Synapses are a fundamental unit of computation in the brain. Far from being passive connections between spiking neurons, synapses display striking short-term dynamics, undergo long-term changes in strength, and sculpt network-level processes in a complex manner. These synaptic dynamics, both in time and across space, may be a fundamental determinant of population-level computations and behavioral output of the brain, yet their role in neuromodulatory circuits is relatively under-explored. First, I developed and validated a set of likelihood-based inference tools to quantify the dynamics of synaptic ensemble composition throughout development. Second, I examined network computations in the serotonergic dorsal raphe nucleus through a dynamical lens, exploring the role of short-term synaptic dynamics at sparse recurrent connections, and of distinct long-range synaptic inputs, in shaping the output of spiking populations. 1. Simulation-based inference of synaptic ensembles. Functional features of synapses are typically inferred by sampling small ensembles of synapses, yet it is unclear if such subsamples exhibit biases. I developed a statistical framework to address this question, using it to demonstrate that common bulk electrical stimulation methods for characterizing the fraction of silent synapses exhibit high bias and variance, and using typical sample sizes, possess insufficient statistical power for accurate inference. I developed and validated a novel synthetic likelihood-based inference approach based on a simulator of the underlying experimental methodology. This new estimator, made available in an object-oriented Python toolbox, reduces bias and variance compared to previously reported methods, and provides a scalable method for examining synaptic dynamics throughout development. These tools were validated by targeted recording from hippocampal CA1 neurons in juvenile mice, where they reveal fundamental tradeoffs between release probability, number of synapses sampled, and statistical power. 2. Synaptic dynamics and population computations in the serotonin system. This part is comprised of two manuscripts. First, in the dorsal raphe nucleus, I uncovered slow, inhibitory recurrent interactions between serotonin neurons that are generated by local serotonin release. These connections were probabilistic, displayed striking short-term facilitation, gated the spiking output of serotonin neurons, and could be activated by long-range excitatory input from lateral habenula, representing threat signals. Targeted physiology and modeling revealed that these recurrent short-term facilitation features generated paradoxical excitation-driven inhibition in response to high-frequency habenula input. These facilitation rules additionally supported winner-take-all dynamics at the population level, providing a contrastive operation between functionally distinct serotonergic ensembles. Behaviorally, activating long-range lateral habenula input to dorsal raphe nucleus generated a transient, frequency-dependent suppression of reward anticipation consistent with these recurrent dynamics, without modulating the underlying reward association itself. These dynamics, we suggest, support sharp behavioral state transitions in changing environments. In a second manuscript, I explored the multiplexing of distinct long-range inputs in serotonergic circuits through spike synchrony. I demonstrated that a population of serotonergic neurons receives input from both lateral habenula and prefrontal cortex. These inputs produced similar subthreshold events, but prefrontal cortex triggered spikes with much higher latencies, supporting a population synchrony code for input identity. These input-specific spike timing patterns could be read out by simple linear decoders with high accuracy, suggesting they could be demultiplexed by downstream circuits receiving sparse innervation by serotonergic axons. We uncovered a novel intracellular calcium conductance in serotonergic neurons that altered the spectral characteristics of membrane voltage in a manner sufficient to generate long-latency, power law-distributed spike times, suggesting a simple dynamical origin for the production of synchronous or asynchronous spiking. This work indicates that serotonergic circuits can multiplex distinct informational streams through population spike synchrony mechanisms. Together, these investigations reveal that the dynamics of short-term facilitation and synaptic ensemble composition can act as the fundamental substrate for flexible computation by spiking networks across the brain.

I rapporten På tal om kvinnor och män (Jämställdhetsmyndigheten, 2020) framkommer att andelen kvinnor bosatta i Sverige som var födda i Asien eller övriga världen med mer än 3 års eftergymnasial utbildning var 27% respektive 24%. Motsvarande andel för kvinnor födda i Sverige var 34%. Har arbetet för jämställdhet resulterat i skillnader i attityd beträffande att en utländsk kvinna bör utbilda sig eller en svensk man? Studien utfördes som en vinjettstudie med mellangruppsdesign (kön x etnicitet) (N = 415). Insamlad data analyserades genom tvåvägs variansanalyser för oberoende mätningar, korrelationstest av typen Pearsons produktmomentkorrelationskoefficienter samt hierarkiska regressionsanalyser. Resultatet visade att deltagarna var signifikant positivare till att en utländsk kvinna skulle utbilda sig än en svensk man. Vidare visade resultaten på att det fanns skillnader i attityd utifrån respondenternas etnicitet samt utbildningsnivå. Skillnaderna i attityd indikerade att arbetet för jämställdhet och jämlikhet i Sverige går i rätt riktning.

