Current research in neurobiology最新文献

Statistical learning (SL) is an innate mechanism by which the brain automatically encodes the n-th order transition probability (TP) of a sequence and grasps the uncertainty of the TP distribution. Through SL, the brain predicts a subsequent event (e_n+1) based on the preceding events (e_n) that have a length of “n”. It is now known that uncertainty modulates prediction in top-down processing by the human predictive brain. However, the manner in which the human brain modulates the order of SL strategies based on the degree of uncertainty remains an open question. The present study examined how uncertainty modulates the neural effects of SL and whether differences in uncertainty alter the order of SL strategies. It used auditory sequences in which the uncertainty of sequential information is manipulated based on the conditional entropy. Three sequences with different TP ratios of 90:10, 80:20, and 67:33 were prepared as low-, intermediate, and high-uncertainty sequences, respectively (conditional entropy: 0.47, 0.72, and 0.92 bit, respectively). Neural responses were recorded when the participants listened to the three sequences. The results showed that stimuli with lower TPs elicited a stronger neural response than those with higher TPs, as demonstrated by a number of previous studies. Furthermore, we found that participants adopted higher-order SL strategies in the high uncertainty sequence. These results may indicate that the human brain has an ability to flexibly alter the order based on the uncertainty. This uncertainty may be an important factor that determines the order of SL strategies. Particularly, considering that a higher-order SL strategy mathematically allows the reduction of uncertainty in information, we assumed that the brain may take higher-order SL strategies when encountering high uncertain information in order to reduce the uncertainty. The present study may shed new light on understanding individual differences in SL performance across different uncertain situations.

Accumulating evidence across multiple sensory modalities suggests that the thalamus does not simply relay information from the periphery to the cortex. Here we review recent findings showing that vestibular neurons within the ventral posteriolateral area of the thalamus perform nonlinear transformations on their afferent input that determine our subjective awareness of motion. Specifically, these neurons provide a substrate for previous psychophysical observations that perceptual discrimination thresholds are much better than predictions from Weber's law. This is because neural discrimination thresholds, which are determined from both variability and sensitivity, initially increase but then saturate with increasing stimulus amplitude, thereby matching the previously observed dependency of perceptual self-motion discrimination thresholds. Moreover, neural response dynamics give rise to unambiguous and optimized encoding of natural but not artificial stimuli. Finally, vestibular thalamic neurons selectively encode passively applied motion when occurring concurrently with voluntary (i.e., active) movements. Taken together, these results show that the vestibular thalamus plays an essential role towards generating motion perception as well as shaping our vestibular sense of agency that is not simply inherited from afferent input.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Increasing evidence points to the thalamus as an important hub in the clinical symptomatology of the disease, with the ‘limbic thalamus’ been described as especially vulnerable. In this work, we examined thalamic atrophy in early-onset AD (EOAD) and late-onset AD (LOAD) compared to young and old healthy controls (YHC and OHC, respectively) using a recently developed cutting-edge thalamic nuclei segmentation method. A deep learning variant of Thalamus Optimized Multi Atlas Segmentation (THOMAS) was used to parcellate 11 thalamic nuclei per hemisphere from T1-weighted MRI in 88 biomarker-confirmed AD patients (49 EOAD and 39 LOAD) and 58 healthy controls (41 YHC and 17 OHC) with normal AD biomarkers. Nuclei volumes were compared among groups using MANCOVA. Further, Pearson's correlation coefficient was computed between thalamic nuclear volume and cortical—subcortical regions, CSF tau levels, and neuropsychological scores. The results showed widespread thalamic nuclei atrophy in EOAD and LOAD compared to their respective healthy control groups, with EOAD showing additional atrophy in the centromedian and ventral lateral posterior nuclei compared to YHC. In EOAD, increased thalamic nuclei atrophy was associated with posterior parietal atrophy and worse visuospatial abilities, while LOAD thalamic nuclei atrophy was preferentially associated with medial temporal atrophy and worse episodic memory and executive function. Our findings suggest that thalamic nuclei may be differentially affected in AD according to the age at symptoms onset, associated with specific cortical—subcortical regions, CSF total tau and cognition.

