Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus.

Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of α-fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies.

Histaminergic Neurotransmission as a Gateway for the Cognitive Effect of Oleoylethanolamide in Contextual Fear Conditioning.

Background: The integrity of the brain histaminergic system is necessary for the unfolding of homeostatic and cognitive processes through the recruitment of alternative circuits with distinct temporal patterns. We recently demonstrated that the fat-sensing lipid mediator oleoylethanolamide indirectly activates histaminergic neurons to exerts its hypophagic effects. The present experiments investigated whether histaminergic neurotransmission is necessary also for the modulation of emotional memory induced by oleoylethanolamide in a contextual fear conditioning paradigm. Methods: We examined the acute effect of i.p. administration of oleoylethanolamide immediately posttraining in the contextual fear conditioning test. Retention test was performed 72 hours after training. To test the participation of the brain histaminergic system in the cognitive effect of oleoylethanolamide, we depleted rats of brain histamine with an i.c.v. injection of alpha-fluoromethylhistidine (a suicide inhibitor of histidine decarboxylase) or bilateral intra-amygdala infusions of histamine H1 or H2 receptor antagonists. We also examined the effect of oleoylethanolamide on histamine release in the amygdala using in vivo microdialysis. Results: Posttraining administration of oleoylethanolamide enhanced freezing time at retention. This effect was blocked by both i.c.v. infusions of alpha-fluoromethylhistidine or by intra-amygdala infusions of either pyrilamine or zolantidine (H1 and H2 receptor antagonists, respectively). Microdialysis experiments showed that oleoylethanolamide increased histamine release from the amygdala of freely moving rats. Conclusions: Our results suggest that activation of the histaminergic system in the amygdala has a "permissive" role on the memory-enhancing effects of oleoylethanolamide. Hence, targeting the H1 and H2 receptors may modify the expression of emotional memory and reduce dysfunctional aversive memories as found in phobias and posttraumatic stress disorder.

The hypophagic factor oleoylethanolamide differentially increases c-fos expression in appetite regulating centres in the brain of wild type and histamine deficient mice.

Histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMN) establish connections with virtually all brain areas. Recent evidence suggests that feeding-related motivation is correlated with the activation of a subpopulation of histamine neurons in the ventral TMN that project to hypothalamic and subcortical areas controlling feeding behaviour. Oleoylethanolamide (OEA) is a hypophagic lipid-amide released by the small intestine in response to daily fat intake that indirectly activates hypothalamic oxytocin-neurons in the paraventricular (PVN) and supraoptic (SON) nuclei. We recently showed that OEA requires the integrity of neuronal histamine to fully display its hypophagic effect. Here we aimed to investigate if differences exist in OEA-induced c-Fos expression in several brain regions of fasted, histidine decarboxylase (HDC)-KO mice that do not synthesize histamine, and wild type (WT) littermates. All the brain regions examined receive histaminergic innervation and are involved in different aspects of feeding behaviour. We found that OEA increased c-Fos expression in the SON, arcuate nucleus (ARC) and the amygdala of WT mice, but not HDC-KO mice, whereas neither genotype nor treatment differences were observed in the lateral and dorsomedial hypothalamus. Furthermore, oxytocin-immunostaining was markedly increased in the neurohypophysis of WT and not in HDC-KO mice. Of note, OEA increased c-Fos expression in the nucleus of solitary tract of both genotypes. Our findings suggest that the TMN serves as a relay station to elaborate peripheral signals that control homeostatic and adaptive behavioural responses.

Investigations of Astrocyte Calcium Signaling and Imaging with Classical and Nonclassical Light.

The application of light in studying and influencing cellular behavior with improved temporal and spatial resolution remains a key objective in fields such as chemistry, physics, medicine, and engineering. In the brain, nonexcitable cells called astrocytes play essential roles in regulating homeostasis and cognitive function through complex calcium signaling pathways. Understanding these pathways is vital for deciphering brain physiology and neurological disorders like Parkinson's and Alzheimer's. Despite challenges in selectively targeting astrocyte signaling pathways due to shared molecular equipment with neurons, recent advancements in laser technology offer promising avenues. However, the effort to use laser light properties to study astroglial cell function is still limited. This work aims to exploit an in-depth pharmacological analysis of astrocyte calcium channels to determine the physiological mechanism induced by exposure to classical nanosecond-pulsed light. We herein report molecular clues supporting the use of visible-nanosecond laser pulses as a promising approach to excite primary rat neocortical astrocytes and unprecedentedly report on the implementation of entangled two-photon microscopy to image them.

Graphene oxide electrodes enable electrical stimulation of distinct calcium signalling in brain astrocytes.

