The mechanisms underlying synaptic transmission at the layer 4 of sensory cortical areas

Die Neuronen in Schicht vier (L4) des cerebralen Kortex spielen eine wichtige Rolle bei der Signalübertragung vom Thalamus zu anderen Kortexbereichen. Das Verständnis der grundlegenden Eigenschaften der synaptischen Übertragung zwischen Neuronen in L4 ermöglicht es uns, ein klarerers Bild davon zu erhalten, wie die neuronalen Netzwerke in L4 kooperieren um sensorische Informationen zu verarbeiten. In dieser Studie haben wir für exzitatorische synaptische Verbindungen innerhalb der L4 des visuellen Kortexes (V1) sowie des somatosensorischen Kortexes (S1) der Maus Parameter untersucht, die die synaptische Stärke beeinflussen, wie quantale Größe (q), die Größe des schnell freisetzbaren Vesikelvorrats (N) und die Freisetzungswahrscheinlichkeit (Pr) Während unter physiologischen Bedingungen in V1-Synapsen nur ein Vesikel pro Freisetzungszone freigesetzt wird, wurde bei S1-Synapsen multivesikuläre Freisetzung (MVR) beobachtet. Darüber hinaus konnten wir eine Sättigung der postsynaptischen Rezeptoren bei S1-Synapsen feststellen. Die anderen gemessenen synaptischen Eigenschaften sind in beiden Kortexregionen ähnlich. Experimente mit Dynamic Clamp deuten darauf hin, dass die niedrigere Freisetzungswahrscheinlichkeit sowie die multivesikuläre Freisetzung bei S1-Synapsen dazu führen, dass weniger synaptische Erregungen genügen, um ein Aktionspotential in der postsynaptischen Zelle auszulösen. Zusätzlich dazu tragen der langsamere Abfall des synaptischen Stroms und die intrinsischen Membraneigenschaften der postsynaptischen Zelle zur verlässlichen Signalübertragung zwischen S1-Neuronen bei.Neurons in layer 4 (L4) of the cortex play an important role in transferring signals from thalamus to other layers of the cortex. Understanding the fundamental properties of synaptic transmission between L4 neurons helps us to gain a clear picture of how the neuronal network in L4 co-operates to process sensory information. In the present study, we have determined the underlying parameters that govern synaptic strength such as quantal size (q), size of readily releasable vesicle pool (N) and release probability (Pr) of excitatory synaptic connections within L4 of the visual cortex (V1) and the somatosensory cortex (S1) in mice. While only a single vesicle is released per release site under physiological conditions at V1 synapses, multivesicular release (MVR) is observed at S1 synapses. In addition, we observed a saturation of postsynaptic receptors at S1 synapses. Other synaptic properties are similar in both cortices. Dynamic clamp experiments suggest that higher Pr and MVR at S1 synapses lower the requirement of the number of synaptic inputs to generate postsynaptic action potentials. In addition, the slower decay of synaptic current and the intrinsic membrane properties of the postsynaptic neuron also contribute to the reliable transmission between S1 neurons

Discriminative power of EEG-based biomarkers in major depressive disorder: A systematic review

Currently, the diagnosis of major depressive disorder (MDD) and its subtypes is mainly based on subjective assessments and self-reported measures. However, objective criteria as Electroencephalography (EEG) features would be helpful in detecting depressive states at early stages to prevent the worsening of the symptoms. Scientific community has widely investigated the effectiveness of EEG-based measures to discriminate between depressed and healthy subjects, with the aim to better understand the mechanisms behind the disorder and find biomarkers useful for diagnosis. This work offers a comprehensive review of the extant literature concerning the EEG-based biomarkers for MDD and its subtypes, and identify possible future directions for this line of research. Scopus, PubMed and Web of Science databases were researched following PRISMA’s guidelines. The initial papers’ screening was based on titles and abstracts; then full texts of the identified articles were examined, and a synthesis of findings was developed using tables and thematic analysis. After screening 1871 articles, 76 studies were identified as relevant and included in the systematic review. Reviewed markers include EEG frequency bands power, EEG asymmetry, ERP components, non-linear and functional connectivity measures. Results were discussed in relations to the different EEG measures assessed in the studies. Findings confirmed the effectiveness of those measures in discriminating between healthy and depressed subjects. However, the review highlights that the causal link between EEG measures and depressive subtypes needs to be further investigated and points out that some methodological issues need to be solved to enhance future research in this field

Extended field-of-view ultrathin microendoscopes with built-in aberration correction for high-resolution functional imaging with minimal invasiveness

TB

The pathobiology of psychomotor slowing in psychosis: altered cortical excitability and connectivity.

