Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain.

Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated in neuronal plasticity and memory formation in the central nervous system, but neither its involvement in pathological pain nor in spinal plasticity has been tested. Here we report a form of neuroglia signalling involving spinal astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation of the Protein Targeting to Glycogen (PTG) in spinal astrocytes. PTG drove glycogen build-up in astrocytes, and blunting glycogen accumulation and turnover by Ptg gene deletion reduced pain-related behaviours and promoted faster recovery by shortening pain maintenance in mice. Furthermore, mechanistic analyses revealed that glycogen dynamics is a critically required process for maintenance of pain by facilitating neuronal plasticity in spinal lamina 1 neurons. In summary, our study describes a previously unappreciated mechanism of astrocyte-neuron metabolic communication through glycogen breakdown in the spinal cord that fuels spinal neuron hyperexcitability.

Formation of mineral-associated organic matter in temperate soils is primarily controlled by mineral type and modified by land use and management intensity.

Formation of mineral-associated organic matter (MAOM) supports the accumulation and stabilization of carbon (C) in soil, and thus, is a key factor in the global C cycle. Little is known about the interplay of mineral type, land use and management intensity in MAOM formation, especially on subdecadal time scales. We exposed mineral containers with goethite or illite, the most abundant iron oxide and phyllosilicate clay in temperate soils, for 5 years in topsoils of 150 forest and 150 grassland sites in three regions across Germany. Results show that irrespective of land use and management intensity, more C accumulated on goethite than illite (on average 0.23 ± 0.10 and 0.06 ± 0.03 mg m-2 mineral surface respectively). Carbon accumulation across regions was consistently higher in coniferous forests than in deciduous forests and grasslands. Structural equation models further showed that thinning and harvesting reduced MAOM formation in forests. Formation of MAOM in grasslands was not affected by grazing. Fertilization had opposite effects on MAOM formation, with the positive effect being mediated by enhanced plant productivity and the negative effect by reduced plant species richness. This highlights the caveat of applying fertilizers as a strategy to increase soil C stocks in temperate grasslands. Overall, we demonstrate that the rate and amount of MAOM formation in soil is primarily driven by mineral type, and can be modulated by land use and management intensity even on subdecadal time scales. Our results suggest that temperate soils dominated by oxides have a higher capacity to accumulate and store C than those dominated by phyllosilicate clays, even under circumneutral pH conditions. Therefore, adopting land use and management practices that increase C inputs into oxide-rich soils that are under their capacity to store C may offer great potential to enhance near-term soil C sequestration.

Adsorption of the hydrophobic organic pollutant hexachlorobenzene to phyllosilicate minerals.

Hexachlorobenzene (HCB), a representative of hydrophobic organic chemicals (HOC), belongs to the group of persistent organic pollutants (POPs) that can have harmful effects on humans and other biota. Sorption processes in soils and sediments largely determine the fate of HCB and the risks arising from the compound in the environment. In this context, especially HOC-organic matter interactions are intensively studied, whereas knowledge of HOC adsorption to mineral phases (e.g., clay minerals) is comparatively limited. In this work, we performed batch adsorption experiments of HCB on a set of twelve phyllosilicate mineral sorbents that comprised several smectites, kaolinite, hectorite, chlorite, vermiculite, and illite. The effect of charge and size of exchangeable cations on HCB adsorption was studied using the source clay montmorillonite STx-1b after treatment with nine types of alkali (M+: Li, K, Na, Rb, Cs) and alkaline earth metal cations (M2+: Mg, Ca, Sr, Ba). Molecular modeling simulations based on density functional theory (DFT) calculations to reveal the effect of different cations on the adsorption energy in a selected HCB-clay mineral system accompanied this study. Results for HCB adsorption to minerals showed a large variation of solid-liquid adsorption constants Kd over four orders of magnitude (log Kd 0.9-3.3). Experiments with cation-modified montmorillonite resulted in increasing HCB adsorption with decreasing hydrated radii of exchangeable cations (log Kd 1.3-3.8 for M+ and 1.3-1.4 for M2+). DFT calculations predicted (gas phase) adsorption energies (- 76 to - 24 kJ mol-1 for M+ and - 96 to - 71 kJ mol-1 for M2+) showing a good correlation with Kd values for M2+-modified montmorillonite, whereas a discrepancy was observed for M+-modified montmorillonite. Supported by further calculations, this indicated that the solvent effect plays a relevant role in the adsorption process. Our results provide insight into the influence of minerals on HOC adsorption using HCB as an example and support the relevance of minerals for the environmental fate of HOCs such as for long-term source/sink phenomena in soils and sediments.

