1,196 research outputs found

    Microcircuit structures of inhibitory connectivity in the rat parahippocampal gyrus

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    Komplexe Berechnungen im Gehirn werden durch das Zusammenspiel von exzitatorischen und hemmenden Neuronen in lokalen Netzwerken ermöglicht. In kortikalen Netzwerken, wird davon ausgegangen, dass hemmende Neurone, besonders Parvalbumin positive Korbzellen, ein „blanket of inhibition” generieren. Dieser Sichtpunkt wurde vor kurzem durch Befunde strukturierter Inhibition infrage gestellt, jedoch ist die Organisation solcher Konnektivität noch unklar. In dieser Dissertation, präsentiere ich die Ergebnisse unserer Studie Parvabumin positiver Korbzellen, in Schichten II / III des entorhinalen Kortexes und Präsubiculums der Ratte. Im entorhinalen Kortex haben wir dorsale und ventrale Korbzellen beschrieben und festgestellt, dass diese morphologisch und physiologisch ähnlich, jedoch in ihrer Konnektivität zu Prinzipalzellen dorsal stärker als ventral verbunden sind. Dieser Unterschied korreliert mit Veränderungen der Gitterzellenphysiologie. Ähnlich zeige ich im Präsubiculum, dass inhibitorische Konnektivität eine essenzielle Rolle im lokalen Netzwerk spielt. Hemmung im Präsubiculum ist deutlich spärlicher ist als im entorhinalen Kortex, was ein unterschiedliches Prinzip der Netzwerkorganisation suggeriert. Um diesen Unterschied zu studieren, haben wir Morphologie und Netzwerkeigenschaften Präsubiculärer Korbzellen analysiert. Prinzipalzellen werden über ein vorherrschendes reziprokes Motif gehemmt die durch die polarisierte Struktur der Korbzellaxone ermöglicht wird. Unsere Netzwerksimulationen zeigen, dass eine polarisierte Inhibition Kopfrichtungs-Tuning verbessert. Insgesamt zeigen diese Ergebnisse, dass inhibitorische Konnektivität, funktioneller Anforderungen der lokalen Netzwerke zur Folge, unterschiedlich strukturiert sein kann. Letztlich stelle ich die Hypothese auf, dass für lokale inhibitorische Konnektivität eine Abweichung von „blanket of inhibition― zur „maßgeschneiderten― Inhibition zur Lösung spezifischer computationeller Probleme vorteilhaft sein kann.Local microcircuits in the brain mediate complex computations through the interplay of excitatory and inhibitory neurons. It is generally assumed that fast-spiking parvalbumin basket cells, mediate a non-selective -blanket of inhibition-. This view has been recently challenged by reports structured inhibitory connectivity, but it’s precise organization and relevance remain unresolved. In this thesis, I present the results of our studies examining the properties of fast-spiking parvalbumin basket cells in the superficial medial entorhinal cortex and presubiculum of the rat. Characterizing these interneurons in the dorsal and ventral medial entorhinal cortex, we found basket cells of the two subregions are more likely to be connected to principal cells in the dorsal compared to the ventral region. This difference is correlated with changes in grid physiology. Our findings further indicated that inhibitory connectivity is essential for local computation in the presubiculum. Interestingly though, we found that in this region, local inhibition is lower than in the medial entorhinal cortex, suggesting a different microcircuit organizational principle. To study this difference, we analyzed the properties of fast-spiking basket cells in the presubiculum and found a characteristic spatially organized connectivity principle, facilitated by the polarized axons of the presubicular fast-spiking basket cells. Our network simulations showed that such polarized inhibition can improve head direction tuning of principal cells. Overall, our results show that inhibitory connectivity is differently organized in the medial entorhinal cortex and the presubiculum, likely due to functional requirements of the local microcircuit. As a conclusion to the studies presented in this thesis, I hypothesize that a deviation from the blanket of inhibition, towards a region-specific, tailored inhibition can provide solutions to distinct computational problems

    Water and Brain Function: Effects of Hydration Status on Neurostimulation and Neurorecording

