bioRxiv Subject Collection: Neuroscience's Journal
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Monday, January 20th, 2025
| Time |
Event |
| 12:30a |
A Causal and Dissociable Role for the Right Inferior Prefrontal Cortex in Empathy for Physical and Social Pain
The right inferior frontal gyrus (rIFG) and dorsomedial prefrontal cortex (dmPFC) are key nodes in the social brain, implicated in empathy for physical and social pain. However, their causal and dissociable contributions remain unclear. In this study, 52 young adults underwent focal transcranial direct current stimulation (f-tDCS) targeting the rIFG or dmPFC in a sham-controlled, double-blind, crossover design. Participants rated the intensity of pain in images depicting social or physical pain during stimulation. Anodal stimulation to the rIFG increased ratings of physical pain and decreased ratings of social pain, suggesting dissociable roles in processing empathy for these two pain types. In contrast, dmPFC stimulation did not modulate ratings, potentially reflecting its role in higher-order social cognitive processes rather than affective empathy. The effects of rIFG stimulation on social pain were significantly stronger in the initial trials, suggesting potential habituation within the rIFG or stimulation-specific effects. These results provide causal, dissociable evidence for the rIFG's involvement in empathy, with its effects differing based on the type of pain. This supports the proposal that distinct neural processes underlie empathy for social versus physical pain. | | 12:30a |
Shared and individual tuning curves for social vision
A stimulus with light is clearly visual; a stimulus with sound is clearly auditory. But what makes a stimulus "social", and how do judgments of socialness differ across people? Here, we characterize both group-level and individual thresholds for perceiving the presence and nature of a social interaction. We take advantage of the fact that humans are primed to see social interactions-e.g., chasing, playing, fighting-even in very un-lifelike stimuli such as animations of geometric shapes. Unlike prior work using these stimuli, we exploit their most advantageous property, which is that their visual features are fully parameterizable. We use this property to construct psychophysics-inspired "social tuning curves" for individual subjects. Social tuning curves are stable within individuals, unique across individuals, and show some relationship to socio-affective traits. Results support the view that social information processing begins early in the perceptual hierarchy. Further, our approach lays the foundation for a generative account of social perception in single subjects. | | 12:30a |
Transcriptional and synaptic regulation of NMDA glutamate receptor-mediated hippocampal plasticity and memory
Synapse-to-nucleus signaling regulates activity-dependent synaptic plasticity underlying memory by linking N-methyl-D-aspartate (NMDA) glutamate receptors (GluN) to gene transcription mediated by the transcription factor cAMP-response element binding protein (CREB), but the underlying gene programs mediating potentiation at excitatory synapses are unknown. Here, we analyzed genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) datasets of mouse and human CREB and the synaptonuclear factor CREB-regulated transcription coactivator1 (CRTC1) to identify relevant target genes and biological pathways coupling neuronal activity to synaptic function/plasticity. Our analyses indicate that CRTC1 specifically couples neuronal activity with synaptic plasticity by binding to conserved promoters of CREB target genes comprising inducible transcription factors (including c-fos, Crem, Npas4 and Nr4a1-3), and neuronal excitability and plasticity genes, including Ntrk2, Homer1, Dlg4 (PSD-95) and the NMDA receptor subunit Grin1 (GluN1). CRTC1/CREB target genes were highly enriched in gene ontology (GO) nuclear terms, including several members of the CREB family, and transcriptional modulators and repressors. Interestingly, GO enrichment and protein-protein interaction (PPI) network analyses revealed that genes mediating synapse-to-nucleus signaling (including most known synaptonuclear factors and direct interacting modulators) are collectively regulated by CREB/CRTC1, and that protein kinase C (PKC) is a key interactor of the CRTC1/14-3-3 complex at synapses. In agreement with these in silico analyses, we show that CRTC1 regulates synaptic activity-dependent phosphorylation and synaptic recruitment of GluN1 mediated by PKC in hippocampal neurons, and that PKC activation reverses NMDA receptor-mediated currents and long-term potentiation (LTP) deficits caused by CRTC1 silencing in the hippocampus. Consistent with genomics and functional data, morphological and behavioral analyses show crucial roles of CRTC1 on dendritic spine structure, plasticity, and hippocampal-dependent associative memory. Our results support a model in which neuronal activity and synaptic inputs are integrated in the nucleus through conserved CREB/CRTC1-regulated transcriptional programs sustaining global synapse-to-nucleus signaling pathways impacting on synaptic plasticity and memory. | | 12:30a |
