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Muscle spindle structure in a mouse model for Pompe disease
Full text linkPompe disease (glycogen storage disease type II) is a rare autosomal recessive lysosomal and glycogen storage disorder, which predominantly affects the skeletal muscle, heart, and nervous system. The cause of Pompe disease are mutations in the Gaa gene encoding for the enzyme acid alpha-glucosidase (GAA), responsible for breaking down glycogen within lysosomes. Lack of the enzyme leads to enlargement and destruction of lysosomes in all tissues but most severely in skeletal muscle causing a myopathy. This explanation was considered incomplete, and another emerging mechanism for explaining Pompe disease is a disruption of the autophagic pathway. Patients with Pompe disease in addition to a progressive and generalized muscle weakness have gait and posture instability, resulting in an increased risk for falling and hospitalization. Previous studies have shown that this instability could only be partly explained by the myopathy. However, an additional reason could be that patients with Pompe disease have an altered proprioception. To address this hypothesis, I investigated the morphology of muscle spindles (the main proprioceptors) of 2.5- and 8.5-month-old Gaa-/-mice qualitatively and quantitatively, in the predominantly slow twitch soleus muscle and predominantly fast twitch extensor digitorum longus muscle. In 2.5-month-old Gaa -/- mice the muscle spindle morphology was not significantly altered compared to wildtype mice, showing only some small autophagic vacuoles. However quantitative analysis demonstrated that the circumferential elements of the sensory nerve terminals had a greater width and were shorter in length, which might be caused by glycogen storage or autophagic build-up. In the 8.5-month-old Gaa -/- mice the muscle spindles showed severe signs of degeneration, including a lack of sensory nerve terminals, disruption of intrafusal fibers, and considerable autophagic build-up. In addition, quantification of the number of muscle spindles in the soleus muscle of the 8.5-month-old Gaa -/- mice, showed a reduced number, which could be caused by the final degeneration of muscle spindles. These degenerative changes occurred in both the predominantly fast-twitch extensor digitorum longus muscle and the predominantly slow-twitch soleus muscle. Therefore, the degeneration of the muscle spindles did not appear to be dependent on the muscle fiber type composition. These findings suggest that the degeneration of the muscle spindles and the resulting proprioceptive deficits may contribute to the gait and posture instability, as well as the frequent falls in patients with Pompe disease
The role of adipocyte Nfe2l1 in cholesterol homeostasis and atherogenesis
Full text linkAdipositas und damit verbundene kardiometabolische Erkrankungen stellen eine große Bedrohung für unsere moderne Gesellschaft und das Gesundheitssystem dar. Bei Patienten mit Adipositas sind Adipozyten chronischem metabolischem Stress ausgesetzt, was die Gesundheit und Plastizität dieser Zellen stark beeinträchtigt. Dies steht mit ektoper Lipidakkumulation, Entzündungen und Insulinresistenz in Verbindung. Das endoplasmatische Retikulum (ER) steuert metabolische Anpassungsmechanismen, die im Falle einer chronischen Überernährung versagen, was letztlich zu einer Dysfunktion der Adipozyten führt. Mechanismen, die die Gesundheit der Adipozyten und die Insulinsensitivität unter solchen Bedingungen fördern, werden jedoch nicht gut verstanden. Der im ER ansässige Transkriptionsfaktor Nfe2l1 (nuclear factor, erythroid derived 2,-like 1) ist ein Regulator der adaptiven Proteinhomöostase. Hier