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Results from item-method directed forgetting suggest that individuals are able to intentionally forget processed information. Most research suggests that either selective rehearsal of to-be-remembered or inhibitory control of to-be-forgotten information is accountable for the effects of intentional forgetting. Some research, however, hypothesized that the time to process information mediates the underlying mechanism. To test this hypothesis, the current study investigated associations between oscillatory power in theta (3–7.5 Hz) and alpha frequencies (8–13 Hz) and intentional forgetting in human participants and explored whether or not these mechanisms depended on processing time. Previously, theta power was shown to be associated with the creation of episodic memory traces and alpha power with inhibition. We therefore expected to find associations between these neural signatures and behavioral effects. Consistent with our hypotheses, we revealed increased theta power for to-be-remembered and increased alpha power for to-be-forgotten information and that the effects of activity in both frequency bands were influenced by the time individuals were given for processing the memory cue. These results suggest that not one but two mechanisms, rehearsal and inhibitory control, are accountable for item-method directed forgetting, both with different temporal profiles., Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).

Human observers automatically extract temporal contingencies from the environment and predict the onset of future events. Temporal predictions are modelled by the hazard function, which describes the instantaneous probability for an event to occur given it has not occurred yet. Here, we tackle the question of whether and how the human brain tracks continuous temporal hazard on a moment-to-moment basis, and how flexibly it adjusts to strictly implicit variations in the hazard function. We applied an encoding-model approach to human electroencephalographic (EEG) data recorded during a pitch-discrimination task, in which we implicitly manipulated temporal predictability of the target tones by varying the interval between cue and target tone (the foreperiod). Critically, temporal predictability was either solely driven by the passage of time (resulting in a monotonic hazard function), or was modulated to increase at intermediate foreperiods (resulting in a modulated hazard function with a peak at the intermediate foreperiod). Forward encoding models trained to predict the recorded EEG signal from different temporal hazard functions were able to distinguish between experimental conditions, showing that implicit variations of temporal hazard bear tractable signatures in the human electroencephalogram. Notably, this tracking signal was reconstructed best from the supplementary motor area (SMA), underlining this area’s link to cognitive processing of time. Our results underline the relevance of temporal hazard to cognitive processing, and show that the predictive accuracy of the encoding-model approach can be utilised to track abstract time-resolved stimuli.Significance StatementExtracting temporal predictions from sensory input allows to process future input more efficiently and to prepare responses in time. In mathematical terms, temporal predictions can be described by the hazard function, modelling the probability of an event to occur over time. Here, we show that the human EEG tracks temporal hazard in an implicit foreperiod paradigm. Forward encoding models trained to predict the recorded EEG signal from different temporal-hazard functions were able to distinguish between experimental conditions that differed in their build-up of hazard over time. These neural signatures of tracking temporal hazard converge with the extant literature on temporal processing and provide new evidence that the supplementary motor area tracks hazard under strictly implicit timing conditions.

Research on social perception in monkeys may benefit from standardized, controllable, and ethologically valid renditions of conspecifics offered by monkey avatars. However, previous work has cautioned that monkeys, like humans, show an adverse reaction toward realistic synthetic stimuli, known as the “uncanny valley” effect. We developed an improved naturalistic rhesus monkey face avatar capable of producing facial expressions (fear grin, lip smack and threat), animated by motion capture data of real monkeys. For validation, we additionally created decreasingly naturalistic avatar variants. Eight rhesus macaques were tested on the various videos and avoided looking at less naturalistic avatar variants, but not at the most naturalistic or the most unnaturalistic avatar, indicating an uncanny valley effect for the less naturalistic avatar versions. The avoidance was deepened by motion and accompanied by physiological arousal. Only the most naturalistic avatar evoked facial expressions comparable to those toward the real monkey videos. Hence, our findings demonstrate that the uncanny valley reaction in monkeys can be overcome by a highly naturalistic avatar.

Local brain signal variability [SD of the BOLD signal (SDBOLD]] correlates with age and cognitive performance, and recently differentiated Alzheimer’s disease (AD) patients from healthy controls. However, it is unknown whether changes to SDBOLD precede diagnosis of AD or mild cognitive impairment. We compared ostensibly healthy older adult humans who scored below the recommended threshold on the Montreal cognitive assessment (MoCA) and who showed reduced medial temporal lobe (MTL) volume in a previous study (“at-risk” group, n = 20), with healthy older adults who scored within the normal range on the MoCA (“control” group, n = 20). Using multivariate partial least-squares analysis we assessed the correlations between SDBOLD and age, MoCA score, global fractional anisotropy, global mean diffusivity, and four cognitive factors. Greater SDBOLD in the MTL and occipital cortex positively correlated with performance on cognitive control/speed tasks but negatively correlated with memory scores in the control group. These relations were weaker in the at-risk group. A post hoc analysis assessed associations between MTL volumes and SDBOLD in both groups. This revealed a negative correlation, most robust in the at-risk group, between MTL SDBOLD and MTL subregion volumetry, particularly the entorhinal and parahippocampal regions. Together, these results suggest that the association between SDBOLD and cognition differs between the at-risk and control groups, which may be because of lower MTL volumes in the at-risk group. Our data indicate relations between MTL SDBOLD and cognition may be helpful in understanding brain differences in individuals who may be at risk for further cognitive decline.

Larval zebrafish possess a number of molecular and genetic advantages for rigorous biological analyses of learning and memory. These advantages have motivated the search for novel forms of memory in these animals that can be exploited for understanding the cellular and molecular bases of vertebrate memory formation and consolidation. Here, we report a new form of behavioral sensitization in zebrafish larvae that is elicited by an aversive chemical stimulus [allyl isothiocyanate (AITC)] and that persists for ≥30 min. This form of sensitization is expressed as enhanced locomotion and thigmotaxis, as well as elevated heart rate. To characterize the neural basis of this nonassociative memory, we used transgenic zebrafish expressing the fluorescent calcium indicator GCaMP6 (Chen et al., 2013); because of the transparency of larval zebrafish, we could optically monitor neural activity in the brain of intact transgenic zebrafish before and after the induction of sensitization. We found a distinct brain area, previously linked to locomotion, that exhibited persistently enhanced neural activity following washout of AITC; this enhanced neural activity correlated with the behavioral sensitization. These results establish a novel form of memory in larval zebrafish and begin to unravel the neural basis of this memory.

