bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, August 3rd, 2025
| Time |
Event |
| 8:33a |
Exercise-induced plasma-derived extracellular vesicles increase adult hippocampal neurogenesis
Aerobic exercise enhances cognition in part by increasing adult hippocampal neurogenesis, angiogenesis, and astrogliogenesis. Since hippocampal atrophy is a hallmark of several neurological and psychiatric conditions- including depression, PTSD, Alzheimers disease, and aging- understanding the mechanisms by which exercise increases neurogenesis has broad therapeutic relevance. One potential mechanism involves extracellular vesicles (EVs), lipid bilayer-enclosed particles released by multiple tissues during exercise that transport bioactive molecular cargo to distant organs, including the brain. In this study, we tested whether plasma-derived EVs from exercising mice (ExerVs) are sufficient to promote hippocampal neurogenesis, astrogliogenesis, and vascular density in sedentary mice. EVs were isolated from the plasma of sedentary or exercising C57BL/6J mice and injected intraperitoneally into sedentary recipients twice weekly for four weeks. To evaluate reproducibility, the study was conducted across two independent cohorts using identical procedures. ExerV-treated mice showed a significant increase in BrdU-positive cells in the granule cell layer compared to both PBS- and SedV-treated controls in both cohorts. Approximately 90% of these cells co-expressed NeuN, indicating neuronal differentiation, while 6% co-expressed S100B;, indicating astrocyte generation. No changes were observed in vascular density across groups. These findings provide initial evidence that systemically delivered exercise-derived EVs can enhance hippocampal neurogenesis and astrogliogenesis in sedentary mice. This proof-of-concept work supports further investigation into ExerVs as a potential therapeutic strategy for conditions associated with hippocampal atrophy. | | 9:49a |
Feature-specific inhibitory connectivity augments the accuracy of cortical representations
To interpret complex sensory scenes, animals exploit statistical regularities to infer missing features and suppress redundant or ambiguous information. Cortical microcircuits might contribute to this cognitive goal by either completing or cancelling predictable activity, but it remains unknown whether, and how, a single circuit can implement these antagonistic computations. To address this central question, we used all-optical physiology to simulate sensory-evoked activity patterns in pyramidal cells (PCs) and somatostatin interneurons (SSTs) in the mouse primary visual cortex. In the absence of external visual input, photostimulation of orientation-tuned PC ensembles drove either completion or cancelation of input-matching representations, depending on the number of photostimulated cells. This dual computational capacity arose from the co-existence of "like-to-like" excitatory interactions between PCs, and a newly discovered "like-to-like" SST-PC connectivity motif, in which SSTs are preferentially recruited by, and in turn suppress, similarly tuned PCs. Finally, we show that photoactivation of tuned SST ensembles during visual processing improved the discriminability of their preferred visual input by suppressing ambiguous activity. Thus, these complementary feature-specific connectivity motifs allow different strategies of contextual modulation to optimize inference by either completion (through PC-PC interactions) or cancelation (via PC-SST-PC loops) of predictable activity, depending on the structure of the input and the network state. | | 9:49a |
Backward Conditioning Reveals Flexibility in Infralimbic Cortex Inhibitory Memories
While the infralimbic cortex (IL) is recognized as critical for behavioral inhibition, the content of the inhibitory memories stored in this region remains elusive. To probe this content, we examined some of the conditions that allow retrieval and facilitation of an inhibitory memory stored in the IL using optogenetic stimulation in female and male rats. We found that IL stimulation did not facilitate an initial fear extinction session. However, prior experience with fear extinction enabled IL stimulation to facilitate subsequent fear extinction. Importantly, the facilitative effects of IL stimulation were not limited to fear extinction experience, as prior exposure to backward fear conditioning also enabled IL stimulation to enhance later fear extinction. The effects were stimulus-specific and did not depend on the motivational context present during the prior experience, as backward appetitive conditioning allowed IL stimulation to facilitate later fear extinction. Additional experiments ruled out stimulus familiarity as an explanation for the facilitative effects of IL stimulation and demonstrated that IL-mediated facilitations occur in procedures other than fear extinction. Together, these findings demonstrate that the IL stores inhibitory memories that are extremely flexible since they can be retrieved and used across many inhibitory procedures and distinct motivational contexts. These features establish the IL as a critical hub for the flexible application of inhibitory knowledge that allows adaptive responses in dynamic environments. | | 10:15a |
