. Finally, chronic administration of the pro-myelination drug clemastine to mice with a history of heavy ethanol consumption further elevated ethanol intake and preference, suggesting that increased myelination may contribute to escalated drinking behavior. Together, these findings suggest that heavy ethanol consumption disrupts OL development, induces enhanced myelination in the NAc, and may drive further ethanol intake, reinforcing addictive behaviors.Significance Statement The myelin sheath is crucial for the development, maintenance, and normal functioning of the brain. Here, we provide evidence for the involvement of myelin alterations in alcohol (ethanol)-drinking behaviors. We show that chronic ethanol intake leads to enhanced myelination in the nucleus accumbens of adult mice. Moreover, we demonstrate that increasing myelination in heavily drinking mice leads to an escalation in ethanol intake. Thus, our results suggest that ethanol affects myelination processes, which, in turn, may affect ethanol-drinking patterns. Understanding the impact of ethanol on myelination could enhance our comprehension of alcohol addiction and open new avenues for treatment.

Navigating space and forming memories based on spatial experience are crucial for survival, including storing memories in an allocentric (map-like) framework and conversion into egocentric (body-centered) action. The hippocampus and parietal cortex (PC) comprise a network for coordinating these reference frames, though the mechanism remains unclear. We used a task requiring remembering previous spatial locations to make correct future action and observed that hippocampus can encode the allocentric place, while PC encodes upcoming actions and relays this to hippocampus. Transformation from location to action unfolds gradually, with 'Came From' signals diminishing and future action representations strengthening. PC sometimes encodes previous spatial locations in a route-based reference frame and conveys this to hippocampus. The signal for the future location appears first in PC, and then in hippocampus, in the form of an egocentric direction of future goal locations, suggesting egocentric encoding recently observed in hippocampus may originate in PC (or another "upstream" structure). Bidirectional signaling suggests a coordinated mechanism for integrating allocentric, route-centered, and egocentric spatial reference frames at the network level during navigation.Significance Statement Our study has broad implications for understanding how the brain coordinates and integrates different spatial reference frames. Our data suggests rats can alternate between multiple neural strategies within the same task. In addition, we find out that similar signals are present in both the hippocampus and the PC but at different times, providing novel insights into the mechanisms underlying spatial navigation and memory. It reveals an intricate system involving an extended brain network that includes the hippocampus, PC, and structures anatomically 'in-between'. The bidirectional signaling suggests this brain network truly operates as a network and not a unidirectional circuit. These findings suggest a focus on brain networks (and not just single regions) is critical for understanding transformations. These processes are fundamental for spatial cognition and related disorders and even for solving problems that may use similar neural machinery, such as building abstract representations from egocentric views, as occurs with object invariance.

Cocaine- and amphetamine-regulated transcript (CART) peptide has been implicated in stress-related behaviors that are regulated by central serotonergic (5-HT) systems in the dorsal raphe nucleus (DRN). Here, we aimed to investigate the interaction between CART and DRN 5-HTergic systems after initially observing CART axonal terminals in the DRN. We found that microinfusion of CART peptide _(55–102) into the DRN-induced anxiogenic effects in male C57BL/6J mice, while central administration of CART reduced c-Fos in 5-HT^DRN neurons. This inhibitory effect of exogenous CART on 5-HT^DRN activity and local 5-HT release was also demonstrated via in vivo fiber photometry coupled with calcium and 5-HT biosensors. CART inputs to the DRN were observed in various subcortical nuclei, but only those in the centrally projecting Edinger–Westphal nucleus (EWcp) were highly responsive to stress. Chemogenetic activation of these DRN-projecting CART^EWcp neurons recapitulated the effects of intra-DRN CART infusion on anxiety-like behavior in males, but not in females, suggesting a sex-specific role for this pathway. Interestingly, CART^EWcp projections to the DRN made direct synaptic contact primarily with non-5-HT neurons, which were also found to express putative CART receptors. Furthermore, chemogenetic stimulation of this CART^EWcp->DRN pathway inhibited 5-HT neurons while increasing activity in local GABAergic neurons. In summary, this study establishes for the first time a neuromodulatory role for CART^EWcp neurons in 5-HT^DRN neurotransmission and suggests that CART may drive anxiety-like behavior by promoting feedforward inhibition of 5-HT neurons.

