As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, Mitofusin2 (MFN2)/mitochondrial assembly regulatory factor (Marf), plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, is not clearly understood. Here, we identified a novel interaction between MFN2/Marf and microtubule affinity-regulating kinase 4 (MARK4)/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the ...

From the perspective of predictive coding, normal aging is accompanied by decreased weighting of sensory inputs and increased reliance on predictions, resulting in the attenuation of prediction errors in older age. Recent electroencephalography (EEG) research further revealed that the age-related shift from sensorium to predictions is hierarchy-selective, as older brains show little reduction in lower-level but significant suppression in higher-level prediction errors. Moreover, the disrupted propagation of prediction errors from the lower-level to the higher-level seems to be linked to deficient maintenance of information in working memory. However, it is unclear whether the hierarchical predictive processing continues to decline with advancing age as working memory. Here, we longitudinally followed a sample of 78 participants from three age groups (including seniors, adults, and adolescents) over three years’ time. Seniors exhibited largely preserved local processing [consisting of comparable mismatch ne...

Age-related cognitive impairment is not expressed uniformly across cognitive domains. Cognitive functions that rely on brain areas that undergo substantial neuroanatomical changes with age often show age-related impairment, whereas those that rely on brain areas with minimal age-related change typically do not. The common marmoset has grown in popularity as a model for neuroscience research, but robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains, is lacking. This presents a major limitation for the development and evaluation of the marmoset as a model of cognitive aging and leaves open the question of whether they exhibit age-related cognitive impairment that is restricted to some cognitive domains, as in humans. In this study, we characterized stimulus–reward association learning and cognitive flexibility in young adults to geriatric marmosets using a Simple Discrimination task and a Serial Reversal task, respectively. We found that aged marmosets show tr...

The alpha phase has been theorized to reflect fluctuations in cortical excitability and thereby impose a cyclic influence on visual perception. Despite its appeal, this notion is not fully substantiated, as both supporting and opposing evidence has been recently reported. In contrast to previous research, this study examined the effect of the peristimulus instead of prestimulus phase on visual detection through a real-time phase-locked stimulus presentation approach. Specifically, we monitored phase data from magnetoencephalography (MEG) recordings over time, with a newly developed algorithm based on adaptive Kalman filtering. This information guided online presentations of masked stimuli that were phased-locked to different stages of the alpha cycle while healthy humans concurrently performed detection tasks. Behavioral evidence showed that the overall detection rate did not significantly vary according to the four predetermined peristimulus alpha phases. Nevertheless, the follow-up analyses highlighted t...

How rapidly can the brain transform vision into action? Work in humans has established that the transformation for visually-guided reaching can be remarkably rapid, with the first phase of upper limb muscle recruitment, the express visuomotor response , beginning within less than 100 ms of visual target presentation. Such short-latency responses limit the opportunities for extensive cortical processing, leading to the hypothesis that they are generated via the subcortical tectoreticulospinal pathway. Here, we examine if non-human primates (NHPs) exhibit express visuomotor responses. Two male macaques made visually-guided reaches in a behavioral paradigm known to elicit express visuomotor responses in humans, while we acquired intramuscular recordings from the deltoid muscle. Across several variants of this paradigm, express visuomotor responses began within 65 ms (range 48–91 ms) of target presentation. Although the timing of the express visuomotor response did not co-vary with reaction time, larger expres...

When listening to speech, the low-frequency cortical response below 10 Hz can track the speech envelope. Previous studies have demonstrated that the phase lag between speech envelope and cortical response can reflect the mechanism by which the envelope-tracking response is generated. Here, we analyze whether the mechanism to generate the envelope-tracking response is modulated by the level of consciousness, by studying how the stimulus-response phase lag is modulated by the Disorder of Consciousness (DoC). It is observed that DoC patients in general show less reliable neural tracking of speech. Nevertheless, the stimulus-response phase lag changes linearly with frequency between 3.5 and 8 Hz, for DoC patients who show reliable cortical tracking to speech, regardless of the consciousness state. The mean phase lag is also consistent across these DoC patients. These results suggest that the envelope-tracking response to speech can be generated by an automatic process that is barely modulated by the consciousn...

From the perspective of predictive coding, normal aging is accompanied by decreased weighting of sensory inputs and increased reliance on predictions, resulting in the attenuation of prediction errors in older age. Recent EEG research further revealed that the age-related shift from sensorium to predictions is hierarchy-selective, as older brains show little reduction in lower-level but significant suppression in higher-level prediction errors. Moreover, the disrupted propagation of prediction errors from the lower-level to the higher-level seems to be linked to deficient maintenance of information in working memory. However, it is unclear whether the hierarchical predictive processing continues to decline with advancing age as working memory. Here we longitudinally followed a sample of 78 participants from three age groups (including seniors, adults, and adolescents) over three years’ time. Seniors exhibited largely preserved local processing (consisting of comparable MMN, delayed P3a, and comparable RON)...

The hypothalamic suprachiasmatic nucleus (SCN) is the central circadian pacemaker in vertebrates. The SCN receives photic information exclusively through melanopsin-expressing retinal ganglion cells (mRGC) to synchronize circadian rhythms with the environmental light cycles. The SCN is composed of two major peptidergic neuron types in the core and shell regions of the SCN. Determining how mRGCs interact with the network of synaptic connections onto and between SCN neurons is key to understand how light regulates the circadian clock and to elucidate the relevant local circuits within the SCN. To map these connections, we used a newly developed Cre-dependent electron microscopy reporter, APEX2, to label the mitochondria of mRGC axons. Serial blockface scanning electron microscopy was then used to resolve the fine 3D structure of mRGC axons and synaptic boutons in the SCN of a male mouse. The resulting maps reveal patterns of connectomic organization in the core and shell of the SCN. We show that these region...

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity. To test whether estradiol affects synaptic plasticity in the DMS, corticostriatal long-term potentiation (LTP) was induced using theta-burst stimulation in ex vivo brain slices from intact male and female C57BL/6 mice. Extracellular field recordings showed that female mice in the diestrus stage of the estrous cycle exhibited LTP similar to male mice, while female mice in estrus did not e...

AMPA receptors (AMPARs) are the major mediators of fast excitatory neurotransmission in the retina as in other parts of the brain. In most neurons, the synaptic targeting, pharmacology and function of AMPARs is influenced by auxiliary subunits including the transmembrane AMPA receptor regulatory proteins (TARPs). However, it is unclear which TARP subunits are present at retinal synapses and how they influence receptor localization and function. Here, we show that TARPɣ2 (stargazin) is associated with AMPARs in the synaptic layers of the mouse, rabbit, macaque and human retina. In most species, TARPɣ2 expression was high where starburst amacrine cells (SACs) ramify and transcriptomic analyses suggest correspondingly high gene expression in mouse and human SACs. Synaptic expression of GluA2, GluA3 and GluA4 was significantly reduced in a mouse mutant lacking TARPɣ2 expression (stargazer mouse; stg ), whereas GluA1 levels were unaffected. AMPAR mediated light-evoked EPSCs in ON-SACs from stg mice were ∼30% sm...