Psychomotor slowing is a frequent symptom of schizophrenia. Short-interval intracortical inhibition assessed by transcranial magnetic stimulation demonstrated inhibitory dysfunction in schizophrenia. The inhibitory deficit results from additional noise during information processing in the motor system in psychosis. Here, we tested whether cortical inhibitory dysfunction was linked to psychomotor slowing and motor network alterations. In this cross-sectional study, we included 60 patients with schizophrenia and psychomotor slowing determined by the Salpêtrière Retardation Rating Scale, 23 patients without slowing and 40 healthy control participants. We acquired single and double-pulse transcranial magnetic stimulation effects from the left primary motor cortex, resting-state functional connectivity and diffusion imaging on the same day. Groups were compared on resting motor threshold, amplitude of the motor evoked potentials, as well as short-interval intracortical inhibition. Regression analyses calculated the association between motor evoked potential amplitudes or cortical inhibition with seed-based resting-state functional connectivity from the left primary motor cortex and fractional anisotropy at whole brain level and within major motor tracts. In patients with schizophrenia and psychomotor slowing, we observed lower amplitudes of motor evoked potentials, while the short-interval intracortical inhibition/motor evoked potentials amplitude ratio was higher than in healthy controls, suggesting lower cortical inhibition in these patients. Patients without slowing also had lower amplitudes of motor evoked potentials. Across the combined patient sample, cortical inhibition deficits were linked to more motor coordination impairments. In patients with schizophrenia and psychomotor slowing, lower amplitudes of motor evoked potentials were associated with lower fractional anisotropy in motor tracts. Moreover, resting-state functional connectivity between the primary motor cortex, the anterior cingulate cortex and the cerebellum increased with stronger cortical inhibition. In contrast, in healthy controls and patients without slowing, stronger cortical inhibition was linked to lower resting-state functional connectivity between the left primary motor cortex and premotor or parietal cortices. Psychomotor slowing in psychosis is linked to less cortical inhibition and aberrant functional connectivity of the primary motor cortex. Higher neural noise in the motor system may drive psychomotor slowing and thus may become a treatment target

SEX-SPECIFIC EFFECTS OF PSYCHEDELIC DRUG ADMINISTRATION ON STRESS-RELATED BRAIN REGION REACTIVITY AND BEHAVIORAL RESPONDING

Psychedelics have experienced renewed interest following studies suggesting rapid-acting and long-lasting therapeutic effects in patients with affective psychiatric disorders. While clinical results look promising, the circuit-level neurobiological mechanisms underlying acute and prolonged effects remain unclear. Many psychiatric disorders involve dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The central amygdala (CeA), paraventricular nucleus of the hypothalamus (PVN), and paraventricular nucleus of the thalamus (PVT) are all key regions in orchestrating the neural and endocrine stress response. Here, we aimed to test how a single administration of psilocin, the psychoactive metabolite of psilocybin, alters reactivity of these regions at both acute and prolonged time points in Sprague Dawley rats. We found that a single dose of psilocin (2mg/kg) produces acute increases in reactivity within the PVT and CeA in females, and acute increases in PVN reactivity and prolonged decreases in CeA reactivity in males. The effects in both CeA and PVN seen in males were driven by those employing an active threat responding behavior strategy. We also observed an effect of psilocin administration on maintenance of reactivity within PVTCeA circuitry in both males and females. All together, these data provide intriguing new insight into the region-specific alterations following a single dose of a psychedelic and may serve as a foundation in uncovering the circuit-level mechanisms underlying the acute and persistent effects of psychedelic drug action.Doctor of Philosoph

Neural Basis and Computational Strategies for Auditory Processing

Our senses are our window to the world, and hearing is the window through which we perceive the world of sound. While seemingly effortless, the process of hearing involves complex transformations by which the auditory system consolidates acoustic information from the environment into perceptual and cognitive experiences. Studies of auditory processing try to elucidate the mechanisms underlying the function of the auditory system, and infer computational strategies that are valuable both clinically and intellectually, hence contributing to our understanding of the function of the brain. In this thesis, we adopt both an experimental and computational approach in tackling various aspects of auditory processing. We first investigate the neural basis underlying the function of the auditory cortex, and explore the dynamics and computational mechanisms of cortical processing. Our findings offer physiological evidence for a role of primary cortical neurons in the integration of sound features at different time constants, and possibly in the formation of auditory objects. Based on physiological principles of sound processing, we explore computational implementations in tackling specific perceptual questions. We exploit our knowledge of the neural mechanisms of cortical auditory processing to formulate models addressing the problems of speech intelligibility and auditory scene analysis. The intelligibility model focuses on a computational approach for evaluating loss of intelligibility, inspired from mammalian physiology and human perception. It is based on a multi-resolution filter-bank implementation of cortical response patterns, which extends into a robust metric for assessing loss of intelligibility in communication channels and speech recordings. This same cortical representation is extended further to develop a computational scheme for auditory scene analysis. The model maps perceptual principles of auditory grouping and stream formation into a computational system that combines aspects of bottom-up, primitive sound processing with an internal representation of the world. It is based on a framework of unsupervised adaptive learning with Kalman estimation. The model is extremely valuable in exploring various aspects of sound organization in the brain, allowing us to gain interesting insight into the neural basis of auditory scene analysis, as well as practical implementations for sound separation in ``cocktail-party'' situations

