bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, March 2nd, 2024
| Time |
Event |
| 9:22p |
Macroscale brain states support the control of semantic cognition
Understanding how the human brain adapts to varying cognitive demands is crucial in neuroscience. Here, we examined how networks involved in controlled semantic retrieval reconfigure themselves to generate neurocognitive states appropriate to different task contexts. We parametrically varied the demands of two semantic tasks - global association and feature matching judgments - and contrasted these effects of cognitive control with those of non-semantic tasks. We then characterized these effects on the cortical surface and within a whole-brain state space, anchored by the top three dimensions of intrinsic connectivity. Our results revealed that demanding semantic association tasks elicited more activation in the anterior regions of the prefrontal and temporal cortex. In contrast, difficult semantic feature matching tasks produced more posterior activation, aligning closely with regions engaged during multiple demanding non-semantic tasks. In both semantic feature matching and non-semantic contexts, the difficulty effects were situated towards the controlled end of a dimension capturing functional separation between cognitive control and default mode regions. Conversely, in semantic association tasks, the difficulty effects elicited similar responses across both cognitive control and default mode networks. Furthermore, controlled association and non-semantic control were located towards the heteromodal end of a heteromodal-unimodal dimension, while semantic feature matching involved a brain state that was more visual and unimodal. These findings demonstrate that a variety of brain states underpin controlled cognition. Specifically, cognitive control regions interact with heteromodal semantic knowledge system to identify contextually relevant conceptual overlaps (e.g., associating 'DOG' with 'BEACH'), and separate from heteromodal memory regions for modality-specific conceptual overlaps (e.g., connecting 'DALMATIAN' with 'BLACK AND WHITE'). | | 9:22p |
NEK1 haploinsufficiency impairs ciliogenesis in human iPSC-derived motoneurons and brain organoids
Primary cilia are microtubule-based organelles acting as specialized signalling antennae that respond to specific stimuli to maintain cellular integrity and homeostasis. Recent studies indicate defective primary cilia in post-mortem human brains and animal models of neurodegenerative conditions, including Amyotrophic Lateral Sclerosis (ALS). Heterozygous loss-of-function mutations (LOF) in NEK1 gene are present in about 1% of familial and sporadic ALS cases. The protein kinase NEK1 regulates various cellular processes, including ciliogenesis, but a clear link between NEK1 LOF mutation in ALS and primary cilia is unknown. In this study we generated a human iPSC line carrying a NEK1 LOF mutation by gene editing, leading to NEK1 protein haploinsufficiency. In differentiated iPSC-motoneurons (MNs) we observed that primary cilia were significantly shorter in NEK1-LOF iPSC-MNs compared to wild-type (WT) iPSC-MNs and that also the percentage of ciliated iPSC-MNs was significantly decreased in NEK1-LOF cells. We also investigated ciliogenesis in NEK1-LOF iPSC-brain organoids confirming that primary cilia were thinner with no apparent alteration in the ultrastructure by transmission electron microscopy. Our data suggest that NEK1 protein plays a role in regulating ciliogenesis in both 2D and 3D human iPSC-derived neuronal models and that NEK1 LOF mutations associated to ALS, leading to NEK1 haploinsufficiency and likely to reduced kinase activity, impair primary cilium formation. The involvement of ciliogenesis dysfunction in ALS deserves further investigation providing novel therapeutic targets and strategies to be addressed for this incurable disease. | | 9:22p |
Gluk4-containing kainate receptors regulate synaptic communication in the motor cortex and reduce axon degeneration in adult mice
Glutamate-gated kainate receptors comprising the Gluk4 subunit (encoded by Grik4) are highly expressed by neurons in the central nervous system. We report that Grik4 mRNA is widely expressed by neurons in the adult mouse motor cortex, where GluK4-containing kainate receptors account for ~60% of the kainate evoked current in layer V pyramidal neurons. To elucidate their role in motor circuit regulation, we analyzed the behavior of mice that lacked the pore forming domain of the GluK4 subunit (Grik4-/- mice). Grik4-/- mice were hyperactive, had an abnormal gait, and impaired motor coordination. At postnatal day (P)60, layer V pyramidal neurons received fewer miniature excitatory post synaptic currents, had a reduced density of thin spines on their basal dendrites, and a reduced density of VGlut1 puncta at the soma, consistent with neurons receiving fewer excitatory synaptic connections. Grik4-/- mice also lost ~44% of their callosal axons between P60 and P180 and the amplitude of the callosal compound action potential was reduced by ~25-30%. RNA sequencing data support the capacity for Grik4 to modulate synaptic and neuroprotective signaling pathways. | | 9:22p |
Orderly specification and precise laminar deployment of cortical glutamatergic projection neuron types through intermediate progenitors
The cerebral cortex comprises diverse types of glutamatergic projection neurons (PNs) generated from radial glial progenitors (RGs) through either direct neurogenesis or indirect neurogenesis (iNG) via intermediate progenitors (IPs). A foundational concept in corticogenesis is the 'inside-out' model whereby successive generations of PNs sequentially migrate to deep then progressively more superficial layers, but its biological significance remains unclear; and the role of iNG in this process is unknown. Using genetic strategies linking PN birth-dating to projection mapping in mice, we found that the laminar deployment of IP-derived PNs substantially deviate from an inside-out rule: PNs destined to non-consecutive layers are generated at the same time, and different PN types of the same layer are generated at non-contiguous times. The overarching scheme of iNG is the sequential specification and precise laminar deployment of projection-defined PN types, which may contribute to the orderly assembly of cortical output channels and processing streams. | | 9:22p |