One of the very first observations made regarding α oscillations (8–14 Hz), is that they increase in power over posterior areas when awake participants close their eyes. Recent work, especially in the context of (spatial) attention, suggests that α activity reflects a mechanism of functional inhibition. However, it remains unclear how eye closure impacts anticipatory α modulation observed in attention paradigms, and how this affects subsequent behavioral performance. Here, we recorded magnetoencephalography (MEG) in 33 human participants performing a tactile discrimination task with their eyes open versus closed. We replicated the hallmarks of previous somatosensory spatial attention studies: α lateralization across the somatosensory cortices as well as α increase over posterior (visual) regions. Furthermore, we found that eye closure leads to (1) reduced task performance; (2) widespread increase in α power; and (3) reduced anticipatory visual α modulation (4) with no effect on somatosensory α lateralization. Regardless of whether participants had their eyes open or closed, increased visual α power and somatosensory α lateralization improved their performance. Thus, we provide evidence that eye closure does not alter the impact of anticipatory α modulations on behavioral performance. We propose there is an optimal visual α level for somatosensory task performance, which can be achieved through a combination of eye closure and top-down anticipatory attention.

Shifts in spatial patterns produced during the execution of a navigational task can be used to track the effects of the accumulation of knowledge and the acquisition of structured information about the environment. Here we provide a quantitative analysis of mice behavior while performing a novel goal localization task in a large, modular arena, the HexMaze. To demonstrate the effects of different forms of previous knowledge we first obtain a precise statistical characterization of animals’ paths with sub-trial resolution and over different phases of learning. The emergence of a flexible representation of the task is accompanied by a progressive improvement of performance, mediated by multiple, multiplexed time scales. We then use a generative mathematical model of the animal behavior to isolate the specific contributions to the final navigational strategy. We find that animal behavior can be accurately reproduced by the combined effect of a goal-oriented component, becoming stronger with the progression of learning, and of a random walk component, producing choices unrelated to the task and only partially weakened in time. Significance Statement This work presents a novel statistical analysis we applied to describe mice behavior during a goal-reaching task in a large, modular environment (HexMaze). By combining sub-trial quantification of animal navigation with mathematical modeling of the task, we aim at developing analysis tools that can match the demands of rich, articulated experimental paradigms. We show how mice progressively incorporate information about the task and the maze structure and how such knowledge accumulation unfolds over multiple time scales. We also demonstrate how mice never completely converge to optimal behavior: even in late phases of learning a substantial part of their behavior can be ascribed to purely random choices with no relationship with the location of the goal.

Visual Abstract, The cochaperone FKBP51, encoded by the Fkbp5 gene, has been identified as central risk factor for anxiety-related disorders and stress system dysregulation. In the brain, the oval bed nucleus of the stria terminalis (ovBNST) has been implicated in stress-induced anxiety. However, the role of Fkbp5 in the ovBNST and its impact on anxiety-like behavior have remained unknown. Here, we show in mice that Fkbp5 in the ovBNST is reactive to acute stress and coexpressed with the stress-regulated neuropeptides Tac2 and Crh. Subsequently, results obtained from viral-mediated manipulation indicate that Fkbp5 overexpression (OE) in the ovBNST results in an anxiolytic-like tendency regarding behavior and endocrinology, whereas a Fkbp5 knock-out (KO) exposed a clear anxiogenic phenotype, indicating that native ovBNST expression and regulation is necessary for normal anxiety-related behavior. Notably, our data suggests that a stress-induced increase of Fkbp5 in the ovBNST may in fact have a protective role, leading to a transient decrease in anxiety and suppression of a future stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation. Together, our findings provide a first insight into the previously unknown relationship and effects of Fkbp5 and the ovBNST on anxiety-like behavior and HPA axis functioning.

With the advent of tools for recording and manipulating activity with high spatiotemporal resolution in defined neural circuits in behaving animals, behavioral neuroscience is now tasked with establishing field-wide standards for implementing and interpreting these powerful approaches. Theoretical frameworks for what constitute proof of fundamental neurobiological principles is an ongoing and frequently debated topic. On the other hand, standardizing interpretation of individual experimental findings to avoid spurious conclusions in practice has received less attention. Even within subfields, similar assays are often used to support widely disparate conclusions which in part has contributed to a slew of studies claiming highly specified functions for cell types and circuits which are often in direct disagreement with one another. In this opinion piece, we discuss common pitfalls in design and interpretation of approaches for recording or manipulating neural activity in animal models of motivated behavior. We emphasize the importance of integrating findings across multiple behavioral assays concomitant with tempered inference regarding specialized neuronal functions as a standardized starting point for parsing circuit control of behavior. Our aim is to stimulate an open and accessible discourse in the literature to address issues of continuity across behavioral neurosciences.

The hippocampus and amygdala are functionally coupled brain regions that play a crucial role in processes involving memory and learning. Because inter-areal communication has been reported both during specific sleep stages and in awake, behaving animals, these brain regions can serve as an archetype to establish that measuring functional interactions is important for comprehending neural systems. To this end, we analyze here a public data set of local field potentials (LFPs) recorded in rats simultaneously from the hippocampus and amygdala during different behaviors. Employing a specific, time-lagged embedding technique, named topological causality, we infer directed interactions between the LFP band powers of the two regions across six frequency bands in a time-resolved manner. The combined power and interaction signals are processed with our own unsupervised tools developed originally for the analysis of molecular dynamics simulations to effectively visualize and identify putative, internal states that are visited by the animals repeatedly. Our proposed methodology minimizes impositions onto the data, such as isolating specific epochs, or averaging across externally annotated behavioral stages, and succeeds in separating internal states by external labels such as sleep or stimulus events. We show that this works better for 2 of the 3 rats we analyzed, and highlight the need to acknowledge individuality in analyses of this type. Importantly, we demonstrate that the quantification of functional interactions is a significant factor in discriminating these external labels, and we suggest our methodology as a general tool for large, multi-site recordings. Significance statement We develop an analysis pipeline for neuroscience data sets. We test it on a published example of multi-electrode recordings of rats in a range of behaviors: running on a track, sleeping, collecting rewards, etc. We adopt nonlinear analysis techniques that are able to quantify directed interactions between different signals, here oscillations of two brain regions in different frequency bands. Using the entire recordings and, importantly, distinguishing each animal, we provide a high-resolution overview of the functional interplay of the two regions. Putative neural states that the animals can be in are derived from a time-aware clustering of the large data sets. When discriminating experimental annotations like run speed, we provide evidence that our methodology outperforms common clustering techniques.