Widespread occurrence of quaternary alkylammonium disinfectants in soils of Hesse, Germany.

Quaternary alkylammonium compounds (QAACs) are cationic organic compounds with amphiphilic properties that are widely used as surfactants and disinfectants in industry, households and agriculture. Several studies suggest that QAACs co-select for antibiotic resistant microorganisms and thus may contribute to the spread of antibiotic resistance in the environment. Data on QAAC occurrence in soil are scarce and limited to soils that are prone to direct exposure to QAACs. Therefore, we conducted a comprehensive study on the occurrence of QAACs in soils of Hesse, a federal state in Germany, covering an area of 21,115 km2. Sixty-five soil samples that comprised different land uses (arable, grassland, forest, vineyard) and area types (rural, agglomeration) were analysed for concentrations of alkyltrimethylammonium (ATMACs, with alkyl chain lengths C8-C16), benzylalkyldimethylammonium (BACs, C8-C18) and dialkyldimethylammonium compounds (DADMACs, C8-C18) via HPLC-MS/MS after ultrasonic-assisted extraction with acidified acetonitrile. QAACs were detected in 97 % of the soil samples irrespective of land use and area type. The most abundant QAAC homologues were DADMACs > BACs > ATMACs. The highest total QAAC concentrations were detected in alluvial soils influenced by the deposition of suspended particles during flood events, with DADMAC-C16 and -C18 as the dominant homologues. The high abundance of long-chain DADMACs suggests that legacy pollution and accumulation govern QAAC concentrations in soils. The presence of QAACs in forest soils points to a potential input via atmospheric deposition. Our work highlights the widespread occurrence of QAACs in soils of Hesse and the need for more research on their entry paths and fate in the soil ecosystem.

Human Stem Cell-Derived TRPV1-Positive Sensory Neurons: A New Tool to Study Mechanisms of Sensitization.

Somatosensation, the detection and transduction of external and internal stimuli such as temperature or mechanical force, is vital to sustaining our bodily integrity. But still, some of the mechanisms of distinct stimuli detection and transduction are not entirely understood, especially when noxious perception turns into chronic pain. Over the past decade major progress has increased our understanding in areas such as mechanotransduction or sensory neuron classification. However, it is in particular the access to human pluripotent stem cells and the possibility of generating and studying human sensory neurons that has enriched the somatosensory research field. Based on our previous work, we describe here the generation of human stem cell-derived nociceptor-like cells. We show that by varying the differentiation strategy, we can produce different nociceptive subpopulations with different responsiveness to nociceptive stimuli such as capsaicin. Functional as well as deep sequencing analysis demonstrated that one protocol in particular allowed the generation of a mechano-nociceptive sensory neuron population, homogeneously expressing TRPV1. Accordingly, we find the cells to homogenously respond to capsaicin, to become sensitized upon inflammatory stimuli, and to respond to temperature stimulation. The efficient and homogenous generation of these neurons make them an ideal translational tool to study mechanisms of sensitization, also in the context of chronic pain.

Neuroscience: Detection of systemic inflammation by the brain.

When confronted with illness, humans and animals undergo critical changes in their behavior and physiology. New research shows how neuronal circuits detect sickness and coordinate illness-specific responses.

Biosolids for safe land application: does wastewater treatment plant size matters when considering antibiotics, pollutants, microbiome, mobile genetic elements and associated resistance genes?

