Is age at menopause decreasing? - The consequences of not completing the generational cohort.

BACKGROUND: Due to contradictory results in current research, whether age at menopause is increasing or decreasing in Western countries remains an open question, yet worth studying as later ages at menopause are likely to be related to an increased risk of breast cancer. Using data from breast cancer screening programs to study the temporal trend of age at menopause is difficult since especially younger women in the same generational cohort have often not yet reached menopause. Deleting these younger women in a breast cancer risk analyses may bias the results. The aim of this study is therefore to recover missing menopause ages as a covariate by comparing methods for handling missing data. Additionally, the study makes a contribution to understanding the evolution of age at menopause for several generations born in Portugal between 1920 and 1970. METHODS: Data from a breast cancer screening program in Portugal including 278,282 women aged 45-69 and collected between 1990 and 2010 are used to compare two approaches of imputing age at menopause: (i) a multiple imputation methodology based on a truncated distribution but ignoring the mechanism of missingness; (ii) a copula-based multiple imputation method that simultaneously handles the age at menopause and the missing mechanism. The linear predictors considered in both cases have a semiparametric additive structure accommodating linear and non-linear effects defined via splines or Markov random fields smoothers in the case of spatial variables. RESULTS: Both imputation methods unveiled an increasing trend of age at menopause when viewed as a function of the birth year for the youngest generation. This trend is hidden if we model only women with an observed age at menopause. CONCLUSION: When studying age at menopause, missing ages must be recovered with an adequate procedure for incomplete data. Imputing these missing ages avoids excluding the younger generation cohort of the screening program in breast cancer risk analyses and hence reduces the bias stemming from this exclusion. In addition, imputing the not yet observed ages of menopause for mostly younger women is also crucial when studying the time trend of age at menopause otherwise the analysis will be biased.

Selective transfer of nerve to supinator to restore digital extension in central cord syndrome: An anatomical study and a case report.

BACKGROUND: Nerve transfers are increasingly used to restore upper extremity function in patients with spinal cord injury. However, the role of nerve transfers for central cord syndrome is still being established. The purpose of this study is to report the anatomical feasibility and clinical use of nerve transfer of supinator motor branches (NS) to restore finger extension in a central cord syndrome patient. MATERIALS AND METHODS: The posterior interosseous nerve (PIN), its superficial division, and branches were dissected in 14 fresh cadavers, with a mean age of 65 (58-79). Measurements included number and length of branches of donor and recipient, diameters, regeneration distance from coaptation site to motor entry point and axonal counts. A NS transfer to extensor carpi ulnaris (ECU), extensor digiti quinti (EDQ) and extensor digitorum communis (EDC) was performed in a 28-year-old patient, with central cord syndrome after a motorcycle accident, who did not recover active finger extension at 10 months post injury. RESULTS: The PIN consistently divided into a deep and superficial branch between 1.5 cm proximal to, and 2 cm distal to the distal boundary of the supinator. The superficial branch provided a first common branch to the ECU and EDQ. In 12/14 dissections, the EDC was innervated by a 4 cm long branch that entered the muscle on its radial deep surface. In all cases, the superficial branch of the PIN could be separated in a retrograde fashion from the PIN and coapted with NS. The mean myelinated fiber count in nerve to EDC was 401 ± 190 compared to 398 ± 75 in the NS. At 48 months after surgery, with the wrist at neutral, the patient recovered full metacarpophalangeal extension scoring M4. Supination was preserved with the elbow extended or flexed. CONCLUSIONS: Restoration of finger extension in central cord syndrome is possible with a selective transfer of the NS to EDC, and is anatomically feasible with a short regeneration distance and favorable axonal count ratio.

Peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture: a state-of-the-art review.