Dopaminergic brain areas are crucial for cognition and their dysregulation is linked to neuropsychiatric disorders typically treated with pharmacological interventions. These treatments often have side effects and variable effectiveness, underscoring the need for alternatives. We introduce the first demonstration of neurofeedback using local field potentials (LFP) from the ventral tegmental area (VTA). This approach leverages the real-time temporal resolution of LFP and ability to target deep brain. In our study, two male rhesus macaque monkeys (Macaca mulatta) learned to regulate VTA beta power using a customized normalized metric to stably quantify VTA LFP signal modulation. The subjects demonstrated flexible and specific control with different strategies for specific frequency bands, revealing new insights into the plasticity of VTA neurons contributing to oscillatory activity that is functionally relevant to many aspects of cognition. Excitingly, the subjects showed transferable patterns, a key criterion for clinical applications beyond training settings. This work provides a foundation for neurofeedback-based treatments, which may be a promising alternative to conventional approaches and open new avenues for understanding and managing neuropsychiatric disorders.Significance statement This study demonstrates, for the first time, that neurofeedback using local field potentials (LFP) from the ventral tegmental area (VTA) is feasible in non-human primates. By leveraging the temporal resolution and ability to target deep brain regions, this approach provides a novel way to modulate brain activity linked to dopamine-related functions. The findings reveal that subjects can flexibly control VTA LFP signals and transfer learned strategies to new settings, offering potential for developing neurofeedback-based treatments. This research opens new avenues for managing neuropsychiatric disorders, presenting an alternative to traditional pharmacological interventions that often have side effects and limited effectiveness. The study highlights the plasticity of VTA neurons and their relevance to cognition and mood regulation.

The gustatory system allows animals to assess the nutritive value and safety of foods prior to ingestion. The first step in gustation is the interaction of taste stimuli with one or more specific sensory receptors that are generally believed to be present on the apical surface of the taste receptor cells. However, this assertion is rarely tested. We recently identified OTOP1 as a proton channel and showed that it is required for taste response to acids (sour) and ammonium. Here, we examined the cellular and subcellular localization of OTOP1 by tagging the endogenous OTOP1 protein with an N-terminal HA epitope (HA-OTOP1). Using both male and female HA-OTOP1 mice and high-resolution imaging, we show that OTOP1 is strictly localized to the apical tips of taste cells throughout the tongue and oral cavity. Interestingly, immunoreactivity is observed in the actin-rich taste pore above the tight junctions defined by zonula occludens-1 (ZO-1) and also immediately below these junctions. Surprisingly, OTOP1 immunoreactivity is not restricted to Type III taste receptor cells (TRCs) that mediate sour taste but is also observed in glia-like Type I TRCs proposed to perform housekeeping functions, a result that is corroborated by scRNA-seq data. The apical localization of OTOP1 supports the contention that OTOP1 functions as a taste receptor and suggests that OTOP1 may be accessible to orally available compounds that could act as taste modifiers.

Stimulus-driven attention allows us to react to relevant stimuli (and imminent danger!) outside our current focus of attention. But irrelevant stimuli can also disrupt attention; for example, during listening to speech. The degree to which sound captures attention is called salience, which can be estimated by existing, behaviorally validated, computational models (Huang & Elhilali, 2017). Here we examined whether neurophysiological responses to task-irrelevant sounds indicate the degree of distraction during a sustained-listening task and how much this depends on individual hearing thresholds. N = 47 Danish-speaking adults (28/19 female/male; mean age: 60.1, SD: 15.9 years) with heterogenous hearing thresholds (PTA; mean: 25.5, SD: 18.0 dbHL) listened to continuous speech while one-second-long, task-irrelevant natural sounds (distractors) of varying computed salience were presented at unpredictable times and locations. Eye tracking and electroencephalography were used to estimate pupil response and neural tracking, respectively. The task-irrelevant sounds evoked a consistent pupil response (PR), distractor-tracking (DT) and a drop of target-tracking (ΔTT), and statistical modelling of these three measures within subjects showed that all three are enhanced for sounds with higher computed salience. Participants with larger PR showed a stronger drop in target tracking (ΔTT) and performed worse in target speech comprehension. We conclude that distraction can be inferred from neurophysiological responses to task-irrelevant stimuli. These results are a first step towards neurophysiological assessment of attention dynamics during continuous listening, with potential applications in hearing-care diagnostics.Significance statement Successful speech-in-noise comprehension in daily life does not only depend on the acuity of the auditory input, but also cognitive factors like attentional control. Being able to measure distraction-dependent neurophysiological responses to peripheral, task-irrelevant stimuli would enable monitoring the extent to which the attentional focus is instantaneously captured away from a target under sustained attention. Here we show that especially pupil response and neural tracking of distractor sounds reflect the degree to which people with both normal and elevated hearing thresholds are distracted. Such a measure could be used to non-invasively track the focus of attention and thus could find application in hearing care diagnostics, where cognitive factors like attentional control are being increasingly recognized as important.