Roles of the ventral hippocampus and medial prefrontal cortex in spatial reversal learning and attentional set-shifting.

Neural components enabling flexible cognition and behavior are well-established, and depend mostly on proper intercommunication within the prefrontal cortex (PFC) and striatum. However, dense projections from the ventral hippocampus (vHPC) alter the functioning of the medial PFC (mPFC). Dysfunctional hippocampo-prefrontal connectivity negatively affects the integrity of flexible cognition, especially in patients with schizophrenia. In this study, we aimed to test the role of the vHPC and mPFC in a place avoidance task on a rotating arena using two spatial flexibility task variants - reversal learning and set-shifting. To achieve this, we inactivated each of these structures in adult male Long-Evans rats by performing bilateral local muscimol (a GABAA receptor agonist) injections. A significantly disrupted performance was observed in reversal learning in the vHPC-inactivated, but not in the mPFC-inactivated rats. These results confirm the notion that the vHPC participates in some forms of behavioral flexibility, especially when spatial cues are needed. It seems, rather unexpectedly, that the mPFC is not taxed in these flexibility tasks on a rotating arena.

Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity.

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500-1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

Does the use of hormonal contraceptives affect the mental rotation performance?

Oral contraceptive pill (OC) is one of the most popular form of contraception. Despite both behavioral and neuroimaging evidence of its significant impact on female brain and cognitive functions, much remains to be discovered regarding OCs targets in the brain and mechanisms of action. In the present study mental rotation performance was compared between women using anti-androgenic oral contraceptives (n = 35), naturally cycling (NC) women (n = 33) and men (n = 29). On average, OC users were less accurate than NC women and men. Men performed the task more accurately than NC women, but the difference reached significance only in the highest angular disparity condition (150 deg). The response time was positively related with progesterone level while accuracy was negatively related with 17ß-estradiol level, in NC, but not OC women. The comparison of slope and intercept values (parameters relating response time to angular disparity) revealed the main result of present study: OC users exhibited significantly lower slope compared to men and NC women, but there were no differences in intercept between groups. These results suggest that OC users instead of using rotation in mind strategy implemented some alternative method(s). We conclude that lower performance accuracy of OC users could be related to a less efficient performance strategy.

Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice.

The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (AT1R). It is well established that an intrinsic independent brain RAS exists. Abnormal AT1R activation both in the periphery and in the brain probably contributes to the development of Alzheimer's disease (AD) pathology that is characterized, among others, by brain inflammation. Moreover, treatment with drugs that block AT1R (AT1R blockers, ARBs) ameliorates most of the clinical risk factors leading to AD. Previously we showed that short period of intranasal treatment with telmisartan (a brain penetrating ARB) reduced brain inflammation and ameliorated amyloid burden (a component of Alzheimer's plaques) in AD transgenic mouse model. In the present study, we aimed to examine the long-term effect of intranasally administrated telmisartan on brain inflammation features including microglial activation, astrogliosis, neuronal loss and hippocampus-dependent cognition in five-familial AD mouse model (5XFAD). Five month of intranasal treatment with telmisartan significantly reduced amyloid burden in the cortex and hippocampus of 5XFAD mice as compared with the vehicle-treated 5XFAD group. Similar effects were also observed for CD11b staining, which is a marker for microglial accumulation. Telmisartan also significantly reduced astrogliosis and neuronal loss in the cortex of 5XFAD mice compared with the vehicle-treated group. Improved spatial acquisition of the 5XFAD mice following long-term intranasal administration of telmisartan was also observed. Taken together, our data suggest a significant role for AT1R blockage in mediating neuronal loss and cognitive behavior, possibly through regulation of amyloid burden and glial inflammation.

Medial entorhinal cortex and medial septum contribute to self-motion-based linear distance estimation.

