bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, June 22nd, 2024
| Time |
Event |
| 3:30a |
Covert actions of epidural stimulation on spinal locomotor circuits
Spinal circuitry produces the rhythm and patterning of locomotion. However, both descending and sensory inputs are required to initiate and adapt locomotion to the environment. Spinal cord injury (SCI) disrupts descending controls of the spinal cord, producing paralysis. Epidural stimulation (ES) is a promising clinical therapy for motor control recovery and is capable of reactivating the lumbar spinal locomotor networks, yet little is known about the effects of ES on locomotor neurons. Previously, we found that both sensory afferent pathways and serotonin exert mixed excitatory and inhibitory actions on lumbar interneurons involved in the generation of the locomotor rhythm, identified by the transcription factor Shox2. However, after chronic complete SCI, sensory afferent inputs to Shox2 interneurons become almost exclusively excitatory and Shox2 interneurons are supersensitive to serotonin. Here, we investigated the effects of ES on these SCI-induced changes. Inhibitory input from sensory pathways to Shox2 interneurons was maintained and serotonin supersensitivity was not observed in SCI mice that received daily sub-motor threshold ES. Interestingly, the effects of ES were maintained for at least three weeks after the ES was discontinued. In contrast, the effects of ES were not observed in Shox2 interneurons from mice that received ES after the establishment of the SCI-induced changes. Our results demonstrate mechanistic actions of ES at the level of identified spinal locomotor circuit neurons and the effectiveness of early treatment with ES on preservation of spinal locomotor circuitry after SCI, suggesting possible therapeutic benefits prior to the onset of motor rehabilitation. | | 5:04a |
Gut-immune reactivity underlies sex differences in the maternal immune activation preclinical model of autism
The gut microbiome plays a vital role in health and disease, including neurodevelopmental disorders like autism spectrum disorder (ASD). ASD affects 4:1 males-to-females, and sex differences are apparent in gut microbiota composition among ASD individuals and in animal models of this condition, such as the maternal immune activation (MIA) mouse model. However, few studies have included sex as a biological variable when assessing the role of gut microbiota in mediating ASD symptoms. Using the MIA model of ASD, we assessed whether gut microbiota contributes to the sex differences in the presentation of ASD-like behaviors. Gut microbiota transplantation from MIA or vehicle/control male and female mice into healthy, otherwise unmanipulated, 4-week-old C57Bl/6 mice was performed for 6 treatments over 12 days. Colonization with male, but not female, MIA microbiota was sufficient to reduce sociability, increase repetitive burying behavior, decrease microbiota diversity and increase neuroinflammation with more pronounced deficits in male recipients. Colonization with both male and female donor microbiota altered juvenile ultrasonic vocalizations and anxiety-like behavior in recipients of both sexes, and there was an accompanied change in the gut microbiota and serum cytokine IL-4 and IL-7 levels of all recipients of MIA gut microbiota. In addition to the increases in gut microbes associated with pathological states, the female donor microbiota profile also had increases in gut microbes with known neural protective effects (e.g., Lactobacillus and Rikenella). These results suggest that gut reactivity to environmental insults, such as in the MIA model, plays a pivotal role in shaping the sex disparity observed in ASD development. | | 5:04a |
Bidirectional valence coding in amygdala intercalated clusters:A neural substrate for the opponent-process theory of motivation
Processing emotionally meaningful stimuli and eliciting appropriate valence-specific behavior in response is a critical brain function for survival. Thus, how positive and negative valence are represented in neural circuits and how corresponding neural substrates interact to cooperatively select appropriate behavioral output are fundamental questions. In previous work, we identified that two amygdala intercalated clusters show opposite response selectivity to fear- and anxiety-inducing stimuli - negative valence (Hagihara et al. 2021). Here, we further show that the two clusters also exhibit distinctly different representations of stimuli with positive valence, demonstrating a broader role of the amygdala intercalated system beyond fear and anxiety. Together with the mutually inhibitory connectivity between the two clusters, our findings suggest that they serve as an ideal neural substrate for the integrated processing of valence for the selection of behavioral output. | | 9:19a |
Beyond brain size: disentangling the effect of sex and brain size on brain morphometry and cognitive functioning
