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Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior. Chronic stress induces maladaptive changes in the neural networks and it’s associated with mood disorders. Here, the authors show that repeated exposure to short-term stress can resolve pre-existing chronic stress induced depressive-like behaviour in mice.

Chronic stress causes maladaptive changes in the brain that lead to depressive behavior. In the present study, we investigate whether chronic stress alters gut microbiota compositions that are related to stress-induced maladaptive changes in the brain. Mice treated with daily 2-h restraint for 14 days (CRST) exhibit depressive-like behavior. Sequence readings of 16S rRNA genes prepared from fecal samples taken from CRST-treated mice suggest that chronic stress induces gut microbiota changes that are pronounced in the post-stress period, relative to those that occur in the 14-day stress phase. The genus Lactobacillus is one such microbiota substantially changed following chronic stress. In contrast, intraperitoneal injection of extracellular vesicles (EVs) isolated from culture media of the Gram-positive probiotic Lactobacillus plantarum is sufficient to ameliorate stress-induced depressive-like behavior. Interestingly, EVs from the Gram-positive probiotic Bacillus subtilis and EVs from the Gram-negative probiotic Akkermansia muciniphila also produce anti-depressive-like effects. While chronic stress decreases the expression of MeCP2, Sirt1, and/or neurotrophic factors in the hippocampus, EVs from the three selected probiotics differentially restore stress-induced changes of these factors. These results suggest that chronic stress produces persistent changes in gut microbiota composition, whereas purified EVs of certain probiotics can be used for treatment of stress-induced depressive-like behavior.

Mounting evidence suggests that probiotics are beneficial for treating Alzheimer’s disease (AD). However, the mechanisms by which specific probiotics modify AD pathophysiology are not clearly understood. In this study, we investigated whether Lactobacillus paracasei -derived extracellular vesicles ( Lpc -EV) can directly act on neuronal cells to modify amyloid-beta (Aβ)-induced transcriptional changes and Aβ pathology in the brains of Tg-APP/PS1 mice. Lpc -EV treatment in HT22 neuronal cells counteracts Aβ-induced downregulation of Brain-derived neurotrophic factor (Bdnf) , Neurotrophin 3 (Nt3) , Nt4/5 , and TrkB receptor, and reverses Aβ-induced altered expression of diverse nuclear factors, including the downregulation of Methyl-CpG binding protein 2 (Mecp2) and Sirtuin 1 (Sirt1) . Systematic siRNA-mediated knockdown experiments indicate that the upregulation of Bdnf, Nt3, Nt4/5 , and TrkB by Lpc -EV is mediated via multiple epigenetic factors whose activation converges on Mecp2 and Sirt1 . In addition, Lpc -EV reverses Aβ-induced downregulation of the Aβ-degrading proteases Matrix metalloproteinase 2 (Mmp-2) , Mmp-9 , and Neprilysin (Nep) , whose upregulation is also controlled by MeCP2 and Sirt1. Lpc -EV treatment restores the downregulated expression of Bdnf, Nt4/5, TrkB , Mmp-2, Mmp-9 , and Nep ; induces the upregulation of MeCP2 and Sirt1 in the hippocampus; alleviates Aβ accumulation and neuroinflammatory responses in the brain; and mitigates cognitive decline in Tg-APP/PS1 mice. These results suggest that Lpc -EV cargo contains a neuroactive component that upregulates the expression of neurotrophic factors and Aβ-degrading proteases ( Mmp-2, Mmp-9 , and Nep ) through the upregulation of MeCP2 and Sirt1, and ameliorates Aβ pathology and cognitive deficits in Tg-APP/PS1 mice. Alzheimer’s disease: bacteria-derived vesicles help to combat neurodegeneration Small molecular membrane-bound vesicles released by probiotic bacteria can help to counteract the negative effects of amyloid-beta (Aβ), a protein that clumps inside the brain and is associated with the progression of Alzheimer’s disease. A team led by Yoon-Keun Kim from MD Healthcare Inc. and Pyung-Lim Han from Ewha Womans University, both in Seoul, South Korea, showed that these molecular packets — known as extracellular vesicles and derived from Lactobacillus bacteria found in the mouth and gut — can mitigate against Aβ-induced changes in gene expression in mouse neurons. By delivering neuroactive components, the packets also reversed cognitive decline, prevented further accumulation of Aβ and lessened inflammation in the brains of mice engineered to develop an Alzheimer’s-like disease. The findings help to explain the beneficial effects of probiotics in people with this devastating neurodegenerative condition.

