The moderator effect of age in the association between mood and adiposity in the elderly is specific for the subcutaneous adipose compartment: An MRI study.

The positive association between obesity and depressive mood in young- and middle-age individuals is a phenomenon with major clinical implications in public health. Interestingly, the trend of this association in older individuals is not clear, given the conflicting results of multiple studies. Since aging is accompanied by changes in body fat distribution, we questioned whether age is a modulator of such association. This study explores the role of age in the association between mood and general (body mass index [BMI]) and abdominal adiposity (waist circumference [WC]) in older adults characterizing the different abdominal adipose tissue compartments (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]) with magnetic resonance imaging (MRI) techniques. METHODS: One hundred twenty aged community-dwelling individuals (≥50 y of age) were assessed regarding depressive mood (Geriatric Depression Scale) and adiposity (BMI and WC). From these, 96 were assessed for SAT and VAT using MRI. RESULTS: Using multiple linear regression models, depressive mood was positively associated with BMI, WC, and VAT. Age was a significant moderator of the association between depressive mood and BMI, WC, and SAT: positive in younger participants and null or negative in older participants. On the other hand, higher VAT was significantly associated with a more depressive mood, independently of age. CONCLUSIONS: This study identifies age as a relevant moderator in the association between depressive mood and adiposity in the elderlies. Furthermore, the body fat compartment analysis revealed that the effect of age is specific for the SAT, suggesting its protective role in depressive mood.

Impact of iodine supplementation during preconception, pregnancy and lactation on maternal thyroid homeostasis and offspring psychomotor development: protocol of the IodineMinho prospective study.

BACKGROUND: Iodine deficiency is the most common cause of preventable brain harm and cognitive impairment in children. Portuguese women of childbearing age, pregnant women and their progeny were shown to have inadequate iodine intake. Consequently, the Portuguese Health Authorities have recommended a daily supplementation with 150-200 µg iodine in preconception, pregnancy, and lactation. The IodineMinho study intends to evaluate whether (i) this recommendation impacted on the prevalence of iodine deficiency in pregnant women from the Minho region of Portugal, (ii) the time of initiation of iodine supplementation (if any) influences the serum levels of thyroid hormones at several intervals during pregnancy and (iii) there are serum thyroid-hormone parameters in the 1st trimester of pregnancy that predict psychomotor development of the child at 18 months of age. METHODS: Most Portuguese women are followed throughout pregnancy in community Family Health Units, where family physicians may choose to follow the National recommendation or other, concerning iodine sufficiency. This study will recruit women (N = 304) who intend to become pregnant or are already pregnant from 10 representative Units. Physician's approach and prescriptions, sociodemographic, nutrition and clinical information will be obtained at baseline and throughout pregnancy. To evaluate endocrine function, blood and urine samples will be collected at recruitment, once in each trimester of pregnancy, at delivery and 3 months after delivery. Breastmilk samples will be collected for iodine and energy content analysis. Children will be evaluated for psychomotor development at 18 months. Maternal thyroid volume will be evaluated by ultrasound scan at baseline, in the 3rd trimester and at 3 months after delivery. DISCUSSION: Iodine deficiency early during development precludes children from achieving full intellectual capabilities. This protocol describes a study that is innovative and unique in its detailed and comprehensive evaluation of maternal and child endocrine and psychomotor parameters. By evaluating the effectiveness of the iodine supplementation recommendation, it will contribute to the public health systems' efforts to provide excellence in maternal and infant care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04288531 . Registered 28 February 2020-Retrospectively registered.

The choroid plexus as a sex hormone target: Functional implications.

The choroid plexuses (CPs) are highly vascularized branched structures that protrude into the ventricles of the brain, and form a unique interface between the blood and the cerebrospinal fluid (CSF). In recent years, novel functions have been attributed to this tissue such as in immune and chemical surveillance of the central nervous system, brain development, adult neurogenesis and circadian rhythm regulation. Sex hormones (SH) are widely recognized as modulators in several neurodegenerative diseases, and there is evidence that estrogens and androgens regulate several fundamental biological functions in the CPs. Therefore, SH are likely to affect the composition of the CSF impacting on brain homeostasis. This review will look at implications of the CPs' sex-related specificities.