untersuchte ich die Rolle von Nfe2l1 bei der Anpassung von Adipozyten an die metabolischen Herausforderungen der Adipositas und deren Auswirkungen auf kardiometabolische Erkrankungen. Mit einem Cre-loxP-Mausmodell mit Adipozyten-spezifischer Nfe2l1-Deletion (Adipoq-Cre), sowohl auf einem regulären B6-Hintergrund als auch auf einem ApoE-defizienten (ApoE-/-) Hintergrund für Atherosklerose-Studien, etablierte ich Nfe2l1 als einen Schlüsselregulator der Gesundheit und Insulinsensitivität von Adipozyten in diätinduzierter Adipositas (diet-induced obesity, DIO) und Atherosklerose. Mäuse ohne Adipozyten-Nfe2l1 zeigten während der DIO eine schwere Adipozytendysfunktion mit niedrigeren Adipo-kinspiegel, Steatose und Insulinresistenz. Auf einer westlichen Diät (WD) entwickelten ApoE-/- Adipoq-Cre Nfe2l1-Mäuse ein lipoatrophie-ähnliches Syndrom, was zu Dyslipidämie, systemischer Entzündung und Atherosklerose führte. Auf Gewebeebene verursachte der Verlust von Adipozyten-Nfe2l1 eine ausgeprägte Entzündungsreaktion mit Infiltration von Makrophagen und T-Zellen, vermittelt durch den stress-induzierten Transkriptionsfaktor Atf3 in den Adipozyten. Die Behandlung primärer oder 3T3-L1-Adipozyten mit Cholesterin und Proteasominhibitoren replizierte teilweise diese kom-plexe Entzündung. Überraschenderweise führte der Knockdown von Nfe2l1 nicht zu einer Verstärkung der cholesterininduzierten Entzündung. Knockdown von Atf3 linderte jedoch die entzündliche Komponente. Zuletzt zeigte ich eine inverse Korrelation zwischen dem gesamten Nfe2l1-Proteasomweg und dem Body-Mass-Index (BMI) bei der menschlichen Adipositas auf. Meine Ergebnisse verknüpfen zelluläre Protein- und Cholesterinhomöostase in weißen Adipozyten mit kardiometabolischer Gesundheit. Nfe2l1 schützt Adipozyten vor lipidinduzierter Entzündung, was die Insulinsensitivität bewahrt. Atf3 trat dabei als Schlüsselmediator der Entzündung des Fettgewebes in Reaktion auf Cholesterin hervor. Die Förderung der Proteinhomöostase in Adipozyten könnte daher die Adipozytendysfunktion bei Adipositas lindern und potenziell kardiometabolische Komplikationen abwenden.Obesity and its associated cardiometabolic diseases pose significant threats to our modern society and public health. During obesity, adipocytes are subjected to chronic metabolic stress, compromising their health and plasticity, which has been linked to ectopic lipid accumulation, inflammation, and insulin resistance. The endoplasmic reticulum (ER) governs metabolic adaptation mechanisms that fail in the event of chronic over-nutrition, which ultimately leads to adipocyte dysfunction. However, the mechanisms preserving adipocyte health and insulin sensitivity under such conditions are not well understood. The ER-resident transcription factor Nfe2l1 (nuclear factor, erythroid derived 2,-like 1) is a regulator of adaptive proteostasis under increased proteasomal activity demand. Here, I investigated the role of Nfe2l1 in the adaptation of adipocytes to the metabolic challenges of obesity and its impact on cardiometabolic diseases. Using a Cre-loxP mouse model with adipocyte-specific Nfe2l1 deletion (Adipoq-Cre), both on a regular B6 background and an ApoE-deficient (ApoE-/-) background for atheroscle-rosis studies, this research established adipocyte Nfe2l1 as a key regulator of adipocyte health and insulin sensitivity in diet-induced obesity (DIO) and atherosclerosis. Mice lacking adipocyte Nfe2l1 displayed severe adipocyte dysfunction during DIO, characterized by lower adipokine levels, steatosis, and insulin resistance. On a Western Diet (WD), ApoE-/- Adipoq-Cre Nfe2l1 mice developed a lipoatrophy-like syndrome and exhibited a more unfavorable metabolic phenotype