DYT1 dystonia is a hereditary neurological movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A ( TOR1A ), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients’ skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport of mRNAs and proteins, whereas they lack the perinuclear “blebs” that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulate...

Flexible adaptation to changing environments is a representative executive control function implicated in the fronto-parietal network that requires appropriate extraction of goal-relevant information through perception of the external environment. It remains unclear, however, how the flexibility is achieved under situations where goal-relevant information is uncertain. To address this issue, the current study examined neural mechanisms for task switching in which task-relevant information involved perceptual uncertainty. Twenty-eight human participants of both sexes alternated behavioral tasks in which they judged motion direction or color of visually presented colored dot stimuli that moved randomly. Task switching was associated with fronto-parietal regions in the left hemisphere, and perception of ambiguous stimuli involved contralateral homologous fronto-parietal regions. On the other hand, in stimulus-modality-dependent occipitotemporal regions, task coding information was increased during task switch...

Humans show a pervasive bias for processing self- over other-related information, including in working memory (WM), where people prioritize the maintenance of self- (over other-) associated cues. To elucidate the neural mechanisms underlying this self-bias, we paired a self- vs. other-associated spatial WM task with functional magnetic resonance imaging (fMRI) and transcranial direct current stimulation (tDCS) of human participants of both sexes. Maintaining self- (over other-) associated cues resulted in enhanced activity in classic WM regions (frontoparietal cortex), and in superior multivoxel pattern decoding of the cue locations from visual cortex. Moreover, ventromedial prefrontal cortex (VMPFC) displayed enhanced functional connectivity with WM regions during maintenance of self-associated cues, which predicted individuals’ behavioral self-prioritization effects. In a follow-up tDCS experiment, we targeted VMPFC with either excitatory (anodal), inhibitory (cathodal), or sham tDCS. Cathodal tDCS elimi...

Faces of different people elicit distinct functional MRI (fMRI) patterns in several face-selective regions of the human brain. Here we used representational similarity analysis to investigate what type of identity-distinguishing information is encoded in three face-selective regions: fusiform face area (FFA), occipital face area (OFA), and posterior superior temporal sulcus (pSTS). In a sample of 30 human participants (22 females, 8 males), we used fMRI to measure brain activity patterns elicited by naturalistic videos of famous face identities, and compared their representational distances in each region with models of the differences between identities. We built diverse candidate models, ranging from low-level image-computable properties (pixel-wise, GIST, and Gabor-jet dissimilarities), through higher-level image-computable descriptions (OpenFace deep neural network, trained to cluster faces by identity), to complex human-rated properties (perceived similarity, social traits, and gender). We found marke...

Neuronal firing patterns are crucial to underpin circuit level behaviors. In cerebellar Purkinje cells (PCs), both spike rates and pauses are used for behavioral coding, but the cellular mechanisms causing code transitions remain unknown. We use a well-validated PC model to explore the coding strategy that individual PCs use to process parallel fiber (PF) inputs. We find increasing input intensity shifts PCs from linear rate-coders to burst-pause timing-coders by triggering localized dendritic spikes. We validate dendritic spike properties with experimental data, elucidate spiking mechanisms, and predict spiking thresholds with and without inhibition. Both linear and burst-pause computations use individual branches as computational units, which challenges the traditional view of PCs as linear point neurons. Dendritic spike thresholds can be regulated by voltage state, compartmentalized channel modulation, between-branch interaction and synaptic inhibition to expand the dynamic range of linear computation o...

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute (1-day post-injury; dpi), subacute (7 dpi), and chronic (30 dpi) time-points. Microglia were depleted with PLX5622, a CSF1R antagonist, prior to midline fluid percussion injury in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. Gene expression associated with inflammation and neuropathology were robustly increased acutely after injury (1 dpi) and the majority of this expression was microglia-independent. At 7 and 30 dpi, however, microglial depletion reversed TBI-related expression of genes associated with inflammation, interferon signaling, and neuropathology. Myriad suppressed genes at subacute and chronic endpoints were attributed to neurons. To under...

Attending to a stimulus enhances the neuronal responses to it, while responses to non-attended stimuli are not enhanced and may even be suppressed. Although the neural mechanisms of response enhancement for attended stimuli have been intensely studied, the neural mechanisms underlying attentional suppression remain largely unknown. It is uncertain whether attention acts to suppress the processing in sensory cortical areas that would otherwise process the non-attended stimulus or the subcortical input to these cortical areas. Moreover, the neurochemical mechanisms inducing a reduction or suppression of neuronal responses to non-attended stimuli are as yet unknown. Here, we investigated how attention directed towards visual processing cross-modally acts to suppress vestibular responses in the human brain. By using functional magnetic resonance spectroscopy (fMRS) in a group of female and male subjects we find that attention to visual motion downregulates in a load-dependent manner the concentration of excita...

Prediction of periodic event timing is an important function for everyday activities, while the exact neural mechanism remains unclear. Previous studies in nonhuman primates have demonstrated that neurons in the cerebellar dentate nucleus and those in the caudate nucleus exhibit periodic firing modulation when the animals attempt to detect a single omission of isochronous repetitive audiovisual stimuli. To understand how these subcortical signals are sent and processed through the thalamocortical pathways, we examined single neuron activities in the central thalamus of two macaque monkeys (one female and one male). We found that three types of neurons responded to each stimulus in the sequence in the absence of movements. Reactive-type neurons showed sensory adaptation and gradually waned the transient response to each stimulus. Predictive-type neurons steadily increased the magnitude of the suppressive response, similar to neurons previously reported in the cerebellum. Switch-type neurons initially showed...

Promoting oligodendrocyte differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector TCF7l2 was upregulated in MS lesions and had been proposed to inhibit oligodendrocyte differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP4)-mediated signaling. Disrupting TCF7l2 in mice of both sexes results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activation in vivo . Mechanistically, TCF7l2 binds to Bmp4 gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arreste...

A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use disorder. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epigenome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.