Path integration is a navigation strategy that requires animals to integrate self-movements during exploration to determine their position in space. The medial entorhinal cortex (MEC) has been suggested to play a pivotal role in this process. Grid cells, head-direction cells, border cells as well as speed cells within the MEC collectively provide a dynamic representation of the animal position in space based on the integration of self-movements. All these cells are strongly modulated by theta oscillations, thus suggesting that theta rhythmicity in the MEC may be essential for integrating and coordinating self-movement information during navigation. In this study, we first show that excitotoxic MEC lesions, but not dorsal hippocampal lesions, impair the ability of rats to estimate linear distances based on self-movement information. Next, we report similar deficits following medial septum inactivation, which strongly impairs theta oscillations in the entorhinal-hippocampal circuits. Taken together, these findings demonstrate a major role of the MEC and MS in estimating distances to be traveled, and point to theta oscillations within the MEC as a neural mechanism responsible for the integration of information generated by linear self-displacements.

Prenatal and postnatal polybrominated diphenyl ether exposure and visual spatial abilities in children.

Polybrominated diphenyl ethers (PBDEs) are associated with impaired visual spatial abilities in toxicological studies, but no epidemiologic study has investigated PBDEs and visual spatial abilities in children. The Health Outcomes and Measures of the Environment Study, a prospective birth cohort (2003-2006, Cincinnati, OH), was used to examine prenatal and childhood PBDEs and visual spatial abilities in 199 children. PBDEs were measured at 16±3 weeks gestation and at 1, 2, 3, 5, and 8 years using gas chromatography/isotope dilution high-resolution mass spectrometry. We used the Virtual Morris Water Maze to measure visual spatial abilities at 8 years. In covariate-adjusted models, 10-fold increases in BDE-47, -99, and -100 at 5 years were associated with shorter completion times by 5.2s (95% Confidence Interval [CI] -9.3, -1.1), 4.5s (95% CI -8.1, -0.9), and 4.7s (95% CI -9.0, -0.3), respectively. However, children with higher BDE-153 at 3 years had longer completion times (ß=5.4s, 95% CI -0.3, 11.1). Prenatal PBDEs were associated with improved visual spatial memory retention, with children spending a higher percentage of their search path in the correct quadrant. Child sex modified some associations between PBDEs and visual spatial learning. Longer path lengths were observed among males with increased BDE-47 at 2 and 3 years, while females had shorter paths. In conclusion, prenatal and postnatal BDE-28, -47, -99, and -100 at 5 and 8 years were associated with improved visual spatial abilities, whereas a pattern of impairments in visual spatial learning was noted with early childhood BDE-153 concentrations.

The modulatory effect of CA1 GABAb receptors on ketamine-induced spatial and non-spatial novelty detection deficits with respect to Ca(2+).

Glutamate and γ-aminobutyric acid (GABA) are among the most abundant neurotransmitters in the central nervous system. Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and the performance of cognitive tasks. The present study was designed to assess the effects of dorsal hippocampal (CA1) GABAb receptors on ketamine-induced spatial and non-spatial memory deficits with regard to the role of Ca(2+) as a defining factor. Spatial and non-spatial novelty detection of male NMRI mice were investigated in a circular open-field apparatus. According to our results, the intraperitoneal injection of ketamine at its higher dose (0.1 mg/kg) impaired both spatial and non-spatial novelty detection. Moreover, the intra-CA1 injection of baclofen (a GABAb receptor agonist) at higher doses (0.02 and 0.2 µg/mouse) impaired the spatial but not non-spatial novelty detection. In addition, phaclofen (a GABAb receptor antagonist at 0.2 µg/mouse) impaired both spatial and non-spatial novelty detection. Baclofen restored and induced a modulatory effect on ketamine-induced responses in the spatial and non-spatial novelty detection task, respectively. On the contrary, phaclofen restored and induced a modulatory effect on ketamine-induced responses in the non-spatial and spatial novelty detection task, respectively. Finally, the subthreshold dose of SKF96365 (a Ca(2+) channel blocker) impaired only the spatial but not non-spatial restoration effects of baclofen or phaclofen following a higher dose of ketamine. Such findings suggest that the ketamine-induced impairment of memory consolidation may occur through GABAb receptors of the CA1 neurons. Moreover, baclofen and phaclofen were shown to possibly exert their effects on the ketamine-induced spatial novelty detection deficits through Ca(2+) channels.

Effects of glucose load on cognitive functions in elderly people.