compared to Adipoq-Cre Nfe2l1 on DIO, resulting in enhanced dyslipidemia, systemic inflammation, and atherosclerosis. On the tissue level, loss of adipocyte Nfe2l1 caused a complex inflammatory response with a pronounced infiltration of macrophages and T cells mediated by the stress-induced transcription factor Atf3 in the adipocytes. Treating primary or 3T3-L1 adipo-cytes with cholesterol and proteasome inhibitors partially replicated this complex inflammation. Surprisingly, knockdown of Nfe2l1, which led to downregulation of the proteasome-pathway, did not enhance cholesterol-induced inflammation. However, silencing Atf3 alleviated the inflammatory component. Finally, this study revealed an inverse correlation between the entire Nfe2l1-proteasome-pathway and body mass index (BMI) in humans, emphasizing the relevance of Nfe2l1 in human obesity. My findings link cellular proteostasis and cholesterol homeostasis in white adipocytes to cardiometabolic health. Nfe2l1 protected adipocyte health from lipid-induced inflammation, which preserved insulin sensitivity in vivo. Importantly, Atf3 emerged as a key mediator of adi-pose tissue inflammation in response to lipids, most notably cholesterol. Promoting proteostasis in adipocytes may thus alleviate adipocyte dysfunction in obesity, potentially averting adverse cardiometabolic outcomes
EEG-Neurofeedback: Entwicklung und Evaluation eines depressionsspezifischen Trainingsprotokolls
Full text linkHintergrund
EEG-Neurofeedback ist eine vielversprechende Behandlungsmöglichkeit bei depressiven Erkrankungen. Die Zahl an qualitativ hochwertigen Studien ist jedoch immer noch gering. Ziel dieser Pilotstudie war es, auf dem Stand der aktuellen Forschung die Effekte eines eigens entwickelten EEG-Neurofeedback-Trainingsprotokolls bei depressiven Erwachsenen im Vergleich zu Gesunden zu untersuchen. Dafür wurde die Hypothese formuliert, dass die EEG-Neurofeedback-Behandlung die psychische Belastung und depressiven Symptome reduzieren kann. Es wurde zudem der Einfluss von Motivation, Kontrollüberzeugung und Selbstwirksamkeitserleben auf die Wirksamkeit des Trainings betrachtet.
Methode
Von 23 erwachsenen Versuchspersonen erfüllten zehn die ICD-10-Kriterien für eine depressive Störung. Die restlichen 13 Testpersonen dienten als gesunde Kontrollgruppe. Alle Versuchspersonen durchliefen 15 Neurofeedback-Sitzungen mit einer Trainingsdauer von 40 Minuten über eine Dauer von ca. vier Monaten. Das EEG-Neurofeedback wurde auf den Positionen FC3 (Verstärkung bei 13-20 Hz) und Pz (Verstärkung bei 10-15 Hz) durchgeführt. Zu Beginn und am Ende der gesamten Behandlung wurden folgende Fragebögen erhoben: SCL-90®-S, TICS, BDI-II, STAI, STAXI und PSQI. In jeder Sitzung wurde die Motivation, die Kontrollüberzeugung und das Selbstwirksamkeitserleben mithilfe einer numerischen Rating-Skala erfasst.
Ergebnisse
Das EEG-Neurofeedback konnte bei depressiven Patienten und Patientinnen zu einer signifikanten Reduktion der depressiven Symptomatik (p < .001) beitragen. Zudem wurde eine signifikante Verringerung der subjektiv empfundenen Beeinträchtigung durch körperliche und psychische Symptome (p = .007), des Erlebens von chronischem Stress (p < .001) sowie des Emotionserlebens von Angst/Ängstlichkeit als Trait (p < .001) im Vergleich zur gesunden Kontrollgruppe erreicht. Beim Emotionserleben von Angst/Ängstlichkeit als State (p = .078) und von Ärger (State: p = .077, Trait: p = .084) sowie bei der Schlafqualität (p = .842) zeigte sich kein signifikanter Interaktionseffekt beim Vergleich zwischen Depressiven und Gesunden. Motivation, Kontrollüberzeugung und Selbstwirksamkeitserleben zeigten generell keinen signifikanten Effekt auf die Wirksamkeit des Trainings.