Elaborating the connections of a closed-loop forebrain circuit in the rat: Circumscribed evidence for novel topography within a cortico-striato-pallidal triple descending projection, with thalamic feedback, to the anterior lateral hypothalamic area
Motivated behaviors are regulated by distributed forebrain networks. Traditional approaches have often focused on individual brain regions and connections that do not capture the topographic organization of forebrain connectivity. We performed co-injections of anterograde and retrograde tract tracers in rats to provide novel high-spatial resolution evidence of topographic connections that elaborate a previously identified closed-loop forebrain circuit implicated in affective and motivational processes. The nodes of this circuit include select regions of the medial prefrontal cortex (defined here more specifically as the cingulate region, CNG), a dorsomedial portion of the nucleus accumbens (ACBdm), a portion of the medial substantia innominata (SIm), and the anterior lateral hypothalamic area (LHAa). The circuit also reportedly receives a feedback loop from the anterior region of the paraventricular thalamic nucleus (PVTa). In this draft report, we provide detailed circumscribed evidence supporting these regions as interconnected nodes, and provide several novel findings concerning the topographic organization of their projections. First, we identified the ACBdm based on its unique connectivity. Anterograde labeling from anterior paraventricular thalamic nucleus (PVTa) and retrograde labeling from medial substantia innominata (SIm) and lateral hypothalamic area (LHA) were restricted to the dorsomedial ACB (ACBdm). Strikingly, this labeling formed a longitudinal column extending along virtually the entire anteroposterior axis of ACBdm. Subsequent analysis revealed a convergence of ACBdm axon terminals and retrogradely labeled neurons from LHA within the anterior SIm. Furthermore, we identified cortical CNG regions related to this circuit. These regions contained retrograde labeling from both ACBdm and LHA, and anterograde labeling from PVTa. These cortical subdomains included regions previously implicated in the circuit but for which detailed organization has been unknown: (1) a region between the posterior prelimbic and infralimbic areas; (2) posterior part of basolateral and basomedial amygdalar nuclei, and (3) anterior pole of ventral subiculum. Our circumscribed findings, which await additional samples and analysis, support the existence of a topographically organized closed-loop circuit and identify two additional novel features: (1) direct evidence for an elaborate core rostrocaudal topography for a cortico-striato-pallidal motif comprising a triple descending projection to the LHA via direct, indirect, and hyperdirect pathways, and (2) a thalamic feedback system with specific projections to each cortical and striatal node of the circuit. We discuss the implications of this newly elaborated circuit for understanding the neural basis of motivational processes. | | 12:30a |
Takens' theorem to assess EEG traces: regional variations in brain dynamics
Takens theorem (TT) proves that the behaviour of a dynamical system can be effectively reconstructed within a multidimensional phase space. This offers a comprehensive framework for examining temporal dependencies, dimensional complexity and predictability of time series data. We applied TT to investigate the physiological regional differences in EEG brain dynamics of healthy subjects, focusing on three key channels: FP1 (frontal region), C3 (sensorimotor region), and O1 (occipital region). We provided a detailed reconstruction of phase spaces for each EEG channel using time-delay embedding. The reconstructed trajectories were quantified through measures of trajectory spread and average distance, offering insights into the temporal structure of brain activity that traditional linear methods struggle to capture. Variability and complexity were found to differ across the three regions, revealing notable regional variations. FP1 trajectories exhibited broader spreads, reflecting the dynamic complexity of frontal brain activity associated with higher cognitive functions. C3, involved in sensorimotor integration, displayed