Our lives revolve around sharing emotional stories (i.e., happy and sad stories) with other people. Such emotional communication enhances the similarity of story comprehension and neural across speaker-listener pairs. The Social Information Model (EASI) suggests that such emotional communication may influence interpersonal closeness. However, few studies have examined speaker-listener interpersonal brain synchronization during emotional communication and whether it is associated with meaningful aspects of the speaker-listener interpersonal relationship. Here, one speaker watched emotional videos and communicated the content of the videos to thirty-two people as listeners (happy/sad/neutral group). Both speaker and listeners’ neural activities were recorded using EEG. After listening, we assessed the interpersonal closeness between the speaker and listeners. Compared to the sad group, sharing happy stories showed a better recall quality and a higher rating of interpersonal closeness. The happy group showed higher IBS in the frontal cortex and left temporoparietal cortex than the sad group. The relationship between frontal IBS and interpersonal closeness was moderated by sharing happy/sad stories. Exploratory analysis using support vector regression showed that the IBS could also predict the ratings of interpersonal closeness. These results suggest that frontal IBS could serve as an indicator of whether sharing emotional stories facilitate interpersonal closeness. These findings improve our understanding of emotional communication among individuals that guides behaviors during interpersonal interactions. Significance Statement Despite extensive research on interpersonal communication, little is known about emotional communication (happy/sad) between speaker and listener and whether these two types of emotional communication involve differential neurocognitive mechanisms from a brain-to-brain perspective. We address these questions from the perspective of the brain-to-brain approach and suggest that these two types of emotional communication are associated with differential interpersonal brain synchronization, in particular, subserved by the prefrontal region. Our findings shed light on the effect of sharing emotional (happy/sad) stories on interpersonal closeness and suggest that frontal IBS could serve as an indicator of whether sharing emotional (happy/sad) stories facilitate interpersonal closeness.

Water restriction is commonly used to motivate rodents to perform behavioral tasks; however, its effects on hydration and stress hormone levels are unknown. Here, we report daily body weight and bi-weekly packed red blood cell volume and corticosterone (CORT) in adult male rats across 80 days for three commonly used water restriction schedules. We also assessed renal adaptation to water restriction using postmortem histologic evaluation of renal medulla. A control group received ad libitum water. After one week of water restriction, rats on all restriction schedules resumed similar levels of growth relative to the control group. Normal hydration was observed, and water restriction did not drive renal adaptation. An intermittent restriction schedule was associated with an increase in CORT relative to the control group. However, intermittent restriction evokes a stress response which could affect behavioral and neurobiological results. Our results also suggest that stable motivation in behavioral tasks may only be achieved after one week of restriction.

Children born very preterm (p < 0.001), which was mainly driven by negative affectivity scores (β = −0.281;p = 0.001). Results further showed an association between higher full-scale IQ and better social functioning (β = −0.334,p < 0.001). Girls had higher empathy scores than boys (β = −0.341,p = 0.006). These findings suggest that early alterations of diffusion characteristics of the UF could represent a biological substrate underlying the link between very preterm birth and emotional dysregulation in childhood and beyond.

Forming long-term memories is crucial for adaptive behavior and survival in changing environments. The molecular consolidation processes which underlie the formation of these long-term memories are dependent on protein synthesis in excitatory and SST-expressing neurons. A centrally important, parallel process to this involves the removal of the memory constraint quinone reductase 2 (QR2), which has been recently shown to enhance memory consolidation for novel experiences in the cortex and hippocampus, via redox modulation. However, it is unknown within which cell type in the cortex removal of QR2 occurs, nor how this affects neuronal function. Here, we use novel taste learning in the mouse anterior insular cortex (aIC) to show that similarly to mRNA translation, QR2 removal occurs in excitatory and SST-expressing neurons. Interestingly, both novel taste and QR2 inhibition reduce excitability specifically within SST, but not excitatory neurons. Furthermore, reducing QR2 expression in SST, but not in PV or excitatory neurons, is sufficient to enhance taste memory. Thus, QR2 mediated intrinsic property changes of SST interneurons in the aIC is a central removable factor to allow novel taste memory formation. This previously unknown involvement of QR2 and SST interneurons in resetting aIC activity hours following learning, describes a molecular mechanism to define cell circuits for novel information. Therefore, the QR2 pathway in SST interneurons provides a fresh new avenue by which to tackle age-related cognitive deficits, while shedding new light onto the functional machinations of long-term memory formation for novel information.

Recent work has combined cognitive neuroscience and control theory to make predictions about cognitive control functions. Here, we test a link between whole-brain theories of semantics and the role of the left inferior frontal gyrus (LIFG) in controlled language performance using network control theory (NCT), a branch of systems engineering. Specifically, we examined whether two properties of node controllability, boundary and modal controllability, were linked to semantic selection and retrieval on sentence completion and verb generation tasks. We tested whether the controllability of the left IFG moderated language selection and retrieval costs and the effects of continuous θ burst stimulation (cTBS), an inhibitory form of transcranial magnetic stimulation (TMS) on behavior in 41 human subjects (25 active, 16 sham). We predicted that boundary controllability, a measure of the theoretical ability of a node to integrate and segregate brain networks, would be linked to word selection in the contextually-rich sentence completion task. In contrast, we expected that modal controllability, a measure of the theoretical ability of a node to drive the brain into specifically hard-to-reach states, would be linked to retrieval on the low-context verb generation task. Boundary controllability was linked to selection and to the ability of TMS to reduce response latencies on the sentence completion task. In contrast, modal controllability was not linked to performance on the tasks or TMS effects. Overall, our results suggest a link between the network integrating role of the LIFG and selection and the overall semantic demands of sentence completion.

Visual Abstract, Team flow occurs when a group functions in a high task engagement to achieve a goal, commonly seen in performance and sports. Team flow can enable enhanced positive experiences, as compared with individual flow or regular socializing. However, the neural basis for this enhanced behavioral state remains unclear. Here, we identified neural correlates (NCs) of team flow in human participants using a music rhythm task with electroencephalogram hyperscanning. Experimental manipulations held the motor task constant while disrupting the corresponding hedonic music to interfere with the flow state or occluding the partner’s positive feedback to impede team interaction. We validated these manipulations by using psychometric ratings and an objective measure for the depth of flow experience, which uses the auditory-evoked potential (AEP) of a task-irrelevant stimulus. Spectral power analysis at both the scalp sensors and anatomic source levels revealed higher β-γ power specific to team flow in the left middle temporal cortex (L-MTC). Causal interaction analysis revealed that the L-MTC is downstream in information processing and receives information from areas encoding the flow or social states. The L-MTC significantly contributes to integrating information. Moreover, we found that team flow enhances global interbrain integrated information (II) and neural synchrony. We conclude that the NCs of team flow induce a distinct brain state. Our results suggest a neurocognitive mechanism to create this unique experience.