Fazit
Aus den testpsychologischen Ergebnissen kann geschlossen werden, dass das entwickelte FC3-Pz-Protokoll zu einer Reduktion der psychischen Belastung und depressiven Symptomatik führen kann. Der Einfluss von Motivation, Kontrollüberzeugung und Selbstwirksamkeitserleben scheint dabei keine entscheidende Rolle zu spielen. Die genauen Wirkfaktoren sind noch unklar. Die neurophysiologischen EEG-Daten müssten dafür zusätzlich auf Signifikanz überprüft werden, um eine mögliche Biomarker-Modulation darzulegen. Generell sind weitere randomisiert-kontrollierte Studien und größere Stichproben nötig, um den Effekt von EEG-Neurofeedback auf depressive Störungen zu evaluieren.Background
EEG neurofeedback is a promising treatment option for depressive disorders. However, the number of high-quality studies is still small. The aim of this pilot study was to investigate the effects of a specifically developed EEG neurofeedback training protocol on depressed adults in comparison to healthy ones based on the current state of research. It has been hypothesized that the treatment may reduce mental distress and depressive symptoms. The influence of motivation, locus of control and experience of self-efficacy on the effectiveness of the training was also considered.
Method
Of 23 adult subjects, ten met ICD-10 criteria for depressive disorder. The remaining 13 subjects served as a healthy control group. All test subjects went through 15 neurofeedback sessions with a training duration of 40 minutes over a period of approximately four months. EEG neurofeedback was performed on positions FC3 (reward at 13-20 Hz) and Pz (reward at 10-15 Hz). The following questionnaires were collected at the beginning and at the end of the entire treatment: SCL-90®-S, TICS, BDI-II, STAI, STAXI and PSQI. In each session, motivation, locus of control and experience of self-efficacy were assessed using a numerical rating scale.
Results
EEG neurofeedback was able to contribute to a significant reduction in depressive symptoms (p < .001) in people suffering from depression. In addition, a significant reduction of the subjectively perceived impairment caused by physical and psychological symptoms (p = .007), the experience of chronic stress (p < .001) and the emotional experience of fear/anxiety as trait (p < .001) compared to the healthy control group was achieved. There was neither a significant interaction effect in the emotional experience of fear/anxiety as state (p = .078) and anger (state: p = .077, trait: p = .084) nor in sleep quality (p = .842). Motivation, locus of control and experience of self-efficacy generally showed no significant effect on the effectiveness of the training.
Conclusion
From the psychological test results it can be concluded that the developed FC3-Pz protocol can lead to a reduction in psychological stress and depressive symptoms. The influence of motivation, locus of control and experience of self-efficacy does not seem to play a decisive role. The exact influencing factors remain still unclear. The neurophysiological EEG data would also have to be checked for significance in order to demonstrate possible biomarker modulation. In general, further randomized controlled studies and larger samples are needed to evaluate the effect of EEG neurofeedback on depressive disorders
Effect of facility readiness and providers’ adherence to standard clinical practices on women’s choice to deliver in public or private health facilities in Nepal
Full text linkBackground: The Maternal Mortality Ratio (MMR) of Nepal was 151 deaths per 100,000 live births in 2021, indicating the need for accelerating efforts to meet the Sustainable Development Goal (SDG) of 70 deaths per 100,000 live births by 2030. Health facility (HF) deliveries are increasing in Nepal, and so are the maternal deaths at HFs, indicating sub-optimal quality of delivery care services at HFs. This study aimed to understand the status of HF readiness for providing normal low-risk delivery services, the functionality of basic and comprehensive emergency obstetric and neonatal care (B/CEmONC) services, providers' adherence to standards of care during delivery care provision, and determinants of women’s satisfaction with normal low-risk delivery services.