The choroid plexus in health and in disease: dialogues into and out of the brain.

This article brings the choroid plexus into the context of health and disease. It is remarkable that the choroid plexus, composed by a monolayer of epithelial cells that lie in a highly vascularized stroma, floating within the brain ventricles, gets so little attention in major physiology and medicine text books and in the scientific literature in general. Consider that it is responsible for producing most of the about 150mL of cerebrospinal fluid that fills the brain ventricles and the subarachnoid space and surrounds the spinal cord in the adult human central nervous system, which is renewed approximately 2-3 times daily. As such, its activity influences brain metabolism and function, which will be addressed. Reflect that it contains an impressive number of receptors and transporters, both in the apical and basolateral sides of the epithelial cells, and as such is a key structure for the communication between the brain and the periphery. This will be highlighted in the context of neonatal jaundice, multiple sclerosis and Alzheimer's disease. Realize that the capillaries that irrigate the choroid plexus stroma do not possess tight junctions and that the blood flow to the choroid plexus is five times higher than that in the brain parenchyma, allowing for a rapid sensing system and delivery of molecules such as nutrients and metals as will be revised. Recognize that certain drugs reach the brain parenchyma solely through the choroid plexus epithelia, which has potential to be manipulated in diseases such as neonatal jaundice and Alzheimer's disease as will be discussed. Without further notice, it must be now clear that understanding the choroid plexus is necessary for comprehending the brain and how the brain is modulated and modulates all other systems, in health and in disease. This review article intends to address current knowledge on the choroid plexus, and to motivate the scientific community to consider it when studying normal brain physiology and diseases of the central nervous system. It will guide the reader through several aspects of the choroid plexus in normal physiology, in diseases characteristic of various periods of life (newborns-kernicterus, young adults-multiple sclerosis and the elder-Alzheimer's disease), and how sex-differences may relate to disease susceptibility.

Applicability of the Telephone Interview for Cognitive Status (Modified) in a community sample with low education level: association with an extensive neuropsychological battery.

OBJECTIVE: To explore the applicability of a Portuguese (PT) version of the Telephone Interview for Cognitive Status (TICS), with a delayed recall item [modified (M)], here termed TICSM-PT, against an extensive (in-person) battery of neuropsychological instruments, in a sample of older individuals with low educational level and without clinically manifest/diagnosed cognitive impairment. METHODS: Following translation/back-translation and pilot testing in 33 community dwellers, 142 community dwellers aged 52 to 84 years (mean = 67.45, SD = 7.91) were selected from local health care centres for the study (convenience sampling; stratified age and gender). Cronbach's alpha was used to assess internal consistency, and convergent validity was evaluated through the correlation between TICSM-PT and the Mini Mental State Examination (MMSE), as well as with a comprehensive battery of cognitive instruments. Divergent/discriminant validity was assessed through a battery of psychological instruments. The receiver operating curve was determined for TICSM-PT to classify participants with and without possible indication of cognitive impairment. RESULTS: TICSM-PT showed a satisfactory internal consistency (Cronbach's alpha = 0.705), convergent validity and discriminant validity. TICSM-PT presented a positive association with the global cognitive measures Mini Mental State Examination and the Montreal Cognitive Assessment, and also with most neuropsychological parameters. Receiver operating curve curves presented a sensitivity of 90.6% and specificity of 73.7%. The area under the curve statistic yielded a threshold score equal or below 13.5 for cognitive impairment. CONCLUSION: TICSM-PT is a practical tool for rapid cognitive assessment among older individuals with low educational background.

Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies.

The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping.

History of Neonatal Screening of Congenital Hypothyroidism in Portugal.