The present study aims to describe state-of-the-art of preclinical studies that have investigated peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture. The PubMed, Scopus, and Web of Science databases were searched using the integrative review method. Preclinical articles that involved the study of peripheral receptors and neuromediators on the pain control effects of acupuncture in rats or mice were selected using a predefined search strategy. From this search, 456 articles were found, and 29 of them met the inclusion criteria of the study. The selected articles addressed the following peripheral receptors: opioid (n = 9), adenosine (n = 5), cannabinoid (n = 5), transient receptor potential vanilloid (TRPV) (n = 3), histamine (n = 2), adrenergic (n = 1), muscarinic (n = 1), corticotrophin-releasing factor (CRF) (n = 2), IL-1 (n = 1), and endothelin (n = 1) receptors. The peripheral neuromediators correlated with the peripheral pain control effect were as follows: opioid peptides (n = 4), adenosine (n = 3), histamine (n = 1), substance P (n = 1) calcitonin gene-related peptide (CGRP) (n = 1), anandamide (n = 1), nitric oxide (n = 1), and norepinephrine (n = 1). This review summarizes the methods used to investigate the peripheral effects of acupuncture and discusses the main findings on each family of receptors and neuromediators. Ten families of peripheral receptors and 8 types of neuromediators were correlated with the antihyperalgesic effects of acupuncture in preclinical studies. Considering the benefits of a better understanding of the role of peripheral receptors and neuromediators in the context pain management, the findings of the present study highlight the importance of deepening the exploration of the peripheral mechanisms of acupuncture.

Transfer of the Distal Anterior Interosseous Nerve for Thumb Motion Reconstruction in Radial Nerve Paralysis.

PURPOSE: With nerve or tendon surgery, the results of thumb reconstruction to treat radial nerve paralysis are suboptimal. The goals of this study were to describe the anatomy of the deep branch of the posterior interosseous nerve (PIN) to the thumb extensor muscles (DBPIN), and to report the clinical results of transferring the distal anterior interosseous nerve (DAIN) to the DBPIN. METHODS: The PIN was dissected in 12 fresh upper limbs. Myelinated nerve fibers in the DBPIN and DAIN were counted. Five patients with radial nerve paralysis underwent transfer of the motor branch to the flexor carpi radialis to the PIN and a motor branch of the pronator teres to the extensor carpi radialis brevis. In addition, these patients had selective reconstruction of thumb motion by transferring the DAIN to the DBPIN, through either a combined volar and dorsal approach (n = 2) or a single dorsal approach (n = 3) with division of the interosseous membrane. RESULTS: At the origin of the abductor pollicis longus, the DBPIN divided into a lateral branch that innervated the abductor pollicis longus and extensor pollicis brevis, and a medial branch that innervated the extensor pollicis longus and extensor index proprius. The number of myelinated nerve fibers in the DAIN corresponded to 65% of that of the DBPIN. In each of the 5 patients, full thumb motion at the trapeziometacarpal joint was restored with no, or minimal, extension lag at the metacarpophalangeal (MCP) joint. CONCLUSIONS: The anatomy of the DBPIN is predictable. Transferring the DAIN to the DBPIN is feasible through a single dorsal approach, allowing full recovery of thumb motion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Correction to: Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.

The original version of this article contains an error. The Author Francisco José Cidral-Filho incorrectly listed as Francisco José Cidra-Filho. The correct spelling is presented above. The original article has been corrected.

Electroacupuncture induces antihyperalgesic effect through endothelin-B receptor in the chronic phase of a mouse model of complex regional pain syndrome type I.