The 40 Hz auditory steady state response (ASSR) is an EEG response of local neural synchrony that is evoked by the repeated presentation of a 40 Hz click train. While the principal cortical generators of this response appear to be the bilateral primary auditory cortices as they show the largest phase locking and evoked power, other regions across the cortical mantle synchronize too, including the prefrontal cortex (PFC) that receives input from the primary auditory cortex and is involved in higher order cognitive functions. In schizophrenia, it is hypothesized that NMDA-mediated disruption in PFC function contributes to cognitive deficits including working memory and executive function. In rodents, NMDA antagonists reliably disrupt set shifting, a working memory task linked to PFC function. It is however not known if NMDA antagonism would disrupt the 40 Hz ASSR in PFC. In the following study, we equipped a group of female SD rats with epidural electrodes targeting the PFC (2.5 mm anterior and 0.8 mm lateral to bregma) and the primary auditory cortex (4.5 mm caudal, 7.5 mm lateral and 3.5 mm ventral to bregma). Two epidural screw electrodes on cerebellum served as ground and reference. After recovery from surgery and acclimation, rats were pretreated with small to modest doses of the NMDA antagonist MK801 (0.025, 0.05 and 0.1 mpk) or saline (1 ml/kg, sc) in a cross-over design, tethered to EEG cables and the EEG signal was amplified and acquired (Signal 7.0; CED1401 Micro 3). Trains of square waves (~ 1 ms duration; 40/s) were generated and played through the house speakers at ~ 65 dB SPL. EEG was acquired as 4 s sweeps while the click train played between 1-2 s of each sweep; 75 trials were recorded from each subject. Sixty minutes after vehicle treatment, robust EEG entrainment was noted in both the temporal cortex as well as the PFC. As expected, the EEG signal power from the temporal cortex was notably larger compared to the PFC. Nevertheless, both regions showed clear 40 Hz entrainment to click trains. However, MK801 effect on the 40 Hz ASSR was disparate across the two regions. In the prefrontal cortex, the intertrial coherence (ITC) of the 40 Hz ASSR was strongly disrupted by MK801 at all doses (P<0.001; Dunnett’s test). Evoked power was significantly reduced only at the highest dose (P<0.0001). In primary auditory cortex, relative to vehicle treatment, evoked power showed a significant increase after 0.025 mpk and 0.05 mpk dose but declined significantly after the 0.1 mpk dose (P<0.05). However, ITC was unaffected (P>0.05). These results indicate that gamma neural synchrony in the PFC is more vulnerable to NMDA antagonist- mediated disruption, as compared to the primary auditory cortex. Moreover, it suggests that executive and cognitive functions may be more readily compromised by NMDA-mediated transmission disturbance even as auditory processing is enhanced or unaffected.

Moderne Herzschrittmacher sind mit zahlreichen Algorithmen ausgestattet, die sie zu bemerkenswerten therapeutischen und diagnostischen Werkzeugen machen. Die zunehmende Komplexität bringt jedoch unbeabsichtigt neue Herausforderungen mit sich. In dieser Arbeit beschreiben wir eine neue Herzschrittmacher-Induzierte Arrhythmie die oft zum Vorhofflimmern führt.:1. Introduction................................................................................................ 3 1.1. A flashback to the beginning of cardiac pacemakers ............................. 3 1.2. Early pacemakers and significant advances .......................................... 5 1.3. Fast-forward to modern pacemakers ...................................................... 6 1.4. Current challenges .................................................................................. 8 1.5. Identification of a new pacemaker induced arrhythmia .......................... 10 1.6. Methods and results ............................................................................... 11 1.7. Patient characteristics ............................................................................ 13

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Synchronization of visual and auditory stimuli is important for creating a convincing sound designin games. Understanding the factors that constitute synchrony is both a question of synchrony inthe physical space but also an experience based on perception. Developing on a simpleflash-and-click test used by Eijk (2008), a test was designed to determine the point of synchrony in agame engine environment, a system that inherently has latencies. Test subjects were tasked withfinding a point of subjective synchrony (PSS), meaning the point where they perceived auditoryand visual stimuli to be synchronized. The visual stimulus was a commonly occurring rifle modeland three sound designs with different characteristics were implemented into the Unreal 4 Engine.The latencies of the system were calculated and summed with the PSS value of van Eijk’s (2008)flash-and-click test to create a hypothesized PSS. The results showed that the PSS for the testsubject group aligned with the PSS values given by van Eijk (2008) and that this test has potentialfor testing synchrony in game engine environments.

Emergence of the metacommunity concept has explicitly recognized the interplay of local and regional processes. The metacommunity concept has already made a substantial contribution to the better understanding of the community composition and dynamics in a regional context. However, long-term field data for testing of available metacommunity models are still scarce and the extent to which these models apply to the real world remains unknown and some of their assumptions untested. Tests conducted so far have largely sought to fit data on the entire regional set of species to one of several metacommunity models, implicitly assuming that all species, members of the metacommunity, can be modelled in the same manner (using a single model). However, species differ in their habitat use to the extent that such uniform treatment may be inappropriate. Furthermore, in testing the metacommunity models, all metacommunity studies relay on snapshots of species distribution to assess the relative importance of local and regional processes. However, snapshot patterns may be insufficient for producing a reliable picture of metacommunity dynamics and processes shaping it. I hypothesised that the relative importance of local (competition, predation or abiotic filtering or constraints) and regional (interaction of populations with landscape, migration or dispersal) processes may vary with species' traits, including habitat specialization. The perception of importance of local and regional processes in structuring community composition obtained via static approach may vary from that obtained by considering the temporal dynamics of component species. My general approach used a model system comprising natural rock pools microcosms. I have also employed experimental approach in the laboratory. I found that different metacommunity models suit for different groups of habitat specialization. I also found this to be true whether the analyses are based on snapshot data or describing temporal dynamics of species populations. These results suggest that a metacommunity system exhibits an internal differentiation of structuring processes. Specifically, from the metacommunity perspective, the dynamics of habitat specialists are best explained by a combination of species sorting and mass effects models, while that of habitat generalists is best explained by patch dynamics and neutral models. / Thesis / Doctor of Philosophy (PhD)

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