eNeuro最新文献

Episodic memory, the ability to recall specific events and experiences, is a cornerstone of human cognition with profound clinical implications. While animal studies have provided valuable insights into the neuronal underpinnings of episodic memory, research has largely relied on a limited subset of tasks that model only some aspects of episodic memory. In this narrative review, we provide an overview of rodent episodic-like memory tasks that expand the methodological repertoire and diversify the approaches used in episodic-like memory research. These tasks assess various aspects of human episodic memory, such as integrated what-where-when or what-where memory, source memory, free recall, temporal binding, and threshold retrieval dynamics. We review each task's general principle and consider whether alternative non-episodic mechanisms can account for the observed behavior. While our list of tasks is not exhaustive, we hope it will guide researchers in selecting models that align with their specific research objectives, leading to novel advancements and a more comprehensive understanding of mechanisms underlying specific aspects of episodic memory.

Uncovering the relationships between neural circuits, behavior, and neural dysfunction may require rodent pose tracking. While open-source toolkits such as DeepLabCut have revolutionized markerless pose estimation using deep neural networks, the training process still requires human intervention for annotating key points of interest in video data. To further reduce human labor for neural network training, we developed a method that automatically generates annotated image datasets of rodent paw placement in a laboratory setting. It uses invisible but fluorescent markers that become temporarily visible under UV light. Through stroboscopic alternating illumination, adjacent video frames taken at 720 Hz are either UV or white light illuminated. After color filtering the UV-exposed video frames, the UV markings are identified and the paw locations are deterministically mapped. This paw information is then transferred to automatically annotate paw positions in the next white light-exposed frame that is later used for training the neural network. We demonstrate the effectiveness of our method using a KineWheel-DeepLabCut setup for the markerless tracking of the four paws of a harness-fixed mouse running on top of the transparent wheel with mirror. Our automated approach, made available open-source, achieves high-quality position annotations and significantly reduces the need for human involvement in the neural network training process, paving the way for more efficient and streamlined rodent pose tracking in neuroscience research.

Peak-alpha frequency varies across individuals and mental states, but it also forms a negative gradient from posterior to anterior regions in association with increases in cortical thickness and connectivity, reflecting a cortical hierarchy in temporal integration. Tracking the spatial standard deviation of peak-alpha frequency in scalp EEG, we observed that a posterior-to-anterior gradient dynamically formed and dissolved. Periods of high spatial standard deviation yielded robustly negative posterior-to-anterior gradients-the "gradient state"-while periods of low spatial standard deviation yielded globally converged peak-alpha frequency-the "uniform state." The state variations were characterized by a combination of slow (0.3-0.5 Hz) oscillations and random-walk-like fluctuations. They were relatively independently correlated with peak-alpha frequency variations in anterior regions and peak-alpha power variations in central regions driven by posterior regions (together accounting for ∼50% of the state variations), suggesting that two distinct mechanisms modulate the state variations: an anterior mechanism that directly adjusts peak-alpha frequencies and a posterior-central mechanism that indirectly adjusts them by influencing synchronization. The state variations likely reflect general operations as their spatiotemporal characteristics remained unchanged while participants engaged in a variety of tasks (breath focus, vigilance, working memory, mental arithmetic, and generative thinking) with their eyes closed or watched a silent nature video. The ongoing state variations may dynamically balance two global processing modes, one that facilitates greater temporal integration (and potentially also information influx) toward anterior regions in the gradient state and the other that facilitates flexible global communication (via phase locking) in the uniform state.