Soil fertilization with wastewater treatment plant (WWTP) biosolids is associated with the introduction of resistance genes (RGs), mobile genetic elements (MGEs) and potentially selective pollutants (antibiotics, heavy metals, disinfectants) into soil. Not much data are available on the parallel analysis of biosolid pollutant contents, RG/MGE abundances and microbial community composition. In the present study, DNA extracted from biosolids taken at 12 WWTPs (two large-scale, six middle-scale and four small-scale plants) was used to determine the abundance of RGs and MGEs via quantitative real-time PCR and the bacterial and archaeal community composition was assessed by 16S rRNA gene amplicon sequencing. Concentrations of heavy metals, antibiotics, the biocides triclosan, triclocarban and quaternary ammonium compounds (QACs) were measured. Strong and significant correlations were revealed between several target genes and concentrations of Cu, Zn, triclosan, several antibiotics and QACs. Interestingly, the size of the sewage treatment plant (inhabitant equivalents) was negatively correlated with antibiotic concentrations, RGs and MGEs abundances and had little influence on the load of metals and QACs or the microbial community composition. Biosolids from WWTPs with anaerobic treatment and hospitals in their catchment area were associated with a higher abundance of potential opportunistic pathogens and higher concentrations of QACs.

Soil phosphorus status and P nutrition strategies of European beech forests on carbonate compared to silicate parent material.

Sustainable forest management requires understanding of ecosystem phosphorus (P) cycling. Lang et al. (2017) [Biogeochemistry, https://doi.org/10.1007/s10533-017-0375-0] introduced the concept of P-acquiring vs. P-recycling nutrition strategies for European beech (Fagus sylvatica L.) forests on silicate parent material, and demonstrated a change from P-acquiring to P-recycling nutrition from P-rich to P-poor sites. The present study extends this silicate rock-based assessment to forest sites with soils formed from carbonate bedrock. For all sites, it presents a large set of general soil and bedrock chemistry data. It thoroughly describes the soil P status and generates a comprehensive concept on forest ecosystem P nutrition covering the majority of Central European forest soils. For this purpose, an Ecosystem P Nutrition Index (ENI P ) was developed, which enabled the comparison of forest P nutrition strategies at the carbonate sites in our study among each other and also with those of the silicate sites investigated by Lang et al. (2017). The P status of forest soils on carbonate substrates was characterized by low soil P stocks and a large fraction of organic Ca-bound P (probably largely Ca phytate) during early stages of pedogenesis. Soil P stocks, particularly those in the mineral soil and of inorganic P forms, including Al- and Fe-bound P, became more abundant with progressing pedogenesis and accumulation of carbonate rock dissolution residue. Phosphorus-rich impure, silicate-enriched carbonate bedrock promoted the accumulation of dissolution residue and supported larger soil P stocks, mainly bound to Fe and Al minerals. In carbonate-derived soils, only low P amounts were bioavailable during early stages of pedogenesis, and, similar to P-poor silicate sites, P nutrition of beech forests depended on tight (re)cycling of P bound in forest floor soil organic matter (SOM). In contrast to P-poor silicate sites, where the ecosystem P nutrition strategy is direct biotic recycling of SOM-bound organic P, recycling during early stages of pedogenesis on carbonate substrates also involves the dissolution of stable Ca-Porg precipitates formed from phosphate released during SOM decomposition. In contrast to silicate sites, progressing pedogenesis and accumulation of P-enriched carbonate bedrock dissolution residue at the carbonate sites promote again P-acquiring mechanisms for ecosystem P nutrition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10533-021-00884-7.

Background concentrations and spatial distribution of heavy metals in Albania's soils.