moderate variability, reflecting its functional role in coordinating sensory inputs and motor outputs. O1, responsible for visual processing, showed constrained and stable trajectories, consistent with repetitive and structured visual dynamics. These findings align with the functional specialization of different cortical areas, suggesting that the frontal, sensorimotor and occipital regions operate with autonomous temporal structures and nonlinear properties. This distinction may have significant implications for advancing our understanding of normal brain function and enhancing the development of brain-computer interfaces. In sum, we demonstrated the utility of TT in revealing regional variations in EEG traces, underscoring the value of nonlinear dynamics. | | 12:30a |
Integrative Gene Co-expression Network Analysis Reveals Protein-Coding and lncRNA Genes Associated with Alzheimer's Disease Pathology
IntroductionAlzheimers disease (AD) is a complex neurodegenerative disorder involving widespread molecular disruptions, many of which remain poorly understood. While AD pathology progresses through distinct brain regions, it is unclear whether these regions are similarly affected. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cellular processes, but their roles in AD remain largely unexplored. A comprehensive analysis of the complex molecular interactions underlying AD, particularly the roles of lncRNAs in their interactions with protein-coding genes and the comparison of networks across brain regions, could offer valuable insights into the diseases progression and underlying mechanisms.
MethodTo address this, we applied consensus weighted gene co-expression network analysis using a meta-analytic approach to 396 postmortem brain RNA-seq samples to explore AD pathophysiology mechanisms.
ResultsOur study revealed significant network rewiring in AD, with pronounced alterations in the temporal cortex compared to the frontal cortex. While the temporal cortex showed adaptive changes in gene interactions, the frontal cortex exhibited a loss of healthy correlations, potentially reflecting different levels of disease progression. We identified key players in the temporal cortex AD network, including 46 protein-coding genes and 27 lncRNAs. Using the established functions of protein-coding genes as anchors, we provided functional annotations for over 100 lncRNAs across two brain regions, identifying potential lncRNAs involved in AD pathology and highlighting their roles in both healthy and diseased states.
ConclusionWe provided novel insights into the molecular interactions underlying AD and introduced new candidate protein-coding and lncRNA genes for further experimental validation and therapeutic exploration. | | 12:30a |
Persistent interferon signaling that causes sensory neuron plasticity and pain in arthritis
While the inflammatory processes in rheumatoid arthritis have been described, mechanisms driving pain are poorly defined. Here, we used a multitude of approaches to uncover the neural basis, mediators, intracellular signaling pathway and the mechanism of inflammatory pain. In cartilage autoantibody-induced arthritis mice, an early immune-activation and a cytokine storm were mainly driven by vascular cells and monocyte/macrophages in the dorsal root ganglion. However, persistently elevated interferons and receptor-activation of the MNK1/2-eIF4E signaling pathway at all disease phases caused sensory-motor dysfunction and pain by inducing hyperexcitability and sensitization of Gfra3+ sensory neurons. Like mice, human sensory neurons expressed interferon receptors and interferons were elevated only in individuals with painful rheumatoid arthritis. Signaling pathway inhibition in vivo reversed pain and restored limb function. The finding that joint pain before and during arthritis is caused by a defined cytokine and signaling pathway holds promise for targeted therapies for pain relief in arthritis. | | 9:31a |
Reciprocal interaction between cortical SST and PV interneurons in regulating top-down retinothalamic refinement
Refinement of thalamic circuits is crucial for the proper maturation of sensory circuits. In the visual system, this process is regulated by corticothalamic feedback during the experience-dependent phase of development. Yet the cortical circuits modulating this feedback remain elusive. Here, we demonstrate opposing roles for cortical somatostatin (SST) and parvalbumin (PV) interneurons in shaping retinogeniculate connectivity during the thalamic sensitive period (P20-30). Early in the refinement process, SST interneurons promote the strengthening and pruning of retinal inputs in the thalamus, as evidenced by disrupted synaptic refinement following their ablation. In contrast, PV interneurons, which mature later, act as a brake on this refinement, with their ablation leading to enhanced pruning of retinogeniculate connections. Notably, manipulating the relative balance between these inhibitory circuits can regulate sensory deprivation-induced retinogeniculate remodeling. Taken together, our findings show that cortical SST and PV interneuron circuits drive reciprocal antagonism that gate experience-dependent feedforward thalamic refinement. | | 9:31a |