Astrocytes are responsible for maintaining homoeostasis and cognitive functions through calcium signalling, a process that is altered in brain diseases. Current bioelectronic tools are designed to study neurons and are not suitable for controlling calcium signals in astrocytes. Here, we show that electrical stimulation of astrocytes using electrodes coated with graphene oxide and reduced graphene oxide induces respectively a slow response to calcium, mediated by external calcium influx, and a sharp one, exclusively due to calcium release from intracellular stores. Our results suggest that the different conductivities of the substrate influence the electric field at the cell-electrolyte or cell-material interfaces, favouring different signalling events in vitro and ex vivo. Patch-clamp, voltage-sensitive dye and calcium imaging data support the proposed model. In summary, we provide evidence of a simple tool to selectively control distinct calcium signals in brain astrocytes for straightforward investigations in neuroscience and bioelectronic medicine.

The emerging science of Glioception: Contribution of glia in sensing, transduction, circuit integration of interoception.

Interoception is the process by which the nervous system regulates internal functions to achieve homeostasis. The role of neurons in interoception has received considerable recent attention, but glial cells also contribute. Glial cells can sense and transduce signals including osmotic, chemical, and mechanical status of extracellular milieu. Their ability to dynamically communicate "listening" and "talking" to neurons is necessary to monitor and regulate homeostasis and information integration in the nervous system. This review introduces the concept of "Glioception" and focuses on the process by which glial cells sense, interpret and integrate information about the inner state of the organism. Glial cells are ideally positioned to act as sensors and integrators of diverse interoceptive signals and can trigger regulatory responses via modulation of the activity of neuronal networks, both in physiological and pathological conditions. We believe that understanding and manipulating glioceptive processes and underlying molecular mechanisms provide a key path to develop new therapies for the prevention and alleviation of devastating interoceptive dysfunctions, among which pain is emphasized here with more focused details.

Graphene glial-interfaces: challenges and perspectives.

Graphene nanosheets are mechanically strong but flexible, electrically conductive and bio-compatible. Thus, due to these unique properties, they are being intensively studied as materials for the next generation of neural interfaces. Most of the literature focused on optimizing the interface between these materials and neurons. However, one of the most common causes of implant failure is the adverse inflammatory reaction of glial cells. These cells are not, as previously considered, just passive and supportive cells, but play a crucial role in the physiology and pathology of the nervous system, and in the interaction with implanted electrodes. Besides providing structural support to neurons, glia are responsible for the modulation of synaptic transmission and control of central and peripheral homeostasis. Accordingly, knowledge on the interaction between glia and biomaterials is essential to develop new implant-based therapies for the treatment of neurological disorders, such as epilepsy, brain tumours, and Alzheimer's and Parkinson's disease. This work provides an overview of the emerging literature on the interaction of graphene-based materials with glial cells, together with a complete description of the different types of glial cells and problems associated with them. We believe that this description will be important for researchers working in materials science and nanotechnology to develop new active materials to interface, measure and stimulate these cells.

Nutritional and hematological factors associated with the progression of Alzheimer's disease: a cohort study.

OBJECTIVE: We studied the users of the Specialized Drug Distribution Program of the public health network. METHODS: A prospective cohort examined the elderly at two intervals of three years and included 30 patients in phase I and 16 in phase II. The methodology was composed of home visits, anthropometric, nutritional and hematological evaluation. For the progression of AD, the Clinical Dementia Rating (CDR) scale was used. RESULTS: According to the CDR, the disease evolved, since in 2014 most of the patients were in CDR 3. In the analysis of the micronutrients, only the B vitamins (B1, B2, B3, B5, B6) presented a significant reduction in 2014. The consumption of carbohydrates and lipids increased in the 2014 evaluation, and protein consumption decreased. As for the average weight of the elderly, there was an increase in 2014, 65.9 (± 15.6) Kg, with a BMI of 26.75 (± 4, 5), in 2011 the average weight was 62.44 kg (± 14, 36), BMI 24.64 (± 4.97). CONCLUSION: The hypothesis that patients are likely to be overweight or obese before the development of AD and that this may be associated with an increased risk of dementia is suggested.

Nutritional evaluation of geriatric patients with Alzheimer's disease in Southern Brazil: case-control study.

