bioRxiv Subject Collection: Neuroscience's Journal

High spatiotemporal resolution radial encoding single vessel fMRI
High-field preclinical functional MRI (fMRI) has enabled the high spatial resolution mapping of vessel-specific hemodynamic responses, i.e. single-vessel fMRI. In contrast to investigating neuronal sources of the fMRI signal, single vessel fMRI focuses on elucidating its vascular origin, which can be readily implemented to identify vascular changes relevant to vascular dementia or cognitive impairment. However, the limited spatial and temporal resolution of fMRI has hindered hemodynamic mapping of intracortical microvessels. Here, we implemented the radial encoding MRI scheme to measure BOLD signals of individual vessels penetrating the rat somatosensory cortex. Radial encoding MRI is employed to map cortical activation with a focal field of view (FOV), allowing vessel-specific functional mapping with 50x50 m in-plane resolution at 1 to 2 Hz sampling rate. Besides detecting refined hemodynamic responses of intracortical micro-venules, the radial encoding-based single-vessel fMRI enables the differentiation of the intravascular and extravascular effects from the draining venules.

Experience shapes initial exploration for non-generalizable spatial learning
Experience can change how individuals learn. Learning to solve a new problem can be accelerated by generalizing known rules in the new context, but the impact of experience on solving problems where generalization cannot be applied remains unclear. To study the impact of experience on solving new problems that are distinct from previously learned tasks, we examined how rats learned a new spatial navigation task after having previously learned different sets of spatial navigation tasks. The new task differed from the previous tasks in spatial layout and navigation rule, and could not be solved by applying previously learned rules. We found that different experience histories did not impact task performance in the new task. However, by examining navigation choices made by rats, we found exploration patterns during the early stage of learning in the new task was dependent on experience history. We identified these behavioral differences by analyzing each rat's navigation choices and by modeling their choice sequences with a modified distance dependent Chinese restaurant process. We further pinpointed the behavioral difference to sequential turn/no turn decisions made at choice points. Our results indicate that experience can influence problem-solving strategies when learning to solve new problems. Individuals with distinct experience histories can approach new problems from different starting points but converge on the same solution.

High stakes slow responding, but do not help overcome Pavlovian biases in humans
"Pavlovian" or "motivational" biases are the phenomenon that the valence of prospective outcomes modulates action invigoration: Reward prospect invigorates action, while punishment prospect suppresses it. While effects of the valence of prospective outcomes are well established, it is unclear how the magnitude of outcomes modulates these biases. In this pre-registered study (N = 55), we manipulated stake magnitude (high vs. low) in an orthogonalized Motivational Go/ NoGo Task. We tested whether higher stakes (a) strengthen biases or (b) elicit cognitive control recruitment, enhancing the suppression of biases in motivationally incongruent conditions. Confirmatory tests yielded that high stakes slowed down responses independently of the Pavlovian biases, especially in motivationally incongruent conditions, without affecting response selection. Reinforcement-learning drift-diffusion models (RL-DDMs) fit to the data suggested that this effect was best captured by stakes prolonging the non-decision time, but not affecting the response threshold as in typical speed-accuracy tradeoffs. In sum, these results suggest that high stakes result in a slowing-down of the decision process without affecting the expression of Pavlovian biases in behavior. We speculate that this slowing under high stakes might reflect heightened cognitive control, which is however ineffectively used, or reflect positive conditioned suppression, i.e., the suppression of locomotion by high-value immanent rewards, as phenomenon previously observed in rodents that might also exist in humans. Pavlovian biases and slowing under high stakes seem to arise in parallel to each other.

Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network
Distributed hypothalamic-midbrain neural circuits orchestrate complex behavioral responses during social interactions. How population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include continuous-state linear dynamical system (LDS) and discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states. Overall, these analysis approaches provide an unbiased strategy to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.

Distributed evidence accumulation across macaque large-scale neocortical networks during perceptual decision making
Despite the traditional view of parietal cortex as an important region for perceptual decision-making, recent evidence suggests that sensory accumulation occurs simultaneously across many cortical regions. We explored this hypothesis by integrating connectivity, cellular and receptor density datasets and building a large-scale macaque brain model able to integrate conflicting sensory signals and perform a decision-making task. Our results reveal sensory evidence accumulation supported by a distributed network of temporal, parietal and frontal regions, with flexible sequential decision pathways which depend on task difficulty. The model replicates experimental lesioning effects and reveals that the causal irrelevance of parietal areas like LIP for decision performance is explained by compensatory mechanisms within a distributed integration process. The model also reproduces observed temporal gating effects of distractor timing during and after the integration process. Overall, our work hints at perceptual integration during decision-making as a broad distributed phenomenon and provides multiple testable predictions.

