Although the physical and mental benefits of friendships are clear, the neurobiological mechanisms driving mutual social preferences are not well understood. Studies in humans suggest friends are more genetically similar, particularly for targets within the 3′,5′-cyclic adenosine monophosphate (cAMP) cascade. Unfortunately, human studies can not provide conclusive evidence for such a biological driver of friendship given that other genetically related factors tend to co-segregate with friendship (e.g., geographical proximity). As such, here we use mice under controlled conditions to test the hypothesis that homophily in the cAMP-degrading enzyme phosphodiesterase 11A4 (PDE11A4) can dictate mutual social preference. Using C57BL/6J and BALB/cJ mice in two different behavioral assays, we showed that mice with two intact alleles of Pde11a prefer to interact with Pde11 wild-type (WT) mice of the same genetic background over knockout (KO) mice or novel objects; whereas, Pde11 KO mice prefer to interact with Pde11 KO mice over WT mice or novel objects. This mutual social preference was seen in both adult and adolescent mice, and social preference could be eliminated or artificially elicited by strengthening or weakening PDE11A homodimerization, respectively. Stereotactic delivery of an isolated PDE11A GAF-B domain to the mouse hippocampus revealed the membrane-associated pool of PDE11A-cAMP-CREB signaling specifically within the CA1 subfield of hippocampus is most critical for regulating social preference. Our study here not only identifies PDE11A homophily as a key driver of mutual social preference across the lifespan, it offers a paradigm in which other mechanisms can be identified in a controlled fashion.
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.
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.
The hippocampus has previously been implicated in both cognitive and endocrine functions1–15. We simultaneously measured electrophysiological activity from the hippocampus and interstitial glucose concentrations in the body of freely behaving rats to identify an activity pattern that may link these disparate functions of the hippocampus. Here we report that clusters of sharp wave-ripples recorded from the hippocampus reliably predicted a decrease in peripheral glucose concentrations within about 10 min. This correlation was not dependent on circadian, ultradian or meal-triggered fluctuations, could be mimicked with optogenetically induced ripples in the hippocampus (but not in the parietal cortex) and was attenuated to chance levels by pharmacogenetically suppressing activity of the lateral septum, which is the major conduit between the hippocampus and the hypothalamus. Our findings demonstrate that a function of the sharp wave-ripple is to modulate peripheral glucose homeostasis, and offer a mechanism for the link between sleep disruption and blood glucose dysregulation in type 2 diabetes16–18.
Highlights •We recorded intracranial signals in human primary and nonprimary auditory cortex •A superior temporal gyrus onset zone activates parallel to primary auditory areas •Stimulation of superior temporal gyrus impairs speech perception •Stimulation of primary auditory cortex does not affect speech perception Summary Speech perception is thought to rely on a cortical feedforward serial transformation of acoustic into linguistic representations. Using intracranial recordings across the entire human auditory cortex, electrocortical stimulation, and surgical ablation, we show that cortical processing across areas is not consistent with a serial hierarchical organization. Instead, response latency and receptive field analyses demonstrate parallel and distinct information processing in the primary and nonprimary auditory cortices. This functional dissociation was also observed where stimulation of the primary auditory cortex evokes auditory hallucination but does not distort or interfere with speech perception. Opposite effects were observed during stimulation of nonprimary cortex in superior temporal gyrus. Ablation of the primary auditory cortex does not affect speech perception. These results establish a distributed functional organization of parallel information processing throughout the human auditory cortex and demonstrate an essential independent role for nonprimary auditory cortex in speech processing.
Olfactory systems must detect and discriminate amongst an enormous variety of odorants1. To contend with this challenge, diverse species have converged on a common strategy in which odorant identity is encoded through the combinatorial activation of large families of olfactory receptors1–3, thus allowing a finite number of receptors to detect a vast chemical world. Here we offer structural and mechanistic insight into how an individual olfactory receptor can flexibly recognize diverse odorants. We show that the olfactory receptor MhOR5 from the jumping bristletail4 Machilis hrabei assembles as a homotetrameric odorant-gated ion channel with broad chemical tuning. Using cryo-electron microscopy, we elucidated the structure of MhOR5 in multiple gating states, alone and in complex with two of its agonists—the odorant eugenol and the insect repellent DEET. Both ligands are recognized through distributed hydrophobic interactions within the same geometrically simple binding pocket located in the transmembrane region of each subunit, suggesting a structural logic for the promiscuous chemical sensitivity of this receptor. Mutation of individual residues lining the binding pocket predictably altered the sensitivity of MhOR5 to eugenol and DEET and broadly reconfigured the receptor’s tuning. Together, our data support a model in which diverse odorants share the same structural determinants for binding, shedding light on the molecular recognition mechanisms that ultimately endow the olfactory system with its immense discriminatory capacity.
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.
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.