Complex regional pain syndrome (CRPS) is a disorder that involves abnormal inflammation and nerve dysfunction frequently resistant to a broad range of treatments. Peripheral nerve stimulation with electroacupuncture (EA) has been widely used in different clinical conditions to control pain and inflammation; however, the use of EA in the treatment of CRPS is under investigation. In this study, we explore the effects of EA on hyperalgesia and edema induced in an animal model of chronic post-ischemia pain (CPIP model) and the possible involvement of endothelin receptor type B (ETB) in this effect. Female Swiss mice were subjected to 3 h hind paw ischemia/reperfusion CPIP model. EA treatment produced time-dependent inhibition of mechanical and cold hyperalgesia, as well as edema in CPIP mice. Peripheral administration (i.pl.) of BQ-788 (10 nmol), an ETB antagonist, prevented EA-induced antihyperalgesia while intrathecal administration prolonged EA's effect. Additionally, peripheral pre-treatment with sarafotoxin (SRTX S6c, 30 pmol, ETB agonist) increased EA anti-hyperalgesic effect. Furthermore, the expression of peripheral ETB receptors was increased after EA treatments, as measured by western blot. These results may suggest that EA's analgesic effect is synergic with ETB receptor activation in the periphery, as well as central (spinal cord) ETB receptor blockade. These data support the use of EA as a nonpharmacological approach for the management of CRPS-I, in an adjuvant manner to ETB receptor targeting drugs.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a trinucleotide expansion in the HD gene, resulting in an extended polyglutamine tract in the protein huntingtin. HD is traditionally viewed as a movement disorder, but cognitive and neuropsychiatric symptoms also contribute to the clinical presentation. Depression is one of the most common psychiatric disturbances in HD, present even before manifestation of motor symptoms. Diagnosis and treatment of depression in HD-affected individuals are essential aspects of clinical management in this population, especially owing to the high risk of suicide. This study investigated whether chronic administration of the antioxidant probucol improved motor and affective symptoms as well as hippocampal neurogenic function in the YAC128 transgenic mouse model of HD during the early- to mild-symptomatic stages of disease progression. The motor performance and affective symptoms were monitored using well-validated behavioral tests in YAC128 mice and age-matched wild-type littermates at 2, 4, and 6 months of age, after 1, 3, or 5 months of treatment with probucol (30 mg/kg/day via water supplementation, starting on postnatal day 30). Endogenous markers were used to assess the effect of probucol on cell proliferation (Ki-67 and proliferation cell nuclear antigen (PCNA)) and neuronal differentiation (doublecortin (DCX)) in the hippocampal dentate gyrus (DG). Chronic treatment with probucol reduced the occurrence of depressive-like behaviors in early- and mild-symptomatic YAC128 mice. Functional improvements were not accompanied by increased progenitor cell proliferation and neuronal differentiation. Our findings provide evidence that administration of probucol may be of clinical benefit in the management of early- to mild-symptomatic HD.

Studying the relationship between a woman's reproductive lifespan and age at menarche using a Bayesian multivariate structured additive distributional regression model.

Studies addressing breast cancer risk factors have been looking at trends relative to age at menarche and menopause. These studies point to a downward trend of age at menarche and an upward trend for age at menopause, meaning an increase of a woman's reproductive lifespan cycle. In addition to studying the effect of the year of birth on the expectation of age at menarche and a woman's reproductive lifespan, it is important to understand how a woman's cohort affects the correlation between these two variables. Since the behavior of age at menarche and menopause may vary with the geographic location of a woman's residence, the spatial effect of the municipality where a woman resides needs to be considered. Thus, a Bayesian multivariate structured additive distributional regression model is proposed in order to analyze how a woman's municipality and year of birth affects a woman's age of menarche, her lifespan cycle, and the correlation of the two. The data consists of 212,517 postmenopausal women, born between 1920 and 1965, who attended the breast cancer screening program in the central region of Portugal.

Structured additive regression modeling of age of menarche and menopause in a breast cancer screening program.

Breast cancer risk is believed to be associated with several reproductive factors, such as early menarche and late menopause. This study is based on the registries of the first time a woman enters the screening program, and presents a spatio-temporal analysis of the variables age of menarche and age of menopause along with other reproductive and socioeconomic factors. The database was provided by the Portuguese Cancer League (LPCC), a private nonprofit organization dealing with multiple issues related to oncology of which the Breast Cancer Screening Program is one of its main activities. The registry consists of 259,652 records of women who entered the screening program for the first time between 1990 and 2007 (45-69-year age group). Structured Additive Regression (STAR) models were used to explore spatial and temporal correlations with a wide range of covariates. These models are flexible enough to deal with a variety of complex datasets, allowing us to reveal possible relationships among the variables considered in this study. The analysis shows that early menarche occurs in younger women and in municipalities located in the interior of central Portugal. Women living in inland municipalities register later ages for menopause, and those born in central Portugal after 1933 show a decreasing trend in the age of menopause. Younger ages of menarche and late menopause are observed in municipalities with a higher purchasing power index. The analysis performed in this study portrays the time evolution of the age of menarche and age of menopause and their spatial characterization, adding to the identification of factors that could be of the utmost importance in future breast cancer incidence research.

1α,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats.

