bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, December 30th, 2023
| Time |
Event |
| 12:18a |
A spectrum of altered non-rapid eye movement sleep in schizophrenia
Background: Multiple facets of sleep neurophysiology, including electroencephalography (EEG) metrics such as non-rapid eye movement (NREM) spindles and slow oscillations (SO), are altered in individuals with schizophrenia (SCZ). However, beyond group-level analyses which treat all patients as a unitary set, the extent to which NREM deficits vary among patients is unclear, as are their relationships to other sources of heterogeneity including clinical factors, illness duration and ageing, cognitive profiles and medication regimens. Using newly collected high density sleep EEG data on 103 individuals with SCZ and 68 controls, we first sought to replicate our previously reported (Kozhemiako et. al, 2022) group-level mean differences between patients and controls (original N=130). Then in the combined sample (N=301 including 175 patients), we characterized patient-to-patient variability in NREM neurophysiology. Results: We replicated all group-level mean differences and confirmed the high accuracy of our predictive model (Area Under the ROC Curve, AUC = 0.93 for diagnosis). Compared to controls, patients showed significantly increased between-individual variability across many (26%) sleep metrics, with patterns only partially recapitulating those for group-level mean differences. Although multiple clinical and cognitive factors were associated with NREM metrics including spindle density, collectively they did not account for much of the general increase in patient-to-patient variability. Medication regimen was a greater (albeit still partial) contributor to variability, although original group mean differences persisted after controlling for medications. Some sleep metrics including fast spindle density showed exaggerated age-related effects in SCZ, and patients exhibited older predicted biological ages based on an independent model of ageing and the sleep EEG. Conclusion: We demonstrated robust and replicable alterations in sleep neurophysiology in individuals with SCZ and highlighted distinct patterns of effects contrasting between-group means versus within-group variances. We further documented and controlled for a major effect of medication use, and pointed to greater age-related change in NREM sleep in patients. That increased NREM heterogeneity was not explained by standard clinical or cognitive patient assessments suggests the sleep EEG provides novel, nonredundant information to support the goals of personalized medicine. Collectively, our results point to a spectrum of NREM sleep deficits among SCZ patients that can be measured objectively and at scale, and that may offer a unique window on the etiological and genetic diversity that underlies SCZ risk, treatment response and prognosis. | | 3:48a |
Functionally linked amygdala and prefrontal cortical regions are innervated by both single and double projecting cholinergic neurons
Cholinergic cells have been proposed to project simultaneously to those cortical areas that are mutually interconnected with each other. We tested this hypothesis by investigating the cholinergic innervation of functionally linked cortical regions: the basal amygdala nucleus (BA) and dorsal part of the medial prefrontal cortex (dmPFC) as well as the basomedial amygdala nucleus (BMA) and ventral part of the mPFC (vmPFC). Using retrograde tracing, we found that basal forebrain cholinergic neurons projecting to the BA and BMA were in the ventral pallidum/substantia innominata (VP/SI) and horizontal limb of the diagonal band of Broca (HDB), respectively. Anterograde viral tracing confirmed that VP/SI cholinergic neurons preferentially targeted the BA and dmPFC. In contrast, HDB cholinergic cells innervated the BMA and vmPFC. We also demonstrated that a portion of cholinergic neurons projected both to the amygdala and mPFC. Furthermore, we revealed that the vesicular glutamate transporter type 3 (VGLUT3) was present typically in cholinergic boutons in the BA but not BMA, whereas their vesicular GABA transporter (VGAT) content could not be detected in adult mice. Our data thus revealed that cholinergic innervation of the dmPFC-BA and vmPFC-BMA originates from two distinct neuronal populations, which innervate interconnected target regions in a mutually exclusive manner. The dual innervation strategy, i.e., the existence of cholinergic cell populations with single as well as simultaneous projections to the amygdala and mPFC, provides the possibility for both synchronous and independent control of the operation in these cortical areas, a structural arrangement that may maximize computational support for functionally linked regions. | | 3:48a |
Small-molecule degraders reduce Aβ production through CAPRIN1-mediated lysosomal degradation of APP in Alzheimer iPSC-derived neurons