Intranasal Delivery of shRNA to Knockdown the 5HT-2A Receptor Enhances Memory and Alleviates Anxiety
Short-hairpin RNAs (shRNA) targeting knockdown of specific genes hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. However, whether shRNA constructed molecules can modify neuronal circuits underlying certain behaviors has not been explored. We designed shRNA to knockdown the human HTR2A gene in vitro using iPSC-differentiated neurons. Multi-electrode array (MEA) results showed the knockdown of the 5HT-2A mRNA and receptor protein led to a decrease in spontaneous electrical activity. In vivo, intranasal delivery of AAV9 vectors containing shRNA resulted in a decrease in anxiety-like behavior in mice and a significant improvement in memory in both mice (104%) and rats (92%) compared to vehicle-treated animals. Our demonstration of a non-invasive shRNA delivery platform that can bypass the blood-brain barrier has broad implications for treating numerous neurological mental disorders. Specifically, targeting the HTR2A gene presents a novel therapeutic approach for treating chronic anxiety and age-related cognitive decline.

The Primary Cilium and its Hedgehog Signaling in Nociceptors Contribute to Inflammatory and Neuropathic Pain
The primary cilium, a 1-3 micrometer long hair-like structure protruding from the surface of almost all cells in the vertebrate body, is critical for neuronal development and also functions in the adult. As the migratory neural crest settles into dorsal root ganglia (DRG) sensory neurons elaborate a single primary cilium at their soma that is maintained into adult stages. While it is not known if primary cilia are expressed in nociceptors, or their potential function in the mature DRG neuron, recent studies have shown a role for Hedgehog, whose signaling demonstrates a dependence on primary cilia, in nociceptor sensitization. Here we report the expression of primary cilia in rat and mouse nociceptors, where they modulate mechanical nociceptive threshold, and contribute to inflammatory and neuropathic pain. When siRNA targeting Ift88, a primary cilium-specific intra-flagellar transport (IFT) protein required for ciliary integrity, was administered by intrathecal injection, in the rat, it resulted in loss of Ift88 mRNA in DRG, and primary cilia in neuronal cell bodies, which was associated with an increase in mechanical nociceptive threshold, and abrogation of hyperalgesia induced by the pronociceptive inflammatory mediator, prostaglandin E2, and painful peripheral neuropathy induced by a neurotoxic chemotherapy drug, paclitaxel. To provide further support for the role of the primary cilium in nociceptor function we also administered siRNA for another IFT protein, Ift52. Ift52 siRNA results in loss of Ift52 in DRG and abrogates paclitaxel-induced painful peripheral neuropathy. Attenuation of Hedgehog-induced hyperalgesia by Ift88 knockdown supports a role for the primary cilium in the hyperalgesia induced by Hedgehog, and attenuation of paclitaxel chemotherapy-induced neuropathy (CIPN) by cyclopamine, which attenuates Hedgehog signaling, suggests a role of Hedgehog in CIPN. Our findings support a role of nociceptor primary cilia in the control of mechanical nociceptive threshold and in inflammatory and neuropathic pain, the latter, at least in part, Hedgehog dependent.

A computational account of joint SSRI and anti-inflammatory treatment
We present a computational model that elucidates the interplay between inflammation, serotonin levels, and brain activity. The model delineates how inflammation impacts extracellular serotonin, while cerebral activity reciprocally influences serotonin concentration. Understanding the reciprocal interplay between the immune system and brain dynamics is important, as unabated inflammation can lead to relapsing depression. The model predicts dynamics within the prefrontal cortex (PFC) and subcallosal cingulate cortex (SCC), mirroring patterns observed in depressive conditions. It also accommodates pharmaceutical interventions that encompass anti-inflammatory and antidepressant agents, concurrently evaluating their efficacy with regard to the severity of depressive symptoms.

TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43.
TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of [~]50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.