Differential gene expression and chromatin accessibility in the rat medial prefrontal cortex mediating individual variability in vulnerability to opioid use
Opioid use disorder (OUD) is a neuropsychological disease that causes immense distress to individuals and the society. Despite the abundant clinical and preclinical studies demonstrating substantial individual differences in OUD vulnerability, the neurobiological mechanisms underlying such individual variability in OUD vulnerability remain unclear, hindering the progress in the development of more effective therapeutics. To address this question, we investigated the transcriptome (RNA-seq) and genome-wide chromatin accessibility (ATAC-seq) in the medial prefrontal cortex (mPFC) of male and female rats given morphine and exhibiting differential vulnerability to OUD as measured in behavioral paradigms capturing different phases of the disorder: Withdrawal-Induced Anhedonia (WIA), Demand, and Reinstatement. Ingenuity Pathway Analysis (IPA) of RNA-seq revealed greater changes in canonical pathways in Resilient (vs. Saline) rats in comparison to Vulnerable (vs. Saline) rats across 3 paradigms, suggesting brain adaptations that might contribute to resilience to OUD. Weighted Gene Co-Expression Network Analysis and IPA analyses suggested an involvement of myelination and oligodendrocyte processes, and neuroinflammation responses in the vulnerability associated with WIA and Demand paradigm, respectively. HOMER motif analysis of ATAC-seq showed changes in accessibility to a small set of transcription factor (TF) binding sites, some that were shared across the 3 paradigms and others that were unique to each. In conclusion, we have identified changes in biological pathways, TFs, and their binding motifs that vary with paradigm and disease vulnerability. These findings point to the involvement of distinct transcriptional and epigenetic mechanisms in response to opioid exposure, vulnerability to OUD, and different stages of the disorder. | | 10:32p |
Investigating cross-sectional and longitudinal relationships between brain structure and distinct dimensions of externalizing psychopathology in the ABCD Sample
Externalizing psychopathology in childhood is a predictor of poor outcomes across the lifespan. Children exhibiting elevated externalizing psychopathology also commonly show emotion dysregulation and callous-unemotional (CU) traits. Examining cross-sectional and longitudinal neural correlates across dimensions linked to externalizing psychopathology during childhood may clarify shared or distinct neurobiological vulnerability for psychopathological impairment later in life. We used tabulated brain structure and behavioural data from baseline, year 1, and year 2 timepoints of the Adolescent Brain Cognitive Development Study (ABCD; baseline n=10,534). We fit separate linear mixed effect models to examine whether baseline brain structures in frontolimbic and striatal regions (cortical thickness or subcortical volume) were associated with externalizing symptoms, emotion dysregulation, and/or CU traits at baseline and over a two-year period. At baseline, cortical thickness in the right rostral middle frontal gyrus and bilateral pars orbitalis was positively associated with CU traits (B=|0.027 to 0.033|, pcorrected=0.009 to 0.03). Subcortical volume in the left caudate, right amygdala, and bilateral nucleus accumbens was negatively associated with emotion dysregulation (B=|0.026 to 0.037|, pcorrected=<0.001 to 0.02). Over the two-year follow-up period, higher baseline cortical thickness in the left pars triangularis and rostral middle frontal gyrus predicted greater decreases in externalizing symptoms (F=6.33 to 6.94, pcorrected=0.014). The results of the current study suggest that unique regions within frontolimbic and striatal networks may be more strongly associated with different dimensions of externalizing psychopathology. The longitudinal findings indicate that brain structure in early childhood may provide insight into structural features that influence behaviour over time. | | 11:46p |
Phosphatidic acid is an endogenous negative regulator of PIEZO2 channels and mechanical sensitivity
Mechanosensitive PIEZO2 ion channels play roles in touch, proprioception, and inflammatory pain. Currently, there are no small molecule inhibitors that selectively inhibit PIEZO2 over PIEZO1. The TMEM120A protein was shown to inhibit PIEZO2 while leaving PIEZO1 unaffected. Here we find that TMEM120A expression elevates cellular levels of phosphatidic acid and lysophosphatidic acid (LPA), aligning with its structural resemblance to lipid-modifying enzymes. Intracellular application of phosphatidic acid or LPA inhibited PIEZO2, but not PIEZO1 activity. Extended extracellular exposure to the non-hydrolyzable phosphatidic acid and LPA analogue carbocyclic phosphatidic acid (ccPA) also inhibited PIEZO2. Optogenetic activation of phospholipase D (PLD), a signaling enzyme that generates phosphatidic acid, inhibited PIEZO2, but not PIEZO1. Conversely, inhibiting PLD led to increased PIEZO2 activity and increased mechanical sensitivity in mice in behavioral experiments. These findings unveil lipid regulators that selectively target PIEZO2 over PIEZO1, and identify the PLD pathway as a regulator of PIEZO2 activity. |
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