During postdiction, the last stimulus of a sequence changes the perception of the preceding ones: in the rabbit illusion, a three-flash series presented regularly in time, but not in space, is – illusory - perceived as spatially regular. Such a reorganization of (spatial) perception could be driven by internal priors, e.g. favoring slow motion for the rabbit illusion. Although postdiction is a ubiquitous phenomenon, its neural underpinnings remain poorly understood. Here, we focused on the role of priors during postdiction and hypothesized that these could be reflected by alpha oscillations (8-12Hz), previously observed to correlate with idiosyncratic biases. We presented human participants with ambiguous visual stimuli that elicited the rabbit illusion on about half the trials, allowing us to contrast MEG-EEG brain responses to the same physical events causing distinct percepts. Given that a strong prior will increase the overall probability of perceiving the illusion, we used the percentage of perceived illusion as a proxy for an individual’s prior. We found that high fronto-parietal alpha power was associated with perceiving the sequence according to individual biases: participants with high susceptibility to the illusion would report the illusion, while participants with low susceptibility would report the veridical sequence. Additionally, we found that pre-stimulus alpha phase in occipital and frontal areas dissociated illusory from non-illusory trials. These results point to a dissociated relation of the power and timing of alpha band activity to illusory perception, with power reflecting prior expectations and phase influencing behavioral performance, potentially due to the modulation of sensory uncertainty.Significance StatementLate events may sometimes influence how earlier events are perceived, as if the arrow of time was reversed in the brain. This surprising phenomenon, called postdiction, is observed in the rabbit illusion, and highlights a predominant mechanism for perceptual processes. Perception builds up from the combination of prior expectations with incoming sensory evidence, which takes time. We showed that pre-stimulus neural activity, and more specifically alpha oscillations (8-12Hz), play a double role in postdiction. Fronto-parietal alpha power reflects individual prior expectation, while occipital and frontal alpha phase predicts illusory perception. Postdiction might actually be a means of compensating for the neural delays inherent in perceptual processes, so that the arrow of perceptual time matches the arrow of physical time.

Behavioral flexibility enables the ability to adaptively respond to changes in contingency requirements to maintain access to desired outcomes, and deficits in behavioral flexibility have been documented in many psychiatric disorders. Previous research has shown a correlation between behavioral flexibility measured in a reversal learning test and Syn3, the gene encoding synapsin III, which negatively regulates phasic dopamine release. Syn3 expression in the hippocampus, striatum, and neocortex is reported to be negatively correlated with reversal learning performance, so here, we utilized a global knockout line to investigate reversal learning in mice homozygous wildtype, heterozygous null, and homozygous null for the Syn3 gene. Compared to wildtype animals, we found a reversal specific effect of genetic Syn3 deficiency that resulted in a greater proportional increase in trials required to reach a preset performance criteria during contingency reversal, despite no observed genotype effects on the ability to acquire the initial discrimination. Behavioral flexibility scores, which quantified the likelihood of switching subsequent choice behavior following positive or negative feedback, became significantly more negative in reversal only for Syn3 homozygous null mice, suggesting a substantial increase in perseverative behavior in the reversal phase. Syn3 ablation reduced the number of anticipatory responses made per trial, often interpreted as a measure of waiting impulsivity. Overall, Syn3 expression negatively affected behavioral flexibility in a reversal specific manner but may have reduced waiting impulsivity. Significance Statement Adaptations to changes in the environment are facilitated by behavioral flexibility, and inflexible behavior is observed in several mental health disorders. The Syn3 gene encodes synapsin III, a protein that negatively regulates phasic dopamine release by sequestering vesicles away from the ready-releasable pool. Previous research has shown a positive genetic correlation between Syn3 expression in brain and behavioral flexibility in a reversal learning task. Here, we show that mice carrying null alleles of the Syn3 gene exhibit less flexible responding following contingency reversal. These data reveal novel information about genetic mechanisms that may contribute to the impaired flexibility observed in multiple psychiatric conditions.

Visual Abstract, Recent studies suggest that choice behavior in reinforcement learning tasks is shaped by the level of outcome controllability. In particular, Pavlovian bias (PB) seems to be enhanced under low levels of control, manifesting in approach tendencies toward rewards and response inhibition when facing potential losses. The medial prefrontal cortex (mPFC) has been implicated both in evaluating outcome controllability and in the recruitment of cognitive control (CC) to suppress maladaptive PB during reinforcement learning. The current study tested whether high-definition transcranial direct current stimulation (HD-tDCS) above the mPFC of healthy humans can influence PB, and counteract the previously documented, deleterious behavioral effects of low outcome controllability on decision-making. In a preregistered, between-group, double-blind study (N = 103 adults, both sexes), we tested the interaction between controllability and HD-tDCS on parameters of choice behavior in a Go/NoGo task. Relative to sham stimulation, HD-tDCS resulted in more robust performance improvement following reduced control, an effect that was more pronounced in appetitive trials. In addition, we found evidence for weaker PB when HD-tDCS was administered during low controllability over outcomes. Computational modeling revealed that parameter estimates of learning rate and choice randomness were modulated by controllability, HD-tDCS and their interaction. Overall, these results highlight the potential of our HD-tDCS protocol for interfering with choice arbitration under low levels of control, resulting in more adaptive behavior.