This research aimed to determine the background and precautionary values of Cd, Cr, Cu, Ni, Pb, Zn, Co, As, and Hg and provide the spatial distribution of these metals in Albania's soils using statistical and geostatistical methods. Since the distribution of the data was commonly not Gaussian, they were transformed into their natural logarithm for deriving background concentrations and precautionary values. Background concentrations were defined as antilog of the median. Precautionary concentration values for soil protection were defined as antilog of 90th percentile of the ln-transformed data. Background concentrations in forest soils were larger compared to those in soils under other land use types. The largest background concentrations for Cd, Cr, Ni, Cu, Co, and Zn were found in forest soils formed on magmatic rocks, while largest concentrations of Pb and Hg were found in soils formed on flysch and molasse. The background values and precautionary concentration values (in brackets) (mg kg-1) for agricultural soils across flysch/molasses and quaternary deposits were as follows: Cd 0.24 (0.82), Cr 131.63 (527.42), Cu 41.26 (72.75), Ni 287.15 (632.70), Pb 19.11 (284.86), Zn 81.80 (113.90). The largest background values for Cd and Zn were found in Phaeozems, for Cr, Pb, and Co in Luvisols and Cambisols, and for Cu, Hg, and Ni in Fluvisols. The proposed background concentrations and precautionary values complete the picture of metal contents in European soils, can be used as reference concentrations for the Albanian environmental legislation, and allow the identification of potential contamination hot spots.

A synaptic temperature sensor for body cooling.

Deep brain temperature detection by hypothalamic warm-sensitive neurons (WSNs) has been proposed to provide feedback information relevant for thermoregulation. WSNs increase their action potential firing rates upon warming, a property that has been presumed to rely on the composition of thermosensitive ion channels within WSNs. Here, we describe a synaptic mechanism that regulates temperature sensitivity of preoptic WSNs and body temperature. Experimentally induced warming of the mouse hypothalamic preoptic area in vivo triggers body cooling. TRPM2 ion channels facilitate this homeostatic response and, at the cellular level, enhance temperature responses of WSNs, thereby linking WSN function with thermoregulation for the first time. Rather than acting within WSNs, we-unexpectedly-find TRPM2 to temperature-dependently increase synaptic drive onto WSNs by disinhibition. Our data emphasize a network-based interoceptive paradigm that likely plays a key role in encoding body temperature and that may facilitate integration of diverse inputs into thermoregulatory pathways.

TRPM4 keeps up the pace.

The study by Li et al., provides a detailed pharmacological characterization of the ionic mechanisms that underlie rhythmic activity of retrotrapezoid nucleus neurons that control breathing. Specifically, the authors demonstrate a role of the transient receptor potential melastatin 4 (TRPM4) ion channel in the generation of subthreshold excitatory oscillations. Additionally, they propose that the ion channel contributes to tonic action potential (AP) firing - referred to as "pacemaking" - of these brainstem neurons with relevance for respiratory breathing and homeostasis in vivo.

Astrocytes mediate the effect of oxytocin in the central amygdala on neuronal activity and affective states in rodents.

Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.

Smectite clay minerals reduce the acute toxicity of quaternary alkylammonium compounds towards potentially pathogenic bacterial taxa present in manure and soil.

Quaternary alkylammonium compounds (QAACs) are a group of cationic surfactants which are disinfectants with numerous industrial and agricultural applications and frequently released into the environment. One recent hypothesis is that bacteria present in soil will be protected from acute toxic effects of QAACs in the presence of expandable layer silicates due to interlayer sorption. We therefore studied bacterial growth kinetics with high temporal resolution and determined minimal inhibitory concentrations (MICs) of two QAACs, benzyldimethyldodecylammonium chloride (BAC-C12) and didecyldimethylammonium chlorid (DADMAC-C10), for eight strains of different bacterial taxa (Escherichia coli, Acinetobacter, Enterococcus faecium, Enterococcus faecalis, and Pseudomonas fluorescens) in relation to QAAC sorption to smectite and kaolinite. The MICs of BAC-C12 and DADMAC-C10 were in the absence of smectite and kaolinite in the order of 10 to 30 µg mL-1 and 1.0 to 3.5 µg mL-1 for all strains except the more sensitive Acinetobacter strain. For all tested strains and both tested QAACs, the presence of smectite increased apparent MIC values while kaolinite had no effect on MICs. Sorption curves without bacteria showed that smectite sorbed larger amounts of QAACs than kaolinite. Correcting nominal QAAC concentrations employed in toxicity tests for QAAC sorption using the sorption curves explained well the observed shifts in apparent MICs. Transmission electron microscopy (TEM) demonstrated that the interlayer space of smectite expanded from 13.7 ± 1 Å to 19.9 ± 1.5 Å after addition of BAC-C12. This study provides first evidence that low charge 2:1 expandable layer silicates can play an important role for buffering QAAC toxicity in soils.

