Multisensory Stimulation Reverses Memory Impairment in Adrß3KO Male Mice.

Norepinephrine plays an important role in modulating memory through its beta-adrenergic receptors (Adrß: ß1, ß2 and ß3). Here, we hypothesized that multisensory stimulation would reverse memory impairment caused by the inactivation of Adrß3 (Adrß3KO) with consequent inhibition of sustained glial-mediated inflammation. To test this, 21- and 86-day-old Adrß3KO mice were exposed to an 8-week multisensory stimulation (MS) protocol that comprised gustatory and olfactory stimuli of positive and negative valence; intellectual challenges to reach food; the use of hidden objects; and the presentation of food in ways that prompted foraging, which was followed by analysis of GFAP, Iba-1 and EAAT2 protein expression in the hippocampus (HC) and amygdala (AMY). The MS protocol reduced GFAP and Iba-1 expression in the HC of young mice but not in older mice. While this protocol restored memory impairment when applied to Adrß3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsened the memory of Adrß3KO mice. In the AMY of Adrß3KO older mice, we observed an increase in GFAP and EAAT2 expression when compared to wild-type (WT) mice that MS was unable to reduce. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied immediately after weaning in Adrß3KO animals and indicates that the control of neuroinflammation mediates this response.

Multisensory Stimulation Improves Cognition and Behavior in Adult Male Rats Born to LT4-treated Thyroidectomized Dams.

Gestational hypothyroidism can impair development, cognition, and mood. Here, we tested whether multisensory stimulation (MS) improves the phenotype of rats born to surgically thyroidectomized (Tx) dams suboptimally treated with LT4. 8-week-old female Tx Wistar rats were kept on daily LT4 (0.7 µg/100 g body weight) dosed by gavage (serum TSH and T4 levels indicated moderate hypothyroidism) and 3 weeks later placed for breeding. MS of the litter started at age 60 days and lasted for 8 weeks. It consisted of twice per week of physical, cognitive, sensorial, and food stimuli. The offspring were assessed before and after MS for standardized tests of locomotor activity, cognition, and mood. Gestational hypothyroidism resulted in reduced litter size and increased offspring mortality. The pups exhibited delayed physical development, impairment of short- and long-term memory, and anxiety- and depressive-like behaviors. Nonetheless, ambulatory activity, social memory, and social preference were not affected by gestational hypothyroidism. MS restored short-term memory and anxiety while improving depressive like-behaviors. MS did not improve long-term memory. MS also did not modify the performance of control litter born to intact dams. We conclude that cognition and mood impairments caused by moderate gestational hypothyroidism were reversed or minimized in rats through MS. Further studies should define the molecular mechanisms involved.

Triiodothyronine Treatment reverses Depression-Like Behavior in a triple-transgenic animal model of Alzheimer's Disease.

Alzheimer disease's (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. The central nervous system is an important target of thyroid hormones (TH). An inverse association between serum triiodothyronine (T3) levels and the risk of AD symptoms and progression has been reported. We investigated the effects of T3 treatment on the depression-like behavior in male transgenic 3xTg-AD mice. Animals were divided into 2 groups treated with daily intraperitoneal injections of 20 ng/g of body weight (b.w.) L-T3 (T3 group) or saline (vehicle, control group). The experimental protocol lasted 21 days, and behavioral tests were conducted on days 18-20. At the end of the experiment, the TH profile and hippocampal gene expression were evaluated. The T3-treated group significantly increased serum T3 and decreased thyroxine (T4) levels. When compared to control hippocampal samples, the T3 group exhibited attenuated glycogen synthase kinase-3 (GSK3), metalloproteinase 10 (ADAM10), amyloid-beta precursor-protein (APP), serotonin transporter (SERT), 5HT1A receptor, monocarboxylate transporter 8 (MCT8) and bone morphogenetic protein 7 (BMP-7) gene expression, whereas augmented superoxide dismutase 2 (SOD2) and Hairless gene expression. T3-treated animals also displayed reduced immobility time in both the tail suspension and forced swim tests, and in the latter presented a higher latency time compared to the control group. Therefore, our findings suggest that in an AD mouse model, T3 supplementation promotes improvements in depression-like behavior, through the modulation of the serotonergic related genes involved in the transmission mediated by 5HT1A receptors and serotonin reuptake, and attenuated disease progression.