The involvement of calcium-mediated signaling pathways in the mechanism of action of 1α,25-dihydroxyvitamin D(3) (1,25D) is currently demonstrated. In this study we found that 1,25D induces nongenomic effects mediated by membrane vitamin D receptor (VDRm) by modulating intermediate filament (IF) phosphorylation and calcium uptake through L-type voltage-dependent calcium channels (L-VDCC) in cerebral cortex of 10 day-old rats. Results showed that the mechanism of action of 1,25D involves intra- and extracellular calcium levels, as well as the modulation of chloride and potassium channels. The effects of L-VDCCs on membrane voltage occur over a broad potential range and could involve depolarizing or hyperpolarizing coupling modes, supporting a cross-talk among Ca(2+) uptake and potassium and chloride channels. Also, the Na(+)/K(+)-ATPase inactivation by ouabain mimicked the 1,25D action on (45)Ca(2+) uptake. The Na(+)/K(+)-ATPase inhibition observed herein might lead to intracellular Na(+) accumulation with subsequent L-VDCC opening and consequently increased (45)Ca(2+) (calcium, isotope of mass 45) uptake. Moreover, the 1,25D effect is dependent on the activation of the following protein kinases: cAMP-dependent protein kinase (PKA), Ca(2+)/calmodulin-dependent protein kinase (PKCaMII), phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase p38 (p38(MAPK)). The modulation of calcium entry into neural cells by the 1,25D we are highlighting, might take a role in the regulation of a plethora of intracellular processes. Considering that vitamin D deficiency can lead to brain illness, 1,25D may be a possible candidate to be used, at least as an adjuvant, in the pharmacological therapy of neuropathological conditions.

Triceps and cutaneous radial nerve branches investigated via an axillary anterior arm approach: new findings in a fresh-cadaver anatomical study.

OBJECTIVE: The authors sought to describe the anatomy of the radial nerve and its branches when exposed through an axillary anterior arm approach. METHODS: Bilateral upper limbs of 10 fresh cadavers were dissected after dyed latex was injected into the axillary artery. RESULTS: Via the anterior arm approach, all triceps muscle heads could be dissected and individualized. The radial nerve overlaid the latissimus dorsi tendon, bounded by the axillar artery on its superior surface, then passed around the humerus, together with the lower lateral arm and posterior antebrachial cutaneous nerve, between the lateral and medial heads of the triceps. No triceps motor branch accompanied the radial nerve's trajectory. Over the latissimus dorsi tendon, an antero-inferior bundle, containing all radial nerve branches to the triceps, was consistently observed. In the majority of the dissections, a single branch to the long head and dual innervations for the lateral and medial heads were observed. The triceps long and proximal lateral head branches entered the triceps muscle close to the latissimus dorsi tendon. The second branch to the lateral head stemmed from the triceps lower head motor branch. The triceps medial head was innervated by the upper medial head motor branch, which followed the ulnar nerve to enter the medial head on its anterior surface. The distal branch to the triceps medial head also originated near the distal border of the latissimus dorsi tendon. After a short trajectory, a branch went out that penetrated the medial head on its posterior surface. The triceps lower medial head motor branch ended in the anconeus muscle, after traveling inside the triceps medial head. The lower lateral arm and posterior antebrachial cutaneous nerve followed the radial nerve within the torsion canal. The lower lateral brachial cutaneous nerve innervated the skin over the biceps, while the posterior antebrachial cutaneous nerve innervated the skin over the lateral epicondyle and posterior surface of the forearm. The average numbers of myelinated fibers were 926 in the long and 439 in the upper lateral head and 658 in the upper and 1137 in the lower medial head motor branches. CONCLUSIONS: The new understanding of radial nerve anatomy delineated in this study should aid surgeons during reconstructive surgery to treat upper-limb paralysis.

Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals.

Early-life environmental intervention may increase the number of neurons, astrocytes, and cellular proliferation in the hippocampus of rats.

