Journal of Neuroscience最新文献

Growth hormone (GH) action in the brain regulates neuroendocrine axes, energy and glucose homeostasis, and several neurological functions. The lateral hypothalamic area (LHA) contains numerous neurons that respond to a systemic GH injection by expressing the phosphorylated STAT5, a GH receptor (GHR) signaling marker. However, the potential role of GHR signaling in the LHA is unknown. In this study, we demonstrated that ∼70% of orexin- and leptin receptor (LepR)-expressing neurons in the LHA are responsive to GH. Male mice carrying inactivation of the Ghr gene in the LHA were generated via bilateral injections of an adeno-associated virus. In ad libitum-fed mice, GHR ablation in LHA neurons did not significantly change energy and glucose homeostasis. Subsequently, mice were subjected to 5 d of 40% food restriction. Food restriction decreased body weight, energy expenditure, and carbohydrate oxidation. These effects were similarly observed in control and LHA^ΔGHR mice. While food-deprived control mice progressively increased ambulatory/exploratory activity and food-seeking behavior, LHA^ΔGHR mice did not show hyperactivity induced by food restriction. GHR ablation in the LHA reduced the percentage of orexin neurons expressing c-Fos during food restriction. Additionally, an acute GH injection increased the expression of c-Fos in LHA^ORX neurons. Inactivation of Ghr in LepR-expressing cells did not prevent hyperactivity in food-deprived mice, whereas whole-brain Ghr knock-out mice showed reduced ambulatory activity during food restriction. Our findings indicate that GHR signaling in the LHA regulates the activity of orexin neurons and is necessary to increase food-seeking behavior in food-deprived male mice.

The human auditory cortex is organized according to the timing and spectral characteristics of speech sounds during speech perception. During listening, the posterior superior temporal gyrus is organized according to onset responses, which segment acoustic boundaries in speech, and sustained responses, which further process phonological content. When we speak, the auditory system is actively processing the sound of our own voice to detect and correct speech errors in real time. This manifests in neural recordings as suppression of auditory responses during speech production compared with perception, but whether this differentially affects the onset and sustained temporal profiles is not known. Here, we investigated this question using intracranial EEG recorded from seventeen pediatric, adolescent, and adult patients with medication-resistant epilepsy while they performed a reading/listening task. We identified onset and sustained responses to speech in the bilateral auditory cortex and observed a selective suppression of onset responses during speech production. We conclude that onset responses provide a temporal landmark during speech perception that is redundant with forward prediction during speech production and are therefore suppressed. Phonological feature tuning in these "onset suppression" electrodes remained stable between perception and production. Notably, auditory onset responses and phonological feature tuning were present in the posterior insula during both speech perception and production, suggesting an anatomically and functionally separate auditory processing zone that we believe to be involved in multisensory integration during speech perception and feedback control.

Viewing brain function through the lens of other physiological processes has critically added to our understanding of human cognition. Further advances though may need a closer look at the interactions between these physiological processes themselves. Here we characterize the interplay of the highly periodic, and metabolically vital respiratory process and fluctuations in arousal neuromodulation, a process classically seen as nonperiodic. In the data from three experiments (N = 56 / 27 / 25 women and men), we tested for covariations in respiratory and pupil size (arousal) dynamics. After substantiating a robust coupling in the largest dataset, we further show that coupling strength decreases during task performance compared with rest and that it mirrors a decreased respiratory rate when participants take deeper breaths. Taken together, these findings suggest a stronger link between respiratory and arousal processes than previously thought. Moreover, these links imply a stronger coupling during periods of rest, and the effect of respiratory rate on the coupling suggests a driving role. As a consequence, studying the role of neuromodulatory arousal on cortical function may also need to consider respiratory influences.

Merkel cell-neurite complexes (MNCs) are enriched in touch-sensitive areas, including whisker hair follicles and the glabrous skin of the rodent's paws, where tactile stimulation elicits slowly adapting type 1 (SA1) tactile impulses to encode for the sense of touch. Recently, we have shown with rodent whisker hair follicles that SA1 impulses are generated through fast excitatory synaptic transmission at MNCs and driven by acid-sensing ion channels (ASICs). However, it is currently unknown whether, besides whisker hair follicles, ASICs also play an essential role in generating SA1 impulses from MNCs of other body parts in mammals. In the present study, we attempted to address this question by using the skin-nerve preparations made from the hindpaw glabrous skin and tibial nerves of both male and female rodents and applying the pressure-clamped single-fiber recordings. We showed that SA1 impulses elicited by tactile stimulation to the rat hindpaw glabrous skin were largely diminished in the presence of amiloride and diminazene, two ASIC channel blockers. Furthermore, using the hindpaw glabrous skin and tibial nerve preparations made from the mice genetically deleted of ASIC3 channels (ASIC3^-/-), we showed that the frequency of SA1 impulses was significantly lower in ASIC3^-/- mice than in littermate wild-type ASIC3^+/+ mice, a result consistent with the pharmacological experiments with ASIC channel blockers. Our findings suggest that ASIC channels are essential for generating SA1 impulses to underlie the sense of touch in the glabrous skin of rodent hindpaws.

In daily life, we coordinate both simultaneous and sequential bimanual movements to manipulate objects. Our ability to rapidly account for different object dynamics suggests there are neural mechanisms to quickly deal with them. Here we investigate how actions of one arm can serve as a contextual cue for the other arm and facilitate adaptation. Specifically, we examine the temporal characteristics that underlie motor memory formation and recall, by testing the contextual effects of prior, simultaneous, and post contralateral arm movements in both male and female human participants. To do so, we measure their temporal generalization in three bimanual interference tasks. Importantly, the timing context of the learned action plays a pivotal role in the temporal generalization. While motor memories trained with post adaptation contextual movements generalize broadly, motor memories trained with prior contextual movements exhibit limited generalization, and motor memories trained with simultaneous contextual movements do not generalize to prior or post contextual timings. This highlights temporal tuning in sensorimotor plasticity: different training conditions yield substantially different temporal generalization characteristics. Since these generalizations extend far beyond any variability in training times, we suggest that the observed differences may stem from inherent differences in the use of prior, current, and post adaptation contextual information in the generation of natural behavior. This would imply differences in the underlying neural circuitry involved in learning and executing the corresponding coordinated bimanual movements.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (App^G-F mice) to avoid potential deleterious effects of the Swedish mutation and generated App^G-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, the introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.

Humans possess a remarkable ability to rapidly access diverse information from others' faces with just a brief glance, which is crucial for intricate social interactions. While previous studies using event-related potentials/fields have explored various face dimensions during this process, the interplay between these dimensions remains unclear. Here, by applying multivariate decoding analysis to neural signals recorded with optically pumped magnetometer magnetoencephalography, we systematically investigated the temporal interactions between invariant and variable aspects of face stimuli, including race, gender, age, and expression. First, our analysis revealed unique temporal structures for each face dimension with high test-retest reliability. Notably, expression and race exhibited a dominant and stably maintained temporal structure according to temporal generalization analysis. Further exploration into the mutual interactions among face dimensions uncovered age effects on gender and race, as well as expression effects on race, during the early stage (∼200-300 ms postface presentation). Additionally, we observed a relatively late effect of race on gender representation, peaking ∼350 ms after the stimulus onset. Taken together, our findings provide novel insights into the neural dynamics underlying the multidimensional aspects of face perception and illuminate the promising future of utilizing OPM-MEG for exploring higher-level human cognition.