Age Worsens the Cognitive Phenotype in Mice Carrying the Thr92Ala-DIO2 Polymorphism.

The Thr92Ala-Dio2 polymorphism has been associated with reduced cognition in 2-month-old male mice and increased risk for cognitive impairment and Alzheimer's disease in African Americans. This has been attributed to reduced thyroid hormone (TH) signaling and endoplasmic reticulum (ER) stress in the brain. Here we studied the Thr92Ala-Dio2 mouse model and saw that older male mice (7-8-month-old) exhibited a more severe cognition impairment, which extended to different aspects of declarative and working memories. A similar phenotype was observed in 4-5-month-old female mice. There were no structural alterations in the prefrontal cortex (PFC) and hippocampus of the Thr92Ala-Dio2 mouse. Nonetheless, in both male and female PFC, there was an enrichment in genes associated with TH-dependent processes, ER stress, and Golgi apparatus, while in the hippocampus there was additional enrichment in genes associated with inflammation and apoptosis. Reduced TH signaling remains a key mechanism of disease given that short-term treatment with L-T3 rescued the cognitive phenotype observed in males and females. We conclude that in mice, age is an additional risk factor for cognitive impairment associated with the Thr92Ala-Dio2 polymorphism. In addition to reduced TH signaling, ER-stress, and involvement of the Golgi apparatus, hippocampal inflammation and apoptosis were identified as potentially important mechanisms of a disease.

Long-term obesity is associated with depression and neuroinflammation.

OBJECTIVE: Obesity is characterized by a state of chronic, low-intensity systemic inflammation frequently associated with insulin resistance and dyslipidemia. METHODS: Given that chronic inflammation has been implicated in the pathogenesis of mood disorders, we investigated if chronic obesity that was initiated early in life - lasting through adulthood - could be more harmful to memory impairment and mood fluctuations such as depression. RESULTS: Here we show that pre-pubertal male rats (30 days old) treated with a high-fat diet (40%) for 8-months gained ~50% more weight when compared to controls, exhibited depression and anxiety-like behaviors but no memory impairment. The prefrontal cortex of the obese rats exhibited an increase in the expression of genes related to inflammatory response, such as NFKb, MMP9, CCl2, PPARb, and PPARg. There were no alterations in genes known to be related to depression. CONCLUSION: Long-lasting obesity with onset in prepuberal age led to depression and neuroinflammation but not to memory impairment.

Temporal assessment of root and shoot colonization of elephant grass (Pennisetum purpureum Schum.) host seedlings by Gluconacetobacter diazotrophicus strain LP343.

Gluconacetobacter diazotrophicus is a species of great agronomic potential due to its growth-promotion traits. Its colonization process in different plants has been reported. However, there have been no studies regarding its structural colonization in elephant grass. This is a fast-growing C4-Poaceae plant, and its application in Brazil is mainly aimed at feeding dairy cattle, due to its high nutritional value. Also, in the last decade, this grass has been applied in the production of biofuels. The present study aimed to monitor the colonization process of strain LP343 of G. diazotrophicus inoculated in elephant grass seedlings of PCEA genotype, by using a mCherry-tagged bacterium. Samples of roots and shoots collected at different periods were visualized by confocal laser-scanning microscopy. The colony-counting assay was used to compare the number of cells recovered in different niches and a qPCR was performed for the quantification of endophytic cells in root and shoot tissues. Results suggested that the strain LP343 quickly recognized the PCEA roots as host, attached to the elephant grass roots at 6 h, and 7 days after inoculation were able to colonize the xylem vessels of roots and shoots of elephant grass. This study advances our knowledge about the colonization process of G. diazotrophicus species in elephant grass, contributing to future studies involving the plant-bacteria interaction cultivated under gnotobiotic conditions.