Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying ...mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal-dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Optic nerve atrophy represents the most common form of hereditary optic neuropathies leading to vision impairment. The recently described Bosch‐Boonstra‐Schaaf optic atrophy (BBSOA) syndrome denotes ...an autosomal dominant genetic form of neuropathy caused by mutations or deletions in the NR2F1 gene. Herein, we describe a mouse model recapitulating key features of BBSOA patients—optic nerve atrophy, optic disc anomalies, and visual deficits—thus representing the only available mouse model for this syndrome. Notably, Nr2f1‐deficient optic nerves develop an imbalance between oligodendrocytes and astrocytes leading to postnatal hypomyelination and astrogliosis. Adult heterozygous mice display a slower optic axonal conduction velocity from the retina to high‐order visual centers together with associative visual learning deficits. Importantly, some of these clinical features, such the optic nerve hypomyelination, could be rescued by chemical drug treatment in early postnatal life. Overall, our data shed new insights into the cellular mechanisms of optic nerve atrophy in BBSOA patients and open a promising avenue for future therapeutic approaches.
Synopsis
This study proposes Nr2f1 heterozygous mice as a model of BBSOA syndrome, an optic nerve (ON) atrophy associated with intellectual disability. Nr2f1 mutants reveal ON hypomyelination, astrogliosis and reduced axonal conductance velocity. Treatment with Miconazole rescues ON myelination defects.
Mouse Nr2f1 and human NR2F1 expression profiles are highly conserved in the developing retina and ON.
Nr2f1 heterozygous and homozygous mutant mice recapitulate the human disease, displaying optic disc abnormalities, cerebral visual impairment and ON atrophy.
Nr2f1 regulates retinal ganglion cell differentiation and accurate balance between ON oligodendrocytes and astrocytes.
Nr2f1 modulates ON axonal conductance velocity and is involved in associative visual learning.
Miconazole treatment at early postnatal ages rescues ON myelination level, hence representing a promising therapeutic approach for optic neuropathies.
This study proposes Nr2f1 heterozygous mice as a model of BBSOA syndrome, an optic nerve (ON) atrophy associated with intellectual disability. Nr2f1 mutants reveal ON hypomyelination, astrogliosis and reduced axonal conductance velocity. Treatment with Miconazole rescues ON myelination defects.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Scope
Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins ...partaking in innate immunity, such as surfactant protein D (SPD) and mannan‐binding lectin (MBL).
Methods and results
We evaluated haplotypes of the bitter‐taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 1.06–6.11, p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 0.99/1.85, p = 0.049), being more robust in subjects aged <40 years (OR = 1.9 1.06/3.42, p = 0.031).
Conclusion
Current data reinforce the impact of TAS2R38 gene on phenotypic and clinical outputs affecting obesity, showing significant associations with extreme weight conditions (i.e., obesity and anorexia nervosa), and changes in both olfactory capacity and immune traits.