Soil water solutes reduce the critical micelle concentration of quaternary ammonium compounds.

Quaternary alkyl ammonium compounds (QAACs) are produced in large quantities for use as surfactants and disinfectants and also found in soils, sediments, and surface waters, where they are potentially involved in the selection of antibiotic resistance genes. Micelle formation influences fate and effects of QAACs. The critical micelle concentration (CMC) of six homologs of benzylalkylammonium chlorides (BAC) was determined in deionized water, 0.01 M CaCl2 solution, and aqueous soil extracts, using both spectrofluorometric and tensiometric methods. Additionally, eight organic model compounds were employed at concentrations of 15 mg C L-1 as background solutes in order to test the effect of dissolved organic carbon (DOC) on CMCs. Results found CMCs decreased with an increasing length of the alkyl chain from 188 mM for BAC-C8 to 0.1 mM for BAC-C18. Both methods yielded similar results for measurements in water and CaCl2 solution; however, the spectrofluorescence method did not work for soil extracts due to fluorescence quenching phenomena. In soil extracts, CMCs of BAC-C12 were reduced below 3.7 mM, while the CMC reduction in soil extracts was less pronounced for BAC-C16. Besides ionic strength, molecular structures of BACs and dissolved organic compounds also affected the CMC. The number of carboxyl groups and small molecular weights of the DOC model compounds reduced the CMCs of BAC-C12 and BAC-C16 at pH 6. This study highlights that CMCs can be surpassed in soil solution, pore waters of sediments, or other natural waters even at (small) concentrations of QAACs typically found in the environment.

A fast and robust method for the extraction and analysis of quaternary alkyl ammonium compounds from soil and sewage sludge.

Alkyltrimethylammonium compounds (ATMACs), dialkyldimethylammonium compounds (DADMACs) and benzylalkyldimethylethylammonium compounds (BACs) are quaternary alkylammonium compounds (QAAC), which are released into the environment in large quantities after their use in cleaning agents and disinfectants. Despite their potential role as selective agents promoting resistance against QAACs as well as antibiotics, there is a lack of data for QAACs in soil due to the lack of sensitive analytical methods. Therefore, we present a robust and fast method for the extraction and quantification of concentrations of these compounds in soil and sewage sludge. The method is based on ultrasonic extraction (USE) with a mixture of acetonitrile and HCl followed by a solid phase extraction (SPE) cleaning step and a subsequent quantification of concentrations with high performance liquid chromatography with mass spectrometry (HPLC-MS/MS) in multi mass reaction mode (MRM). The proposed method is suitable for the quantification of ATMACs (chain length C-8 to C-16), BACs (C-8 to C-18) and DADMACs (C-8 to C-16). The achieved limits of quantification (LOQ) range from 0.1 µg kg-1 to 2.1 µg kg-1. The recovery rates of spiked soil samples for non-deuterated homologues were between 47% and 57%. The analysis of sewage sludge samples and soil samples revealed that BAC-C12 was the most abundant QAAC with concentrations up to 38600 µg kg-1 in sewage sludge and up to 81 µg kg-1 in a Mexican soil that was irrigated with wastewater. Overall, the presented methods open perspectives for effectively studying fate and effects of QAACs in soils.

Leaching of natural colloids from forest topsoils and their relevance for phosphorus mobility.