Congenital hypothyroidism (CH) leads to growth and development delays and is preventable with early treatment. Neonatal screening for CH was initiated in Portugal in 1981. This study examines the history of CH screening in the country. Data were obtained from annual reports and from the national database of neonatal screening laboratory. The CH screening strategy primarily relies on the thyroid-stimulating hormone (TSH), followed by total thyroxine measurement as the second tier for confirmation. The TSH cutoff started at 90 mIU/L, decreasing to the actual 10 mIU/L. The coverage of the screening program has increased rapidly; although voluntary, it reached about 90% in 6 years and became universal in 10 years. Guideline and cutoff updates led to the identification of over 200 additional cases, resulting in specific retesting protocols for preterm and very-low-birth-weight babies. The actual decision tree considers CH when TSH levels are above 40 mIU/L. Data from the CH screening also provide an indication of the iodine status of the population, which is presently indicative of iodine insufficiency. The Portuguese neonatal screening for CH is a history of success. It has rapidly and continuously adapted to changes in knowledge and has become a universal voluntary practice within a few years.

Iodineminho Study: Iodine Supplementation and Prevalence of Iodine Deficiency in Pregnant Women.

CONTEXT: Iodine is necessary for the proper brain development. The prevalence of iodine deficiency in Portuguese pregnant women led the health authorities, in 2013, to recommend iodine supplementation for women in preconception, throughout pregnancy and during lactation. OBJECTIVE: To assess the impact of iodine supplementation initiated in the preconception or the first trimester of pregnancy on the prevalence of iodine deficiency and maternal thyroid status. METHODS: An observational prospective cohort study that follows thyroid function and iodine status of women recruited in preconception or in the first trimester of pregnancy. RESULTS: The median urinary iodine concentration (UIC) was significantly higher among women taking iodine supplements (no-supplement group UIC=63µg/L; supplement group UIC =100µg/L, p = 0.002) but still below the levels recommended by the World Health Organization. Only 15% of pregnant women had adequate iodine status and 17% showed UIC < 50 µg/l. There was no influence of whether iodine supplementation started in preconception or in the 1st trimester of gestation (UIC preconception group: 112µg/L vs UIC pregnancy group: 91µg/L, p = 0.569). In the 1st trimester of pregnancy, total thyroxine levels were lower and free triiodothyronine levels were higher in non-supplemented women. Thyroglobulin levels were lower in women who started iodine supplementation in preconception compared to non-supplemented women and women who started iodine supplementation during gestation. CONCLUSION: In the Minho region of Portugal, fertile women have insufficient iodine intake. Additional public health measures are needed since the current recommendations for iodine supplementation for pregnancy are unsatisfactory to achieve an adequate iodine status.

Iodine Availability through Iodized Salt in Portugal: 2010-2021 Sales Evolution and Distribution.

Salt iodization programs are considered the most cost-effective measures to ensure adequate iodine intake in iodine-deficient populations. Portuguese women of childbearing age and pregnant women were reported to be iodine-deficient, which led the health authorities, in 2013, to issue a recommendation for iodine supplementation during preconception, pregnancy and lactation. In the same year, iodized salt became mandatory in school canteens. Of note, no regulation or specific programs targeting the general population, or the impact of iodized salt availability in retailers, are known. The present study analyzed iodized salt supermarket sales from 2010 to 2021 from a major retailer, identifying the proportion of iodized salt in total salt sales and its distribution in mainland Portugal. Data on iodine content were collected through the nutritional label information. Of a total of 33 salt products identified, 3 were iodized (9%). From 2010 to 2021, the weighted sales of iodized salt presented a growing tendency, reaching the maximum of 10.9% of total sales (coarse plus fine salt) in 2021. Iodized salt reached a maximum of 11.6% of total coarse salt in 2021, a maximum of 2.4% of the total fine salt in 2018. The overall sales of iodized salt and their contribution to iodine intake are extremely low, prompting additional studies to understand the consumer's choice and awareness of the benefits of iodized salt.

Iodine supplementation: compliance and association with adverse obstetric and neonatal outcomes.