Glucose is the main fuel for the brain, and manipulation of the glucose supply may consequently affect brain function. The present review was conducted to provide an overview of studies that investigated the acute effects of glucose load on memory and other cognitive functions in elderly people. The effects of sucrose on cognition and suggested mechanisms were also explored. A total of twenty studies met the inclusion criteria. In the majority of studies, episodic memory was investigated and a beneficial role for glucose in that specific cognitive domain was suggested. Other cognitive domains, i.e., working memory, semantic memory, visual memory, information-processing speed, attention, executive function, and visual/spatial function, have been studied less frequently and evidence for a beneficial effect of glucose was equivocal. Mechanisms are suggested to be mainly related to the human body's need for glucose as a metabolic substrate for physiological mechanisms in both central and peripheral processes.

Executive functions in men and postmenopausal women.

INTRODUCTION: This study was designed to assess sex differences in older adults (55-65 years old) in executive functions and to examine the influence of hormone therapy (HT) in postmenopausal women. METHOD: We have assessed task performance in memory, visuospatial, and executive functions in 29 women using HT, 29 women who never used HT, and 30 men. RESULTS: Men outperformed never users in task switching and updating. HT users outperformed never users in updating. HT users outperformed never users and men in visual divided attention. DISCUSSION: The present study support previous findings that sex and HT impact cognition and bring new insights on sex and HT-related differences in executive functions.

Prenatal p,p'-DDE exposure and establishment of lateralization and spatial orientation in Mexican preschooler.

BACKGROUND: Prenatal exposure to p,p'-DDE is associated with impairments in motor development during the first year of life, with no related repercussions on mental or motor development at 12-30 months and with impairments in cognitive areas, but not in perceptual and motor areas at preschool age. However, its association with particular psychomotor factors, such as establishment of lateralization and spatial orientation, essential elements to the overall learning and specifically reading, writing and spelling in preschoolers, has not been independently evaluated, since cognitive and motor areas have only been explored globally. OBJECTIVE: To determine the association between prenatal exposure to p,p'-DDE and the establishment of lateralization and spatial orientation in children 5 years of age. MATERIALS AND METHODS: Establishment of lateralization and spatial orientation was evaluated using the McCarthy Scale of Children's Abilities, with 167 children 5 years of age who participated in a birth cohort in the state of Morelos, Mexico. The information available for each child included: serum concentrations of p,p'-DDE of the mother during at least one trimester of pregnancy, mothers' intelligence quotients, stimulation at home and anthropometry. A logistic regression model was used to calculate the association between prenatal exposure to p,p'-DDE and lateralization and a multiple linear regression model was used for the association with spatial orientation. RESULTS: A two-fold increase in p,p'-DDE in lipid base during the second trimester of pregnancy was associated with a significant reduction, -0.18 points (95% CI -0.41; 0.04, in the spatial orientation index, with no impairment in the establishment of hemispheric dominance. Attending preschool and the maternal intelligence quotient were the main determinants of spatial orientation and the establishment of hemispheric dominance. CONCLUSIONS: Prenatal exposure to p,p'-DDE may affect the 5 year old's ability to identify spatial orientation of oneself and surrounding objects. Given the observed role of attending preschool in the functions studied, early attendance in formal education might serve as a stimulation strategy for preschoolers. These preliminary results should be verified and expanded in further prospective studies with DDE.

A systematic review of the impact of oral contraceptives on cognition.

Combined oral contraceptives (OCs) are the most commonly prescribed medication in women of reproductive age, but despite widespread use, their effect on cognitive performance remains controversial. Given strong evidence for the neurological impact of reproductive hormones, a clear rationale for investigation exists. This systematic review sought to identify, collate and critically appraise studies assessing the impact of OCs on cognition in healthy premenopausal women. Ovid MEDLINE, PsychINFO and EMBASE were comprehensively searched using relevant keywords for original peer-reviewed observational studies or randomised trials published after 1960. Of 1289 references screened, 22 studies were eligible for inclusion. Assembled evidence supports a cognitive impact of OCs restricted to specific domains; however, the quality of evidence is poor. The most consistent finding is improved verbal memory with OC use. Evidence is also emerging that differing progestin androgenicity may lead diverse OC formulations to differentially impact certain cognitive domains, such as visuospatial ability. At present, evidence is inconclusive, contradictory and limited by methodological inconsistencies. There is scope for further research in this area to definitively determine the cognitive impact of OCs.