INTRODUCTION Obesity and its associated complications are serious global concerns. Despite growing public health initiatives, obesity rates continue to rise. Thus, there is a critical need to identify pathways that affect adiposity. Recent studies indicate that the immune system can regulate adipose tissue and its metabolic function. Type 2 immune cells, such as type 2 innate lymphoid cells (ILC2s) and eosinophils, increase the metabolic rate, whereas regulatory T cells (T reg cells) promote insulin sensitivity. RATIONALE Thymic stromal lymphopoietin (TSLP) is an epithelial cell cytokine that is expressed at barrier sites such as the skin, lung, and gut. Because TSLP has been shown to activate type 2 immune cells and expand T reg cells, we hypothesized that TSLP could counteract obesity and its associated complications. RESULTS The effect of TSLP on obesity was tested by administering a Tslp -expressing adeno-associated virus serotype 8 (TSLP-AAV) to mice. Compared with mice administered control-AAV, mice given TSLP-AAV displayed selective white adipose tissue (WAT) loss, which protected against diet-induced and genetic models of obesity, insulin resistance, and nonalcoholic steatohepatitis (NASH). Unexpectedly, TSLP-induced WAT loss was not dependent on ILC2s, eosinophils, or T reg cells. Rather, it resulted from direct activation of either CD4 + or CD8 + αβ T cell receptor (TCRαβ) T cells by TSLP in an antigen-independent manner. The adoptive transfer of T cells from the lymph nodes of TSLP-AAV–injected mice also caused WAT loss in TSLP receptor–deficient ( Tslpr –/– ) mice, suggesting that TSLP-stimulated T cells retain their ability to induce WAT loss. TSLP-induced WAT loss was not associated with decreased food intake, increased fecal caloric excretion, or increased energy metabolism. Instead, the WAT loss was associated with a notable greasy hair appearance. Thin-layer chromatography analysis of extracted hair lipids from TSLP-AAV–injected mice showed that the oleaginous substance was enriched for sebum-specific lipids. Sebum is a calorically dense substance produced by sebocytes in sebaceous glands (SGs) and helps form both the physical and immune-protective skin barrier. Skin histological analysis showed that TSLP promoted sebum secretion and turnover of sebocytes. Sebum hypersecretion was responsible for TSLP-induced WAT loss because TSLP did not induce WAT loss in asebia mice, which harbor hypomorphic SGs. TSLP also induced the migration of T cells to SGs, which was required for the enhanced sebum secretion. Inhibition of T cell migration prevented TSLP-induced sebum hypersecretion and subsequent WAT loss. At homeostasis, TSLP and T cells controlled steady-state sebum secretion. Both Tslpr –/– and T cell–deficient mice exhibited decreased sebum secretion at baseline. Many of the fatty acids within sebum have bactericidal properties, and antimicrobial peptides (AMPs) are also secreted as part of sebum for barrier protection. Accordingly, Tslpr –/– mice expressed lower levels of sebum-associated AMPs in the skin, suggesting that endogenous TSLP plays a role in skin barrier function. This TSLP-sebum axis was also applicable to humans because the expression of TSLP and sebum-associated genes were positively correlated in skin samples from healthy individuals. CONCLUSION Our findings support a model in which TSLP overexpression causes WAT loss by inducing skin T cell migration and increasing sebum hypersecretion. Additionally, TSLP and T cells homeostatically regulate sebum production and skin AMP expression, highlighting an unexpected role for the adaptive immune system in the maintenance of skin barrier function.
cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes are immune sensors that synthesize nucleotide second messengers and initiate antiviral responses in bacterial and animal cells. Here, we discover Enterobacter cloacae CD-NTase-associated protein 4 (Cap4) as a founding member of a diverse family of >2,000 bacterial receptors that respond to CD-NTase signals. Structures of Cap4 reveal a promiscuous DNA endonuclease domain activated through ligand-induced oligomerization. Oligonucleotide recognition occurs through an appended SAVED domain that is an unexpected fusion of two CRISPR-associated Rossman fold (CARF) subunits co-opted from type III CRISPR immunity. Like a lock and key, SAVED effectors exquisitely discriminate 2′–5′- and 3′–5′-linked bacterial cyclic oligonucleotide signals and enable specific recognition of at least 180 potential nucleotide second messenger species. Our results reveal SAVED CARF family proteins as major nucleotide second messenger receptors in CBASS and CRISPR immune defense and extend the importance of linkage specificity beyond mammalian cGAS-STING signaling.