Previous research has indicated that reward-paired cues can enhance disadvantageous risky choice in both humans and rodents. Systemic administration of a serotonin 2C receptor antagonist can attenuate this cue-induced risk preference in rats. However, the neurocognitive mechanisms mediating this effect are currently unknown. We therefore assessed whether the serotonin 2C receptor antagonist RS 102221 is able to attenuate cue-enhanced risk preference via its actions in the lateral orbitofrontal cortex (lOFC) or prelimbic (PrL) area of the medial prefrontal cortex (mPFC). A total of 32 male Long–Evans rats were trained on the cued version of the rat gambling task (rGT), a rodent analog of the human Iowa gambling task, and bilateral guide cannulae were implanted into the lOFC or PrL. Intra-lOFC infusions of the 5-HT2C antagonist RS 102221 reduced risky choice in animals that showed a preference for the risky options of the rGT at baseline. This effect was not observed in optimal decision-makers, nor those that received infusions targeting the PrL. Given prior data showing that 5-HT2C antagonists also improve reversal learning through the same neural locus, we hypothesized that reward-concurrent cues may amplify risky decision-making through cognitive inflexibility. We therefore devalued the sugar pellet rewards used in the cued rGT (crGT) through satiation and observed that decision-making patterns did not shift unless animals also received intra-lOFC RS 102221. Collectively, these data suggest that the lOFC is one critical site through which reward-concurrent cues promote risky choice patterns that are insensitive to reinforcer devaluation, and that 5-HT2C antagonism may optimize choice by facilitating exploration. Significance Statement Lights and sounds signaling reward are used extensively in electronic gaming machines. Recent data indicate that these win-associated cues can increase disadvantageous risky choice. Administering a serotonin 2C receptor antagonist can ameliorate this effect in rats, potentially by increasing flexibility in decision-making. The orbitofrontal cortex (OFC) is critically involved in mediating flexible behavior. Thus, the present study evaluated whether serotonin 2C antagonism in the OFC can reduce disadvantageous risky choice via alterations to behavioral flexibility. Results implicate the OFC as one critical locus, and an increase in flexibility as a potential cognitive mechanism, through which cue-enhanced risky decision-making may improve. This could point to potential therapeutic interventions for problematic gambling that target the control of cues over behavior.

Cross-sectional versus longitudinal comparisons of age-related change have often revealed differing results. In the current study, we employed within-subject task-based fMRI to investigate changes in voxel-based activations and behavioral performance across the lifespan in the Reference Ability Neural Network (RANN) cohort, at both baseline and 5-year follow-up. We analyzed fMRI data from between 127 and 159 participants (20-80 years), on a battery of tests relating to each of four cognitive reference abilities (RAs). We applied a Gaussian age kernel to capture continuous change across the lifespan using a 5-year sliding window centered on each age in our participant sample, with a subsequent division into young, middle, and old age brackets. This method was applied separately to both cross-sectional approximations of change and real longitudinal changes adopting a comparative approach. We then focused on longitudinal measurements of neural change to identify regions expressing peak changes and fluctuations of sign change across our sample. Our results revealed several regions expressing divergence between cross-sectional and longitudinal measurements in each domain and age bracket; behavioral comparisons between measurements showed differences in change curves for all four domains, with processing speed displaying the steepest declines. In the longitudinal change measurement, we found lack of support for age-related frontal increases across analyses types, instead finding more posterior regions displaying peak increases in activation, particularly in the old age bracket. Our findings encourage greater focus on longitudinal measurements of age-related changes, which display appreciable differences from cross-sectional approximations. Significance Statement Knowledge of the aging process is mostly informed by cross-sectional studies. The fewer studies that have looked at longitudinal aging trajectories display variable consensus with cross-sectional findings. The current study provides a direct comparison between cross-sectional and longitudinal measurements of change in both neural activation and behavioral performance across several cognitive domains, providing insight into similarities versus discrepancies. Furthermore, it adopts a method of analysis used in the MRI 4D atlas literature to quantify continuous change across the lifespan through construction of neural activation “templates” that are generated from age-weighted averaging across the entire sample. Longitudinal measurements of change could then further be probed for characteristics such as peaks and change fluctuations, enabling a better understanding of true age-related changes.

For proper execution of goal-directed behaviors, individuals require both a general representation of the goal and an ability to monitor their own progress toward that goal. Here, we examine how dorsomedial striatum (DMS), a region pivotal for forming associations among stimuli, actions, and outcomes, encodes the execution of goal-directed action sequences that require self-monitoring of behavior. We trained rats to complete a sequence of at least 5 consecutive lever presses (without visiting the reward port) to obtain a reward and recorded the activity of individual cells in DMS while rats performed the task. We found that the pattern of DMS activity gradually changed during the execution of the sequence, permitting accurate decoding of sequence progress from neural activity at a population level. Moreover, this sequence-related activity was blunted on trials where rats did not complete a sufficient number of presses. Overall, these data suggest a link between DMS activity and the execution of behavioral sequences that require monitoring of ongoing behavior. Significance statement Dorsomedial striatal activity was recorded during a task requiring rats to track progress in the execution of lever press sequences. Dorsomedial striatal activity evolved across the behavioral sequence with a ramp-like pattern of activity, permitting accurate decoding of sequence progress at the population level. Additionally, the magnitude of sequence-related activity was blunted on incomplete trials, suggesting that DMS activity may be critical for proper monitoring and execution of behavioral sequences. This study demonstrates that DMS neurons encode progress toward a goal during execution of action sequences when animals are required to track their own behavior for efficient performance.

The importance of the primary cilium was initially highlighted by the class of human genetic disorders known as ciliopathies. Patients with ciliopathies such as Bardet-Biedl and Alström syndrome exhibit hyperphagia-associated obesity as a core clinical phenotype. How primary cilia contribute to energy homeostasis and feeding behavior is complex and unclear, but cilia appear important in both developmental and homeostatic processes. Primary cilia are important signaling centers, required for hedgehog signaling and localization of specific G protein-coupled receptors (GPCRs) with known roles in feeding behavior in mammals. The hedgehog pathway is best known for its role in developmental patterning, but now has recognized roles in adult tissues as well. In the postnatal brain, cilia and hedgehog signaling are important for growth and maintenance of neural progenitors, however, the role of hedgehog signaling in the differentiated adult brain is less clear. Here, we provide a detailed analysis of the expression of core components of the hedgehog signaling pathway in the adult mouse hypothalamus with an emphasis on feeding centers. We show that hedgehog pathway genes continue to be expressed in differentiated neurons important for regulation of feeding behavior. Furthermore, we demonstrate for the first time that pathway activity is regulated at the transcriptional level by fasting. These data suggest that hedgehog signaling is involved in the proper functioning of brain regions which regulate feeding behavior and that hedgehog pathway dysfunction may play a role in the obesity observed in certain ciliopathies.Significance StatementHere we investigate the expression of hedgehog pathway components in the adult mouse hypothalamus. Using dual labeling in situ hybridization we show that core components of the signaling pathway are expressed in multiple neuronal cell types within the hypothalamic feeding centers. Our findings also support previous findings that astrocytes are responsive to hedgehog signaling, as determined by Gli1 and Ptch1 expression. Using qPCR analysis, we show that hypothalamic hedgehog pathway activity is upregulated in response to fasting and this response is nuclei specific. These data not only provide a more detailed understanding of hedgehog pathway expression in the adult mouse hypothalamus but also provide direct evidence of a novel role for hedgehog signaling in the physiological response to fasting.

