Interoception, the sensing and interpretation of internal bodily signals, is increasingly invoked to explain heterogeneity in autism, yet empirical findings remain inconsistent. A major reason is methodological: the field remains cardio-centric and relies heavily on heartbeat counting tasks and trait questionnaires, which are vulnerable to cognitive strategies, attention, expectancy effects, and confounds such as alexithymia and anxiety. Autism research further indicates that interoception is multidimensional (accuracy, sensibility, metacognitive awareness) and developmentally dynamic, with evidence for dissociations across components and compensation across the lifespan. We argue that progress requires reframing interoception as an inference problem: the brain estimates hidden physiological states from noisy sensory evidence under context-dependent precision weighting (predictive processing/active inference). Building on this framework, we propose a participatory, multimodal research program for autism that integrates (i) lived experience as hypothesis-shaping data, (ii) virtual reality (VR) as an experimental testbed to manipulate embodiment, sensory load, agency cues, and feedback, and (iii) computational physiological modelling to estimate latent cardiovascular–respiratory and autonomic-control parameters, which could subsequently constrain separately specified models of perceptual inference.
Cortical modules are thought to provide anatomical frameworks for local microcircuits. However, the mechanisms regulating the morphological organization of these modules during development remain poorly understood. In the rat granular retrosplenial cortex, layer 1 contains prominent dendritic bundle-centered modules formed by the apical dendrites of layer 2 neurons and aligned with specific afferent inputs. I investigated the molecular mechanisms regulating the architecture of these dendritic bundles, focusing on TrkC, a high-affinity receptor for neurotrophin-3. Reanalysis of developmental gene expression data showed that neurotrophin-3 was transiently enriched in layer 2 before dendritic bundle formation, whereas TrkC expression was maintained at above-average levels and became modestly elevated after bundle formation. Pathway analysis further suggested developmental changes in neurotrophin pathways. To examine whether perturbation of TrkC-related signaling affects dendritic bundle architecture, I overexpressed a truncated TrkC construct lacking the intracellular tyrosine kinase domain in layer 2 neurons via in utero electroporation. Overexpression of this construct expanded dendritic bundle territories in upper layer 1. Sparse single-cell labeling revealed that this bundle-level phenotype was accompanied by increased branching of the apical dendrites of individual layer 2 neurons. These findings suggest that TrkC-related signaling may regulate the morphology of dendritic bundles by restricting excessive branching of apical dendrites during development. Thus, regulation of dendritic branching may contribute to the refinement of the distinctive dendritic bundle architecture of the granular retrosplenial cortex.
The neuromuscular junction (NMJ) is a synapse that connects the nerve terminal of a motor neuron to a skeletal muscle fiber. The mechanisms underlying NMJ formation have been elucidated primarily through studies in animal models. However, elucidation of the pathophysiological mechanisms of human neuromuscular diseases and identification of potential therapeutic agents require the establishment of a human NMJ model. In this study, we established a human NMJ model using a compartmentalized culture system with cells derived from human induced pluripotent stem (iPS) cells, which enables quantitative and reproducible assessment of NMJ formation. During extended NMJ culture, morphological changes in the NMJ were observed, along with alterations in the expression of genes related to NMJ and skeletal muscle development, suggesting progressive NMJ maturation. The functionality of the formed NMJs was also confirmed using fluorescent live-cell imaging. These findings suggest that this human NMJ culture model may be applicable for investigating the pathological mechanisms of human neuromuscular diseases and exploring therapeutic agents.
Ashwin Jainarayanan, Aishwarya Vedula, Neeraj Soni
Glioblastoma (GBM), a high-grade glioma, is the most common primary brain tumor in adults, with a dismal prognosis and a very high recurrence rate. Major challenges to effective treatment arise from the tumor’s locally aggressive, diffusely infiltrative nature and extensive intratumoral heterogeneity. Recent advances in cancer neuroscience have uncovered bidirectional neuron-glioma interactions including the formation of functional neuron-glioma synapses (NGS). Neuronal activity drives tumor growth and its synaptic integration into neural circuits; tumor-induced circuit remodeling reciprocally influences neural activity. In parallel, emerging evidence implicates the immunological synapse- a dynamic interface between T cells and antigen-presenting cells analogous to its neural counterpart- as a key driver of GBM pathogenesis and progression. The tumor microenvironment (TME) in GBM is characterized by local immunosuppression, immune evasion, and resistance to immunotherapy. Notably, neural and immune synapses share fundamental architectural and functional principles–spatial confinement of signaling, receptor clustering and adhesion-mediated stabilization, directional information transfer, and use-dependent plasticity–and an expanding catalog of molecular hubs operates across both interfaces. In this context, glioblastoma can be reconceptualized as a disease of coupled neural and immune synaptic networks cooperating to drive tumor progression. Therapeutic strategies targeting these hubs may offer advantages over current approaches by simultaneously disrupting tumor-promoting neuronal input and enhancing antitumor immunity, providing a “double hit” with the potential to dismantle the network architecture sustaining tumor growth and resilience.
Ugur Damar, Paul MacMullin, Sameer Dhamne, Alexander Rotenberg
Repetitive transcranial magnetic stimulation (rTMS) modulates cortical plasticity in a frequency-dependent manner, resulting in predictable and lasting augmentation or attenuation of corticospinal excitability. These rTMS effects on synaptic plasticity are partly mediated by N-methyl-D-aspartate receptors (NMDARs) and share features with long-term depression (LTD) or long-term potentiation (LTP) of excitatory synaptic transmission. In this study, we investigated whether SGE 301 (an NMDAR positive allosteric modulator) alters rTMS-mediated motor cortical plasticity in pentobarbital-anesthetized rats. We tested two modalities: 1 Hz for the low-frequency rTMS (lf-rTMS) and 10 Hz for the high-frequency rTMS (hf-rTMS) to induce LTD-like and LTP-like plasticity, respectively. We compared corticospinal excitability before and after rTMS by measuring peak-to-peak motor evoked potential (MEP) amplitudes across a range of stimulator outputs. In the lf-rTMS experiment, the magnitude of the reduction of MEP amplitude was similar between the vehicle and SGE-301 groups. In the hf-rTMS experiment, however, the LTP-like plasticity observed in the vehicle group was completely reversed by SGE-301. In conclusion, SGE-301 engages cortical plasticity mechanisms in vivo and selectively prevents hf-rTMS-induced LTP-like plasticity without altering lf-rTMS-induced LTD-like plasticity. These findings support the utility of preclinical rTMS as a translational tool for detecting central target engagement by neuroplasticity-modulating compounds.
