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Frontiers in Aging Neuroscience 2024There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a...
There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.
PubMed: 38813533
DOI: 10.3389/fnagi.2024.1384554 -
Turkish Journal of Medical Sciences 2023Williams-Beuren syndrome (WBS) is a rare genetic disorder with delays in language and cognitive development, but, with increased awareness of clinical features and a...
BACKGROUND/AIM
Williams-Beuren syndrome (WBS) is a rare genetic disorder with delays in language and cognitive development, but, with increased awareness of clinical features and a reliable diagnostic test, WBS is becoming more widely recognized in childhood. Adaptive behavior skills and/or maladaptive behavior are important for the prognosis of individuals with WBS. The aim of this study was to investigate the clinical and developmental characteristics of patients with WBS and further increase awareness about it by evaluating the adaptive skills and maladaptive behaviors of the patients.
MATERIALS AND METHODS
The data of WBS patients followed-up at the Developmental Behavioral Pediatrics Unit were reviewed. Patient data on perinatal and postnatal history, developmental stages, physical and neurological examination findings were collected. The International Guide for Monitoring Child Development (GMCD) was administered to each child. In addition, semistructured interviews were conducted with the parents using the Vineland Adaptive Behavior Scales, Second edition (Vineland-II).
RESULTS
A total of 12 patients diagnosed with WBS via detection of the 7q11.23 deletion, of whom 6 were girls, were retrospectively reviewed. The mean age at the time of review was 54.6 ± 32.5 months. The mean age at first presentation to the Developmental Behavioral Pediatrics Outpatient Clinic was 15 ± 11.5 months. In the first developmental evaluation using the GMCD, there was a delay in fine and gross motor domains in 6 patients, in the language domains in 4 patients, and in all of the domains in 2 patients. Findings with Vineland-II showed socialization and communication domains as strengths, but the daily living skills and motor skills domains were weaknesses. In terms of maladaptive behavior, the patients tended to frequently have behavioral problems, neurodevelopmental disease, anxiety disorders, eating problems, and sleeping problems.
CONCLUSION
This retrospective review of 12 patients indicated a general delay in overall development, and confirmed impairment in both adaptive and maladaptive functioning in WBS.
Topics: Humans; Williams Syndrome; Female; Child, Preschool; Male; Infant; Retrospective Studies; Adaptation, Psychological; Child; Child Development
PubMed: 38812996
DOI: 10.55730/1300-0144.5701 -
Nature Communications May 2024G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation....
G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HTR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HTR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HTR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by G protein activation, whereas psychosis-related behavior is modulated through G stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.
Topics: Humans; Receptor, Serotonin, 5-HT2A; Animals; Psychotic Disorders; Memory Disorders; Serotonin; Male; Signal Transduction; HEK293 Cells; Mice; Schizophrenia; Brain; Female; GTP-Binding Protein alpha Subunits, Gq-G11
PubMed: 38811567
DOI: 10.1038/s41467-024-48196-2 -
Translational Psychiatry May 2024Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully...
Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.
Topics: Animals; Bipolar Disorder; Mice; Cadherins; Disease Models, Animal; Mice, Knockout; Locomotion; Body Temperature; Protocadherins; Male; Circadian Rhythm; Behavior, Animal; Proto-Oncogene Proteins c-fos; Mice, Inbred C57BL; Prepulse Inhibition
PubMed: 38806495
DOI: 10.1038/s41398-024-02952-6 -
Proceedings of the National Academy of... Jun 2024The RNA tailing machinery adds nucleotides to the 3'-end of RNA molecules that are implicated in various biochemical functions, including protein synthesis and RNA...
The RNA tailing machinery adds nucleotides to the 3'-end of RNA molecules that are implicated in various biochemical functions, including protein synthesis and RNA stability. Here, we report a role for the RNA tailing machinery as enzymatic modifiers of intracellular amyloidogenesis. A targeted RNA interference screen identified Terminal Nucleotidyl-transferase 4b (TENT4b/Papd5) as an essential participant in the amyloidogenic phase transition of nucleoli into solid-like Amyloid bodies. Full-length-and-mRNA sequencing uncovered starRNA, a class of unusually long untemplated RNA molecules synthesized by TENT4b. StarRNA consists of short rRNA fragments linked to long, linear mixed tails that operate as polyanionic stimulators of amyloidogenesis in cells and in vitro. Ribosomal intergenic spacer noncoding RNA (rIGSRNA) recruit TENT4b in intranucleolar foci to coordinate starRNA synthesis driving their amyloidogenic phase transition. The exoribonuclease RNA Exosome degrades starRNA and functions as a general suppressor of cellular amyloidogenesis. We propose that amyloidogenic phase transition is under tight enzymatic control by the RNA tailing and exosome axis.
Topics: Humans; Amyloid; Phase Transition; RNA Stability; RNA; Polyribonucleotide Nucleotidyltransferase
PubMed: 38805292
DOI: 10.1073/pnas.2316734121 -
PeerJ 2024Unionoid freshwater mussels (Bivalvia: Unionidae) are free-living apart from a brief, obligately parasitic, larval stage that infects fish hosts, and gravid female...