The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

Aging increases vulnerability to stress-induced neuronal dysfunction, yet the underlying mechanisms remain unclear. Here, in young mice (2 months), chronic stress elevates basal serum glucocorticoid (GC) levels and induces despair-like behavior, as well as impaired sociability. By contrast, aged mice (14.5 months) naturally exhibit elevated basal GC levels, but do not display depressive-like behavior or sociability deficits, although further analysis reveals a social memory impairment. However, exposure to subthreshold stress in aged mice further elevates basal GC levels and induces both emotional and sociability impairments. Notably, repeated mild stress reverses these stress-induced physiological and behavioral impairments in young and aged mice. Neural activity-dependent c-Fos expression mapping identifies the ventral subiculum (vSub) as a potential upstream neural hub that regulates both serum GC responses and emotional and social behaviors. Chemogenetic activation of the vSub, particularly the vSub-to-dorsal bed nucleus of the stria terminalis circuitry, reverses stress-induced increases in basal GC levels and the associated behavioral deficits. Transcriptomic analysis reveals that the vSub gene expression profile in aged mice significantly overlaps with that of young mice exposed to chronic stress, notably characterized by Fkbp5 upregulation. Targeted knockdown of Fkbp5 within the vSub mitigates stress-induced increases in GC levels and rescues behavioral deficits. Moreover, repeated short-term mild stress or low-dose GC treatment ameliorates stress-induced physiological and behavioral impairments, accompanied by downregulation of Fkbp5 in the vSub. Collectively, these results suggest that the aged brain acquires chronic stress-like signatures, heightening its vulnerability to maladaptive outcomes, and that repeated short-term mild stress can restore emotional and social function by normalizing vSub Fkbp5 -dependent signaling. Aging brain shows stress vulnerability and recovery pathways As we age, our brains undergo changes that make us more vulnerable to stress. This study explores how enhanced sensitivity to stress in aging brains can be overcome. Researchers have demonstrated that aging is accompanied by the accumulation of stress hormone-dependent changes in the brain, which can be reversed by a method known as ‘repeated mild stress’, involving short daily sessions of gentle restraint or rocking. Researchers measured changes in behavior and brain chemistry, focusing on specific brain areas such as the ventral subiculum, which are functionally downregulated in aged brains as in young mice under chronic stress. The study found that repeated mild stress helped reverse stress-induced behavioral problems and the reduced neural activity changes in both young and aged mice. This suggests that mild stress could be a potential therapy for stress-related issues in aging brains. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ‐induced pathology and progressive cognitive decline. The incidence of AD is growing globally, yet a prompt and effective remedy is not available. Aging is the greatest risk factor for AD. Brain aging proceeds with reduced vascularization, which can cause low oxygen (O2) availability. Accordingly, the question may be raised whether O2 availability in the brain affects AD pathology. We found that Tg‐APP/PS1 mice treated with 100% O2 at increased atmospheric pressure in a chamber exhibited markedly reduced Aβ accumulation and hippocampal neuritic atrophy, increased hippocampal neurogenesis, and profoundly improved the cognitive deficits on the multiple behavioral test paradigms. Hyperoxygenation treatment increased the expression of BDNF, NT3, and NT4/5 through the upregulation of MeCP2/p‐CREB activity in HT22 cells in vitro and in the hippocampus of mice. In contrast, siRNA‐mediated inhibition of MeCP2 or TrkB neurotrophin receptors in the hippocampal subregion, which suppresses neurotrophin expression and neurotrophin action, respectively, blocked the therapeutic effects of hyperoxygenation on the cognitive impairments of Tg‐APP/PS1 mice. Our results highlight the importance of the O2‐related mechanisms in AD pathology, which can be revitalized by hyperoxygenation treatment, and the therapeutic potential of hyperoxygenation for AD.

