Interneurons in the dorsal striatum provide essential modulatory control over the projecting neurons, known as medium spiny neurons (MSNs), regulating the output of this brain structure, which is critical for motor control, decision-making, and learning. The diversity of interneurons has been recently determined based on single-cell transcriptomic analyses identifying novel populations as the Pthlh -expressing interneurons, one of the most abundant and distinctive inhibitory populations in the human and mouse striatum. Here, we generated a novel Pthlh cre knock-in mouse line that enables comprehensive study of this critical population. Quantitative histological analyses show that this line effectively targets the Pthlh interneuron class, which appears as a stable population across age, sex and the anterior-posterior axis. To elucidate their functional role, we performed selective chemogenetic inhibition of Pthlh interneurons, which caused significant impairments in striatum-dependent cognitive functions and reduced exploratory behaviorur. Importantly, selective silencing did not affect basal locomotion, motor coordination, or anxiety-like behavior. Monosynaptic rabies tracing revealed that Pthlh interneurons receive dense local input from MSN subtypes and diverse long-range afferents from thalamic and different cortical regions. We further confirm that this population displays electrophysiological heterogeneity encompassing fast-spiking and fast-spiking-like phenotypes. Overall, our findings establish Pthlh interneurons as a major inhibitory class essential for cognitive processing—but not gross motor function—acting as key integrators of local MSN feedback and thalamocortical signals. The novel Pthlh cre mouse line provides a valuable resource for future studies of inhibitory diversity in basal ganglia function and related neurological disorders.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration. While the role of glial cells in PD is increasingly recognized, the coordinated multicellular responses driving PD within the dorsal striatum remain poorly understood. By integrating single-nucleus RNA sequencing of 56 donors with targeted spatial transcriptomics, we disentangle regional from PD-related molecular programs across astrocytes, microglia and oligodendroglia. We identify PD-associated glial subpopulations organized into two distinct multicellular programs: one inflammatory and one UPR-associated, where each patient is dominated by one of these programs. Notably, these programs partition the molecular changes typically associated with PD into two specific, non-overlapping signatures. Multi-region analysis revealed these signatures are globally enriched across the sampled areas and Lewy body disease stages, from brainstem-predominant to neocortical, demonstrating that PD is characterized by mutually exclusive, brain-wide glial multicellular states. Our findings redefine glial alterations in PD as systemic and multicellular, providing a framework for patient stratification and the development of targeted, state-specific therapeutic interventions.

OBJECTIVE:The circadian clock anticipates daily repetitive events to adapt physiological processes. In mammals, the circadian system consists of a master clock in the suprachiasmatic nucleus (SCN), which synchronizes subordinate tissue clocks, including extra-SCN central nervous system (CNS) clocks involved in functions such as sleep and appetite regulation. Appetite is controlled by both homeostatic and non-homeostatic (hedonic) circuits. Homeostatic appetite addresses energy needs, while hedonic feeding targets cravings for palatable, calorie-dense foods. The adipokine leptin is a major appetite regulator, interacting with the circadian clock. Although leptin's role in satiation through its action in the mediobasal hypothalamus (MBH) is well established, its involvement in the circadian regulation of feeding remains poorly understood. We hypothesized that circadian gating of leptin signaling in the CNS controls homeostatic and hedonic appetite across the day. METHODS:We analyzed food intake rhythms in mice with a loss of leptin (ob/ob mice) or clock function (Per1/2 or Bmal1 KO) and in mice with specific disruption of leptin circadian gating in the CNS (ObRb.Bmal1). RESULTS:We found that in leptin-deficient mice hedonic appetite increases specifically in the early rest phase. In contrast, clock-deficient Per1/2 mutant mice exhibit blunted rhythms in both hedonic and homeostatic appetite control. Finally, when clock function is disrupted in leptin-sensitive neurons only, mice display a lower sensitivity to palatable food, along with reduced initial weight gain and adipose hypertrophy under obesogenic diet conditions. CONCLUSIONS:Our data describe a local clock-controlled central leptin gating mechanism that modulates hedonic food intake rhythms and impacts metabolic homeostasis.

Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinson’s disease (PD) is poorly understood. We performed sn-RNA-seq and image-based spatial transcriptomics of human caudate nucleus and putamen (dorsal striatum) from PD and control brain donors to elucidate the diversity of oligodendroglia and how they are affected by the disease. We profiled a total of 200.000 oligodendroglial nuclei, defining 15 subclasses, from precursor to mature cells, 4 of which are disease-associated. These PD-specific populations are characterized by the overexpression of heat shock proteins, as well as distinct expression signatures related to immune responses, myelination alterations, and disrupted cell signaling pathways. We have also identified impairments in cell communication and oligodendrocyte development, evidenced by changes in neurotransmitter receptors expression and cell adhesion molecules. In addition, we observed significant disruptions in oligodendrocyte development, with aberrant differentiation trajectories and shifts in cell proportions, particularly in the transition from mature oligodendrocytes to disease-associated states. Quantitative immunohistochemical analysis revealed decreased myelin levels in the PD striatum, which correlated with transcriptomic alterations. Furthermore, spatial transcriptomics mapping revealed the distinct localization of disease-associated populations within the striatum, with evidence of impaired myelin integrity. Thus, we uncover oligodendroglia as a critical cell type in PD and a potential new therapeutic target for myelin-based interventions.

Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangle the complex neurological and psychiatric diseases affecting this brain structure. We performed snRNA-seq of postmortem human caudate nucleus and putamen samples to elucidate the diversity and abundance of interneuron populations and their transcriptional structure in the human dorsal striatum. We propose a new taxonomy of striatal interneurons with eight main classes and fourteen subclasses and provide their specific markers and some quantitative FISH validation, particularly for a novel PTHLH-expressing population. For the most abundant populations, PTHLH and TAC3, we found matching known mouse interneuron populations based on key functional genes such as ion channels and synaptic receptors. Remarkably, human TAC3 and mouse Th populations share important similarities including the expression of the neuropeptide tachykinin 3. Finally, we were able to integrate other published datasets supporting the generalizability of this new harmonized taxonomy.

Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. We explored these genes and created an expression panel that assesses liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH action under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state.

Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THRB manipulation in fatty liver diseases.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

It is well established that maternal thyroid hormones play an important role for the developing fetus; however, the consequences of maternal hyperthyroidism for the offspring remain poorly understood. Here we show in mice that maternal 3,3’,5-triiodothyronine (T3) treatment during pregnancy leads to improved glucose tolerance in the adult male offspring and hyperactivity of brown adipose tissue (BAT) thermogenesis in both sexes starting early after birth. The activated BAT provides advantages upon cold exposure, reducing the strain on other thermogenic organs like muscle. This maternal BAT programming requires intact maternal thyroid hormone receptor β (TRβ) signaling, as offspring of mothers lacking this receptor display the opposite phenotype. On the molecular level, we identify distinct T3 induced alterations in maternal serum metabolites, including choline, a key metabolite for healthy pregnancy. Taken together, our results connect maternal TRβ activation to the fetal programming of a thermoregulatory phenotype in the offspring.

