Processing auditory sequences involves multiple brain networks and is crucial to complex perception associated with music appreciation and speech comprehension. We used time-resolved cortical imaging in a pitch change detection task to detail the underlying nature of human brain network activity, at the rapid time scales of neurophysiology. In response to tone sequence presentation to the participants, we observed slow inter-regional signaling at the pace of tone presentations (2-4 Hz) that was directed from auditory cortex toward both inferior frontal and motor cortices. Symmetrically, motor cortex manifested directed influence onto auditory and inferior frontal cortices via bursts of faster (15-35 Hz) activity. These bursts occurred precisely at the expected latencies of each tone in a sequence. This expression of interdependency between slow/fast neurophysiological activity yielded a form of local cross-frequency phase-amplitude coupling in auditory cortex, which strength varied dynamically and peaked w...

Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomic and clinical studies show that it also has a role in reward-processing. However, the way in which the movement-related and the reward-related neural activity interact at the level of the cerebellar cortex and contribute toward learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when 2 male monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol–hand association and a novel symbol–hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys' reaction times, or the novelty of the visual symbols. ...

Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were obtained in up to 13 gray matter (GM) and adjacent white matter (WM) cortical brain regions sampled from 53 tauopathy and 66 TDP-43 proteinopathy autopsy patients. First, we constructed a weighted non-directed graph for each group, where nodes are defined as GM and WM regions sampled and edges in the graph are weighted using the group-level Pearson's correlation coefficient for each pairwise node comparison. Additionally, we performed mediation analyses to test mediation effects of WM pathology between anterior frontotemporal and posterior parietal GM nodes. We find greater correlation (i.e., edges) between GM and WM node pairs in tauopathies compared with TDP-4...

The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. Dual leucine-zipper kinase [DLK; MAP kinase kinase kinase 12; MAP3K12] is an evolutionarily conserved MAP3K implicated in neuronal injury signaling from Caenorhabditis elegans to mammals. However, whether DLK or its close homolog leucine zipper kinase (LZK; MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here, we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but al...

The Protocadherin-10 (PCDH10) gene is associated with autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and major depression (MD). The PCDH10 protein is a homophilic cell adhesion molecule that belongs to the δ2-protocadherin family. PCDH10 is highly expressed in the developing brain, especially in the basolateral nucleus of the amygdala (BLA). However, the role of PCDH10 in vivo has been debatable: one paper reported that a Pcdh10 mutant mouse line showed changes in axonal projections; however, another Pcdh10 mutant mouse line was reported to have failed to detect axonal phenotypes. Therefore, the actual roles of PCDH10 in the brain remain to be elucidated. We established a new Pcdh10 KO mouse line using the CRISPR/Cas9 system, without inserting gene cassettes to avoid non-specific effects, examined the roles of PCDH10 in the brain, and studied the behavioral consequences of Pcdh10 inactivation. Here we show that Pcdh10 KO mice do not show defects in axonal development. Instead, we find...

Ubiquitin-specific protease (USP) 2 participates in glucose metabolism in peripheral tissues such as the liver and skeletal muscle. However, the glucoregulatory role of USP2 in the central nervous system is not well known. In this study, we focus on USP2 in the ventromedial hypothalamus (VMH), which has dominant control over systemic glucose homeostasis. ISH using a Usp2 -specific probe showed that Usp2 mRNA is present in VMH neurons, as well as other glucoregulatory nuclei, in the hypothalamus of male mice. Administration of a USP2-selective inhibitor, ML364 (20 ng/head), into the VMH elicited a rapid increase in the circulating glucose level in male mice, suggesting USP2 has a suppressive role on glucose mobilization. ML364 treatment also increased serum norepinephrine concentration, while it negligibly affected serum levels of insulin and corticosterone. ML364 perturbated mitochondrial oxidative phosphorylation in neural SH-SY5Y cells, and subsequently promoted the phosphorylation of AMP-activated prote...

Emotion recognition abilities are fundamental to our everyday social interaction. A large number of clinical populations show impairments in this domain, with emotion recognition atypicalities being particularly prevalent among disorders exhibiting a dopamine system disruption (e.g., Parkinson’s disease). Although this suggests a role for dopamine in emotion recognition, studies employing dopamine manipulation in healthy volunteers have exhibited mixed neural findings and no behavioural modulation. Interestingly, whilst a dependence of dopaminergic drug effects on individual baseline dopamine function has been well established in other cognitive domains, the emotion recognition literature so far has failed to account for these possible interindividual differences. The present within-subjects study therefore tested the effects of the dopamine D2 antagonist haloperidol on emotion recognition from dynamic, whole-body stimuli while accounting for interindividual differences in baseline dopamine. 33 healthy mal...

The location of sounds can be described in multiple coordinate systems that are defined relative to ourselves, or the world around us. Evidence from neural recordings in animals point towards the existence of both head-centered and world-centered representations of sound location in the brain; however, it is unclear whether such neural representations have perceptual correlates in the sound localization abilities of non-human listeners. Here, we establish novel behavioral tests to determine the coordinate systems in which ferrets can localize sounds. We found that ferrets could learn to discriminate between sound locations that were fixed in either world-centered or head-centered space, across wide variations in sound location in the alternative coordinate system. Using probe sounds to assess broader generalization of spatial hearing, we demonstrated that in both head and world-centered tasks, animals used continuous maps of auditory space to guide behavior. Single trial responses of individual animals wer...

Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction o...

Response inhibition is a primary executive control function that allows the withholding of inappropriate responses, and requires appropriate perception of the external environment to achieve a behavioral goal. It remains unclear, however, how response inhibition is achieved when goal-relevant information involves perceptual uncertainty. Twenty-six human participants of both sexes performed a go/no-go task where visually presented random-dot motion stimuli involved perceptual uncertainties. The right inferior frontal cortex (rIFC) was involved in response inhibition, and the middle temporal (MT) region showed greater activity when dot motions involved less uncertainty. A neocortical temporal region in the superior temporal sulcus (STS) specifically showed greater activity during response inhibition in more perceptually certain trials. In this STS region, activity was greater when response inhibition was successful than when it failed. Directional effective connectivity analysis revealed that in more coheren...