It is imperative to study sex differences in brain morphology and function. However, there are major observable and unobservable confounding factors that can contribute to the estimated differences. Males have larger head sizes than females. Head size differences not only act as a confounding factor in studying sex differences in the brain, but also impact its anatomy and functioning. In this work, we seek to disentangle the effect of head size from sex in studying sex differentiated aging trajectories, its relation to canonical functional networks and cytoarchitectural classes, brain allometry, cognition. Using the UK Biobank (UKBB) neuroimaging data (N = 35,732 participants, 19,281 females, 44-82 years of age), we created a subsample (N = 11,294) where females (N = 5,657) and males were matched by their total intracranial volume (TIV) and age, a subsample that maintains the UKBB sample distribution, one matched only by age, and one that exaggerated the TIV difference between sexes. We then modeled the aging trajectories at both regional and vertex-wise levels in the four subsamples, and compared the estimations of the models. Our results show that when females and males have the same head size, the overall sex estimations tend towards zero, suggesting that most of the variability results from head size differences. Our approach also revealed bidirectional sex differences in brain neuroanatomy previously masked by the effect of head size. Further, the scaling relationship between regional and total brain volume remains fairly consistent across the lifespan and is not sex differentiated overall. We evaluated how the results of cognitive tests with perceived sex differences are influenced and explained by head size and found that although the correlation between TIV and cognitive scores is low, the matching process changes the direction of the effect sizes of differences between sexes in "verbal and numerical reasoning" and "working memory" cognitive domains. Taken together, employing a matching approach that is widely used in causal modeling studies, we provide new evidence for disentanglement of sex differences in the brain from head size as a biological confound. | | 9:19a |
FOXP2-immunoreactive, corticothalamic pyramidal cells in neocortical layers 6a and 6b are tightly regulated by neuromodulatory systems
The FOXP2/Foxp2 gene is involved in fine motor control in many vertebrate species; in humans, it is one of the candidate genes thought to play a prominent role in language production. Several studies suggest that in the neocortex, Foxp2 is exclusively expressed in a subset of corticothalamic (CT) pyramidal cells (PCs) in layer 6 (L6). However, the morphological and intrinsic electrophysiological, synaptic and neuromodulatory properties of Foxp2-expressing L6 PCs remain largely unknown. Here we systematically characterise these properties for FOXP2-positive (FOXP2+) PCs across L6 in the rat somatosensory cortex. We find that L6 FOXP2+ PCs are distinct in all of these properties from those of L6 FOXP2-negative (FOXP2-) neuronal cell types. We show that L6 FOXP2+ PCs project exclusively to thalamus. In upper L6 (L6a), FOXP2+ PCs innervate either the first-order thalamus or both first and higher-order thalamic nuclei. FOXP2+ PCs in deep L6 (L6b) project almost exclusively to higher-order thalamus. Synaptic connections established by L6a and L6b FOXP2+ PCs exhibit low synaptic release probability, whereas L6 corticocortical PCs have a high release probability. Both L6a and L6b FOXP2+ PCs respond strongly to acetylcholine (ACh), which in the absence of TTX results in firing of action potential (AP) trains. Notably, L6b but not L6a FOXP2- PCs are highly sensitive to ACh. In addition, L6b FOXP2+ PCs close to the white matter border show strong responses to dopamine that develop into prolonged AP firing. Our data suggest that FOXP2 is a marker for CT PCs in L6 that are strongly controlled by neurotransmitters such as ACh and dopamine. These findings are in line with a pivotal role for both L6a and L6b CT PCs as modulators of thalamic activity. | | 10:30a |
Linguistic inputs must be syntactically parsable to fully engage the language network
Human language comprehension is remarkably robust to ill-formed inputs (e.g., word transpositions). This robustness has led some to argue that syntactic parsing is largely an illusion, and that incremental comprehension is more heuristic, shallow, and semantics-based than is often assumed. However, the available data are also consistent with the possibility that humans always perform rule-like symbolic parsing and simply deploy error correction mechanisms to reconstruct ill-formed inputs when needed. We put these hypotheses to a new stringent test by examining brain responses to a) stimuli that should pose a challenge for syntactic reconstruction but allow for complex meanings to be built within local contexts through associative/shallow processing (sentences presented in a backward word order), and b) grammatically well-formed but semantically implausible sentences that should impede semantics-based heuristic processing. Using a novel behavioral syntactic reconstruction paradigm, we demonstrate that backward-presented sentences indeed impede the recovery of grammatical structure during incremental comprehension. Critically, these backward-presented stimuli elicit a relatively low response in the language areas, as measured with fMRI. In contrast, semantically implausible but grammatically well-formed sentences elicit a response in the language areas similar in magnitude to naturalistic (plausible) sentences. In other words, the ability to build syntactic structures during incremental language processing is both necessary and sufficient to fully engage the language network. Taken together, these results provide strongest to date support for a generalized reliance of human language comprehension on syntactic parsing. | | 10:30a |
Alzheimer's disease-like features in resting state EEG/fMRI of cognitively intact and healthy middle-aged APOE/PICALM risk carriers
Introduction: Genetic susceptibility is a primary factor contributing to etiology of late-onset Alzheimer's disease (LOAD). The exact mechanisms and timeline through which APOE/PICALM influence brain functions and contribute to LOAD remain unidentified. This includes their effects on individuals prior to the development of the disease. Methods: APOE/PICALM alleles were assessed to determine the genetic risk of LOAD in 79 healthy, middle-aged participants who underwent EEG and fMRI recordings. The resting-state signal was analyzed to estimate relative spectral power, complexity (Higuchi's algorithm), and connectivity (coherence in EEG and ICA-based connectivity in fMRI). Results: The main findings indicated that individuals at risk for LOAD exhibited reduced signal complexity and the so-called "slowing of EEG" which are well-known EEG markers of AD. Additionally, these individuals showed altered functional connectivity in fMRI (within attention related areas). Discussion: Risk alleles of APOE/PICALM may affect brain integrity and function prior to the onset of the disease | | 10:30a |