Unionoid freshwater mussels (Bivalvia: Unionidae) are free-living apart from a brief, obligately parasitic, larval stage that infects fish hosts, and gravid female mussels have evolved a spectrum of strategies to infect fish hosts with their larvae. In many North American species, this involves displaying a mantle lure: a pigmented fleshy extension that acts as an aggressive mimic of a host fish prey, thereby eliciting a feeding response that results in host infection. The mantle lure of is of particular interest because it is apparently polymorphic, with two distinct primary lure phenotypes. One, described as "darter-like", has "eyespots", a mottled body coloration, prominent marginal extensions, and a distinct "tail". The other, described as "worm-like", lacks those features and has an orange and black coloration. We investigated this phenomenon using genomics, captive rearing, biogeographic, and behavioral analyses. Within-brood lure variation and within-population phylogenomic (ddRAD-seq) analyses of individuals bearing different lures confirmed that this phenomenon is a true polymorphism. The relative abundance of the two morphs appears stable over ecological timeframes: the ratio of the two lure phenotypes in a River Raisin (MI) population in 2017 was consistent with that of museum samples collected at the same site six decades earlier. Within the River Raisin, four main "darter-like" lure motifs visually approximated four co-occurring darter species (, and ), and the "worm-like" lure resembled a widespread common leech, . Darters and leeches are typical prey of (smallmouth bass), the primary fish host of . field recordings of the "darter" and "leech" lure display behaviors, and the lure display of co-occurring congener , were captured. Despite having putative models in distinct phyla, both lure morphs have largely similar display behaviors that differ significantly from that of sympatric individuals. Some minor differences in the behavior between the two morphs were observed, but we found no clear evidence for a behavioral component of the polymorphism given the criteria measured. Discovery of discrete within-brood inheritance of the lure polymorphism implies potential control by a single genetic locus and identifies as a promising study system to identify regulatory genes controlling a key adaptive trait of freshwater mussels.
Topics: Animals; Female; Biological Mimicry; Unionidae; Fresh Water; Polymorphism, Genetic; Phenotype; Host-Parasite Interactions; Phylogeny; Pigmentation
PubMed: 38803583
DOI: 10.7717/peerj.17359 -
Frontiers in Molecular Neuroscience 2024Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by... (Review)
Review
Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in , SAX-1 in , CBK1, DBF20 in and orb6 in . These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.
PubMed: 38803357
DOI: 10.3389/fnmol.2024.1371086 -
Journal of Neuroinflammation May 2024Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our...
Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
Topics: Animals; Mice; Aquaporin 4; Astrocytes; Hyperammonemia; Sepsis-Associated Encephalopathy; Male; Brain-Gut Axis; Mice, Inbred C57BL; Ammonia; Brain; Fecal Microbiota Transplantation
PubMed: 38802927
DOI: 10.1186/s12974-024-03135-2 -
Cerebral Cortex (New York, N.Y. : 1991) May 2024The ε4 allele of the APOE gene heightens the risk of late onset Alzheimer's disease. ε4 carriers, may exhibit cognitive and neural changes early on. Given the known...
The ε4 allele of the APOE gene heightens the risk of late onset Alzheimer's disease. ε4 carriers, may exhibit cognitive and neural changes early on. Given the known memory-enhancing effects of physical exercise, particularly through hippocampal plasticity via endocannabinoid signaling, here we aimed to test whether a single session of physical exercise may benefit memory and underlying neurophysiological processes in young ε3 carriers (ε3/ε4 heterozygotes, risk group) compared with a matched control group (homozygotes for ε3). Participants underwent fMRI while learning picture sequences, followed by cycling or rest before a memory test. Blood samples measured endocannabinoid levels. At the behavioral level, the risk group exhibited poorer associative memory performance, regardless of the exercising condition. At the brain level, the risk group showed increased medial temporal lobe activity during memory retrieval irrespective of exercise (suggesting neural compensatory effects even at baseline), whereas, in the control group, such increase was only detectable after physical exercise. Critically, an exercise-related endocannabinoid increase correlated with task-related hippocampal activation in the control group only. In conclusion, healthy young individuals carrying the ε4 allele may present suboptimal associative memory performance (when compared with homozygote ε3 carriers), together with reduced plasticity (and functional over-compensation) within medial temporal structures.
Topics: Humans; Alzheimer Disease; Male; Female; Exercise; Magnetic Resonance Imaging; Adult; Young Adult; Memory; Endocannabinoids; Genetic Predisposition to Disease; Association Learning; Apolipoprotein E4; Hippocampus; Brain; Heterozygote
PubMed: 38802684
DOI: 10.1093/cercor/bhae205 -
Scientific Reports May 2024The striatum plays a crucial role in providing input to the basal ganglia circuit and is implicated in the pathological process of Parkinson's disease (PD). Disruption...
The striatum plays a crucial role in providing input to the basal ganglia circuit and is implicated in the pathological process of Parkinson's disease (PD). Disruption of the dynamic equilibrium in the basal ganglia loop can be attributed to the abnormal functioning of the medium spiny neurons (MSNs) within the striatum, potentially acting as a trigger for PD. Exercise has been shown to mitigate striatal neuronal dysfunction through neuroprotective and neurorestorative effects and to improve behavioral deficits in PD model mice. In addition, this effect is offset by the activation of MSNs expressing dopamine D2 receptors (D2-MSNs). In the current study, we investigated the underlying neurobiological mechanisms of this effect. Our findings indicated that exercise reduces the power spectral density of the beta-band in the striatum and decreases the overall firing frequency of MSNs, particularly in the case of striatal D2-MSNs. These observations were consistent with the results of molecular biology experiments, which revealed that aerobic training specifically enhanced the expression of striatal dopamine D2 receptors (DR). Taken together, our results suggest that aerobic training aimed at upregulating striatal DR expression to inhibit the functional activity of D2-MSNs represents a potential therapeutic strategy for the amelioration of motor dysfunction in PD.
Topics: Animals; Physical Conditioning, Animal; Receptors, Dopamine D2; Corpus Striatum; Mice; Disease Models, Animal; Parkinson Disease; Male; Neurons; Mice, Inbred C57BL; Motor Activity; Medium Spiny Neurons
PubMed: 38802497
DOI: 10.1038/s41598-024-63045-4