Methods: Publicly available data from the Nepal Health Facility Survey 2015 and 2021 was used. Data of 457 HFs in 2015 and 804 in 2021 for readiness; 47 B/CEmONC HFs in 2015 and 95 in 2021 for functionality; and 320 women in 2021 for adherence to standards of care and determinants of women’s satisfaction were analysed. Weighted t-tests compared changes in HF readiness and B/CEmONC functionality over time; principal component analysis constructed satisfaction variables; and multivariate logistic regressions analysed determinants of women’s satisfaction.
Results: The HF readiness index improved significantly from 37.9% in 2015 to 43.7% in 2021, with private HFs performing slightly better than public HFs. The functionality of B/CEmONC signal functions in the designated HFs were low. Compliance with the standards of delivery care varied largely across different indicators. Provider-client interaction, audio-visual privacy, and the display of health statistics were associated with higher satisfaction levels. The availability of maternity waiting rooms and education materials and the implementation of the Maternity Incentive Scheme were associated with lower satisfaction levels.
Conclusion: To meet the SDG of MMR reduction, Nepal needs to improve quality of care by strengthening the supply chain system, ensuring trained providers, increasing the use of guidelines, supporting private HFs, promoting provider-client interaction, and addressing the operational challenges of the Maternity Incentive Scheme
Charakteristika und Behandlungsergebnisse von stationär behandelten Patienten mit Zwangsstörung
Full text linkEvaluation der Rauchfrei-Hotline der Bundeszentrale für gesundheitliche Aufklärung
Full text linkHintergrund: Tabakkonsum stellt weltweit eine erhebliche Bedrohung für die öffentliche Gesundheit dar und verursacht jährlich zahlreiche vermeidbare Todesfälle und Beeinträchtigungen. Um den negativen Auswirkungen des Rauchens auf die Gesundheit zu begegnen, sind Präventionsmaßnahmen allein unzureichend. Eine Vielzahl evidenzbasierter Rauchentwöhnungsbehandlungen muss für Rauchende verfügbar gemacht werden. Eine wirksame Maßnahme zur Reduzierung des Tabakkonsums ist die Implementierung von Rauchstopptelefonen, sogenannten Quitlines. In Deutschland wurde hierfür die Rauchfrei-Hotline der BZgA eingerichtet.
Ziele: Das Ziel dieser Dissertation ist es, die Wirksamkeit der Rauchfrei-Hotline der BZgA zu evaluieren und die Ergebnisse in zwei Publikationen darzulegen. Die Forschungsfragen beinhalten die kurz- und langfristige Wirksamkeit der Telefonberatung auf die Abstinenz, die Veränderung in spezifischen Behandlungskomponenten sowie die Nutzung weiterer Hilfsmittel zur Rauchentwöhnung (z. B. NRT, E-Zigaretten) zusätzlich zur Intervention. Die Ergebnisse liefern Informationen zur Entwicklung oder Modifikation von Beratungsprotokollen, welche z. B. auf Grund neuartiger Konsumformen notwendig werden.
Methode: Durchgeführt wurde eine zwei-armig randomisierte, kontrollierte Studie mit Datenerhebungen zu Baseline sowie drei Monate (Post-Befragung) und zwölf Monate (Follow-Up-Befragung) nach Beginn der Intervention. Täglich Rauchende, die einen Rauchstopp durchführen wollten, erhielten entweder bis zu sechs telefonische Beratungsgespräche (Interventionsgruppe) oder eine Selbsthilfebroschüre (Kontrollgruppe). Primäre Endpunkte umfassten die Sieben-Tage-Punkt-Prävalenz-Abstinenz zu drei und zwölf Monaten sowie die anhaltende Abstinenz (von der Post- zur Follow-Up-Befragung). Gemäß den Empfehlungen des SRNT-Netzwerks wurden zwei Definitionen der Abstinenz (Zigaretten und Tabak) verwendet. Sekundäre Endpunkte umfassten Veränderungen in Behandlungskomponenten (z. B. rauchbezogene Kognitionen und Bewältigungsstrategien) von der Post- zur Follow-Up-Erhebung), die subjektiv wahrgenommene Wirksamkeit der Behandlungskomponenten und die Zufriedenheit mit der Intervention. Darüber hinaus wurde die Nutzung zusätzlicher Hilfsmittel erfasst, um Abstinenzraten umfassender interpretieren zu können.