Decreased KCC2 expression in the human spinal dorsal horn associated with chronic pain and long-term opioid use
Loss of GABAergic and glycinergic inhibitory efficacy in the spinal dorsal horn is associated with neuropathic pain and opioid-induced hyperalgesia in rodent models. Downregulation of the KCC2 chloride extrusion transporter is a key mechanism underlying this decreased inhibitory efficacy, but to-date there is no evidence supporting or opposing this hypothesis in humans. Here we demonstrate that KCC2 expression is decreased in superficial dorsal horn neurons of organ donors who died with a documented history of pain, or of long-term opioid use. We show profoundly decreased KCC2 dorsal horn membrane expression in a primary cohort associated with either chronic pain or opioid use, and in a replication cohort of mixed chronic pain and opioid use history. These results show that decreased dorsal horn inhibitory efficacy likely promotes chronic pain in humans and support the development of therapeutics augmenting KCC2 function as a treatment for chronic pain and opioid use disorders. | | 9:31a |
NAc-DBS selectively enhances memory updating without effect on retrieval
Deep brain stimulation (DBS) has emerged as a widely used therapeutic option when pharmacological treatments prove ineffective or refractory for psychiatric patients. The nucleus accumbens (NAc) represents a frequently targeted site in DBS interventions due to its demonstrated safety profile and therapeutic efficacy in obsessive-compulsive disorder, major depression, and anorexia nervosa. However, limited mechanistic understanding hampers its broader clinical applicability. This study sought to delineate the distinct behavioural dimensions modulated by NAc-DBS, its impact on distinct facets of memory, and to elucidate the underlying brain-network mechanism of action. We developed a novel spatial navigation task for rats and employed a high-dimensional behavioural analysis complemented by fMRI to dissect the cognitive, behavioural and neurobiological effects of NAc-DBS. Active NAc-DBS produced a selective enhancement of long-term memory encoding without affecting memory recall or working memory. We found no effect of NAc-DBS on motor, appetitive or stress-related behaviours. Sustained neuronal activation in the NAc, septum, entorhinal and insular cortex demonstrated no desensitization to chronic NAc-DBS, which triggered a functional reorganization among dopaminergic-related structures. These findings suggest that NAc-DBS induces a functional reorganization in the mesocorticolimbic system, potentially mimicking a dopaminergic novelty signal to enhance memory updating. This provides a mechanistic basis for the therapeutic use of NAc-DBS, particularly in improving cognitive flexibility in psychiatric disorders. | | 9:31a |
7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease
Oxidative stress is a prominent feature of Alzheimer's disease. Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we discovered that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. Interestingly, when 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC in the brains of these mice. Taken together, these findings suggest that 7-KC, acting through microglia, contributes to increased astrocyte oxidative stress in AD. This study sheds light on the complex interplay between cholesterol oxidation, microglia activation, and astrocyte oxidative stress in the pathogenesis of AD. | | 9:31a |
Targeted Antisense Oligonucleotide Treatment Rescues Developmental Alterations in Spinal Muscular Atrophy Organoids
Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type I donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that restored SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in newly identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing new insights for optimizing treatment strategies. | | 10:50a |
Predictive Coding algorithms induce brain-like responses in Artificial Neural Networks