The leaching of P from the upper 20cm of forest topsoils influences nutrient (re-)cycling and the redistribution of available phosphate and organic P forms. However, the effective leaching of colloids and associated P forms from forest topsoils was so far sparsely investigated. We demonstrated through irrigation experiments with undisturbed mesocosm soil columns, that significant proportions of P leached from acidic forest topsoils were associated with natural colloids. These colloids had a maximum size of 400nm. By means of Field-flow fractionation the leached soil colloids could be separated into three size fractions. The size and composition was comparable to colloids present in acidic forest streams known from literature. The composition of leached colloids of the three size classes was dominated by organic carbon. Furthermore, these colloids contained large concentrations of P which amounted between 12 and 91% of the totally leached P depending on the type of the forest soil. The fraction of other elements leached with colloids ranged between 1% and 25% (Fe: 1-25%; Corg: 3-17%; Al: <4%; Si, Ca, Mn: all <2%). The proportion of colloid-associated P decreased with increasing total P leaching. Leaching of total and colloid-associated P from the forest surface soil did not increase with increasing bulk soil P concentrations and were also not related to tree species. The present study highlighted that colloid-facilitated P leaching can be of higher relevance for the P leaching from forest surface soils than dissolved P and should not be neglected in soil water flux studies.

Cellular populations and thermosensing mechanisms of the hypothalamic thermoregulatory center.

Temperature affects all aspects of life down to the diffusion rates of biologically active molecules and reaction rates of enzymes. The reciprocal argument holds true as well and every biological process down to enzymatic reactions influences temperature. In order to assure biological stability, mammalian organisms possess the remarkable ability to maintain internal body temperature within a narrow range, which in humans and mice is close to 37 °C, despite wide environmental temperature variations and different rates of internal heat production. Nevertheless, body temperature is not a static property but adaptively regulated upon physiological demands and in the context of pathological conditions. The brain region that has been primarily associated with internal temperature regulation is the preoptic area and the anterior portion of the hypothalamus. Similar to a thermostat, this brain area detects deep brain temperature, integrates temperature information from peripheral body sensors, and-based on these inputs--controls body temperature homeostasis. Discovered more than a century ago, we still know comparatively little about the molecular and cellular make-up of the hypothalamic thermoregulatory center. After a brief historic outline that led to the discovery of the thermoregulatory center, we here review recent studies that have considerably advanced our understanding of hypothalamic thermoregulation. We touch upon proposed mechanisms of intrinsic deep brain temperature detection and focus on newly identified hypothalamic cell populations that mediate thermoregulatory responses and that provide novel entry points not only to shed light on the mechanistic underpinnings of the thermoregulatory center but also to probe its therapeutic value.

Human vs. Mouse Nociceptors - Similarities and Differences.

The somatosensory system allows us to detect a diverse range of physical and chemical stimuli including noxious ones, which can initiate protective reflexes to prevent tissue damage. However, the sensation of pain can - under pathological circumstances - outlive its usefulness and perpetrate ongoing suffering. Rodent model systems have been tremendously useful to help understand basic mechanisms of pain perception. Unfortunately, the translation of this knowledge into novel therapies has been challenging. We have investigated similarities and differences of human and mouse peptidergic (TRKA expressing) nociceptors using dual-color fluorescence in situ hybridization of dorsal root ganglia. By comparing the transcripts of a selected group of well-established nociceptive markers, we observed significant differences for some of them. We found co-expression of Trpv1, a key player for sensitization and inflammatory pain, with TrkA in a larger population in humans compared to mice. Similar results could be obtained for Nav1.8 and Nav1.9, two voltage gated sodium channels implicated in pathological forms of pain. Additionally, co-expression of Ret and TrkA was also found to be more abundant in human neurons. Moreover, the neurofilament heavy polypeptide was detected in all human sensory DRG neurons compared to a more selective expression pattern observed in rodents. To our knowledge, this is the first time that such detailed comparative analysis has been performed and we believe that our findings will direct future experimentation geared to understand the difficulties we face in translating findings from rodent models to humans.

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1.

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.