Constitutive and conditional epitope-tagging of endogenous G protein coupled receptors in Drosophila
To visualize the cellular and subcellular localization of neuromodulatory G-protein coupled receptors (GPCRs) in Drosophila, we implement a molecular strategy recently used to add epitope tags to ionotropic receptors at their endogenous loci. Leveraging evolutionary conservation to identify sites more likely to permit insertion of a tag, we generated constitutive and conditional tagged alleles for Drosophila 5-HT1A, 5-HT2A, 5-HT2B, Oct{beta}1R, Oct{beta}2R, two isoforms of OAMB, and mGluR. The conditional alleles allow for the restricted expression of tagged receptor in specific cell types, an option not available for any previous reagents to label these proteins. We show that 5-HT1A and 5-HT2B localize to the mushroom bodies and central complex respectively, as predicted by their roles in sleep. By contrast, the unexpected enrichment of Oct{beta}1R in the central complex and of 5-HT1A and 5-HT2A to nerve terminals in lobular columnar cells in the visual system suggest new hypotheses about their function at these sites. Using an additional tagged allele of the serotonin transporter, a marker of serotonergic tracts, we demonstrate diverse spatial relationships between postsynaptic 5-HT receptors and presynaptic 5-HT neurons, consistent with the importance of both synaptic and volume transmission. Finally, we use the conditional allele of 5-HT1A to show that it localizes to distinct sites within the mushroom bodies as both a postsynaptic receptor in Kenyon cells and a presynaptic autoreceptor.

Significance StatementIn Drosophila, despite remarkable advances in both connectomic and genomic studies, antibodies to many aminergic GPCRs are not available. We have overcome this obstacle using evolutionary conservation to identify loci in GPCRs amenable to epitope-tagging, and CRISPR/Cas9 genome editing to generated eight novel lines. This method also may be applied to other GPCRs and allows cell-specific expression of the tagged locus. We have used the tagged alleles we generated to address several questions that remain poorly understood. These include the relationship between pre- and post-synaptic sites that express the same receptor, and the use of relatively distant targets by pre-synaptic release sites that may employ volume transmission as well as standard synaptic signaling.

Is there a neural common factor for visual illusions?
It is tempting to map interindividual variability in human perception to variability in brain structure or neural activity. Indeed, it has been shown that susceptibility to size illusions correlates with the size of primary visual cortex V1. Yet contrary to common belief, illusions correlate only weakly at the perceptual level, raising the question of how they can correlate with a localized neural measure. In addition, mounting evidence suggests that there is substantial interindividual variability not only in neural function and anatomy but also in the mapping between the two, which further challenges the findings of a neural common factor for illusions. To better understand these questions, here, we re-evaluated previous studies by correlating illusion strengths in a battery of 13 illusions with the size of visual areas and population receptive field sizes. We did not find significant correlations either at the perceptual level or between illusion susceptibility and visual functional neuroanatomy.

Sensorimotor Impairment in Ageing and Neurocognitive Disorders: Beat Synchronisation and Adaptation to Tempo Changes
Background: Understanding the nature and extent of sensorimotor decline in ageing individuals and those with neurocognitive disorders NCD, such as Alzheimer's disease, is essential for designing effective music-based interventions. Objective: Our understanding of rhythmic functions remains incomplete, particularly in how ageing and NCD affect sensorimotor synchronisation and adaptation to tempo changes. This study aims to fill this knowledge gap. Methods: Patients from a memory clinic participated in a tapping task, synchronising with metronomic and musical sequences, some of which contained sudden tempo changes. After exclusions, 51 patients were included in the final analysis. Results: Participants' mini-mental state examination scores were associated with tapping consistency. Additionally, age negatively influenced consistency when synchronising with a musical beat, whereas consistency remained stable across age when tapping with a metronome. Conclusions: The ability to extract a beat from a musical signal diminishes with age, whereas the capacity to maintain a beat remains relatively constant. However, both processes may decline at moderate or severe stages of NCD. Moreover, the results indicate that the initial decline of attention and working memory with age may impact perception and synchronisation to a musical beat, whereas progressive NCD-related cognitive decline results in more widespread sensorimotor decline, affecting tapping irrespective of audio type. These findings underline the importance of customising rhythm-based interventions to the needs of older adults and individuals with NCD, taking into consideration their cognitive as well as their rhythmic aptitudes.