INTRODUCTION: The amyloid cascade of amyloid {beta} (A{beta}) production from amyloid precursor protein (APP) plays a key role in the pathogenesis of Alzheimer disease (AD). However, disease-modifying therapies to disrupt this amyloid cascade remain an unmet challenge. METHODS: Using neurons and organoids differentiated from induced pluripotent stem cells (iPSCs) derived from sporadic and familiar AD patients, we identified small-molecule degraders that reduce A{beta} through screening of our library of cytoplasmic activation/proliferation-associate protein 1 (CAPRIN1)-targeted small-molecules. RESULTS: The small-molecule degraders act as molecular glues that bind CAPRIN1 and APP and enhance the protein-protein interaction. Tracking CAPRIN1 and APP in neurons revealed that the degraders induce CAPRIN1-mediated APP degradation through the endosomal-lysosomal pathway and thus reduce Abeta; peptide production in AD iPSC neurons and extracellular deposition in AD iPSC organoids. DISCUSSION: The small-molecule degraders provide new therapeutics through targeted protein degradation of APP and disruption of the amyloid cascade in AD brain. | | 11:33p |
Principles of visual cortex excitatory microcircuit organization
Microcircuit function is determined by patterns of connectivity and short-term plasticity that vary with synapse type. Elucidating microcircuit function therefore requires synapse-specific investigation. The state of the art for synapse-specific measurements has long been paired recordings. Although powerful, this method is slow, leading to a throughput problem. To improve yield, we therefore created optomapping -- an approximately 100-fold faster 2-photon optogenetic method -- which we validated with paired-recording data. Using optomapping, we tested 15,433 candidate excitatory inputs to find 1,184 connections onto pyramidal, basket, and Martinotti cells in mouse primary visual cortex, V1. We measured connectivity, synaptic weight, and short-term dynamics across the V1 layers. We found log-normal synaptic strength distributions, even in individual inhibitory cells, which was previously not known. We reproduced the canonical circuit for pyramidal cells but found surprising and differential microcircuit structures, with excitation of basket cells concentrated to layer 5, and excitation of Martinotti cells dominating in layer 2/3. Excitation of inhibitory cells was denser, stronger, and farther-reaching than excitation of excitatory cells, which promotes stability and difference-of-Gaussian connectivity. We gathered an excitatory short-term plasticitome, which revealed that short-term plasticity is simultaneously target-cell specific and dependent on presynaptic cortical layer. Peak depolarization latency in pyramidal cells also emerged as more heterogeneous, suggesting heightened sensitivity to redistribution of synaptic efficacy. Optomapping additionally revealed high-order connectivity patterns including shared-input surplus for interconnected pyramidal cells in layer 6. Optomapping thus offered both resolution to the throughput problem and novel insights into the principles of neocortical excitatory fine structure.
HIGHLIGHTSO_LI2-photon optomapping of microcircuits is verified as fast, accurate, and reliable
C_LIO_LISynaptic weights distribute log-normally even for individual inhibitory neurons
C_LIO_LIMaximal excitation of basket and Martinotti cells in layer 5 and 2/3, respectively
C_LIO_LIShort-term plasticity depends on layer in addition to target cell
C_LI | | 11:33p |
Task goals shape the relationship between decision and movement speed
The speed at which we move is linked to the speed at which we decide to make these movements. Yet, the principles guiding such relationship remain unclear: while some studies point towards a shared invigoration process boosting decision and movement speed jointly, others rather indicate a tradeoff between both levels of control, with slower movements accompanying faster decisions. Here, we aimed (1) at further investigating the existence of a shared invigoration process linking decision and movement and (2) at testing the hypothesis that such a link is masked when detrimental to the reward rate. To this aim, we tested 62 subjects who performed the tokens task in two experiments (separate sessions): Experiment 1 evaluated how changing decision speed affects movement speed while Experiment 2 assessed how changing movement speed affects decision speed. In the latter experiment, subjects were either encouraged to favor decision speed (fast decision group) or decision accuracy (slow decision group). Various mixed model analyses revealed a coregulation of decision (urgency) and movement speed in Experiment 1 and in the fast decision group of Experiment 2, but not in the slow decision group despite the fact that these same subjects displayed a coregulation effect in Experiment 1. Altogether, our findings support the idea that coregulation occurs as a default mode but that this form of control is diminished or supplanted by a tradeoff relationship, contingent on reward rate maximization. Drawing from these behavioral observations, we propose that multiple processes contribute to shaping the speed of decisions and movements.