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    Introduction: TMS and EEG are used to study normal neurophysiology, diagnose, and treat clinical neuropsychiatric conditions, but can produce variable results or fail. Both techniques depend on electrical volume conduction, and thus brain volumes. Hydration status can affect brain volumes and functions (including cognition), but effects on these techniques are unknown. We aimed to characterize the effects of hydration on TMS, EEG, and cognitive tasks. Methods: EEG and EMG were recorded during single-pulse TMS, paired-pulse TMS, and cognitive tasks from 32 human participants on dehydrated (12-hour fast/thirst) and rehydrated (1 Liter oral water ingestion in 1 hour) testing days. Hydration status was confirmed with urinalysis. MEP, ERP, and network analyses were performed to examine responses at the muscle, brain, and higher-order functioning. Results: Rehydration decreased motor threshold (increased excitability) and shifted the motor hotspot. Significant effects on TMS measures occurred despite being re-localized and re-dosed to these new parameters. Rehydration increased SICF of the MEP, magnitudes of specific TEP peaks in inhibitory protocols, specific ERP peak magnitudes and reaction time during the cognitive task. Rehydration amplified nodal inhibition around the stimulation site in inhibitory paired-pulse networks and strengthened nodes outside the stimulation site in excitatory and CSP networks. Cognitive performance was not improved by rehydration, although similar performance was achieved with generally weaker network activity. Discussion: Results highlight differences between mild dehydration and rehydration. The rehydrated brain was easier to stimulate with TMS and produced larger responses to external and internal stimuli. This is explainable by the known physiology of body water dynamics, which encompass macroscopic and microscopic volume changes. Rehydration can shift 3D cortical positioning, decrease scalp cortex distance (bringing cortex closer to stimulator/recording electrodes), and cause astrocyte swelling-induced glutamate release. Conclusions: Previously unaccounted variables like osmolarity, astrocyte and brain volumes likely affect neurostimulation/neurorecording. Controlling for and carefully manipulating hydration may reduce variability and improve therapeutic outcomes of neurostimulation. Dehydration is common and produces less excitable circuits. Rehydration should offer a mechanism to macroscopically bring target cortical areas closer to an externally applied neurostimulation device to recruit greater volumes of tissue and microscopically favor excitability in the stimulated circuits

    Cell-type specific cholinergic modulation in anterior cingulate and lateral prefrontal cortices of the rhesus macaque

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    The lateral prefrontal cortex (LPFC) and the anterior cingulate cortex (ACC) are two key regions of the frontal executive control network. Ascending cholinergic pathways differentially innervate these two functionally distinct cortices to modulate arousal and motivational signaling for higher-order functions. The action of acetylcholine (ACh) in sensory cortices is constrained by layer, anatomical cell type, and subcellular localization of distinct receptors, but little is known about the nature and organization of frontal-cholinergic circuitry in primates. In this dissertation, we characterized the anatomical localization of muscarinic acetylcholine receptors (mAChRs), m1 and m2–the predominant subtypes in the cortex–and their expression profiles on distinct cell types and pathways in ACC and LPFC of the rhesus monkey, using immunohistochemistry, anatomical tract-tracing, whole cell patch-clamp recordings, and single nucleus RNA sequencing. In the first series of studies (Chapter 2), we used immunohistochemistry and high-resolution confocal microscopy to reveal regional differences in m1 and m2 receptor localization on excitatory pyramidal and inhibitory neuron subpopulations and subcellular compartments in ACC (A24) versus LPFC (A46) of adult rhesus monkeys (Macaca mulatta; aged 7-11 yrs; 4 males and 2 females). The ACC exhibited a greater proportion of m2+ inhibitory neurons and a greater density of presynaptic m2+ receptors localized on inhibitory (VGAT+) terminations on pyramidal neurons compared to the LPFC. This result suggests a greater cholinergic suppression of GABAergic neurotransmission in ACC. In a second set of experiments (Chapter 3), we examined the heterogeneity of m1 and m2 laminar expression in functionally distinct ACC areas A24, A25, and A32. These differ in their connections with higher order cortical areas and limbic structures, such as the amygdala (AMY). The density of m1+ and/or m2 expressing (m1+/m2+) pyramidal neurons was significantly greater in A24 compared to A25 and to A32, while A25 exhibited a significantly greater density of m2+VGAT+ terminals. In addition, we examined the substrates for cholinergic modulation of long-range cortico-limbic processing using bidirectional neural tracers to label one specific subtype, the AMY-targeting projection neurons in these ACC areas. Compared to A24 and A32, the limbic ventral A25 had a greater density of m1+/m2+ AMY-targeting pyramidal neurons across upper layers 2-3 and deep layers 5-6, suggesting stronger cholinergic modulation of amygdalar outputs. Lastly (Chapter 4), we assessed the functional effects of cholinergic modulation on excitatory and inhibitory synaptic activity as well as the molecular signatures related to m1 and m2 receptor expression. In experiments using in vitro whole-cell patch-clamp recordings of layer 3 pyramidal neurons in ACC and LPFC, we found that application of the cholinergic agonist carbachol (CCh) significantly decreased the frequency of excitatory postsynaptic currents (EPSCs) to a greater extent in ACC A24 than in LPFC A46. Using single nucleus RNA sequencing, we found that enriched m1 and m2 transcriptional profiles in distinct cell-types and frontal areas (ACC A24 and LPFC A46) had differentially expressed genes associated with down-stream signaling cascades related to synaptic signaling and plasticity. Together, these data reveal the anatomical, functional, and transcriptomic neural substrates of diverse cholinergic modulation of local excitatory and inhibitory circuits and long-range cortico-limbic pathways in functionally-distinct ACC and LPFC frontal areas that are important for cognitive-emotional integration