Hippocampal neural disinhibition, i.e. reduced GABAergic inhibition, is a key feature of schizophrenia pathophysiology. The hippocampus is an important part of the neural circuitry that controls fear conditioning and can also modulate prefrontal and striatal mechanisms, including dopamine signalling, which play a role in salience modulation. Therefore, hippocampal neural disinhibition may contribute to impairments in fear conditioning and salience modulation reported in schizophrenia. To test this hypothesis, we examined the effect of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and salience modulation, as reflected by latent inhibition (LI), in a conditioned emotional response procedure (CER). A flashing light was used as the conditioned stimulus (CS) and conditioned suppression was used to index conditioned fear. In Experiment 1, VH disinhibition via infusion of the GABA-A receptor antagonist picrotoxin prior to CS pre-exposure and conditioning markedly reduced fear conditioning to both the CS and context; LI was evident in saline-infused controls, but could not be detected in picrotoxin-infused rats due to the low level of fear conditioning to the CS. In Experiment 2, VH picrotoxin infusions prior to CS pre-exposure only did not affect the acquisition of fear conditioning or LI. Together, these findings indicate that VH neural disinhibition disrupts contextual and elemental fear conditioning, without affecting the acquisition of LI. The disruption of fear conditioning resembles aversive conditioning deficits reported in schizophrenia and may reflect disruption of neural processing within the hippocampus and its projection sites.Significance StatementHippocampal disinhibition, reduced GABAergic inhibition, is a feature of schizophrenia, but how this contributes to psychological deficits remains to be clarified. Here, we focused on impairments patients show on classical-conditioning assays: aberrant salience allocation to stimuli that healthy participants have learnt to ignore and reduced fear conditioning, which have been linked to psychosis and negative symptoms, respectively. These impairments may be related to hippocampal disinhibition because the hippocampus modulates neural substrates of salience allocation and is part of the fear-conditioning neural circuit. Combining selective pharmacological manipulation of the hippocampus with a conditioning assay in rats, we found hippocampal disinhibition disrupted fear conditioning, without evidence for aberrant salience allocation. This suggests hippocampal disinhibition contributes to fear conditioning deficits in schizophrenia.

The lateral habenula (LHb) is a phylogenetically primitive brain structure that plays a key role in learning to inhibit distinct responses to specific stimuli. This structure is activated by primary aversive stimuli, cues predicting an imminent aversive event, unexpected reward omissions, and cues associated with the omission of an expected reward. The most widely described physiological effect of LHb activation is acutely suppressing midbrain dopaminergic signaling. However, recent studies have identified multiple means by which the LHb promotes this effect as well as other mechanisms of action. These findings reveal the complex nature of LHb circuitry. The present paper reviews the role of this structure in learning from reward omission. We approach this topic from the perspective of computational models of behavioral change that account for inhibitory learning to frame key findings. Such findings are drawn from recent behavioral neuroscience studies that use novel brain imaging, stimulation, ablation, and reversible inactivation techniques. Further research and conceptual work are needed to clarify the nature of the mechanisms related to updating motivated behavior in which the LHb is involved. As yet, there is little understanding of whether such mechanisms are parallel or complementary to the well-known modulatory function of the more recently evolved prefrontal cortex.

Untreated age-related hearing loss increases audiovisual integration and impacts resting state functional brain connectivity. Further, there is a relation between crossmodal plasticity and audiovisual integration strength in cochlear implant patients. However, it is currently unclear whether amplification of the auditory input by hearing aids influences audiovisual integration and resting state functional brain connectivity. We conducted a randomized controlled pilot study to investigate how the McGurk illusion, a common measure for audiovisual integration, and resting state functional brain connectivity of the auditory cortex are altered by six-month hearing aid use. Thirty-two older participants with slight-to-moderate, symmetric, age-related hearing loss were allocated to a treatment or waiting control group and measured one week before and six months after hearing aid fitting with functional magnetic resonance imaging. Our results showed a statistical trend for an increased McGurk illusion after six months of hearing aid use. We further demonstrated that an increase in McGurk susceptibility is related to a decreased hearing aid benefit for auditory speech intelligibility in noise. No significant interaction between group and time point was obtained in the whole-brain resting state analysis. However, a region of interest (ROI)-to-ROI analysis indicated that hearing aid use of six months was associated with a decrease in resting state functional connectivity between the auditory cortex and the fusiform gyrus and that this decrease was related to an increase of perceived McGurk illusions. Our study, therefore, suggests that even short-term hearing aid use alters audiovisual integration and functional brain connectivity between auditory and visual cortices.Significance StatementIn this study, we showed that first time hearing aid use of six months was related to a decrease in resting state functional connectivity between the auditory cortex and the fusiform gyrus. The decreased connectivity was associated with an increase in perceived McGurk illusions. Further, this increase in McGurk illusions was correlated with decreased hearing aid benefit in auditory speech in noise intelligibility. Our study therefore suggests that hearing aid fitting impacts functional connectivity between auditory and visual regions and audiovisual integration (susceptibility to the McGurk illusion). Further our results suggest, that an increased McGurk susceptibility seems to inhibit the beneficial effect of the hearing aid when tested in auditory only conditions.

Signal transmission in the brain propagates via distinct oscillatory frequency bands but the aperiodic component, 1/f activity, almost always co-exists which most of the previous studies have not sufficiently taken into consideration. We used a recently proposed parameterization model that delimits the oscillatory and aperiodic components of neural dynamics on lifespan aging data collected from human participants using magnetoencephalography (MEG). Since healthy aging underlines an enormous change in local tissue properties, any systematic relationship of 1/f activity would highlight their impact on the self-organized critical functional states. Furthermore, we have used patterns of correlation between aperiodic background and metrics of behavior to understand the domain general effects of 1/f activity. We suggest that age-associated global change in 1/f baseline alters the functional critical states of the brain affecting the global information processing impacting critically all aspects of cognition, e.g., metacognitive awareness, speed of retrieval of memory, cognitive load, and accuracy of recall through adult lifespan. This alteration in 1/f crucially impacts the oscillatory features peak frequency (PF) and band power ratio, which relates to more local processing and selective functional aspects of cognitive processing during the visual short-term memory (VSTM) task. In summary, this study leveraging on big lifespan data for the first time tracks the cross-sectional lifespan-associated periodic and aperiodic dynamical changes in the resting state to demonstrate how normative patterns of 1/f activity, PF, and band ratio (BR) measures provide distinct functional insights about the cognitive decline through adult lifespan.