Neonatal handling reduces the stress response in adulthood due to a feedback mechanism. The present study analyzed the effects of repeated neonatal environmental intervention (daily handling during the first 10 days after birth) on neuron-, astroglial cell density, and cellular proliferation of the hippocampal (CA1, CA2, and CA3) pyramidal cell layers in female rats. Pups were divided into two groups, nonhandled and handled, which were submitted to repeated handling sessions between postnatal days 1 and 10. Histological and immunohistochemical procedures were used to determine changes in neuron density, astroglial cell density, and cellular proliferation. We found an increase in neuron density in each pyramidal cell layer of the hippocampus (CA1, CA2, and CA3) in female rats (11 and 90 day old) that were handled during the neonatal period. Furthermore, we found an increase in astroglial cell density in both hemispheres of the brain in the handled group. Finally, we observed an increase in cellular proliferation in both hippocampi (CA1, CA2, and CA3) of the brain in female pups (11 days old) handled during the neonatal period. This study demonstrates that an early-life environmental intervention may induce morphological changes in a structure involved with several functions, including the stress response. The results of the current study suggest that neonatal handling may influence the animals' responses to environmental adversities later in life.

Transfer of axillary nerve branches to reconstruct elbow extension in tetraplegics: a laboratory investigation of surgical feasibility.

In spinal cord injuries at the C6 level, elbow extension is lost and needs reconstruction. Traditionally, elbow extension has been reconstructed by muscle transfers, which improve function only moderately. We have hypothesized that outcomes could be ameliorated by nerve transfers rather than muscle transfers. We anatomically investigated nerve branches to the teres minor and posterior deltoid as donors for transfer to triceps motor branches. In eight formalin-fixed cadavers, the axillary nerve, the teres minor branch, the posterior deltoid branch, the triceps long and upper medial head motor branches, and the thoracodorsal nerve were dissected bilaterally, their diameters measured and their myelinated fibers counted. To simulate surgery, using an axillary approach in two fresh cadavers, we transferred the teres minor or the posterior deltoid branch to the triceps long head and to the thoracodorsal nerve. The posterior division of the axillary nerve gave off the teres minor motor branch and then the branch to the posterior deltoid, terminating as the superior lateral brachial cutaneous nerve. The diameters of the teres minor motor branch, posterior deltoid, triceps long and upper medial head branches, and the thoracodorsal nerve all were ∼2 mm, with minimal variation. The nerves varied little in their numbers of myelinated fibers, being consistently about 1,000. Via an axillary approach, either the teres minor or the posterior deltoid branch could be transferred directly to the thoracodorsal nerve or to triceps branches without any tension.

Patterns of median nerve branching in the cubital fossa: implications for nerve transfers to restore motor function in a paralyzed upper limb.

OBJECTIVE: The purpose of this study was to describe the anatomy of donor and recipient median nerve motor branches for nerve transfer surgery within the cubital fossa. METHODS: Bilateral upper limbs of 10 fresh cadavers were dissected after dyed latex was injected into the axillary artery. RESULTS: In the cubital fossa, the first branch was always the proximal branch of the pronator teres (PPT), whereas the last one was the anterior interosseous nerve (AIN) and the distal motor branch of the flexor digitorum superficialis (DFDS) on a consistent basis. The PT muscle was also innervated by a distal branch (DPT), which emerged from the anterior side of the median nerve and provided innervation to its deep head. The palmaris longus (PL) motor branch was always the second branch after the PPT, emerging as a single branch together with the flexor carpi radialis (FCR) or the proximal branch of the flexor digitorum superficialis. The FCR motor branch was prone to variations. It originated proximally with the PL branch (35%) or distally with the AIN (35%), and less frequently from the DPT. In 40% of dissections, the FDS was innervated by a single branch (i.e., the DFDS) originating close to the AIN. In 60% of cases, a proximal branch originated together with the PL or FCR. The AIN emerged from the posterior side of the median nerve and had a diameter of 2.3 mm, twice that of other branches. When dissections were performed between the PT and FCR muscles at the FDS arcade, we observed the AIN lying lateral and the DFDS medial to the median nerve. After crossing the FDS arcade, the AIN divided into: 1) a lateral branch to the flexor pollicis longus (FPL), which bifurcated to reach the anterior and posterior surfaces of the FPL; 2) a medial branch, which bifurcated to reach the flexor digitorum profundus (FDP); and 3) a long middle branch to the pronator quadratus. The average numbers of myelinated fibers within each median nerve branch were as follows (values expressed as the mean ± SD): PPT 646 ± 249; DPT 599 ± 150; PL 259 ± 105; FCR 541 ± 199; proximal FDS 435 ± 158; DFDS 376 ± 150; FPL 480 ± 309; first branch to the FDP 397 ± 12; and second branch to the FDP 369 ± 33. CONCLUSIONS: The median nerve's branching pattern in the cubital fossa is predictable. The most important variation involves the FCR motor branch. These anatomical findings aid during nerve transfer surgery to restore function when paralysis results from injury to the radial or median nerves, brachial plexus, or spinal cord.