Cortical Experience-dependent Plasticity and Mesostriatal Dopaminergic Dysfunction in a Mouse Model of Angelman Syndrome

Sensory experience guides development of neocortical circuits. This activity-dependent circuit maturation is required for normal sensory and cognitive abilities, which are distorted in neurodevelopmental disorders. Here we have tested whether experience-dependent cortical modifications require Ube3a, an E3 ubiquitin ligase whose dysregulation has been implicated in both autism and Angelman syndrome (AS). Using the visual cortex as a model system for neocortical plasticity, we found that the genetic deletion of UBE3A attenuates activity-dependent synaptic strengthening and weakening in visual cortical slices. Chronic recordings of visual evoked potentials (VEPs) from awake mice also exhibited deficits in critical period ocular dominance plasticity, an in vivo assay for experience-dependent synaptic weakening. Stimulus-specific response potentiation (SRP) of VEPs was used as an assay of experience-dependent synaptic strengthening. Contrary to the results observed in in vitro slice preparations, we observed developmentally enhanced potentiation of VEPs, including increased power of spontaneous local field potentials (LFP) in AS mice. WT and AS mice achieved similar increases in VEP amplitude with a longer period of visual stimulation, indicating the threshold for potentiation was lower in AS mice. Augmented plasticity and increased spontaneous LFP power were absent from mice maternally expressing Ube3a in inhibitory neurons alone. Our results suggest that sensory experience-dependent cortical potentiation is enhanced in adult AS mice due to reduced inhibition. Previous studies also suggest that abnormal dopamine neurotransmission may underlie some of the motor deficits exhibited in AS. A clinical trial of levodopa (L-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models. We found that AS mice exhibited behavioral deficits that correlated with abnormal dopamine signaling. These deficits were not due to loss of dopaminergic neurons or impaired dopamine synthesis. Unexpectedly, AS mice exhibited increased dopamine release in the mesolimbic pathway while also exhibiting a decrease in dopamine release in the nigrostriatal pathway, as measured with fast-scan cyclic voltammetry. These findings demonstrate the complex effects of UBE3A loss on dopamine signaling in subcortical motor pathways that may inform ongoing clinical trials of L-DOPA therapy in patients with AS.Doctor of Philosoph

ELUCIDATING THE NATURE AND DEVELOPMENT OF NEURAL MECHANISMS ASSOCIATED WITH ANXIOUS APPREHENSION AND ANXIOUS AROUSAL ACROSS ADOLESCENCE

Work on adult anxiety has found that anxious apprehension, marked by chronic worry, and anxious arousal, marked by elevated sympathetic hyperarousal, are instantiated in different neurobiological systems and involve different information processing dysfunctions. However, little is known regarding how these transdiagnostic types of anxiety develop. The present dissertation seeks to apply this transdiagnostic approach to anxiety to the study of adolescent neurodevelopment. Study 1 established that anxious arousal and anxious apprehension are distinguishable via self-report, supporting that these traits are meaningfully different as early as 11 years old. Neurobiologically, anxious arousal positively correlated with dmPFC-amygdala structural connectivity, interpreted as an elevated propensity to amplify anxiety responses, whereas anxious apprehension positively correlated with right iFG structural connectivity, interpreted as reflecting elevated inhibition of immediate threat processing. Evidence was not found for neural correlates of anxiolytic dysfunction in anxious arousal, nor for neural correlates of increased internal mental rehearsal in anxious apprehension. Study 2 built on Study 1 by examining how intrinsic connectivity was related to types of anxiety both cross-sectionally and longitudinally. Study 2 found no evidence that a priori defined functional pathways mapped onto types of anxiety. In contrast, a data-driven approach revealed that functional amygdala connectivity can predict variation in anxious arousal at both waves, whereas functional iFG connectivity can predict variation in anxious apprehension in wave 2. Taken together, the present dissertation establishes that anxious arousal and anxious apprehension emerge in early adolescence, and may be marked by different kinds of information processing dysfunctions. Future work needs to more rigorously test if inferences about information processing associated with neural correlates found here are valid.Doctor of Philosoph