A Framework to Determine Active Connectivity within the Mouse Brain
Tremendous effort has focused on determining the physical connectivity within the mouse brain. However, the strength of connections within the brain constantly changes throughout the 24-hour day. Here, we combine experimental and computational methods to determine an "active connectivity" of the physical connections between the most active neurons. Brain cells of freely behaving mice are genetically marked with the activity- dependent TRAP2 system, imaged, digitized, and their connectivity is inferred from the latest brain atlases. We apply our methods to determine the most active networks in the early light and early dark hours of the day, two periods with distinct differences in sleep, wake, and feeding behavior. Increased signaling is seen through the visceral and agranular insular (AI) regions in the early day as peripheral stimuli are integrated. On the other hand, there is an increase in the activity of the retrosplenial cortex (RSP) and the anterior cingulate cortex (ACC) during the early night, when more sustained attention is required. Our framework carves a window to the three-dimensional networks of active connections in the mouse brain that underlie spontaneous behaviors or responses to environmental changes, thus providing the basis for direct computer simulations and analysis of such networks in the future.

From Inhibition to Excitation and Why: The Role of Temporal Urgency in Modulating Corticospinal Activity
Previous research on movement preparation identified a period of corticospinal suppression about 200 ms prior to movement initiation. This phenomenon has been observed for different types of motor tasks typically used to investigate movement preparation (e.g., reaction time, self-initiated, and anticipatory actions). However, we recently discovered that this phenomenon is not observed when actions must be initiated under time pressure. In the present study, we investigated urgency effects on corticospinal suppression throughout the time course of an anticipatory timing task. Participants were required to perform timing actions under two urgency scenarios, high and low, and we applied single-pulse transcranial magnetic stimulation at different times during the time course of preparation. We analysed the time course of excitability under high and low scenarios in relation to expected and actual movement onset times. Our results confirmed our earlier findings that corticospinal suppression is not observed when participants perform actions under high urgency scenarios. In addition, we found no evidence that this preparatory suppression could be shifted in time to occur later under high urgency scenarios. Moreover, we found evidence that responses prepared under high urgency are more likely to be disrupted by external events (e.g., TMS pulses). These results suggest that preparatory suppression might be a strategy employed by the central nervous system to shield motor actions from interference of external events (e.g., loud sounds) when time allows. Given these data, we propose conceptual models that could account for the absence of preparatory suppression under time pressure to act.

Pupil dilation reflects effortful action invigoration in overcoming aversive Pavlovian biases
"Pavlovian" or "motivational" biases describe the phenomenon that the valence of prospective outcomes modulates action invigoration: Reward prospect invigorates action, while punishment prospect suppresses it. The adaptive role of these biases in action selection is still unclear. One idea is that these biases constitute a fast-and-frugal decision strategy in situations characterized by novelty, surprise, and threat, e.g., in presence of a predator, which demand a quick response. In this pre-registered study (N = 35), we tested whether such a threatening situation--induced via subliminally presented angry vs. neutral faces--lead to increased reliance on Pavlovian biases. Also, we measured trial-by-trial arousal by tracking pupil diameter while participants performed an orthogonalized Motivational Go/NoGo Task. Pavlovian biases were present in responses, reaction times, and even gaze, with lower gaze dispersion under aversive cues, indicative of "freezing of gaze". The subliminally presented faces did not affect responses, nor reaction times, nor pupil diameter, questioning the effectiveness of this manipulation. However, pupil dilations encoded the task demands, with stronger dilations for Go responses particularly for aversive cues, potentially reflecting the process of learning to recruit effort to overcome aversive inhibition. Taken together, these results point at pupil diameter reflecting effortful action invigoration to overcome freezing induced by aversive cues--a facet of cognitive control unique to the employed task. We discuss our results in the context of noradrenaline and effort expenditure, but also in light of the "value of work" theory of striatal dopamine and the role of basal ganglia pathways in invigorating and suppressing movements.