Ergebnisse: Insgesamt wurden n = 905 Teilnehmende randomisiert (Intention-to-treat-Analyse). Die Interventionsgruppe (n = 477) zeigte statistisch signifikant höhere kurzfristige Tabakabstinenzraten (41,1 % vs. 23,1 %; OR = 2,3; 95 %-KI [1,7, 3,1]) und erreichte mit höherer Wahrscheinlichkeit langfristige Zigarettenabstinenz (31,7 % vs. 17,8 %) und langfristige Tabakabstinenz (30,8 % vs. 15,2 %) im Vergleich zur Kontrollgruppe (n = 428), mit entsprechenden Odds-Ratios (OR) von 2,2 (95 %-KI [1,6, 3,0]) und 2,5 (95 %-KI [1,8, 3,5]). Teilnehmende beider Studiengruppen, die die Intervention erhielten (n = 653; Complete-Case-Analyse), zeigten statistisch signifikante Zuwächse in rauchbezogenen Kognitionen und Bewältigungsstrategien, wobei die Interventionsgruppe höhere Zuwächse als die Kontrollgruppe aufwies. Dieses Muster wurde auch hinsichtlich der wahrgenommenen Wirksamkeit der Interventionskomponenten und der Zufriedenheit mit der Intervention beobachtet. E-Zigaretten waren das am häufigsten genutzte zusätzliche Hilfsmittel zur Rauchentwöhnung (46,0 %), gefolgt von elektronischen Medien (31,0 %) und NRT (26,2 %).
Schlussfolgerungen: Die Ergebnisse liefern erstmalig empirische Evidenz für die Wirksamkeit der proaktiven Telefonberatung durch die deutsche Rauchfrei-Hotline der BZgA hinsichtlich der Förderung der Abstinenz von Zigaretten und Tabak. Dies unterstreicht ihr Potenzial als wirksame öffentliche Gesundheitsintervention zur Reduzierung der mit dem Rauchen verbundenen Krankheitslast. Eine erhöhte Bekanntmachung und Nutzung der Hotline könnten ihre Auswirkungen auf die Rauchstopp-Raten in Deutschland verbessern. Darüber hinaus sollte das Beratungsprotokoll auf Grund der zunehmenden Popularität neuartiger Konsumprodukte von Nikotin und Tabak Informationen zu deren Risiken und Potenzial als Rauchentwöhnungshilfen integrieren.Background: Tobacco consumption poses a significant threat to public health worldwide, leading to numerous preventable deaths and disabilities annually. To reverse the negative impact of smoking on health, prevention efforts are not enough. A variety of evidence-based cessation treatments need to be made available to smokers. An effective measure for reducing tobacco consumption is the implementation of telephone counselling services. In Germany, the national Quitline for smoking cessation by the Federal Centre for Health Education (BZgA) has been established for this purpose.
Objectives: This dissertation aims to evaluate the effectiveness of the national German quitline for smoking cessation and to publish two studies demonstrating the results. Key research questions include the short- and long-term effectiveness of telephone counselling on smoking abstinence, the effectiveness of specific treatment components, and the use of additional cessation aids (e.g., nicotine replacement therapy, e-cigarettes) alongside the intervention. The results provide information on the development or modification of quitline counselling protocols, e.g., due to novel consumer products.