Diurnal (i.e., 24 hr) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T 3 ) state was induced in mice by supplementing T 3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day-dependent manner. A 24-hr transcriptome profiling of liver tissue identified 37 robustly and time independently T 3 -associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10–15% of the liver transcriptome as rhythmic in control and T 3 groups, but only 4% of the liver transcriptome (1033 genes) were rhythmic across both conditions – amongst these, several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state-dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T 3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In summary, we provide evidence that tonic changes in T 3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Die zunehmende Aufweichung von festen Tagesrhythmenin der modernen Gesellschaft stort die zeitlicheKoordination physiologischer Prozesse im Korper. Dieresultierende interne Desynchronisation begunstigt dieEntwicklung zahlreicher Krankheiten, insbesondere immetabolischen Bereich – von Verdauungsstorungenuber Adipositas bis hin zu Typ-2-Diabetes. Die Kombinationaus Chronodisruption und Schlafmangel beeintrachtigtzudem die Sensitivitat und Effektivitat der Immunabwehr. Umgekehrt kann eine Stabilisierung des zirkadianenSystems die Resilienz gegen viele Krankheitenerhohen. Das Feld der Chronobiologie hat sich in denletzten Jahren von einer Grundlagendisziplin zu einerklinisch angewandten Wissenschaft, der Chronomedizin,entwickelt. Neben der tageszeitlich optimiertenGabe von Medikamenten bietet insbesondere die Stabilisierungdes zirkadianen Systems durch Verhaltensinterventionenneue Ansatze fur die Pravention und Therapievieler Volkskrankheiten.

In mammals, a network of cellular circadian clocks organizes physiology and behavior along the 24‐h day cycle. The traditional hierarchical model of circadian clock organization with a central pacemaker and peripheral slave oscillators has recently been challenged by studies combining tissue‐specific mouse mutants with transcriptome analyses. First, a surprisingly small number of tissue rhythms are lost when only local clocks are ablated and, second, transcriptional circadian rhythms appear to be regulated by a complex mix of local and systemic factors. As reviewed here, these findings suggest a more integrated model of clock network interaction with the central pacemaker as the main source of behavioral and systemic–physiological rhythms and peripheral clocks controlling some local rhythms while at the same time acting as gatekeepers that temporally adjust cellular responses to external stimuli.

Background: Pathological conditions of the thyroid hormone (TH) system are routinely diagnosed by using serum concentrations of thyrotropin (TSH), which is sufficient in most cases. However, in certain conditions, such as resistance to TH due to mutations in THRB (RTHb) or TSH-releasing pituitary adenoma (TSHoma), TSH may be insufficient for a correct diagnosis, even in combination with serum TH concentrations. Likewise, under TH replacement therapy, these parameters can be misleading and do not always allow optimal treatment. Hence, additional biomarkers to assess challenging clinical conditions would be highly beneficial. Methods: Data from untargeted multi-omics analyses of plasma samples from experimental thyrotoxicosis in human and mouse were exploited to identify proteins that might represent possible biomarkers of TH function. Subsequent mouse studies were used to identify the tissue of origin and the involvement of the two different TH receptors (TR). For in-depth characterization of the underlying cellular mechanisms, primary mouse cells were used. Results: The analysis of the plasma proteome data sets revealed 16 plasma proteins that were concordantly differentially abundant under thyroxine treatment compared with euthyroid controls across the two species. These originated predominantly from liver, spleen, and bone. Independent studies in a clinical cohort and different mouse models identified CD5L as the most robust putative biomarker under different serum TH states and treatment periods. In vitro studies revealed that CD5L originates from proinflammatory M1 macrophages, which are similar to liver-residing Kupffer cells, and is regulated by an indirect mechanism requiring the secretion of a yet unknown factor from hepatocytes. In agreement with the role of TRα1 in immune cells and the TRβ-dependent hepatocyte-derived signaling, the in vivo regulation of Cd5l expression depended on both TR isoforms. Conclusion: Our results identify several novel targets of TH action in serum, with CD5L as the most robust marker. Although further studies will be needed to validate the specificity of these targets, CD5L seems to be a promising candidate to assess TH action in hepatocyte-macrophage crosstalk.