Comment on 'Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation'
Acetylcholine is widely believed to modulate the release of dopamine in the striatum of mammals. Experiments in brain slices clearly show that synchronous activation of striatal cholinergic interneurons is sufficient to drive dopamine release via axo-axonal stimulation of nicotinic acetylcholine receptors. However, evidence for this mechanism in vivo has been less forthcoming. A recent paper in eLife (Mohebi et al., 2023) reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1. Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons. Our findings indicate that measurements of dopamine using the red-shifted fluorescent sensor RdLight1 should be interpreted with caution when combined with optogenetics. In light of this and other publications that did not observe large acetylcholine-evoked dopamine transients in vivo, the conditions under which such release occurs in behaving animals remain unknown.

Dynamics of burst synchronization induced by excitatory inputs on midbrain dopamine neurons
Dopamine (DA) signals play critical roles in reward-related behavior, decision making, and learning. Yet the mainstream notion that DA signals are encoded by the temporal dynamics of individual DA cell activity is increasingly contested with data supporting that DA signals prefer to be encoded by the spatial organization of DA neuron populations. However, how distributed and parallel excitatory afferent inputs simultaneously induce burst synchronization (BS) is unclear. Our previous work implies that the burst could presumably transition from an integrator to a resonator if the excitatory inputs increase further. Here the responses of networked DA neurons to different intensity of excitatory inputs are investigated. It is found that as NMDA conductance increases, the network will transition from resting state to burst asynchronization (BA) state and then to BS state, showing a bounded BA and BS region in the NMDA conductance space. Furthermore, it is found that as muscarinic receptors modulated Ca2+ dependent cationic (CAN) conductance increases, both boundaries between resting and BA, and between BA and BS gradually decrease. Phase plane analysis on DA reduced model unveils that the burst transition to a resonator underpins the changes in the network dynamics. Slow-fast dissection analysis on DA full model uncovers that the underlying mechanism of the roles and synergy of NMDA and muscarinic receptors in inducing the burst transition emerge from the enlargement of nonlinear positive feedback relationship between more Ca2+ influx provided by additional NMDA current and more ICAN modulated by added muscarinic receptors. Moreover, the lag in DA volume transmission has no effect on excitatory inputs-elicited resonator BS except for requiring more excitatory inputs. These findings shed new lights on understanding the collective behavior of DA cells population regulated by the distributed excitatory inputs, and might provide a new perspective for understanding the abnormal DA release in pathological states.

Author summaryThe importance of DA signals is beyond doubt, so their encoding mechanism has very important biological significance and draws widespread attention. Yet the mainstream notion that DA cells individual provide a uniform, broadly distributed signal is increasingly contested with data supporting both homogeneity across dopamine cell activity and diversity in DA signals in target regions. Our article proposes that diverse distributed and parallel excitatory inputs can not only regulate the temporal dynamics of individual DA cell activity, but also simultaneously and synergistically regulate the network dynamics of DA cell populations by changing the local dynamics of DA cells, namely the burst transition from integrators to resonators. According to our perspective, many data that are difficult to interpret by the notion of the DA neuron individual coding can be well explained, such as burst asynchronization coding DA ramping signals, the scale of burst synchronization coding the amplitude of phase DA release, inhibitory DA autoreceptors facilitating resonator burst synchronization by postinhibitory rebound, etc. This study aims to elucidate the working mechanism of the DA system in physiological states such as positive reinforcement, and then to provide a new research perspective and foundation for understanding the abnormal DA release in pathological states.

Ventral Pallidum and Amygdala Cooperate to Restrain Reward Approach from Overriding Defensive Behaviors
Foraging decisions involve assessing potential risks and prioritizing food sources, which can be challenging when confronted with changing and conflicting circumstances. A crucial aspect of this decision-making process is the ability to actively suppress defensive reactions to threats (fear) and focus on achieving specific goals. The ventral pallidum (VP) and basolateral amygdala (BLA) are two brain regions that play key roles in regulating behavior motivated by either rewards or threats. However, it is unclear whether these regions are necessary in decision-making processes involving competing motivational drives during conflict. Our aim was to investigate the requirements of the VP and BLA for foraging choices in conflicts involving fear suppression. Here, we used a novel foraging task and pharmacological techniques to inactivate either the VP or BLA, or to disconnect these brain regions before conducting a conflict test. Our findings showed that BLA is necessary for making calculated risky choices during conflicts, whereas VP is necessary for invigorating the drive to obtain food, regardless of the presence of conflict. Importantly, our research revealed that the connection between VP and BLA is critical in limiting risk behaviors when searching for food that requires effort in conflict situations. This study provides a new perspective on the collaborative function of VP and BLA in driving behavior, aimed at achieving goals in the face of danger.