New & NoteWorhtyThe principles guiding the relationship between decision and movement speed are unclear. In the present behavioral study involving two experiments conducted on 62 human subjects, we report findings indicating a relationship that varies as a function of the task goals. Coregulation emerges as a default mode of control that fades when detrimental to the reward rate, possibly due to the influence of other processes that can selectively shape the speed of our decisions and movements. | | 11:33p |
Diversity and connectivity of principal neurons in the lateral and basal nuclei of the mouse amygdala
The basolateral amygdala is a non-layered cortical structure playing a role in various cognitive processes. Despite many studies focusing on local information processing within the circuits of the basolateral amygdala, the characteristics of excitatory principal neurons (PNs) are still not fully revealed. Here, we combined neuroanatomical, electrophysiological, and tracing techniques to determine the single-cell features, dendritic and axonal projections of PNs within the lateral (LA) and basal amygdala (BA). Using a mouse reporter line, we found that cholecystokinin (CCK) expression defines two spatially and functionally segregated groups of PNs both in the LA and BA. PNs in CCK-positive (CCK+) areas of the LA (LAa) had small somata and short dendrites which matched their single-cell electrophysiological properties. PNs in CCK-negative (CCK-) areas of the LA (LAp) and all BA had similarly ramified dendrites and single-cell features with some differences. Importantly, the dendritic arbors of PNs were restricted to the subnuclei defined by CCK expression, which corresponded to various extra-amygdalar afferents indicating specific inputs on distinct PN groups. Axonal arborization patterns of PNs within the basolateral amygdala and surrounding areas showed consistency to their soma location. For instance, BA PNs that projected to the medial prefrontal cortex but not to the lateral nucleus of the central amygdala were present in CCK+ areas. In contrast, those BA PNs that projected to the lateral part of the central nucleus were found in the subnucleus lacking CCK. Our study revealed that the basolateral amygdala is composed of functionally different subnuclei with specific inputs and outputs. This structural arrangement may empower the LA and BA to flexibly channel processed information toward their downstream regions, which can be a key requirement for diverse amygdala functions in cognitive operation. | | 11:33p |
Objective sleep quality predicts subjective sleep ratings: a multiday observational study
In both clinical and observational studies, sleep quality is usually assessed by subjective self-report. The literature is mixed about how accurately these self-reports track objectively (e.g. via polysomnography) assessed sleep quality, with frequent reports of a very low or no association. However, previous research on this question focused on between-subject designs, which may be confounded by trait-level variables. In the current study, we used the novel Budapest Sleep, Experiences and Traits Study (BSETS) dataset to investigate if within-subject differences in subjectively reported sleep quality are related to sleep macrostructure and quantitative EEG variables assessed using a mobile EEG headband. We found clear evidence that within-subject variations in sleep onset latency, wake after sleep onset, total sleep time, and sleep efficiency affect self-reported sleep quality in the morning. These effects were replicated if detailed sleep composition metrics (percentage and latency of specific vigilance states) or two alternative measures of subjective sleep quality are used instead. We found no effect of the number of awakenings or relative EEG delta and sigma power. Between-subject effects (relationships between individual mean values of sleep metrics and subjective sleep quality) were also found, highlighting that analyses focusing only on these may be erroneous. Our findings show that while previous investigations of this issue may have been confounded by between-subject effects, objective sleep quality is indeed reflected in subjective sleep ratings. | | 11:33p |
Fluoxetine treatment during postnatal and juvenile temporal epochs evokes diametrically opposing changes in anxio-depressive behaviors, gene expression, mitochondrial function, and neuronal architecture in the medial prefrontal cortex
BackgroundThe selective serotonin reuptake inhibitor, fluoxetine is reported to evoke distinct effects on anxio-depressive behaviors based on the temporal window of administration. Here, we systematically addressed the influence of postnatal or juvenile fluoxetine treatment on anxio-depressive behavior, gene expression, mitochondrial biogenesis, and neuronal cytoarchitecture in adulthood.
MethodsRat pups received postnatal fluoxetine (PNFlx) or juvenile fluoxetine (JFlx) treatment from postnatal day 2 (P2)-P21 or P28-48 respectively, and were assessed for changes in anxio-depressive behaviors, global gene expression, mitochondrial biogenesis/function, and dendritic cytoarchitecture in the medial prefrontal cortex (mPFC) in adulthood.
ResultsPNFlx evoked long-lasting increases in anxio-depressive behaviors, whereas JFlx elicited persistent decreases in anxio-depressive behavior, accompanied by differential and minimally overlapping transcriptional changes in the mPFC in adulthood. We noted opposing changes in mitochondrial function and dendritic cytoarchitecture in the mPFC of PNFlx and JFlx animals, with a decline observed following PNFlx and an increase in response to JFlx treatment. Furthermore, the enhanced despair-like behavior in the PNFlx cohort was reversed by adult-onset treatment with nicotinamide, a precursor for NAD+ which enhances mitochondrial bioenergetics.