Objectives: Over 1.9 billion people worldwide are living in areas estimated to be iodine insufficient. Strategies for iodine supplementation include campaigns targeting vulnerable groups, such as women in pre-conception, pregnancy and lactation. Portuguese women of childbearing age and pregnant women were shown to be mildly-to-moderately iodine deficient. As a response, in 2013, the National Health Authority (NHA) issued a recommendation that all women considering pregnancy, pregnant or breastfeeding, take a daily supplement of 150-200 µg iodine. This study explored how the iodine supplementation recommendation has been fulfilled among pregnant and lactating women in Portugal, and whether the reported iodine supplements intake impacted on adverse obstetric and neonatal outcomes. Design and methods: Observational retrospective study on pregnant women who delivered or had a fetal loss in the Braga Hospital and had their pregnancies followed in Family Health Units. Results: The use of iodine supplements increased from 25% before the recommendation to 81% after the recommendation. This was mostly due to an increase in the use of supplements containing iodine only. Iodine supplementation was protective for the number of adverse obstetric outcomes (odds ratio (OR) = 0.791, P = 0.018) and for neonatal morbidities (OR = 0.528, P = 0.024) after controlling for relevant confounding variables. Conclusion: The recommendation seems to have succeeded in implementing iodine supplementation during pregnancy. National prospective studies are now needed to evaluate the impact of iodine supplementation on maternal thyroid homeostasis and offspring psychomotor development and on whether the time of the beginning of iodine supplementation (how early during preconception or pregnancy) is relevant to consider.

Psychomotor development of children from an iodine-deficient region.

OBJECTIVES: To assess the psychomotor development of the progeny of women from a moderately iodine-deficient area for whom thyroid function during pregnancy was measured. STUDY DESIGN: The development of 86 children was assessed by the Bayley Scale of Infant Development at 12, 18, and 24 months. RESULTS: Maternal serum free thyroxine (FT(4)) levels in the first trimester of pregnancy were the major determinant of psychomotor development at 18 and 24 months. Children born from mothers with FT(4) levels <25th percentile (<10 pg/mL) had an OR of 2.1 for mild-to-severe delay. Furthermore, alterations in behavior were already observed at 12 months and were related to subsequent changes in development. Neonatal thyroid status did not influence development. CONCLUSIONS: This study highlights the need to implement active measures of iodine supplementation periconceptionally and during pregnancy and lactation because the negative effects on development and behavior might be prevented through preemptive action.

The Association of Metabolic Dysfunction and Mood Across Lifespan Interacts With the Default Mode Network Functional Connectivity.

Background: Numerous studies suggest a relationship between depression and metabolic syndrome, which is likely influenced by age. Interestingly, functional imaging analysis has shown an association between functional connectivity in the default mode network (DMN-FC) and components of metabolic syndrome, which is explored in this study. Methods: From a larger longitudinal cohort study on healthy aging, 943 individuals were extensively characterized for mood and cognition. Among these, 120 individuals who were selected for displaying extreme cognitive performance within the normal range (good and poor performers) were further studied. Here, in a cross-sectional design, using confirmatory factor analysis (CFA), the association between metabolic dysfunction and depressive mood as a function of age and its relationship with DMN-FC was studied. Results: Metabolic dysfunction was modeled as a second-order latent variable using CFA. First-order latent variables were obesity, glucose dysmetabolism, lipids imbalance, and blood pressure. Using multiple linear regression models, this study observed that metabolic dysfunction, glucose dysmetabolism, and lipids imbalance were linearly associated with depressive mood, and the association with obesity was U-shaped. The association of metabolic dysfunction, obesity, and glucose dysmetabolism with depressive mood is positive for the younger individuals in our sample and vanishes with aging. The FC of the right superior temporal gyrus with the DMN correlated with both obesity and depressive mood. In participants with higher obesity scores, FC increased with higher GDS scores, while in those with lower GDS scores, FC decreased. Age and blood pressure were associated with a more complex pattern of association between FC of the right supramarginal gyrus and GDS score. Conclusion: The association of metabolic dysfunction with depressive mood is influenced by age and relates with differential patterns of DMN-FC. The combination of the effects of age, mood, and metabolic dysfunction is likely to explain the heterogeneity of DMN-FC, which deserves further investigation with larger and longitudinal studies.

Are the 50's, the transition decade, in choroid plexus aging?

The choroid plexus (CP) is an important structure for the brain. Besides its major role in the production of cerebrospinal fluid (CSF), it conveys signals originating from the brain, and from the circulatory system, shaping brain function in health and in pathology. Previous studies in rodents have revealed altered transcriptome both during aging and in various diseases of the central nervous system, including Alzheimer's disease. In the present study, a high-throughput sequencing of the CP transcriptome was performed in postmortem samples of clinically healthy individuals aged 50's through 80's. The data shows an age-related profile, with the main changes occurring in the transition from the 50's to the 60's, stabilizing thereafter. Specifically, neuronal and membrane functions distinguish the transcriptome between the 50's and the 60's, while neuronal and axon development and extracellular structure organization differentiate the 50's from the 70's. These findings suggest that changes in the CP transcriptome occur early in the aging process. Future studies will unravel whether these relate with processes occurring in late- onset brain diseases.

Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study.

Background: Cognition in the elderly is heterogeneous. Senescence of the immune system is increasingly considered as a potential player in cognitive performance. We explored here the interplay between cognitive performance and peripheral immune molecules in healthy older individuals. Methods: A cross-sectional study of clinically well characterized senior healthy individuals (120; 51-87 years old) previously clustered as "Good" and "Poor" performers based on established tests that evaluate memory and executive function. A plasma concentration of 30 immune molecules was assessed by multiplex analysis and correlated with parameters of cognitive performance. Results: Participants with worse cognitive performance ("Poor") exhibited increased concentrations of IL-1ß, IL-8, IL-13, and tumor necrosis factor (TNF) when compared to individuals with a better cognitive performance ("Good"). The cognitive dimensions memory and executive function, when considered separately, displayed a negative association with several immune molecules (IL-1ß, IL-1RA, IL-6, IL-13, IP-10, and TNF with memory and only IL-1ß with executive function), even controlling for age, sex, years of formal education, mood, and use of anti-inflammatory drugs. Regression analysis showed that several of these molecules (IL-1ß, IL-6, IL-8, and IL-13) contribute to predicting whether an individual belongs to the "Good" or "Poor" cognitive performance group. Conclusion: These results strengthen the hypothesis that increased concentrations of peripheral immune molecules, like IL-1ß, are associated with worse cognitive performance in senior healthy individuals. It further highlights that some poorly studied immune molecules should be considered in the context of cognitive aging, such as IL-13, here revealed as a new player in such interaction.

Iron Status is Associated with Mood, Cognition, and Functional Ability in Older Adults: A Cross-Sectional Study.

Several conditions are risk factors for iron deficiency (ID), some of which are highly prevalent in older individuals. Despite the amount of evidence pointing for a role of ID in cognition, mood and physical functional ability, the research addressing these associations in older individuals is still scarce. In the present study, 162 older community-dwelling individuals (29.53% classified as ID) were enrolled in a cross-sectional analysis and characterized regarding cognition, mood, functional ability, general nutritional intake and iron status. Assessment of iron status was performed using several blood biomarkers. Storage and erythropoiesis dimensions were positively associated with memory, along with an interaction (moderator effect) between iron storage and nutritional status. A more depressed mood was negatively associated with (iron) transport, transport saturation and erythropoiesis dimensions, and functional tiredness was positively associated with the erythropoiesis dimension. These observations indicate that lower iron status is associated with depressive mood, functional tiredness and poorer memory ability, with the latter moderated by nutritional status. These findings suggest that using iron as a continuous variable may be useful in finding associations with iron homeostasis, eventually missed when iron levels are considered within the usual classification groups.

25-OH Vitamin D Levels and Cognitive Performance: Longitudinal Assessment in a Healthy Aging Cohort.

Background: Declining serum levels of 25-hydroxyvitamin D [25(OH)D, a biomarker of vitamin D status] with aging is a well-recognized phenomenon. However, scarce information is available on the relation between 25(OH)D levels and cognitive performance over time in older individuals. Our purpose was to evaluate, longitudinally, the association of 25(OH)D with cognitive function in a healthy older adults' cohort. Methods: Sixty-four individuals over 55 years-old with no cognitive impairment, clustered as healthy "Poor" and "Good" cognitive performers, were followed for an average of 18 months. Seasonal-adjusted 25(OH)D serum levels (measured by high-performance liquid chromatography-tandem mass spectrometry) were related, longitudinally, with cognitive (memory and general/executive) composite scores. Results: Overall seasonal-adjusted median serum 25(OH)D level was of 47 nmol/l [interquartile range (IQR), 38-60 nmol/l]. A negative correlation between baseline 25(OH)D and the general/executive composite score was found in the "Poor" cognitive performers (r s = -0.52, p = 0.006), an association lost after adjusting 25(OH)D levels for the season. No effect was found in both groups between seasonal-adjusted 25(OH)D levels and the variation of both memory and general/executive composites during follow-up when adjusted for age, gender and education level. Conclusion: In this healthy older population with no cognitive impairment, lower serum levels of 25(OH)D were not longitudinally associated with poorer cognitive scores.