Methods: A parallel-group, two-arm, superiority, randomized controlled trial with data collected at baseline as well as 3 (post assessment) and 12 months (follow-up assessment) after the start of the intervention was conducted. Daily smokers, willing to quit, received either up to six telephone counselling calls (intervention group) or a self-help brochure (control group). Primary outcome measures included the 7-day point prevalence abstinence at 3-month and 12-month assessments as well as prolonged abstinence (abstinence over the 12 month period). As recommended by the SRNT Treatment Research Network, two definitions of abstinence (cigarette and tobacco) were applied. Secondary outcomes included changes in smoking-related cognitions and coping strategies from pre- to post-assessment, the perceived effectiveness of intervention components, and the satisfaction with the intervention. Further, the use of additional cessation aids was assessed, to contribute to a better interpretation of the findings on abstinence.
Results: A total of n = 905 participants were randomized (intention-to-treat). The intervention group (n = 477) exhibited statistically significantly higher short-term tobacco abstinence (41.1% vs. 23.1%; OR = 2.3, 95% CI [1.7, 3.1]) and was also more likely to achieve long-term cigarette abstinence (31.7% vs. 17.8%) and long-term tobacco abstinence (30.8% vs. 15.2%) compared to the control group (n = 428) with corresponding odds ratios (OR) of 2.2 (95% CI [1.6, 3.0]) and 2.5 (95% CI [1.8, 3.5]). Participants in both study groups who received the intervention (n = 653; complete case) displayed significant improvements in smoking-related cognitions and coping strategies, with the intervention group showing greater enhancements than the control group. This pattern was also found regarding the perceived effectiveness of intervention components and satisfaction with the intervention. E-cigarettes were the most commonly used additional cessation aid (46.0%), followed by electronic media (31.0%) and nicotine replacement therapy (26.2%).
Conclusions: The results provide the first empirical evidence on the effectiveness of proactive telephone counselling by the national German quitline for smoking cessation in promoting abstinence from cigarettes and tobacco. This highlights its potential as an effective public health intervention to reduce the burden of disease associated with smoking. Increased awareness and use of the quitline could enhance its impact on cessation rates in Germany. Additionally, given the rising popularity of novel nicotine consumer products, counselling protocols should incorporate information on their risks and potential as cessation tools
Polarized dendritic development of motion-sensing neurons in Drosophila
Full text linkIn all sighted animals the ability to see motion is crucial for survival, driving extensive research into the neuronal circuits responsible for motion vision across various model organisms. Motion vision in Drosophila has been a cornerstone in systems neuroscience, with recent interest focusing on how this circuitry develops and how the dendritic growth of individual neurons contributes to the overall circuit architecture.
T4 and T5 (T4/T5) neurons, serving as the primary motion detectors in the Drosophila motion detection circuit, play a vital role in the fly’s ability to perceive motion. These neurons exhibit highly asymmetric dendrites, organized into three functional compartments: proximal, medial, and distal. This compartmentalization stems from the spatially segregated connections formed by T4/T5 neurons with their respective input partners, despite these inputs being repeated in every column that T4/T5 neurons extend into.
T4/T5 neurons are divided into four distinct subtypes: a, b, c, and d, each attuned to detecting motion in one of the four cardinal directions. A key morphological distinction among T4/T5 neurons across subtypes is their subtype-specific dendritic orientation, where dendritic branches predominantly extend in the direction opposite to the subtype’s preferred motion direction. This subtype-specific dendritic orientation, alongside their functional compartmentalization, underlies the direction-selective responses of T4/T5 neurons, making them an excellent model for investigating type-specific dendritic growth and its implications in circuit formation. Throughout my PhD, my focus centered on the post-mitotic development of T4/T5 neurons, particularly their dendritic growth. The results of my research are included chronologically in this cumulativestyle dissertation in three manuscripts, two of which are already published in peer-reviewed journals.
In manuscript 1, we conducted a gene screening study using an existing RNA sequencing dataset for mature T4/T5 neurons, coupled with an RNA interference (RNAi) approach. We identified two transcription factors — SoxNeuro and Sox102F — that regulate shared morphological features in T4/T5 dendrites across subtypes. Manipulating the expression levels of either SoxN or Sox102F in T4/T5 neurons led to the mistargeting of their dendrites and axons in their respective neuropils. These morphological changes significantly impaired the flies’ motion detection ability.