Here, we demonstrate that genetic variations that underlie functionality of the TAS2R38, a receptor that regulates the ability to identify bitter‐tasting compounds, may impact on phenotypic and clinical outputs affecting extreme weight conditions (i.e., obesity and anorexia nervosa), being also associated with proteins partaking in innate immunity (i.e., surfactant protein D (SPD) and mannanbinding lectin (MBL)).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Physical exercise is considered to exert a positive neurophysiological effect that helps to maintain normal brain activity in the elderly. Expectations that it could help to fight Alzheimer's disease ...(AD) were recently raised. This study analyzed the effects of different patterns of physical exercise on the 3xTg-AD mouse. Male and female 3xTg-AD mice at an early pathological stage (4-month-old) have had free access to a running wheel for 1 month, whereas mice at a moderate pathological stage(7-month-old) have had access either during 1 or 6 months. The non-transgenic mouse strain was used as a control. Parallel animal groups were housed in conventional conditions. Cognitive loss and behavioral and psychological symptoms of dementia (BPSD)-like behaviors were present in the 3xTg-AD mice along with alteration in synaptic function and ong-term potentiation impairment in vivo. Brain tissue showed AD-pathology and oxidative-related changes. Disturbances were more severe at the older age tested. Oxidative stress was higher in males but other changes were similar or higher in females. Exercise treatment ameliorated cognitive deterioration and BPSD-like behaviors such as anxiety and the startle response. Synaptic changes were partially protected by exercise. Oxidative stress was reduced. The best neuroprotection was generally obtained after 6 months of exercise in 7-month-old 3xTg-AD mice. Improved sensorimotor function and brain tissue antioxidant defence were induced in both 3xTg-AD and NonTg mice. Therefore, the benefits of aerobic physical exercise on synapse, redox homeostasis, and general brain function demonstrated in the 3xTg-AD mouse further support the value of this healthy life-style against neurodegeneration.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique consisting in the application of weak electric currents on the scalp. Although previous studies have ...demonstrated the clinical value of tDCS for modulating sensory, motor, and cognitive functions, there are still huge gaps in the knowledge of the underlying physiological mechanisms. To define the immediate impact as well as the after effects of tDCS on sensory processing, we first performed electrophysiological recordings in primary somatosensory cortex (S1) of alert mice during and after administration of S1-tDCS, and followed up with immunohistochemical analysis of the stimulated brain regions. During the application of cathodal and anodal transcranial currents we observed polarity-specific bidirectional changes in the N1 component of the sensory-evoked potentials (SEPs) and associated gamma oscillations. On the other hand, 20 min of cathodal stimulation produced significant after-effects including a decreased SEP amplitude for up to 30 min, a power reduction in the 20-80 Hz range and a decrease in gamma event related synchronization (ERS). In contrast, no significant changes in SEP amplitude or power analysis were observed after anodal stimulation except for a significant increase in gamma ERS after tDCS cessation. The polarity-specific differences of these after effects were corroborated by immunohistochemical analysis, which revealed an unbalance of GAD 65-67 immunoreactivity between the stimulated versus non-stimulated S1 region only after cathodal tDCS. These results highlight the differences between immediate and after effects of tDCS, as well as the asymmetric after effects induced by anodal and cathodal stimulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Since brain glycogen is stored mainly in astrocytes, the role of this polysaccharide in neurons has been largely overlooked. To study the existence and relevance of an active neuronal glycogen ...metabolism
, we generated a mouse model lacking glycogen synthase specifically in the Camk2a-expressing postnatal forebrain pyramidal neurons (GYS1
), which include the prefrontal cortex and the CA3 and CA1 cell layers of the hippocampus. The latter are involved in memory and learning processes and participate in the hippocampal CA3-CA1 synapse, the function of which can be analyzed electrophysiologically. Long-term potentiation evoked in the hippocampal CA3-CA1 synapse was decreased in alert behaving GYS1
mice. They also showed a significant deficiency in the acquisition of an instrumental learning task - a type of associative learning involving prefrontal and hippocampal circuits. Interestingly, GYS1
animals did not show the greater susceptibility to hippocampal seizures and myoclonus observed in animals completely depleted of glycogen in the whole CNS. These results unequivocally demonstrate the presence of an active glycogen metabolism in neurons
and reveal a key role of neuronal glycogen in the proper acquisition of new motor and cognitive abilities, and in the changes in synaptic strength underlying such acquisition.