GABA Increases Sensory Transmission In Monkeys
Sensory input flow is central to voluntary movements. For almost a century, GABA was believed to modulate this flow by inhibiting sensory axons in the spinal cord to sculpt neural inputs into skilled motor output. Instead, here we show that GABA can also facilitate sensory transmission in monkeys and consequently increase spinal and cortical neural responses to sensory inputs challenging our understanding of generation and perception of movement.

Pharmacological modulation of dopamine D1 and D2 receptors reveals distinct neural networks related to probabilistic learning in non-human primates.
The neurotransmitter dopamine (DA) has a multifaceted role in healthy and disordered brains through its action on multiple subtypes of dopaminergic receptors. How modulation of these receptors controls behavior by altering connectivity across intrinsic brain-wide networks remains elusive. Here we performed parallel behavioral and resting-state functional MRI experiments after administration of two different DA receptor antagonists in macaque monkeys. Systemic administration of SCH-23390 (D1 antagonist) disrupted probabilistic learning when subjects had to learn new stimulus-reward associations and diminished functional connectivity (FC) in cortico-cortical and fronto-striatal connections. By contrast, haloperidol (D2 antagonist) improved learning and broadly enhanced FC in cortical connections. Further comparison between the effect of SCH-23390/haloperidol on behavioral and resting-state FC revealed specific cortical and subcortical networks associated with the cognitive and motivational effects of DA, respectively. Thus, we reveal the distinct brain-wide networks that are associated with the dopaminergic control of learning and motivation via DA receptors.

Bypassing Striatal Learning Mechanisms Using Delayed Feedback to Circumvent Learning Deficits in TBI
ObjectiveFeedback facilitates learning by guiding and modifying behaviors through an action-outcome contingency. As the majority of existing studies have focused on immediate presentation of feedback, the impact of delayed feedback on learning is understudied. Prior work demonstrated that learning from immediate and delayed feedback employed distinct brain regions in healthy individuals, and compared to healthy individuals, individuals with traumatic brain injury (TBI) are impaired in learning from immediate feedback. The goal of the current investigation was to assess the effects of delayed vs. immediate feedback on learning in individuals with TBI and examine brain networks associated with delayed and immediate feedback processing.

SettingNon-profit research organization.

ParticipantsTwenty-eight individuals with moderate-to-severe TBI.

DesignParticipants completed a paired-associate word learning task while undergoing MRI. During the task, feedback was presented either immediately, after a delay, or not at all (control condition).

Main measuresLearning performance accuracy; confidence ratings; post-task questionnaire, blood-oxygen-level dependent signal.

ResultsBehavioral data showed that delayed feedback resulted in better learning performance than immediate feedback and no feedback. In addition, participants reported higher confidence in their performance during delayed feedback trials. During delayed vs. immediate feedback processing, greater activation was observed in the superior parietal and angular gyrus. Activation in these areas has been previously associated with successful retrieval and greater memory confidence.

ConclusionThe observed results might be explained by delayed feedback processing circumventing the striatal dopaminergic regions responsible for learning from immediate feedback that are impaired in TBI. Additionally, delayed feedback evokes less of an affective reaction than immediate feedback, which likely benefited memory performance. Indeed, compared to delayed feedback, positive or negative immediate feedback was more likely to be rated as rewarding or punishing, respectively. Findings have significant implications for TBI rehabilitation and suggest that delaying feedback during rehabilitation might recruit brain regions that lead to better functional outcomes.

Hippocampal sequences span experience relative to rewards
Hippocampal place cells fire in sequences that span spatial environments, and remap, or change their preferred firing locations, across different environments. This sequential firing is common to multiple modalities beyond space, suggesting that hippocampal activity can anchor to the most behaviorally relevant or salient aspects of experience. As reward is a highly salient event, we hypothesized that broad sequences of hippocampal activity can likewise become anchored relative to reward. To test this hypothesis, we performed two-photon imaging of calcium activity in hippocampal area CA1 as mice navigated virtual linear environments with multiple changing hidden reward locations. We found that when the reward moved, a subpopulation of cells remapped to the same relative position with respect to reward, including previously undescribed cells with fields distant from reward. These reward-relative cells constructed sequences that spanned the task structure irrespective of spatial stimuli. The density of the reward-relative sequences increased with task experience as additional neurons were recruited to the reward-relative population. In contrast, a largely separate subpopulation of cells maintained a place code relative to the spatial environment. These findings provide insight into how separate hippocampal ensembles may flexibly encode multiple behaviorally salient reference frames, reflecting the structure of the experience.