    Spatial, temporal, and circuit-specific activation patterns of basolateral amygdala projection neurons during stress

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    In humans and rodents, the amygdala is rapidly activated by stress and hyperactivated in conditions of pathological stress or trauma. However, there is a striking lack of information of the anatomical specificity of amygdala subregions and circuits explicitly activated by stress, and of its role in governing typical responses to stress such as hypothalamic-pituitary-adrenal (HPA) axis activation. The overarching aim of this thesis was to conduct a systematic investigation of the spatial, temporal, and circuit-specific activation patterns of basolateral amygdala (BLA) projection neurons during exposure to acute stress. Additionally, we explicitly tested the role of the BLA in activation of the HPA axis, as this remains a poorly understood process. Chapter 1 describes how the BLA is anatomically well-situated for cognitive evaluation of emotional stimuli and describes the role of the BLA in diverse behavioural and physiological processes via efferent projections to many different brain structures. Chapter 2 identifies a common BLA subregion that is responsive to stressful stimuli, albeit with distinct temporal activation patterns, and which bidirectionally influences HPA axis activity. Chapter 3 maps the topographical distribution of six different populations of projection neurons throughout the BLA, and demonstrates that, although widely activated by stress exposure, inhibition of isolated populations does not influence HPA axis activity. Chapter 4 investigates the topographical distribution and stress-induced activation of BLA neurons expressing corticotropin-releasing hormone receptor type I (CRHR1), which, just like discrete circuits, does not influence HPA axis activity on its own. Together, this emphasizes the heterogeneity of BLA projection populations, while providing evidence that a large, diverse population of BLA projection neurons are activated by exposure to acute psychological stress

    Multi-modal and multi-model interrogation of large-scale functional brain networks

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    Existing whole-brain models are generally tailored to the modelling of a particular data modality (e.g., fMRI or MEG/EEG). We propose that despite the differing aspects of neural activity each modality captures, they originate from shared network dynamics. Building on the universal principles of self-organising delay-coupled nonlinear systems, we aim to link distinct features of brain activity - captured across modalities - to the dynamics unfolding on a macroscopic structural connectome. To jointly predict connectivity, spatiotemporal and transient features of distinct signal modalities, we consider two large-scale models - the Stuart Landau and Wilson and Cowan models - which generate short-lived 40 Hz oscillations with varying levels of realism. To this end, we measure features of functional connectivity and metastable oscillatory modes (MOMs) in fMRI and MEG signals - and compare them against simulated data. We show that both models can represent MEG functional connectivity (FC), functional connectivity dynamics (FCD) and generate MOMs to a comparable degree. This is achieved by adjusting the global coupling and mean conduction time delay and, in the WC model, through the inclusion of balance between excitation and inhibition. For both models, the omission of delays dramatically decreased the performance. For fMRI, the SL model performed worse for FCD and MOMs, highlighting the importance of balanced dynamics for the emergence of spatiotemporal and transient patterns of ultra-slow dynamics. Notably, optimal working points varied across modalities and no model was able to achieve a correlation with empirical FC higher than 0.4 across modalities for the same set of parameters. Nonetheless, both displayed the emergence of FC patterns that extended beyond the constraints of the anatomical structure. Finally, we show that both models can generate MOMs with empirical-like properties such as size (number of brain regions engaging in a mode) and duration (continuous time interval during which a mode appears). Our results demonstrate the emergence of static and dynamic properties of neural activity at different timescales from networks of delay-coupled oscillators at 40 Hz. Given the higher dependence of simulated FC on the underlying structural connectivity, we suggest that mesoscale heterogeneities in neural circuitry may be critical for the emergence of parallel cross-modal functional networks and should be accounted for in future modelling endeavours
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