Human milk oligosaccharides (HMOs) are unique with regard to their diversity, quantity and complexity, particularly in comparison to bovine milk oligosaccharides. HMOs are associated with functional ...development during early life, mainly related to immunity and intestinal health. Whether HMOs elicit a positive effect on cognitive capabilities of lactating infants remains an open question. This study evaluated the role of the most abundant HMO, 2′-fucosyllactose (2′-FL), in synaptic plasticity and learning capabilities in rodents. Mice and rats were prepared for the chronic recording of field excitatory postsynaptic potentials evoked at the hippocampal CA3–CA1 synapse. Following chronic oral administration of 2′-FL, both species showed improvements in input/output curves and in long-term potentiation (LTP) evoked experimentally in alert behaving animals. This effect on LTP was related to better performance of animals in various types of learning behavioral tests. Mice were tested for spatial learning, working memory and operant conditioning using the IntelliCage system, while rats were submitted to a fixed-ratio schedule in the Skinner box. In both cases, 2′-FL-treated animals performed significantly better than controls. In addition, chronic administration of 2′-FL increased the expression of different molecules involved in the storage of newly acquired memories, such as the postsynaptic density protein 95, phosphorylated calcium/calmodulin-dependent kinase II and brain-derived neurotrophic factor in cortical and subcortical structures. Taken together, the data show that dietary 2′-FL affects cognitive domains and improves learning and memory in rodents.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We report on the formation of two novel multifunctional isomorphous (4,4) square-grid 2D coordination polymers based on 1H-indazole-5-carboxylic acid. To the best of our knowledge, these complexes ...are the first examples of 2D-coordination polymers constructed with this novel ligand. We have analysed in detail the structural, magnetic and anti-parasitic properties of the resulting materials. In addition, the capability of inhibiting nitric oxide production from macrophage cells has been measured and was used as an indirect measure of the anti-inflammatory response. Finally, the photocatalytic activity was measured with a model pollutant, i.e. vanillic acid (phenolic compound), with the aim of further increasing the functionalities and applicability of the compounds.
We report on the formation of two isomorphous (4,4) square-grid 2D coordination polymers based on 1H-indazole-5-carboxylic acid. These materials show interesting magnetic, anti-parasitic and anti-inflammatory properties. Display omitted
•New 2D coordination polymers based on 1H-indazole-5-carboxylic acid are reported.•Magnetic studies have been performed.•Compounds show interesting anti-parasitic properties.•Anti-inflammatory activities have been analysed.•Cytotoxicity in macrophages has been measured.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Strigolactones have recently been suggested to be phytohormones that are present in all plants. Strigolactones are released by roots into the rhizosphere, stimulating the seed germination of ...parasitic plants such as
Striga spp. and
Orobanche spp. and play a crucial role in the interaction between plants and symbiotic arbuscular mycorrhizal fungi.
By applying different concentrations of the synthetic strigolactone analogue GR24 to alfalfa (
Medicago sativa) inoculated with
Sinorhizobium meliloti we could show that in alfalfa nodulation is positively affected by the presence of the strigolactone analogue GR24. Moreover, we could show that this increased nodulation cannot be linked with a stimulatory effect of GR24 on the growth or the expression of
nod genes of
S. meliloti.
Putative mechanisms operating in the plant in response to the addition of GR24 and leading to increased nodule formation by rhizobia are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The activity-regulated transcription factor cAMP response element-binding protein (CREB) is an essential component of the molecular switch that controls the conversion of short-term into long-term ...forms of plasticity, including those underlying long-term memory. Previous research in acute brain slices of transgenic animals expressing constitutively active CREB variants has revealed that enhancing CREB activity increases the intrinsic excitability of neurons and facilitates the late phase of long-term potentiation (LTP) in the Schaffer collateral pathway. Here, we report similar changes in plasticity at the Schaffer collateral pathway in alert behaving mice. Forebrain expression of a strong constitutively active CREB variant, VP16-CREB, enhanced in vivo LTP evoked in the Schaffer collateral pathway and caused significant changes in the input/output curve and paired-pulse facilitation in CA3-CA1 synapses, which could be explained by the increased excitability of hippocampal pyramidal neurons. In addition, classical eyeblink conditioning in transgenic mice and control littermates showed larger conditioned responses in mutant mice that were associated to a transient increase in the acquisition rate and in the concomitant learning-dependent change in synaptic strength. The sustained chronic activation of CREB activity, however, impaired the performance in this task. Our experiments demonstrate that the sustained enhancement of CREB function alters the physiology and plasticity of hippocampal circuits in behaving animals and that these changes have important consequences in associative learning.
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