Volatile anesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Anesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This possibility is supported by the finding that taxane chemotherapy consisting of MT-stabilizing drugs reduces the effectiveness of anesthesia during surgery in human cancer patients. In order to experimentally assess the contribution of MTs as functionally relevant targets of volatile anesthetics, we measured latencies to loss of righting reflex (LORR) under 4% isoflurane in male rats injected subcutaneously with vehicle or 0.75 mg/kg of the brain-penetrant MT-stabilizing drug epothilone B (epoB). EpoB-treated rats took an average of 69 s longer to become unconscious as measured by latency to LORR. This was a statistically significant difference corresponding to a standardized mean difference (Cohen's d) of 1.9, indicating a "large" normalized effect size. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results suggest that binding of the anesthetic gas isoflurane to MTs causes unconsciousness and loss of purposeful behavior in rats (and presumably humans and other animals). This finding is predicted by models that posit consciousness as a property of a quantum physical state of neural MTs.

Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition.

ATP1A3 is a Na,K-ATPase gene expressed specifically in neurons in the brain. Human mutations are dominant and produce an unusually wide spectrum of neurological phenotypes, most notably rapid-onset dystonia parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). Here we compared heterozygotes of two mouse lines, a line with little or no expression (Atp1a3^tm1Ling/+) and a knock-in expressing p.Asp801Tyr (D801Y, Atp1a3 ^+/D801Y). Both mouse lines had normal lifespans, but Atp1a3 ^+/D801Y had mild perinatal mortality contrasting with D801N mice (Atp1a3 ^+/D801N), which had high mortality. The phenotypes of Atp1a3^tm1Ling/+ and Atp1a3 ^+/D801Y were different, and testing of each strain was tailored to its symptom range. Atp1a3^tm1Ling/+ mice displayed little at baseline, but repeated ethanol intoxication produced hyperkinetic motor abnormalities not seen in littermate controls. Atp1a3 ^+/D801Y mice displayed robust phenotypes: hyperactivity, diminished posture consistent with hypotonia, and deficiencies in beam walk and wire hang tests. Symptoms also included qualitative motor abnormalities that are not well quantified by conventional tests. Paradoxically, Atp1a3 ^+/D801Y showed sustained better performance than wild type on the accelerating rotarod. Atp1a3 ^+/D801Y mice were overactive in forced swimming and afterward had intense shivering, transient dystonic postures, and delayed recovery. Remarkably, Atp1a3 ^+/D801Y mice were refractory to ketamine anesthesia, which elicited hyperactivity and dyskinesia even at higher dose. Neither mouse line exhibited fixed dystonia (typical of RDP patients), spontaneous paroxysmal weakness (typical of AHC patients), or seizures but had consistent, measurable neurological abnormalities. A gradient of variation supports the importance of studying multiple Atp1a3 mutations in animal models to understand the roles of this gene in human disease.

Hunger and thirst drive animals' consumption behavior and regulate their decision-making concerning rewards. We previously assessed the thirst states of monkeys by measuring blood osmolality under controlled water access and examined how these thirst states influenced their risk-taking behavior in decisions involving fluid rewards. However, hunger assessment in monkeys remains poorly performed. Moreover, the lack of precise measures for hunger states leads to another issue regarding how hunger and thirst states interact with each other in each individual. Thus, when controlling food access to motivate performance, it remains unclear how these two physiological needs are satisfied in captive monkeys. Here, we measured blood ghrelin and osmolality levels to respectively assess hunger and thirst in four captive macaques. Using an enzyme-linked immunosorbent assay, we identified that the levels of blood ghrelin, a widely measured hunger-related peptide hormone in humans, were high after 20 h of no food access (with ad libitum water). This reflects a typical controlled food access condition. One hour after consuming a regular dry meal, the blood ghrelin levels in three out of four monkeys decreased to within their baseline range. Additionally, blood osmolality measured from the same blood sample, the standard hematological index of hydration status, increased after consuming the regular dry meal with no water access. Thus, ghrelin and osmolality may reflect the physiological states of individual monkeys regarding hunger and thirst, suggesting that these indices can be used as tools for monitoring hunger and thirst levels that mediate an animal's decision to consume rewards.