Structural and molecular correlates of cognitive aging in the rat.

Aging is associated with cognitive decline. Herein, we studied a large cohort of old age and young adult male rats and confirmed that, as a group, old  rats display poorer spatial learning and behavioral flexibility than younger adults. Surprisingly, when animals were clustered as good and bad performers, our data revealed that while in younger animals better cognitive performance was associated with longer dendritic trees and increased levels of synaptic markers in the hippocampus and prefrontal cortex, the opposite was found in the older group, in which better performance was associated with shorter dendrites and lower levels of synaptic markers. Additionally, in old, but not young individuals, worse performance correlated with increased levels of BDNF and the autophagy substrate p62, but decreased levels of the autophagy complex protein LC3. In summary, while for younger individuals "bigger is better", "smaller is better" is a more appropriate aphorism for older subjects.

IL-10 modulates depressive-like behavior.

The role of pro-inflammatory cytokines in psychiatric disorders has been the focus of great research attention in recent years. Paradoxically, the same is not true for anti-inflammatory cytokines. In the present study, we assessed the behavioral profile of animals with altered expression of the anti-inflammatory cytokine IL-10. We performed a battery of tests to assess anxiety, depressive-like and cognitive behaviors in mice overexpressing IL-10 (PMT10) and IL-10(-/-) animals; in the later mice we also tested the behavioral effect of IL-10 administration. In the forced-swimming test, IL-10(-/-) females displayed increased depressive-like behavior; importantly, this phenotype was reverted by the injection of IL-10. Moreover, mice overexpressing IL-10 presented a decreased depressive-like behavior. Despite the presence of a similar trend, male animals did not reach significant differences in depressive-like behavior. Assessment in the open-field showed that the absence of IL-10 decreased the percentage of time spent in the center of the arena in both male and female mice, while male animals overexpressing IL-10 revealed an opposite behavior. For both sexes, imbalance in IL-10 levels did not affect spatial reference memory. In conclusion, variations in IL-10 expression are associated with an altered depressive-like behavior, but do not influence cognitive performance. Interestingly, IL-10 imbalance produced more profound behavioral changes in females than in male animals. This is in accordance with clinical data demonstrating an increased susceptibility of women to mood disorders, suggesting an interplay between anti-inflammatory cytokines and sexual steroids.

Adult Hippocampal Neurogenesis Modulation by the Membrane-Associated Progesterone Receptor Family Member Neudesin.

Neudesin (Neuron-derived neurotrophic factor, NENF), a membrane-associated progesterone receptor family (MAPR) member, is a neuron secreted protein with neurotrophic properties during embryonic stages. However, its role in the adult brain is still poorly addressed. In this study we have used neudesin-null (Nenf-/-) mice and performed a characterization of the proliferation state of the adult neurogenic niches, the adult subventricular zone (SVZ) and the hippocampus subgranular zone (SGZ). Nenf-/- males did not presented any deficits in proliferation in the SVZ neither in vivo nor in vitro. On the other hand a decrease in cell proliferation in the SGZ was observed, as well as a decrease in the number of newborn neurons in the dentate gyrus (DG) that was accompanied by impaired context discrimination in a contextual fear conditioning (CFC) task. Since NENF neurotrophic action is suggested to occur via the formation of a progesterone stability complex for the activation of non-genomic cascade, we further evaluated progesterone metabolism in the absence of NENF. Interestingly, expression of progesterone catabolic rate-determining enzyme, 5-α-reductase was upregulated in the DG of Nenf-/-, together with a significant increase in the expression of the δGABAA receptor gene, involved in DG tonic inhibition. Taken together, these findings add in vivo evidence on the neurotrophic properties of NENF in the adult brain. Furthermore, the mechanism of action of NENF in this process might implicate neurosteroids modulation, at least in the DG.