Highlights •In real life, people use a single narrative to remember multiple, separated events •Activity in the hippocampus can bridge separate events to form a coherent narrative •Activity in the hippocampus preferentially supports recall of coherent narratives •The hippocampus may support a narrative architecture for real-life memory Summary Life’s events are scattered throughout time, yet we often recall different events in the context of an integrated narrative. Prior research suggests that the hippocampus, which supports memory for past events, can support the integration of overlapping associations or separate events in memory. However, the conditions that lead to hippocampus-dependent memory integration are unclear. We used functional brain imaging to test whether the opportunity to form a larger narrative (narrative coherence) drives hippocampal memory integration. During encoding of fictional stories, patterns of hippocampal activity, including activity at boundaries between events, were more similar between distant events that formed one coherent narrative, compared with overlapping events taken from unrelated narratives. One day later, the hippocampus preferentially supported detailed recall of coherent narrative events, through reinstatement of hippocampal activity patterns from encoding. These findings demonstrate a key function of the hippocampus: the integration of events into a narrative structure for memory.
The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3–4 months) or old (19–20 months) donor mice into aged recipient mice (19–20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.
Biodiversity is the variety of different forms of life on earth, including the different plants, animals, micro-organisms, the genes they contain and the ecosystem they form. It refers to genetic variation, ecosystem variation, species variation (number of species) within an area, biome or planet. Relative to the range of habitats, biotic communities and ecological processes in the biosphere, biodiversity is vital in a number of ways including promoting the aesthetic value of the natural environment, contribution to our material well-being through utilitarian values by providing food, fodder, fuel, timber and medicine. Biodiversity is the life support system. Organisms depend on it for the air to breathe, the food to eat, and the water to drink. Wetlands filter pollutants from water, trees and plants reduce global warming by absorbing carbon, and bacteria and fungi break down organic material and fertilize the soil. It has been empirically shown that native species richness is linked to the health of ecosystems, as is the quality of life for humans. The ecosystem services of biodiversity is maintained through formation and protection of soil, conservation and purification of water, maintaining hydrological cycles, regulation of biochemical cycles, absorption and breakdown of pollutants and waste materials through decomposition, determination and regulation of the natural world climate. Despite the benefits from biodiversity, today’s threats to species and ecosystems are increasing day by day with alarming rate and virtually all of them are caused by human mismanagement of biological resources often stimulated by imprudent economic policies, pollution and faulty institutions in-addition to climate change. To ensure intra and intergenerational equity, it is important to conserve biodiversity. Some of the existing measures of biodiversity conservation include; reforestation, zoological gardens, botanical gardens, national parks, biosphere reserves, germplasm banks and adoption of breeding techniques, tissue culture techniques, social forestry to minimize stress on the exploitation of forest resources.