Sensory axons projecting to the central nervous system are organized into topographic maps that represent the locations of sensory stimuli. In some sensory systems, even adjacent sensory axons are arranged topographically, forming "fine-scale" topographic maps. Although several broad molecular gradients are known to instruct coarse topography, we know little about the molecular signaling that regulates fine-scale topography at the level of two adjacent axons. Here, we provide evidence that transsynaptic bone morphogenetic protein (BMP) signaling mediates local interneuronal communication to regulate fine-scale topography in the nociceptive system of Drosophila larvae. We first show that the topographic separation of the axon terminals of adjacent nociceptors requires their common postsynaptic target, the A08n neurons. This phenotype is recapitulated by knockdown of the BMP ligand, Decapentaplegic (Dpp), in these neurons. In addition, removing the Type 2 BMP receptors or their effector (Mad transcription factor) in single nociceptors impairs the fine-scale topography, suggesting the contribution of BMP signaling originated from A08n. This signaling is likely mediated by phospho-Mad in the presynaptic terminals of nociceptors to ensure local interneuronal communication. Finally, reducing Dpp levels in A08n reduces the nociceptor-A08n synaptic contacts. Our data support that transsynaptic BMP signaling establishes the fine-scale topography by facilitating the formation of topographically correct synapses. Local BMP signaling for synapse formation may be a developmental strategy that independently regulates neighboring axon terminals for fine-scale topography.

Long-term aluminum (Al) exposure increases the risk of mild cognitive impairment (MCI). The aim of the present study was to investigate the neural mechanisms of Al-induced MCI. In our study, a total of 52 individuals with occupational Al exposure >10 years were enrolled and divided into two groups: MCI (Al-MCI) and healthy controls (Al-HC). Plasma Al concentrations and Montreal Cognitive Assessment (MoCA) score were collected for all participants. And diffusion tensor imaging and resting-state functional magnetic resonance imaging were used to examine changes of white matter (WM) and functional connectivity (FC). There was a negative correlation between MoCA score and plasma Al concentration. Compared with the Al-HC, fractional anisotropy value for the right fornix (cres)/stria terminalis (FX/ST) was higher in the Al-MCI. Furthermore, there was a difference in FC between participants with and without MCI under Al exposure. We defined the regions with differing FC as a "pathway," specifically the connectivity from the right temporal pole to the right FX/ST, then to the right sagittal stratum, and further to the right anterior cingulate and paracingulate gyri and right inferior frontal gyrus, orbital part. In summary, we believe that the observed differences in WM integrity and FC in the right FX/ST between participants with and without MCI under long-term Al exposure may represent the neural mechanisms underlying MCI induced by Al exposure.

Recent advances in extracellular electrophysiology now facilitate the recording of spikes from hundreds or thousands of neurons simultaneously. This has necessitated both the development of new computational methods for spike sorting and better methods to determine spike-sorting accuracy. One long-standing method of assessing the false discovery rate (FDR) of spike sorting-the rate at which spikes are assigned to the wrong cluster-has been the rate of interspike interval (ISI) violations. Despite their near ubiquitous usage in spike sorting, our understanding of how exactly ISI violations relate to FDR, as well as best practices for using ISI violations as a quality metric, remains limited. Here, we describe an analytical solution that can be used to predict FDR from the ISI violation rate (ISI_v). We test this model in silico through Monte Carlo simulation and apply it to publicly available spike-sorted electrophysiology datasets. We find that the relationship between ISI_v and FDR is highly nonlinear, with additional dependencies on firing frequency, the correlation in activity between neurons, and contaminant neuron count. Predicted median FDRs in public datasets recorded in mice were found to range from 3.1 to 50.0%. We found that stochasticity in the occurrence of ISI violations as well as uncertainty in cluster-specific parameters make it difficult to predict FDR for single clusters with high confidence but that FDR can be estimated accurately across a population of clusters. Our findings will help the growing community of researchers using extracellular electrophysiology assess spike-sorting accuracy in a principled manner.