Aging induces cellular and molecular changes including gene expression alteration in the brain, which might be associated with aging-induced decrease in stress coping ability. In the present study, we investigate how aging changes the ability to cope with stress and increases sensitivity to stress. Aged mice show decreased expression of SUV39H1 histone methyltransferase and increased expression of Mkp-1 in the hippocampus. The siRNA-mediated knockdown of SUV39H1 increases Mkp-1 expression and suppresses p-CREB and Bdnf expression in HT22 cells and in the hippocampus of mice. Chromatin immunoprecipitation assays indicate that the levels of SUV39H1 and methylated histone-H3 bound to the promoter of the Mkp-1 in the hippocampus are reduced in aged mice. Aged mice exhibit depression-like behavior following weak stress that does not induce depressive behavior in young mice. Rosmarinic acid, a phenolic compound that increases SUV39H1 expression, reverses stress-induced changes of SUV39H1, Mkp-1, and Bdnf expression in the hippocampus via an overlapping but distinct mechanism from those of fluoxetine and imipramine and produces anti-depressive effects. These results suggest that aging increases susceptibility to stress via downregulation of SUV39H1 and resulting changes in SUV39H1-regulated signaling pathways in the hippocampus.

Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by social communication deficits and repetitive behaviors. Although our current understanding the mechanisms underlying ASD is growing, effective treatment options are still underdevelopment. Extracellular vesicles derived from the probiotic Lactobacillus paracasei (LpEV) have shown neuroprotective effects in both in vitro and in vivo models. Here we investigate whether LpEV can alleviate core symptoms in genetic ASD models that exhibit accumulated developmental deficits. Dopamine receptor D2 (Drd2)-knockout (KO) mice exhibit social behavior deficits and excessive grooming, core symptoms of ASD. LpEV treatment significantly improves these autistic-like behaviors in Drd2-KO mice, suggesting that LpEVs can mitigate the persistent dysregulation of signaling pathways in these mice. RNA sequencing followed by Gene Ontology enrichment analysis of LpEV-treated Drd2-KO mice identifies distinct groups of genes altered in the brain of Drd2-KO mice, which were reversed by LpEV treatment. Notably, a high proportion of these genes overlap significantly with known ASD genes in the SFARI database, strengthening the potential of LpEV to target relevant pathways in ASD. Further investigation identifies oxytocin and oxytocin receptor (Oxtr) as potential therapeutic targets. LpEV treatment significantly improves autistic-like behaviors in Oxtr-KO heterozygous mice, adenylyl cyclase-5 KO mice and Shank3-KO mice, suggesting its therapeutic potential to target ASD through broader mechanisms beyond a single gene pathway. These results highlight the therapeutic potential of LpEV in reversing the accumulated dysregulated signaling pathways leading to ASD symptoms and improving autistic-like behaviors. Probiotic-derived nanovesicles restore behavioral deficits in autism Autism spectrum disorder (ASD) is a condition that affects social interaction and repetitive behaviors. Researchers studied the effects of extracellular vesicles (EVs) from Lactobacillus paracasei , a type of probiotic bacteria, on genetic mouse models of ASD. EVs are tiny particles released by cells that can carry proteins, nucleic acids and other molecules. The study involved treating different genetic models of mice with these EVs to see if they could improve ASD-like symptoms. They found that the EVs improved social behaviors and reduced repetitive actions in the mice. They also discovered changes in the expression of genes closely related to ASD in the brain, suggesting that the EVs might help to correct some of the underlying molecular issues. These findings suggest that Lactobacillus paracasei -derived EVs could be a promising new approach for treating ASD symptoms. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Noninvasive intranasal drug administration has been noted to allow direct delivery of drugs to the brain. In the present study, the therapeutic efficacy of intranasal small interfering RNA (siRNA) delivery was investigated in the postischemic rat brain. Fluorescein isothiocyanate (FITC)-labeled control siRNA was delivered intranasally in normal adult rats using e-PAM-R, a biodegradable PAMAM dendrimer, as gene carrier. Florescence-tagged siRNA was found in the cytoplasm and processes of neurons and of glial cells in many brain regions, including the hypothalamus, amygdala, cerebral cortex, and striatum, in 1 hour after infusion, and the FITC-fluorescence was continuously detected for at least 12 hours. When siRNA for high mobility group box 1 (HMGB1), which functions as an endogenous danger molecule and aggravates inflammation, was delivered intranasally, the target gene was significantly depleted in many brain regions, including the prefrontal cortex and striatum. More importantly, intranasal delivery of HMGB1 siRNA markedly suppressed infarct volume in the postischemic rat brain (maximal reduction to 42.8 ± 5.6% at 48 hours after 60 minutes middle cerebral artery occlusion (MCAO)) and this protective effect was manifested by recoveries from neurological and behavioral deficits. These results indicate that the intranasal delivery of HMGB1 siRNA offers an efficient means of gene knockdown-mediated therapy in the ischemic brain.