As science and technology evolve, there is an increasing need for promotion of international scientific exchange. Collaborations, while offering substantial opportunities for scientists and benefit to society, also present challenges for those working with animal models, such as non-human primates (NHPs). Diversity in regulation of animal research is sometimes mistaken for the absence of common international welfare standards. Here, the ethical and regulatory protocols for 13 countries that have guidelines in place for biomedical research involving NHPs were assessed with a focus on neuroscience. Review of the variability and similarity in trans-national NHP welfare regulations extended to countries in Asia, Europe and North America. A tabulated resource was established to advance solution-oriented discussions and scientific collaborations across borders. Our aim is to better inform the public and other stakeholders. Through cooperative efforts to identify and analyze information with reference to evidence-based discussion, the proposed key ingredients may help to shape and support a more informed, open framework. This framework and resource can be expanded further for biomedical research in other countries.

Anxiety disorders are among the most prevalent psychiatric disorders, with symptoms often beginning early in life. To model the pathophysiology of human pathological anxiety, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in a nonhuman primate model of anxious temperament to selectively increase neuronal activity of the amygdala. Subjects included 10 young rhesus macaques; 5 received bilateral infusions of AAV5-hSyn-HA-hM3Dq into the dorsal amygdala, and 5 served as controls. Subjects underwent behavioral testing in the human intruder paradigm following clozapine or vehicle administration, prior to and following surgery. Behavioral results indicated that clozapine treatment post-surgery increased freezing across different threat-related contexts in hM3Dq subjects. This effect was again observed approximately 1.9 years following surgery, indicating the long-term functional capacity of DREADD-induced neuronal activation. [¹¹C]deschloroclozapine PET imaging demonstrated amygdala hM3Dq-HA specific binding, and immunohistochemistry revealed that hM3Dq-HA expression was most prominent in basolateral nuclei. Electron microscopy confirmed expression was predominantly on neuronal membranes. Together, these data demonstrate that activation of primate amygdala neurons is sufficient to induce increased anxiety-related behaviors, which could serve as a model to investigate pathological anxiety in humans.

We have previously demonstrated that macaque monkeys can behaviorally detect a subtle optogenetic impulse delivered to their inferior temporal (IT) cortex. We have also shown that the ability to detect the cortical stimulation impulse varies depending on some characteristics of the visual images viewed at the time of brain stimulation, revealing the visual nature of the perceptual events induced by stimulation of the IT cortex. Here we systematically studied the effect of the size of viewed objects on behavioral detectability of optogenetic stimulation of the central IT cortex. Surprisingly, we found that behavioral detection of the same optogenetic impulse highly varies with the size of the viewed object images. Reduction of the object size in four steps from 8 to 1 degree of visual angle significantly decreased detection performance. These results show that identical stimulation impulses delivered to the same neural population induce variable perceptual events depending on the mere size of the objects viewed at the time of brain stimulation.

Burst activity is a ubiquitous feature of thalamic neurons and is well documented for visual neurons in the lateral geniculate nucleus (LGN). Although bursts are often associated with states of drowsiness, they are also known to convey visual information to cortex and are particularly effective in evoking cortical responses. The occurrence of thalamic bursts depends on (1) the inactivation gate of T-type Ca²⁺ channels (T-channels), which become de-inactivated following periods of increased membrane hyperpolarization, and (2) the opening of the T-channel activation gate, which has voltage-threshold and rate-of-change (δv/δt) requirements. Given the time/voltage relationship for the generation of Ca²⁺ potentials that underlie burst events, it is reasonable to predict that geniculate bursts are influenced by the luminance contrast of drifting grating stimuli, with the null phase of higher contrast stimuli evoking greater hyperpolarization followed by a larger dv/dt than the null phase of lower contrast stimuli. To determine the relationship between stimulus contrast and burst activity, we recorded the spiking activity of cat LGN neurons while presenting drifting sine-wave gratings that varied in luminance contrast. Results show that burst rate, reliability, and timing precision are significantly greater with higher contrast stimuli compared with lower contrast stimuli. Additional analysis from simultaneous recordings of synaptically connected retinal ganglion cells and LGN neurons further reveals the time/voltage dynamics underlying burst activity. Together, these results support the hypothesis that stimulus contrast and the biophysical properties underlying the state of T-type Ca²⁺ channels interact to influence burst activity, presumably to facilitate thalamocortical communication and stimulus detection.