Neural Speech-Tracking During Selective Attention and Attention-Switching Between Concurrent Talkers: A spatially realistic audiovisual study
Selective attention to a talker in multi-talker scenarios, is associated with enhanced neural speech-tracking of the target talker, relative to competing non-target talkers. This response is proposed to reflect the prioritization and preferential processing of the target speech in auditory and language related regions. Here we investigated whether this neural-bias for tracking target speech, persists also after listeners actively switch their attention to another target talker. Using a spatially-realistic audiovisual design, we studied responses at both the group and individual level.

Participants watched a video lecture (target speech) on a screen in front of them, which they were instructed to pay attention to and answered comprehension questions about its content. Concurrently, audio from an additional lecture, by a different talker, was played though a loudspeaker to their left, which they were told to ignore (non-target speech). Importantly, in the middle of the experiment, the lectures serving as target and non-target switched roles: the lecture that was formerly non-target was presented as a video on the central screen and became the target, and vice versa. We compared behavioral performance and neural speech-tracking of both lectures before and after the switch, to test how effectively participants switched their attention and whether there are carry-over effects from before the switch.

At the group level, we found no significant differences in performance or in the neural-bias towards the target talker before vs. after the switch. This implies that, generally speaking, selective attention was just as effective after the switch as it was before. However, analysis of individual level data revealed a more complex and diverse pattern. We found that the neural group level results were driven by only 25% of participants, who showed consistent neural-bias towards the target talker both before and after the switch. However, 50% of participants showed neural-bias towards the target talker only in one half of the experiment, and an additional 25% showed no difference in the neural representation of the target vs. non-target speech, before or after the switch. We further show that these individual differences cannot be trivially explained by poor signal quality, nor are they associated with behavioral performance. Rather, they suggest that neural-bias towards the target talker is not a prerequisite for selective attention performance, and in many cases target and non-target speech are co-represented in the neural signal. Whether this variability reflects the employment of different listening strategies or insufficient sensitivity of the neural-bias speech-tracking metric remains to be explored in future studies. However, these results challenge the assumptions that modulation of the speech-tracking response can be used as a one-to-one proxy for selective attention to speech in multi-talker contexts.

Neuroprotective Effects Of VEGF-B In A Murine Model Of Aggressive Neuronal Loss With Childhood Onset
In recent decades, the scientific community has faced a major challenge in the search for new therapies that can slow down or alleviate the process of neuronal death that accompanies neurodegenerative diseases. This study aimed at identifying an effective therapy using neurotrophic factors to delay the rapid and aggressive cerebellar degeneration experienced by the Purkinje Cell Degeneration (PCD) mouse, a model of childhood-onset neurodegeneration with cerebellar atrophy (CONDCA). Initially, we analyzed the changes in the expression of several neurotrophic factors related to the degenerative process itself, identifying changes in insulin-like growth factor 1 (IGF-1) and Vascular Endothelial Growth Factor B (VEGF-B) in the affected animals. Then, we administered pharmacological treatments using human recombinant IGF-1 (rhIGF-1) or VEGF-B (rhVEGF-B) proteins, considering their temporal variations during the degenerative process. The effects of these treatments on motor, cognitive, and social behavior, as well as on cerebellar destructuration were analyzed. Whereas treatment with rhIGF-1 did not demonstrate any neuroprotective effect, rhVEGF-B administration at moderate dosages stopped the process of neuronal death and restored motor, cognitive, and social functions altered in PCD mice (and CONDCA patients). Additionally, we demonstrate that this neuroprotective effect was achieved through a partial inhibition or delay of apoptosis. These findings provide strong evidence supporting the use of rhVEGF-B as a pharmacological agent to limit severe cerebellar neurodegenerative processes.