This study explores whether predictive coding (PC) inspired Deep Neural Networks can serve as biologically plausible neural network models of the brain. We compared two PC-inspired training objectives, a predictive and a contrastive approach, to a supervised baseline in a simple Recurrent Neural Network (RNN) architecture. We evaluated the models on key signatures of PC, including mismatch responses, formation of priors, and learning of semantic information. Our results show that the PC-inspired models, especially a locally trained predictive model, exhibited these PC-like behaviors better than a Supervised or an Untrained RNN. Further, we found that activity regularization evokes mismatch response-like effects across all models, suggesting it may serve as a proxy for the energy-saving principles of PC. Finally, we find that Gain Control (an important mechanism in the PC framework) can be implemented using weight regularization. Overall, our findings indicate that PC-inspired models are able to capture important computational principles of predictive processing in the brain, and can serve as a promising foundation for building biologically plausible artificial neural networks. This work contributes to our understanding of the relationship between artificial and biological neural networks, and highlights the potential of PC-inspired algorithms for advancing brain modelling as well as brain-inspired machine learning. | | 10:50a |
Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice
BackgroundMesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown.
ObjectivesWe aimed to identify the long-term antiepileptic and cognitive outcomes and potential underlying mechanisms of hippocampal LFS in chronically epileptic male and female mice.
MethodsWe used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. We applied 1 Hz electrical LFS in the sclerotic hippocampus 6 hours a day, four times a week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels.
ResultsLong-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, LFS relieved spatial memory deficits and reversed pathological long-term potentiation-like changes at perforant path-dentate granule cell synapses. LFS had no significant effect on generalized convulsive seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, excitatory synapse marker expression, or presynaptic vesicles in perforant path fibers.
ConclusionThese findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients. | | 10:50a |
The Innexin 7 gap junction protein contributes to synchronized activity in the Drosophila antennal lobe and regulates olfactory function
In the mammalian olfactory bulb (OB), gap junctions coordinate synchronous activity among mitral and tufted cells to process olfactory information. In insects, gap junctions are also present in the Antennal Lobe (AL), a structure homologous to the mammalian OB. The invertebrate gap junction protein ShakB contributes to electrical synapses between AL Projections Neurons (PNs) in Drosophila. Other gap junction proteins, including Innexin 7 (Inx7), are also expressed in the Drosophila AL, but little is known about their contribution to intercellular communication during olfactory information processing. Here we report spontaneous calcium transients in PNs grown in cell culture that are highly synchronous when these neurons are physically connected. RNAi-mediated knock down of Inx7 in cultured PNs blocks calcium transient neuronal synchronization. In vivo, downregulation of Inx7 in the AL impairs both vinegar-induced electrophysiological calcium responses and behavioral responses to this appetitive stimulus. These results demonstrate that Inx7-encoded gap junctions functionally coordinate PN activity and modulate olfactory information processing in the adult Drosophila AL. | | 11:19a |
Oligodendroglia vulnerability in the human dorsal striatum in Parkinson's disease
Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinsons disease (PD) is poorly understood. We performed snRNA-seq and image-based spatial transcriptomics of human caudate nucleus and putamen (dorsal striatum) from PD and Control brain donors to elucidate the diversity of oligodendroglia and how they are affected by the disease. We have defined fifteen subclasses, from precursor to mature cells, four of which are disease-associated. These PD-specific populations are characterized by the overexpression of heat shock proteins and distinct expression signatures, including immune responses and myelination alterations. We have also identified disruptions in cell communication and oligodendrocyte development, evidenced by changes in neurotransmitter receptors expression and cell adhesion molecules. These transcriptomic changes correlated with impaired myelin integrity and altered oligodendrocyte distribution in the striatum. Thus, we uncover oligodendroglia as a critical cell type in PD and a potential new therapeutic target. |
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