ConclusionsFluoxetine treatment in early postnatal versus juvenile windows evokes opposing and persistent effects on anxio-depressive behavior in adult male rats, along with differential effects on gene expression, mitochondrial function, and dendritic morphology in the mPFC. Collectively, our findings highlight two distinct temporal windows in which fluoxetine exposure programs starkly differing outcomes in mood-related behavior, and posits a role for altered bioenergetics within the mPFC in contributing to these distinctive changes in emotionality. | | 11:33p |
Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition of irrelevant information in people with multiple sclerosis
BackgroundMultiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission. MS leads to cognitive impairment such as reduced information processing speed and impaired working memory (WM). Recent studies have suggested that the 1/f slope of EEG/MEG power spectra can be associated with the excitation/inhibition (E/I) balance. A normal E/I balance is crucial for normal information processing and working memory.
MethodsWe analyzed magnetoencephalographic (MEG) recordings of 38 healthy control subjects and 79 people with multiple sclerosis (pwMS) while performing an n-back working task. We computed and compared the steepness of the 1/f spectral slope through the FOOOF algorithm in the time windows [-1 0] and [0 1] s peristimulus time for both target and distractor stimulus for each brain parcel and for different working memory loads (0-back, 1-back, 2-back).
ResultsThe spectral slope was significantly steeper after the stimulus onset and was correlated with reaction time. We also observed a steeper 1/f slope after distractor stimuli in healthy subjects compared to pwMS. Finally, we observed significant correlations between the 1/f spectral slope modulation and visuospatial working memory functioning in both healthy subjects and pwMS.
ConclusionOur findings are consistent with an increased inhibition following stimulus onset. In pwMS, this increase is reduced, suggesting dysfunctional inhibition of irrelevant information. Finally, this impaired modulation is significantly associated with a pencil-paper test of visuospatial working memory.
HighlightsO_LIThe flatter 1/f slope after distractor stimuli in people with multiple sclerosis (pwMS) compared to healthy subjects suggests a less pronounced inhibition of irrelevant information in pwMS.
C_LIO_LIThe significantly flatter 1/f slope was observed in the left inferior dorsal prefrontal cortex of pwMS in both 1-back and 2-back conditions. This particular brain parcel is known for its key role in motor planning, and the maintenance of sustained attention and working memory and executive functions.
C_LIO_LIA steeper 1/f slope after target and distractor stimuli suggests an increase in inhibition following stimulus onset in both healthy controls (HCs) and people with MS (pwMS).
C_LIO_LIThe 1/f slope modulation correlates with visuospatial working memory performance.
C_LI | | 11:33p |
Whole-brain modelling supports the use of serotonergic psychedelics for the treatment of disorders of consciousness
Disorders of consciousness (DoC) are a challenging and complex group of neurological conditions characterised by absent or impaired awareness. The current range of therapeutic options for DoC patients is limited, offering few non-invasive pharmacological alternatives. This situation has sprung a growing interest in the development of novel treatments, such as the proposal to study the efficacy of 5HT2A receptor agonists (also known as psychedelics) to restore impaired consciousness. Given the ethical implications of exploring novel compounds in non-communicative individuals, we assessed in silico their effects in the whole-brain dynamics of DoC patients. We embedded the whole-brain activity of patients in a low-dimensional space, and then used this representation to visualise the effects of simulated neuromodulation across a range of receptors representing potential drug targets. Our findings show that activation of serotonergic and opioid receptors shifted brain dynamics of DoC patients towards patterns typically seen in conscious and awake individuals, and that this effect was mediated by the brain-wide density of activated receptors. These results showcase the role of whole-brain models in the discovery of novel pharmacological treatments for neuropsychiatric conditions, while also supporting the feasibility of accelerating the recovery of consciousness with serotonergic psychedelics. | | 11:33p |
Amygdala habituation during exposure is associated with failure to reduce phobic symptoms
Exposure therapy is an established treatment for anxiety disorders but the mechanisms underpinning its effectiveness remain unclear. Two theories offer contrasting perspectives: the traditional habituation model posits that a form of stimulus desensitization is required during exposure, while the inhibitory learning model emphasizes the formation of new non-fearful associations. Crucially, while the former may manifest as amygdala habituation, the latter may not. To distinguish between the two models, this study uses functional magnetic resonance imaging to examine the amygdala responses of spider-fearful participants during fear exposure. We hypothesized that intervention success might align with stable or even increased amygdala activation - an indicator of active engagement and re-learning as proposed by the inhibitory learning model. Conversely, decreasing amygdala activity might not be a sign of reduced fear memory as proposed by the habituation model, but could signal mental detachment, leading to suboptimal treatment outcomes. Our results corroborated our hypotheses: individuals with escalating amygdala responses during exposure exhibited better clinical progress, while those showing amygdala habituation benefited less. Our results strengthen the case for the inhibitory learning model and highlight that therapy may not aim to diminish fear per se but rather to engage patients in active processing and association formation. |
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