A systematic review of delayed cerebral ischemia in experimental mouse models after subarachnoid hemorrhage
BackgroundThe occurrence of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage is a main determinant for functional outcome. Despite two decades of animal studies investigating novel treatment strategies, the standard therapy for delayed cerebral ischemia has not changed. This translational gap raises the question to what extent experimental mouse models of subarachnoid hemorrhage can accurately mimic human delayed cerebral ischemia. The objective of this systematic review was to determine whether there are difference in the occurrence and timing of delayed cerebral ischemia between the various experimental mouse models of aneurysmal subarachnoid hemorrhage. Our aim was to identify which mouse model most closely mimics the human pathophysiology following aneurysmal subarachnoid hemorrhage.

MethodsThis study was funded by ZonMw (project number 114024130). The review was preregistered at PROSPERO (protocol ID: CRD42020115578). A comprehensive search was performed in Medline via the PubMed interface and in EMBASE via the Ovid interface up to 2nd November 2018The following exclusion criteria were used in both the title and abstract and full text phase: 1) not an original, full-length research paper, 2) no English language version available, 3) published before 1999, 4) not an animal study, 5) not a mouse study, 6) use of transgenic mice, 7) no subarachnoid hemorrhage induction, 8) no delayed cerebral ischemia measured, 9) reported an observation time less than six hours, 10) cross-over study, or any study design without a control group. Data was extracted by one reviewer. The SYRCLE risk of bias tool was used in duplo by two independent reviewers to assess risks of bias in the included studies, with discrepancies being resolved through discussion. A narrative synthesis of the evidence was performed.

ResultsThe literature search retrieved a total of 1461 papers, of which 71 publications met the inclusion criteria. Most studies were assessed at an unclear risk for most types of bias. Mice models were highly standardized: the C57Bl/6 strain was used in 53 studies (74.6%), only male animals were used in 55 studies (77.5%). To model a subarachnoid hemorrhage, perforation of the anterior cerebral artery / internal carotid artery with a suture was performed in 43 studies (60.6%), while direct injection of blood was performed in 24 studies (33.8%). The presence of delayed cerebral ischemia was established through neurological outcomes (44 studies, 62.0%), ex-vivo histology (39 studies, 54.9%) or in-vivo imaging (10 studies, 14.1%) assessment. Incidence of delayed cerebral ischemia was similarly high for all outcome measures (between 85-87%) and the timing of delayed cerebral ischemia occurrence was similar, despite differences in subarachnoid hemorrhage induction method.

ConclusionOur results show that established perforation and injection-models for experimental subarachnoid hemorrhage are highly standardized. Yet, there is a high inconsistency in definitions of delayed cerebral ischemia in experimental mouse models. Although perforation model results in a higher rate of delayed cerebral ischemia, there is no effect on the time of occurrence after ictus. It is unclear to what extent the delayed cerebral ischemia demonstrated in these animal models is comparable to the clinical situation.

Effects of local brain temperature on somatosensory evoked potentials in rats
Although the focal brain cooling technique is widely used to examine brain function, the effects of variations in cortical temperature on sensory information processing and neural mechanisms remain underexplored. To elucidate the mechanisms of temperature modulation in somatosensory processing, this study aimed to examine how P1 and N1 deflections of somatosensory evoked potentials (SEPs) depend on cortical temperature and how excitatory and inhibitory inputs contribute to this temperature dependency. SEPs were generated through electrical stimulation of the contralateral forepaw in anesthetized rats. The SEPs were recorded while cortical temperatures were altered between 18-37{degrees}C: without any antagonists; with gamma-aminobutyric acid type A (GABAA) receptor antagonist, gabazine; with aminomethylphosphonic acid (AMPA) receptor antagonist (NBQX), or N-Methyl-D-aspartic acid (NMDA) receptor antagonist ([R]-CPP). The effects of different gabazine concentrations (0, 1, and 10 {micro}M) were examined in the 35-38{degrees}C range. The P1/N1 amplitudes and their peak- to-peak differences plotted against cortical temperature showed an inverted U relationship with their maximum at approximately 27.5{degrees}C when no antagonists were administered. The negative correlation between these amplitudes and temperatures [≥]27.5{degrees}C plateaued after gabazine administration, which occurred progressively as the gabazine concentration increased. In contrast, the correlation remained negative after the administration of NBQX and (R)-CPP. GABAergic inhibitory inputs contribute to the negative correlation between SEP amplitude and cortical temperature around the physiological cortical temperature by suppressing SEPs to a greater extent at higher temperatures.