INTRODUCTION: elderly's malnutrition is linked, among other factors, to chronic-degenerative diseases, requiring an improvement in the clinical evaluation of nutritional status of this population. Studies have tried to find out new tools to assess aged-people nutritional status. One of most used scales to investigate nutritional status on geriatric patients is the Mini Nutritional Assessment (MNA). OBJECTIVE: the present study aims to evaluate nutritional status of Alzheimer's disease (AD) patients, by comparison with a control group, via Mini Nutritional Assessment. METHODS: a cross-sectional study, which includes 35 alzheimer's old-people and 43 control old-people, was performed evaluating nutritional status with MNA. RESULTS: total score of MNA in the alzheimer group shows that 71.42% were in malnutrition risk, 14.28% were malnourished and 14.25% presented normal nutritional status. In addition, in the control group 79.06% of patients (n = 34) were classified as having normal nutritional status and 20.93% (n = 9), as being at risk of malnutrition. CONCLUSION: results reinforce the purpose that MNA can be used as a proper instrument to evaluate nutritional status in elderly, mainly in AD, because measuring risk and nutritional status of this population is indispensable.

The Relationship Between Copper, Iron, and Selenium Levels and Alzheimer Disease.

This study aimed to evaluate the concentrations of copper, iron, and selenium in elderly people with Alzheimer disease (AD), comparing the same parameters in a paired group of healthy people, in order to verify if the amount of these metals may influence the cognitive impairment progression. Patients' cognitive impairment was evaluated by Clinical Dementia Rating (CDR). The elementary quantification of erythrocytes was performed by inductively coupled plasma mass spectrometry technique. The statistical analyses were carried out by SPSS software 20.0 version, employing Shapiro-Wilk, Wilcoxon, Kruskall-Wallis, and Spearman correlation tests, considering significant results of p < 0.05. The sample was composed of 34% (n = 11) of women and 66% (n = 21) of men in each group. The AD group was characterized by a higher concentration of copper (p < 0.0001) and iron (p < 0.0001); however, there is no significant difference in selenium level. The analyses of the metal levels in different stages of AD were not significant in CDR-1, however in CDR-2 and CDR-3, elevated levels of copper and iron were observed; in CDR-3 patients, the level of selenium was lower (p < 0.008) compared to that of healthy controls. Patients with Alzheimer disease studied present increase in biometal blood levels, especially of copper and iron, and such increase can be different according to the disease stage and can cause more impairment cognitive functions in AD.

Nutritional and hematological factors associated with the progression of Alzheimer's disease: a cohort study

SUMMARY OBJECTIVE: We studied the users of the Specialized Drug Distribution Program of the public health network. METHODS: A prospective cohort examined the elderly at two intervals of three years and included 30 patients in phase I and 16 in phase II. The methodology was composed of home visits, anthropometric, nutritional and hematological evaluation. For the progression of AD, the Clinical Dementia Rating (CDR) scale was used. RESULTS: According to the CDR, the disease evolved, since in 2014 most of the patients were in CDR 3. In the analysis of the micronutrients, only the B vitamins (B1, B2, B3, B5, B6) presented a significant reduction in 2014. The consumption of carbohydrates and lipids increased in the 2014 evaluation, and protein consumption decreased. As for the average weight of the elderly, there was an increase in 2014, 65.9 (± 15.6) Kg, with a BMI of 26.75 (± 4, 5), in 2011 the average weight was 62.44 kg (± 14, 36), BMI 24.64 (± 4.97). CONCLUSION: The hypothesis that patients are likely to be overweight or obese before the development of AD and that this may be associated with an increased risk of dementia is suggested.

RESUMO OBJETIVO: Foram estudados os usuários do programa de distribuição de medicamentos especializados da rede pública de saúde de Guarapuava, Paraná, Brasil. MÉTODOS: Uma coorte prospectiva, em que os idosos foram examinados em dois momentos, com um intervalo de três anos, com 30 pacientes na fase I e 16 na fase II. A metodologia foi composta por visitas domiciliares, avaliação antropométrica; avaliação nutricional e hematológica. Para a progressão da DA, utilizou-se a escala Clinical Demential Rating (CDR). Os testes de Shapiro-Wilk, teste de Wilcoxon e correlações com associações (Δ%), p < 0,05 para as análises estatísticas. RESULTADOS: A progressão da doença, segundo o CDR, evoluiu, pois, em 2014, a maioria dos pacientes encontrava-se em CDR 3. Na análise dos micronutrientes, somente as vitaminas do complexo B (B1, B2, B3, B5, B6) apresentaram redução significativa em 2014. O consumo de carboidratos e lipídeos aumentou na avaliação de 2014, e o consumo de proteínas diminuiu. Quanto ao peso médio dos idosos, houve um aumento em 2014, 65,9 (± 15,6) kg, com IMC 26,75 (± 4, 5); em 2011, o peso médio foi 62,44 kg (± 14,36), IMC 24,64 (± 4,97). CONCLUSÃO: Não foram encontrados pacientes anêmicos ou desnutridos na amostra. A hipótese de que os pacientes provavelmente já apresentavam sobrepeso ou obesidade antes do desenvolvimento da DA, e que isso pode estar associado com um aumento de risco de demência, pode ser sugerida.