Unveiling Distinct Neuroimmune Responses in Mouse Models of Cervical Spinal Cord Injury: Hemisection versus Hemicontusion
Traumatic cervical spinal cord injury (cSCI) causes severe neurological deficits and long-term disability. Preclinical models such as cervical 2 (C2) hemisection (C2HS), resulting in disrupted communication between the respiratory centers and the phrenic motoneurons (PMN) pool, have been used since decades to study respiratory dysfunction and neuroinflammation after cSCI. Recently, contusive injuries such as C3 hemi-contusion (C3HC) have been increasingly used, as they induce phrenic motoneuron damage and offer a more clinically relevant model of SCI. However, these two different models may engage distinct pathophysiological cascades, raising concerns about the generalizability of findings across injury paradigms. In this study, we compared neuroimmune responses following C2HS or C3HC in mice. Animals underwent C2HS or C3HC, and spinal cord segments (C1-C8) were collected seven days post-injury for immuno-histological analyses around the lesion level and flow cytometry analyses at the lesion level. We observed that C2HS preserved more neurons and exhibited elevated CD86 and F4/80 expression. These markers are typically expressed by activated microglia and are indicative of a response oriented toward phagocytic and reparative functions. This phenotype was associated with limited pro-inflammatory cell infiltration and normalized level of systemic IL-6 in this model. Conversely, C3HC induced more extensive tissue damage, heightened microglial activation, a trend toward increased astrocytic reactivity, and significantly elevated CSPG levels on the contralateral side. Moreover, a persistent NK cell, neutrophil, and CD43 antigen-presenting cells infiltration, along with persistently high circulating IL-6 has been observed following C3HC. These findings demonstrate distinct neuroinflammatory signatures and repairing mechanisms between models, with C2HS promoting a microglia profile toward repair and C3HC leading to a prolonged and potentially harmful immune response. This study underscores, for the first time, how injury type shapes neuroimmune mechanisms, reinforcing the need for lesion-specific therapeutic strategies in cervical spinal cord injury. | | 10:50a |
Evidence for a Transient State of Auditory Hypersensitivity During Initial Onset of Tinnitus, Evidenced by Intensity Dependence of the Auditory Evoked Potential (IDAEP)
Our understanding of tinnitus pathophysiology may be greatly advanced by understanding how the condition evolves from its initial onset or acute stage to its chronic manifestation. Such a transition likely reflects dynamic neurophysiological changes within central auditory and non-auditory networks. Our integrated model of tinnitus posits that sensory precision (sensory weighting) may be heightened during the acute stages of tinnitus to resolve degraded auditory input, but in chronic tinnitus, its role may diminish as plastic processes take over the percept's maintenance. Consequently, we hypothesize that bottom-up neural mechanisms linked to initiation of tinnitus, such as central gain and neural synchrony, are maximal around the time of tinnitus onset, but later subside by way of regression to the mean. We evaluated this hypothesis by measuring central auditory reactivity through the Intensity Dependence of Auditory Evoked Potential (IDAEP), a non-invasive index of higher-order inhibitory processing within the auditory system. A steeper IDAEP slope is associated with heightened sensory reactivity (higher sensitivity to changes in auditory stimuli), indicative of reduced central inhibition. Conversely, a shallower slope reflects greater inhibitory control. Studying a group with acute tinnitus (onset within six weeks), with a repeated assessment after six months from onset, we found an initially increased IDAEP slope in the acute stage, which had significantly reduced at follow-up, supporting our hypothesis that there is increased sensory reactivity during tinnitus onset, which need not persist in order for tinnitus to become chronic. | | 12:45p |
Transcranial magnetic stimulation induced pupil dilations can serve as a cortical excitability measure
The application of non-invasive brain stimulation (NIBS) often relies on proxy estimates of cortical excitability (CE), such as the resting motor threshold (rMT), measured through transcranial magnetic stimulation (TMS). However, estimating the rMT is not always possible, as it requires an intact corticospinal pathway for neural signals to travel from the cortex to the periphery. To broaden the application of NIBS there is a need for additional CE measures. In three experiments combining TMS, transcranial direct current stimulation (tDCS), and eye-tracking, we measured TMS-induced pupil dilations as a potential CE proxy. We present Bayesian evidence (Experiment 1: BF > 9; Experiment 2: BF > 46; Experiment 3: BFs > 6) that TMS-induced pupil dilations serve as an objective CE proxy, with larger pupil size reflecting higher CE. We also show that these effects are not due to auditory, muscle, or sensory confounds. The introduction of this novel measure paves the way for a deeper understanding of CE by enabling objective NIBS measures beyond the motor cortex. Moving away from the reliance on the motor cortex would allow NIBS research and therapy to become more inclusive, allowing access to populations that are affected by damage along the corticospinal pathway. | | 1:15p |