Bidirectional modulation of negative emotional states by parallel genetically-distinct basolateral amygdala pathways to ventral striatum subregions
Distinct basolateral amygdala (BLA) cell populations influence emotional responses in manners thought important for anxiety and anxiety disorders. The BLA contains numerous cell types which can broadcast information into structures that may elicit changes in emotional states and behaviors. BLA excitatory neurons can be divided into two main classes, one of which expresses Ppp1r1b (encoding protein phosphatase 1 regulatory inhibitor subunit 1B) which is downstream of the genes encoding the D1 and D2 dopamine receptors (drd1 and drd2 respectively). The role of drd1+ or drd2+ BLA neurons in learned and unlearned emotional responses is unknown. Here, we identified that the drd1+ and drd2+ BLA neuron populations form two parallel pathways for communication with the ventral striatum. These neurons arise from the basal nucleus of the BLA, innervate the entire space of the ventral striatum, and are capable of exciting ventral striatum neurons. Further, through three separate behavioral assays, we found that the drd1+ and drd2+ parallel pathways bidirectionally influence both learned and unlearned emotional states when they are activated or suppressed, and do so depending upon where they synapse in the ventral striatum, with unique contributions of drd1+ and drd2+ circuitry on negative emotional states. Overall, these results contribute to a model whereby parallel, genetically-distinct BLA to ventral striatum circuits inform emotional states in a projection-specific manner. | | 10:30a |
Pre- and postnatal maternal depressive symptoms associate with localconnectivity of the left amygdala in 5-year-olds.
Maternal pre- and postnatal depressive symptoms influence brain development in offspring. Maternal symptoms may affect child brain development through intrauterine conditions as well as ways of parenting and mother-child interaction. This study investigated whether maternal pre- and postnatal depressive symptoms are associated with child's whole brain regional homogeneity (ReHo) and seed-based connectivity of the bilateral amygdala at 5 years of age based on the sample available from FinnBrain Birth Cohort Study (N = 68; 28 boys, 40 girls). Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) at gestational week 24, 3 months, 6 months, and 12 months postnatal. Children's brain imaging data were acquired with task-free functional magnetic resonance imaging (fMRI) at the age of 5 years in 7 min scans while watching the Inscapes movie. The ReHo and seed-based connectivity maps of the bilateral amygdalae were created from the fMRI data. We found that maternal depressive symptoms were positively associated with ReHo values of the left amygdala. The association was strongest with the maternal depressive symptoms at three months postnatal. Seed-based connectivity analysis did not reveal associations between distal connectivity of the left amygdala region and maternal depressive symptoms. These results suggest that maternal depressive symptoms during pregnancy and especially soon after birth may influence offspring's neurodevelopment related to emotional processing in fundamental ways and may raise the risk of vulnerability of intergenerational transmission for depression and other affective disorders. | | 10:30a |
Visually Evoked 40 Hz Gamma Activity Enhanced by Transcranial Electrical Stimulation
Background: Non-invasive Visual Stimulation (VS) and Transcranial Electrical Stimulation (TES) can modulate neuronal oscillations, including gamma activity at 40 Hz, which is relevant for cognition and disrupted in dementia. Combining both techniques may increase effects, but simultaneously recording Electroencephalography (EEG) activity poses several challenges, so this approach is untested. Objectives: We predicted that combined TES and VS in the lower gamma band would increase Steady-State Visually Evoked Potential (SSVEP) amplitude during and after stimulation, but only when targeting visual areas and at closely matching stimulation frequencies. Methods: We administered combined VS and TES and simultaneously measured effects on EEG gamma activity in healthy participants. In experiment 1 (N=25), VS and TES frequencies were closely matched at ~40 Hz, and TES sites varied between occipito-central, centro-occipital (reversed polarity), and centro-frontal. In experiment 2 (N=25), occipito-central TES was applied at ~40 Hz, and VS frequency varied between 35, 40, and 45 Hz. Every 5-minute VS+TES trial was preceded and followed by a VS-only baseline trial. Electrical artifacts were removed using adaptive template subtraction. Results: TES enhanced gamma SSVEP amplitudes most when applied to occipital and central sites, compared to frontal. Enhancement only occurred when TES and VS frequencies closely matched at ~40 Hz, not when VS was slower (35 Hz) or faster (45 Hz) than TES. The effect was present during, not after, TES. Conclusion: Multimodal visual and electrical stimulation evokes stronger oscillatory gamma activity than visual alone. Non-invasive gamma stimulation against cognitive decline in dementia may benefit from this optimised approach. |
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