INTRODUCTION Fundamental circuit features of the mouse visual system emerge before the onset of vision, allowing the mouse to perceive objects and detect visual motion immediately upon eye opening. How the mouse visual system achieves self-organization by the time of eye opening without structured external sensory input is not well understood. In the absence of sensory drive, the developing retina generates spontaneous activity in the form of propagating waves. Past work has shown that spontaneous retinal waves provide the correlated activity necessary to refine the development of gross topographic maps in downstream visual areas, such as retinotopy and eye-specific segregation, but it is unclear whether waves also convey information that instructs the development of higher-order visual response properties, such as direction selectivity, at eye opening. RATIONALE Spontaneous retinal waves exhibit stereotyped changing spatiotemporal patterns throughout development. To characterize the spatiotemporal properties of waves during development, we used one-photon wide-field calcium imaging of retinal axons projecting to the superior colliculus in awake neonatal mice. We identified a consistent propagation bias that occurred during a transient developmental window shortly before eye opening. Using quantitative analysis, we investigated whether the directionally biased retinal waves conveyed ethological information relevant to future visual inputs. To understand the origin of directional retinal waves, we used pharmacological, optogenetic, and genetic strategies to identify the retinal circuitry underlying the propagation bias. Finally, to evaluate the role of directional retinal waves in visual system development, we used pharmacological and genetic strategies to chronically manipulate wave directionality and used two-photon calcium imaging to measure responses to visual motion in the midbrain superior colliculus immediately after eye opening. RESULTS We found that spontaneous retinal waves in mice exhibit a distinct propagation bias in the temporal-to-nasal direction during a transient window of development (postnatal day 8 to day 11). The spatial geometry of directional wave flow aligns strongly with the optic flow pattern generated by forward self-motion, a dominant natural optic flow pattern after eye opening. We identified an intrinsic asymmetry in the retinal circuit that enforced the wave propagation bias involving the same circuit elements necessary for motion detection in the adult retina, specifically asymmetric inhibition from starburst amacrine cells through γ-aminobutyric acid type A (GABA A ) receptors. Finally, manipulation of directional retinal waves, through either the chronic delivery of gabazine to block GABAergic inhibition or the starburst amacrine cell–specific mutation of the FRMD7 gene, impaired the development of responses to visual motion in superior colliculus neurons downstream of the retina. CONCLUSION Our results show that spontaneous activity in the developing retina prior to vision onset is structured to convey essential information for the development of visual response properties before the onset of visual experience. Spontaneous retinal waves simulate future optic flow patterns produced by forward motion through space, due to an asymmetric retinal circuit that has an evolutionarily conserved link with motion detection circuitry in the mature retina. Furthermore, the ethologically relevant information relayed by directional retinal waves enhances the development of higher-order visual function in the downstream visual system prior to eye opening. These findings provide insight into the activity-dependent mechanisms that regulate the self-organization of brain circuits before sensory experience begins.
Neural circuits underlying brain functions are vulnerable to damage, including ischemic injury, leading to neuronal loss and gliosis. Recent technology of direct conversion of endogenous astrocytes into neurons can simultaneously replenish the neuronal population and reverse the glial scar. However, whether these newly reprogrammed neurons undergo normal development, integrate into the existing neuronal circuit, and acquire functional properties specific for this circuit is not known. We investigated the effect of NeuroD1-mediated direct reprogramming on visual cortical circuit integration and functional recovery in a mouse model of ischemic injury. After performing electrophysiological extracellular recordings and two-photon calcium imaging of reprogrammed cells and mapping the synaptic connections formed onto these cells , we discovered that NeuroD1 reprogrammed neurons were integrated into the cortical microcircuit and acquired direct visual responses. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury.
Visceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.
Highlights •Psychosocial stress shapes representations of memory traces in the human amygdala •Neural representations of central items of a stressful episode are bound together •Representations of remembered central items bind to representations of the stressor •Amygdala similarity patterns explain how stress improves memory for central items Summary Stress influences episodic memory formation via noradrenaline and glucocorticoid effects on amygdala and hippocampus. A common finding is the improvement of memory for central aspects of a stressful episode. This is putatively related to changes in the neural representations of specific experiences, i.e., their memory traces. Here we show that the memory improvement for objects that were encountered in a stressful episode relates to differences in the neural representations of these objects in the amygdala. Using functional magnetic resonance imaging, we found that stress specifically altered the representations of central objects: compared to control objects, they became more similar to one another and more distinct from objects that were not part of this episode. Furthermore, higher similarity of central objects to the main stressor—the faces of the stress-inducing committee members—predicted better memory. This suggests that the central objects were closely integrated into a stressor-centered memory representation. Our findings provide mechanistic insights into how stress shapes the memory trace and have profound implications for neurocognitive models of stressful and emotional memory.