Background: Tachycardia, cardiac hypertrophy, and elevated body temperature are major signs of systemic hyperthyroidism, which are considered to reflect the excessive thyroid hormone (TH) action in the respective peripheral tissues. However, recent observations indicate that the central actions of TH also contribute substantially to cardiovascular regulation and thermogenesis. Methods: In this study, we dissect the individual contributions of peripheral TH action versus the central effects in body temperature regulation and cardiovascular functions by taking advantage of mice lacking the TH transporters monocarboxylate transporter 8 (MCT8) and organic anion transporting polypeptide 1C1 (OATP1C1) (M/O double knock-out [dko]), which exhibit elevated serum triiodothyronine (T3) levels while their brain is in a profoundly hypothyroid state. We compared these animals with wild-type (WT) mice that were treated orally with T3 to achieve similarly elevated serum T3 levels, but are centrally hyperthyroid. For the studies, we used radiotelemetry, infrared thermography, gene expression profiling, Western blot analyses, and enzyme linked immunosorbent assays (ELISA) assays. Results: Our analyses revealed mild hyperthermia and cardiac hypertrophy in T3-treated WT mice but not in M/O dko animals, suggesting that central actions of TH are required for these hyperthyroid phenotypes. Although the average heart rate was unaffected in either model, the M/O dko exhibited an altered heart rate frequency distribution with tachycardic bursts in active periods and bradycardic episodes during resting time, demonstrating that the stabilization of heart rate by the autonomic nervous system can be impaired in centrally hypothyroid animals. Conclusions: Our studies unravel distinct phenotypical traits of hyperthyroidism that depend on an intact central nervous system, and provide valuable insight into the cardiovascular pathology of the Allan-Herndon-Dudley syndrome, a condition caused by the lack of MCT8 in humans.

 In recent years the field of chronobiology has developed from a basic science to a highly translational discipline. Besides classical chronotherapy, i. e. a temporally optimized drug scheduling, stabilization of the circadian system - by behavioral interventions or chronobiologicals - offers several novel targets for prevention and therapy of many widespread diseases.

Was ist neu? Chronodisruption und Metabolismus Die zunehmende Aufweichung von festen Tagesrhythmen in der modernen Gesellschaft stört die zeitliche Koordination physiologischer Prozesse im Körper. Die resultierende interne Desynchronisation begünstigt die Entwicklung zahlreicher Krankheiten, insbesondere im metabolischen Bereich – von Verdauungsstörungen über Adipositas bis hin zu Typ-2-Diabetes. Chronodisruption und Immunsystem Die Kombination aus Chronodisruption und Schlafmangel beeinträchtigt zudem die Sensitivität und Effektivität der Immunabwehr. Umgekehrt kann eine Stabilisierung des zirkadianen Systems die Resilienz gegen viele Krankheiten erhöhen. Chronomedizin Das Feld der Chronobiologie hat sich in den letzten Jahren von einer Grundlagendisziplin zu einer klinisch angewandten Wissenschaft entwickelt. Neben der klassischen Chronotherapie, der tageszeitlich optimierten Gabe von Medikamenten, bietet insbesondere die Stabilisierung des zirkadianen Systems – durch Verhaltensinterventionen oder Chronobiologicals – eine Reihe neuer Ansätze für die Prävention und Therapie vieler Volkskrankheiten.

Thyroid function is conventionally assessed by measurement of thyroid-stimulating hormone (TSH) and free circulating thyroid hormones, which is in most cases sufficient for correct diagnosis and monitoring of treatment efficiency. However, several conditions exist, in which these parameters may be insufficient or even misleading. For instance, both, a TSH-secreting pituitary adenoma and a mutation of thyroid hormone receptor β present with high levels of TSH and circulating hormones, but the optimal treatment is substantially different. Likewise, changes in thyroid hormone receptor α signaling are not captured by routine assessment of thyroid status, as serum parameters are usually inconspicuous. Therefore, new biomarkers are urgently needed to improve the diagnostic management and monitor treatment efficiency for e. g., replacement therapy in hypothyroidism or thyroid hormone resistance. By comparing animal models to human data, the present minireview summarizes the status of this search for new tissue- and pathway-specific biomarkers of thyroid hormone action.