Visual Abstract, Social connections in gregarious species are vital for safety and survival. For these reasons, many bird species form large flocks outside the breeding season. It has been proposed that such large social groups may be maintained via reward induced by positive interactions with conspecifics and via the reduction of a negative affective state caused by social separation. Moreover, within a flock optimal social spacing between conspecifics is important, indicating that individuals may optimize spacing to be close but not too close to conspecifics. The μ-opioid receptors (MORs) in the nucleus accumbens (NAc) are well known for their role in both reward and the reduction of negative affective states, suggesting that MOR stimulation in NAc may play a critical role in flock cohesion. To begin to test this hypothesis, social and nonsocial behaviors were examined in male and female European starlings (Sturnus vulgaris) in nonbreeding flocks after intra-NAc infusion of saline and three doses of the selective MOR agonist d-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO). DAMGO in NAc dose-dependently increased singing behavior and facilitated social approaches while at the same time promoting displacements potentially used to maintain social spacing. These findings support the hypothesis that MORs in NAc promote social interactions important for group cohesion in nonsexual contexts and suggest the possibility that MORs in the NAc play a role in optimizing the pull of joining a flock with the push of potential agonistic encounters.

Animal models suggest that interactions between the hippocampus and ventral tegmental area (VTA) underlie the onset and etiology of psychosis. While a large body of research has separately characterized alterations in hippocampal and VTA function in psychosis, alterations across the VTA and hippocampus have not been characterized in first-episode psychosis (FEP). As the phase of psychosis most proximal to conversion, studies specifically focused on FEP are valuable to psychosis research. Here, we characterize alterations in VTA-hippocampal interactions across male and female human participants experiencing their first episode of psychosis using resting state functional magnetic resonance imaging (rsfMRI). In comparison to age and sex matched healthy controls (HCs), FEP individuals had significantly greater VTA-hippocampal functional coupling but significantly less VTA-striatal functional coupling. Further, increased VTA-hippocampal functional coupling in FEP correlated with individual differences in psychosis-related symptoms. Together, these findings demonstrate alterations in mesolimbic-hippocampal circuits in FEP and extend prominent animal models of psychosis.

Decision-making is traditionally described as a cognitive process of deliberation followed by commitment to an action choice, preceding the planning and execution of the chosen action. However, this is challenged by recent data suggesting that during situated decisions, multiple options are specified simultaneously and compete in pre-motor cortical areas for selection and execution. Previous studies focused on the competition during planning, and leave unaddressed the dynamics of decisions during movement. Does deliberation extend into the execution phase? Are non-selected options still considered? Here we studied a decision-making task in which human participants were instructed to select a reaching path trajectory from an origin to a rectangular target, where reward was distributed non-uniformly at the target. Critically, we applied mechanical perturbations to the arm during movement to study under which conditions such perturbations produce changes of mind. Our results show that participants initially selected the direction of movement towards the highest reward region, and changed their mind most frequently when the two choices offered the same reward, showing that deliberation continues and follows cost-benefit considerations during movement. Furthermore, changes of mind were dependent upon the intensity of the perturbation and the current state of the motor system, including velocity and distance to targets. Although reward remains most relevant, our results indicate that the state of the motor system when the perturbation occurs is a crucial determinant of changes of mind.Significance StatementOur study provides supporting evidence for the notion that deliberation during decision-making continues after movement onset because unselected potential actions are not completely suppressed or discarded. From a neurophysiological perspective, our findings suggest that the competition between actions continues during movement, possibly because the initially unselected neuronal population retains sub-threshold activation, which enables them to take control afterwards. Furthermore, our findings also suggest that decision-makers have a variable degree of commitment to their initial choice, which depends on the relative reward of the offers and on the state of the motor system. The commitment is stronger if initially leading to a high reward, and changes of mind are more frequent at slow speed and when close to the alternate target.

Determining the impact that the KIAA0319 gene has on primate brain morphology can provide insight into the evolution of human cognition and language systems. Here, we tested whether polymorphisms in KIAA0319 in chimpanzees account for gray matter volumetric variation in brain regions implicated in language and communication (particularly within the posterior superior temporal gyrus and inferior frontal gyrus). First, we identified the nature and frequencies of single nucleotide variants (SNVs) in KIAA0319 in a sample of unrelated chimpanzees (Pan troglodytes spp.). Next, we genotyped a subset of SNVs (those important for gene regulation or likely to alter protein structure/function) in a sample of chimpanzees for which in vivo T1-structural magnetic resonance imaging scans had been obtained. We then used source-based morphometry (SBM) to test for whole-brain gray matter covariation differences between chimpanzees with different KIAA0319 alleles. Finally, using histologic sections of 15 postmortem chimpanzee brains, we analyzed microstructural variation related to KIAA0319 polymorphisms in the posterior superior temporal cortex. We found that the SNVs were associated with variation in gray matter within several brain regions, including the posterior superior temporal gyrus (a region associated with language comprehension and production in humans). The microstructure analysis further revealed hemispheric differences in neuropil fraction, indicating that KIAA0319 expression may be involved in regulation of processes related to the formation and maintenance of synapses, dendrites, or axons within regions associated with communication.

Visual Abstract, Survival depends on the ability to adaptively react or execute actions based on previous aversive salient experiences. Although lateral habenula (LHb) activity has been broadly implicated in the regulation of aversively motivated responses, it is not clear under which conditions this brain structure is necessary to regulate defensive responses to a threat. To address this issue, we combined pharmacological inactivations with behavioral tasks that involve aversive and appetitive events and evaluated defensive responses in rats. We found that LHb pharmacological inactivation did not affect cued threat conditioning (fear) and extinction (safety) learning and memory, anxiety-like or reward-seeking behaviors. Surprisingly, we found that LHb inactivation abolished reactive defensive responses (tone-elicited freezing) only when threat (conditioning) and safety memories (extinction and latent inhibition) compete during retrieval. Consistently, we found that LHb inactivation impaired active defensive responses [platform-mediated avoidance (PMA)], thereby biasing choice behavior (between avoiding a threat or approaching food) toward reward-seeking responses. Together, our findings suggest that LHb activity mediates defensive responses only when guided by competing threat and safety memories, consequently revealing a previously uncharacterized role for LHb in experience-dependent emotional conflict.