Processing of inner bodily signals: evidence and insight from adolescence
Interoception, the sense of inner bodily signals, plays a key role in emotional regulation, cognition and mental health. While its relevance in adulthood has been extensively explored, less is known about how these abilities develop during adolescence, a period characterised by significant physical and psychological changes. This study aimed to investigate three distinct dimensions of interoception -- accuracy, sensitivity and awareness -- in adolescents and adults to better understand the developmental profile of this sense. Fifty-four adolescents (aged 12-14) and 50 adults (aged 25-34) completed the Heartbeat Monitoring Task to assess their actual ability to detect heartbeats, their confidence in this ability, and the confidence-accuracy correspondence, and a questionnaire on the tendency to focus on bodily sensations. The study also examined where participants localised bodily sensations during the interoceptive task. The results revealed no significant differences in interoceptive accuracy between the two groups. Both age groups exhibited similar body localisation patterns, primarily focusing on the chest during heartbeat detection. However, adolescents showed significantly lower metacognitive awareness of their ability to perceive internal bodily sensations, and higher focus on interoceptive sensations, as reflected in their higher confidence ratings and questionnaire scores. No significant correlations emerged among the three interoceptive dimensions in either group, which supports the view that these dimensions represent independent components of interoception. These findings suggest that, while basic interoceptive detection may be established by early adolescence, the capacity to accurately reflect on these internal sensations continues to mature into adulthood. The mismatch observed between adolescents' heightened bodily focus and their limited metacognitive insight may partly help explain why adolescence is a period of increased vulnerability to mental health difficulties. | | 1:15p |
Targeting intracranial electrical stimulation to network regions defined within individuals causes network-level effects
Intracranial electrical stimulation (ES) is routinely used therapeutically, diagnostically, and to provide causal evidence in neuroscience studies. However, our understanding of the brain network-level effects of ES remains limited. We applied precision functional mapping (PFM), based on functional magnetic resonance imaging (fMRI), to define large-scale networks within individual epilepsy patients. We show that single-pulse electrical stimulation (SPES) and high-frequency electrical stimulation (HFES) are more likely to evoke within-network responses and elicit network-related behavioral effects, respectively, when applied near to a PFM-defined network region. Network-level effects were more likely when stimulating sites in white matter, in close proximity to the targeted network, and within a region predominantly occupied by the targeted network. Further, network-specific modulation may be achievable by applying lower current intensities at these sites. Our findings support that modulation of specific networks is achievable by targeting ES to a functional anatomic "sweet spot" that can be identified using PFM. | | 4:48p |
Single-cell transcriptome sequencing for opening the blood-brain barrier through specific mode electroacupuncture stimulation
BackgroundThe blood-brain barrier (BBB) interferes with the treatment of central nervous system disorders owing to the complexity of its structure and restrictive function. Thus, it is challenging to develop central nervous system drug delivery strategies. Specific mode electroacupuncture (EA) stimulation can effectively open the BBB in rats.
MethodsHere, we used single-cell RNA sequencing (scRNA-seq) to comprehensively map the cell population in the rat cerebral cortex.
ResultsWe identified 23 cell subsets and eight types of cells in the brain by cell annotation. scRNA-seq revealed transcriptional changes in the cerebral cortex under EA.
ConclusionsOur findings offer valuable insights into the molecular and cellular modifications in the brain resulting from EA intervention and serve as a resource for drug delivery across healthy and diseased states. Innovative approaches to enhance BBB opening will lead to more effective therapeutic plans and enhanced drug delivery. |
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