Distal pronator teres motor branch transfer for wrist extension restoration in radial nerve paralysis.

OBJECTIVE: The authors describe the anatomy of the motor branches of the pronator teres (PT) as it relates to transferring the nerve of the extensor carpi radialis brevis (ECRB) to restore wrist extension in patients with radial nerve paralysis. They describe their anatomical cadaveric findings and report the results of their nerve transfer technique in several patients followed for at least 24 months postoperatively. METHODS: The authors dissected both upper limbs of 16 fresh cadavers. In 6 patients undergoing nerve surgery on the elbow, they dissected the branches of the median nerve and confirmed their identity by electrical stimulation. Of these 6 patients, 5 had had a radial nerve injury lasting 7-12 months, underwent transfer of the distal PT motor branch to the ECRB, and were followed for at least 24 months. RESULTS: The PT was innervated by two branches: a proximal branch, arising at a distance between 0 and 40 mm distal to the medial epicondyle, responsible for PT superficial head innervation, and a distal motor branch, emerging from the anterior side of the median nerve at a distance between 25 and 60 mm distal to the medial epicondyle. The distal motor branch of the PT traveled approximately 30 mm along the anterior side of the median nerve; just before the median nerve passed between the PT heads, it bifurcated to innervate the deep head and distal part of the superficial head of the PT. In 30% of the cadaver limbs, the proximal and distal PT branches converged into a single trunk distal to the medial epicondyle, while they converged into a single branch proximal to it in 70% of the limbs. The proximal and distal motor branches of the PT and the nerve to the ECRB had an average of 646, 599, and 457 myelinated fibers, respectively.All patients recovered full range of wrist flexion-extension, grade M4 strength on the British Medical Research Council scale. Grasp strength recovery achieved almost 50% of the strength of the contralateral side. All patients could maintain their wrist in extension while performing grasp measurements. CONCLUSIONS: The distal PT motor branch is suitable for reinnervation of the ECRB in radial nerve paralysis, for as long as 7-12 months postinjury.

Medium- and long-term functional behavior evaluations in an experimental focal ischemic stroke mouse model.

Cerebrovascular accident (CVA) is one of the leading causes of death and disability worldwide, as well as a major financial burden for health care systems. CVA rodent models provide experimental support to determine possible in vivo therapies to reduce brain injury and consequent sequelae. This study analyzed nociceptive, motor, cognitive and mood functions in mice submitted to distal middle cerebral artery (DMCA) occlusion. Male C57BL mice (n = 8) were randomly allocated to control or DMCA groups. Motor function was evaluated with the tests: grip force, rotarod and open field; and nociceptive threshold with von Frey and hot plate assessments. Cognitive function was evaluated with the inhibitory avoidance test, and mood with the tail suspension test. Evaluations were conducted on the seventh- and twenty-eighth-day post DMCA occlusion to assess medium- and long-term effects of the injury, respectively. DMCA occlusion significantly decreases muscle strength and spontaneous locomotion (p < 0.05) both medium- and long term; as well as increases immobility in the tail-suspension test (p < 0.05), suggesting a depressive-type behavior. However, DMCA occlusion did not affect nociceptive threshold nor cognitive functions (p > 0.05). These results suggest that, medium- and long-term effects of DMCA occlusion include motor function impairments, but no sensory dysfunction. Additionally, the injury affected mood but did not hinder cognitive function.

Prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior and gut dysfunction in mice.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease that is highly comorbid with depression. Gut dysfunction has been proposed as a possible risk factor for both clinical conditions. In the present study, we investigated the ability of treadmill exercise for 4 weeks (5 days/week, 40 min/day) to counteract amyloid ß1-40 peptide (Aß1-40)-induced depressive-like behavior, alterations in morphological parameters of the duodenum, and the abundance of Firmicutes and Bacteroidetes phyla. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased immobility time in the tail suspension test (TST) and reduced time spent sniffing in the female urine sniffing test (FUST), indicating behavioral despair and impairment in reward-seeking behavior. These behavioral alterations, indicative of depressive-like behavior, were accompanied by reduced villus width in the duodenum. Moreover, photomicrographs obtained by transmission electron microscopy revealed abnormal epithelial microvilli in the duodenum from sedentary Aß1-40-exposed mice, characterized by shorter microvilli and heterogeneity in the length of these structures that exhibit a disordered packing. Regarding the ultrastructure of Paneth cells, Aß1-40 administration caused a reduction in the secretory granule diameter, as well as an enlarged peripheral halo. These animals also presented reduced Firmicutes and increased Bacteroidetes abundance, and increased Bacteroidetes/Firmicutes ratio. Most of the alterations observed in Aß1-40-exposed mice were prevented by the practice of physical exercise. Altogether the results provide evidence of the prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior and gut dysfunction in mice, suggesting that physical exercise could be useful for preventing depression associated with AD.

Effects of neonatal handling on social memory, social interaction, and number of oxytocin and vasopressin neurons in rats.

Early-life environmental events can induce profound long-lasting changes in several behavioral and neuroendocrine systems. The neonatal handling procedure, which involves repeated brief maternal separations followed by experimental manipulations, reduces stress responses and sexual behavior in adult rats. The purpose of this study was to analyze the effects of neonatal handling on social behaviors of male and female rats in adulthood, as manifest by the results of social memory and social interaction tests. The number of oxytocin (OT) and vasopressin (VP) neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of hypothalamus were also analyzed. The results did not demonstrate impairment of social memory. Notwithstanding, handling did reduce social investigative interaction and increase aggressive behavior in males, but did not do so in females. Furthermore, in both males and females, handling was linked with reduced number of OT-neurons in the parvocellular region of the PVN, while no differences were detected in the magnocellular PVN or the SON. On the other hand, handled males exhibited increased number of VP-neurons in the magnocellular zone of the PVN. We may conclude that the repeated brief maternal separations can reduce affiliative social behavior in adult male rats. Moreover, the disruption of the mother-infant relationship caused by the handling procedure induced long-lasting morphological changes in critical neuroendocrine areas that are involved in social bonding in mammals.

Experimentally-induced maternal hypothyroidism alters enzyme activities and the sensorimotor cortex of the offspring rats.

In this study, we used an experimental model of congenital hypothyroidism to show that deficient thyroid hormones (TH) disrupt different neurochemical, morphological and functional aspects in the cerebral cortex of 15-day-old offspring. Our results showing decreased glutamine synthetase (GS) activity and Ca2+ overload in the cerebral cortex of hypothyroid pups suggest misregulated glutamate metabolism associated with developmentally induced TH deficiency. The 14C-MeAIB accumulation indicates upregulated System A activity and glutamine uptake by neurons. Energy metabolism in hypothyroid cortical slices was preserved, as demonstrated by unaltered glucose metabolism. We also found upregulated acetylcholinesterase activity, depleting acetylcholine from the synaptic cleft, pointing to disrupted cholinergic system. Increased reactive oxygen species (ROS) generation, lipid peroxidation, glutathione (GSH) depletion, which were associated with glutathione peroxidase, superoxide dismutase and gamma-glutamyltransferase downregulation suggest redox imbalance. Disrupted astrocyte cytoskeleton was evidenced by downregulated and hyperphosphorylated glial fibrillary acidic protein (GFAP). Morphological and structural characterization of the sensorimotor cerebral cortex (SCC) showed unaltered thickness of the SCC. However, decreased size of neurons on the layers II & III and IV in the right SCC and increased NeuN positive neurons in specific SCC layers, suggest that they are differently affected by the low TH levels during neurodevelopment. Hypothyroid pups presented increased number of foot-faults in the gridwalk test indicating affected motor functions. Taken together, our results show that congenital hypothyroidism disrupts glutamatergic and cholinergic neurotransmission, Ca2+ equilibrium, redox balance, cytoskeleton integrity, morphological and functional aspects in the cerebral cortex of young rats.