The perception of our surrounding environment is an amalgamation of stimuli detected by sensory neurons. InCaenorhabditis elegans, olfaction is an essential behavior that determines various behavioral functions such as locomotion, feeding and development. Sensory olfactory cues also initiate downstream neuroendocrine signaling that controls aging, learning, development and reproduction. Innate sensory preferences toward odors (food, pathogens) and reproductive pheromones are modulated by 11 pairs of amphid chemosensory neurons in the head region ofC. elegans. Amongst these sensory neurons, the ASI neuron has neuroendocrine functions and secretes neuropeptides, insulin-like peptide (DAF-28) and the TGF-β protein, DAF-7. Its expression levels are modulated by the presence of food (increased levels) and population density (decreased levels). A recent study has shown that EXP-1, an excitatory GABA receptor regulates DAF-7/TGF-β levels and participates in DAF-7/TGF-β-mediated behaviors such as aggregation and bordering. Here, we show thatexp-1mutants show defective responses toward AWC-sensed attractive odors in a non-autonomous manner through ASI neurons. Our dauer experiments reveal that indaf-7mutants, ASI expressed EXP-1 and STR-2 (a G-protein-coupled receptor; GPCR) that partially maintained reproductive growth of animals. Further, studies suggest that neuronal connections between ASI and AWC neurons are allowed at least partially through ASI secreted DAF-7 or through alternate TGF- β pathway/s regulated by EXP-1 and STR-2. Together, our behavioral, genetic and imaging experiments propose that EXP-1 and STR-2 integrate food cues and allow the animals to display DAF-7/TGF-β neuroendocrine dependent or independent behavioral responses contributing to chemosensensory and developmental plasticity.

Retinoic acid (RA), a metabolite of vitamin A, has many physiological functions, and mounting evidence points to important roles in cognition. In vitro experiments indicate that RA is involved in homeostatic synaptic scaling in the hippocampus, which supports overall network stability during learning. It has been previously determined that disrupted RA signaling in the hippocampus causes deterioration of memory, that RA signaling declines with age in brain, and that application of RA reverses this decline. Here we explore whether RA signaling is altered in an animal model of neurocognitive aging. We utilized a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial inter-individual differences in aged animals. Aged unimpaired (AU) rats perform on par with young, while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4, is decreased in AU rats, and retinol cell surface receptor declines with chronological age. Other affected components of RA signaling include selective increases in AI animals in hippocampal synthesis (RALDH1) and catabolism of RA (CYP26B1), RA receptor α, the RA regulated ionotropic glutamate receptor (GluR1), as well as fragile X mental retardation protein. The results support the conclusion that, surprisingly, increased RA signaling in the aged hippocampus is associated with poor cognitive outcome.SIGNIFICANCE STATEMENTGrowing evidence indicates that retinoic acid (RA) function extends well beyond metabolic control and includes the regulation of memory-related synaptic plasticity. Here we explore whether RA signaling is altered in an animal model of neurocognitive aging. We show that in fact RA function is altered at nearly all levels examined, and these results are unrelated to metabolic aging. Overall, the net effect points in the direction of increased RA signaling in impaired aged animals, which may contribute to disruption in excitation/inhibition balance, a prominent feature of age-related cognitive impairment and suspected early event in the pathogenesis of Alzheimer's disease.

The reproducibility and translation of neuroscience research is assumed to be undermined by introducing environmental complexity and heterogeneity. Rearing laboratory animals with minimal (if any) environmental stimulation is thought to control for biological variability but may not adequately test the robustness of our animal models. Standard laboratory housing is associated with reduced demonstrations of species typical behaviors and changes in neurophysiology that may impact the translation of research results. Modest increases in environmental enrichment (EE), mitigate against insults used to induce animal models of disease, directly calling into question the translatability of our work. This may in part underlie the disconnect between preclinical and clinical research findings. Enhancing environmental stimulation for our model organisms promotes ethological natural behaviors but may simultaneously increase phenotypic trait variability. To test this assumption, we conducted a systematic review and evaluated coefficients of variation between EE and standard housed mice and rats. Given findings of suboptimal reporting of animal laboratory housing conditions, we also developed a methodological reporting table for enrichment use in neuroscience research. Our data show that animals housed in environmental enrichment were not more variable than those in standard housing. Therefore, environmental heterogeneity introduced into the laboratory, in the form of enrichment, does not compromise data integrity. Overall, human life is complicated and by embracing such nuanced complexity into our laboratories we may paradoxically improve upon the rigor and reproducibility of our research.Significance StatementEnvironmental complexity is thought to increase phenotypic variability, undermining research translation. We conducted a systematic review and compared coefficients of variation between environmentally enriched and standard housed laboratory animals. Despite there being no differences in variability across several phenotypic traits, there are stark contrasts in the display of ethological natural behaviors between these housing conditions. Environmental enrichment is recognized as being beneficial for animal welfare and mitigates against insults used to induce animal models of disease. In contrast, standard laboratory cages are recognized as being impoverished and ‘unnatural’. From these observations, it is apparent that our current “gold standard” caging system is not a true control condition as it does not adequately test the robustness of our animal models.

Sevoflurane is widely used in general anesthesia, especially for children. However, prolonged exposure to sevoflurane is reported to be associated with adverse effects on the development of brain in infant monkey. Neural stem cells (NSCs), with potent proliferation, differentiation, and renewing ability, provide an encouraging tool for basic research and clinical therapies for neurodegenerative diseases. We aim to explore the functional effects of injecting NSCs with phosphodiesterase 7A (PDE7A) knock-down in infant mice exposed to sevoflurane. The effects of PDE7A in NSCs proliferation and differentiation were determined by cell counting kit-8 (CCK-8) assay and differentiation-related gene expression assay, respectively. The effects of NSCs with modified PDE7A on mice’s long-term memory and learning ability were assessed by behavioral assays. Our data demonstrated that depleting PDE7A promoted, whereas forcing PDE7A suppressed the activation of cAMP/cAMP-response element binding protein (CREB) signaling as well as cell proliferation and neuronal differentiation of NSCs. Inhibition of PDE7A in NSCs exhibited profound improved effects on long-term memory and learning ability of mice exposed to sevoflurane. Our results for the first time show that knock-down of PDE7A improves the neurogenesis of NSCsin vitroandin vivo, and is beneficial for alleviating sevoflurane-induced brain damage in infant mice.

How does the brain anticipate information in language? When people perceive speech, low-frequency (