The functional specialization of the ventral stream in Perception and the dorsal stream in Action is the cornerstone of the leading model proposed by Goodale and Milner in 1992. This model is based on neuropsychological evidence and has been a matter of debate for almost three decades, during which the dual-visual stream hypothesis has received much attention, including support and criticism. The advent of functional magnetic resonance imaging (fMRI) has allowed investigating the brain areas involved in Perception and Action, and provided useful data on the functional specialization of the two streams. Research on this topic has been quite prolific, yet no meta-analysis so far has explored the spatial convergence in the involvement of the two streams in Action. The present meta-analysis (N = 53 fMRI and PET studies) was designed to reveal the specific neural activations associated with Action (i.e., grasping and reaching movements), and the extent to which visual information affects the involvement of the two streams during motor control. Our results provide a comprehensive view of the consistent and spatially convergent neural correlates of Action based on neuroimaging studies conducted over the past two decades. In particular, occipital-temporal areas showed higher activation likelihood in the Vision compared to the No vision condition, but no difference between reach and grasp actions. Frontal-parietal areas were consistently involved in both reach and grasp actions regardless of visual availability. We discuss our results in light of the well-established dual-visual stream model and frame these findings in the context of recent discoveries obtained with advanced fMRI methods, such as multivoxel pattern analysis.

Mutations in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The pathogenetic mechanisms linked to this gene are a direct consequence of an aberrant intronic expansion of a GGGGCC hexanucleotide located between the 1a and 1b non-coding exons, which can be transcribed to form cytotoxic RNA foci or even translated into aggregation-prone dipeptide repeat proteins. Importantly, the abnormal length of these repeats affects also the expression levels of C9orf72 itself, which suggests haploinsufficiency as additional pathomechanism. Thus, it appears that both toxic gain of function and loss of function are distinct but still coexistent features contributing to the insurgence of the disease in case of C9orf72 mutations. In this study, we aimed at identifying a strategy to address both aspects of the C9orf72-related pathobiochemistry and provide proof-of-principle information for a better understanding of the mechanisms leading to neuronal loss. By using primary neurons overexpressing toxic poly(GA), the most abundant protein product of the GGGGCC repeats, we found that the antiarrhythmic drug propranolol could efficiently reduce the accumulation of aberrant aggregates and increase the survival of C9orf72-related cultures. Interestingly, the improved catabolism appeared to not depend on major degradative pathways such as autophagy and the proteasome. By analyzing the proteome of poly(GA)-expressing neurons after exposure to propranolol, we found that the drug increased lysosomal degradation through a mechanism directly involving C9orf72 protein, whose levels were increased after treatment. Further confirmation of the beneficial effect of the beta blocker on aggregates' accumulation and survival of hiPSC-derived C9orf72-mutant motoneurons strengthened the finding that addressing both facets of C9orf72 pathology might represent a valid strategy for the treatment of these ALS/FTD cases.

The K⁺ channel blocker 4-aminopyridine (4AP) has been extensively used to investigate the mechanisms underlying neuronal network synchronization in both in vitro and in vivo animal models of focal epilepsy. 4AP-induced effects are paralleled by an increase in both excitatory and inhibitory neurotransmitter release, but the mechanisms of action of 4AP on neuronal networks remain unclear. By employing simultaneous whole-cell patch clamp and field potential recordings from hippocampal CA3/4 pyramidal layer of acute brain slices obtained from mice (n = 30), we found that the appearance of epileptiform discharges induced by 4AP (100 μM) is consistently preceded by the transient recurrence of presumptive GABA_B outward currents, which are not mirrored by any field activity. These GABA_B outward currents still occurred during application of ionotropic glutamatergic antagonists (n = 12 cells) but were blocked by the GABA_B receptor antagonist CGP55845 (n = 7). Our findings show that the transient occurrence of distinct GABA_B outward currents precedes the appearance of 4AP-induced neuronal network synchronization leading to epileptiform activity in the rodent hippocampus in vitro.