In manuscript 2, our objective was to uncover the transient transcriptional programs guiding the post-mitotic development of subtype-specific morphological features in T4/T5 neurons. Employing single-cell RNA sequencing at various developmental stages, we identified transcriptional codes distinguishing between subtypes throughout development. Furthermore, we showed how the expression profile of two transcriptional factors, Bifid and Grain, provide a binary combinatorial code to determine the subtype-identity in T4/T5 neurons.
In Manuscript 3, we focused on T4 neurons as we sought to discern whether all T4 neurons adhere to a uniform dendritic growth program or if distinct T4 subtypes exhibit varied growth patterns during dendritic development. Using time-lapse imaging, we observed discrepancies in growth dynamics among the subtypes, presumably influenced by the hexagonal arrangement of columns within the optic lobe. However, from a neuron egocentric perspective, we were able to show that all T4 neurons fundamentally adhere to the same dendritic growth program. Our imaging revealed that all T4 neurons initially extend their dendrites within their putative proximal compartment before advancing into the medial compartment. We envisage that this sequential compartmentalized growth pattern is essential for establishing the functional compartmentalization within T4 dendrites.
In summary, our research sheds light on the transcriptional program governing the post-mitotic development of T4/T5 neurons, revealing the combinatorial code crucial for determining their subtype identity. Additionally, we unraveled the growth program guiding T4 dendrites in establishing their asymmetric, compartmentalized architecture
Spatial and temporal symmetry-breaking in bound states in the continuum metasurfaces
Full text linkControlling and enhancing light-matter interactions at the nanoscale is fundamental to modern photonics. It drives advances in solar energy harvesting, optical communications, and quantum technologies. Metasurfaces, engineered two-dimensional arrays of subwavelength resonators, have transformed this field by offering compact and tunable platforms for manipulating light at the nanoscale. Recently, a new class of high quality factor (Q-factor) resonances in metasurfaces have emerged, called symmetry-protected bound state in the continuum (SP-BIC). These modes enable strong light confinement while remaining tunable via geometric parameters. However, key challenges remain: SP-BIC metasurfaces are mostly
limited to low-loss dielectrics, they require large arrays of resonators to sustain collective modes, and they lack effective active tunability. This thesis advances SP-BIC metasurfaces in multiple aspects: expanding material choices, overcoming array size constraints, and enhancing active control. First, plasmonic SP-BICs are introduced, leveraging both novel three-dimensional nanoprinted geometries and conventional metal-insulator-metal (MIM) designs. These structures combine the strong field enhancement of plasmonics with the high Q-factors of SP-BICs. Thus, they achieve perfect absorbance over broad spectral ranges and provide high sensitivity for molecular sensing. By measuring the near-fields of SP-BIC metasurfaces, new insights into their mode formation were obtained. The results indicate that the mode fully develops in significantly smaller arrays than previously expected and exhibits greater stability against perturbations. These findings motivated the development of dual-gradient metasurfaces, a new platform that continuously
encodes both spectral and coupling parameters within a single structured area. Instead of relying on thousands of identical resonators to sustain one mode, smoothly varying unit cells enable the creation of 27,500 distinct modes in a single metasurface. These dual gradients were later employed for molecular sensing and investigations of ultra strong coupling (USC) in epsilon near zero (ENZ) materials. Finally, new active tuning strategies for SP-BICs are demonstrated. Incorporating the phase-change material VO2 allows for loss-driven quenching of SP-BIC modes with minimal off-resonance switching. Finally, the new concept of restored SP-BICs is introduced, which allows ultrafast radiative loss control using photoexcited charge carriers in silicon. In pump-probe experiments, the SP-BIC mode can be coupled or decoupled from the far-field on femtosecond timescales. The results presented in this thesis provide the foundation for next-generation nanophotonic devices with unprecedented material versatility, scalability, and tunability