Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study.

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.

Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors.

Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines' effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.

Acute stress alters individual risk taking in a time-dependent manner and leads to anti-social risk.

Decision-making processes can be modulated by stress, and the time elapsed from stress induction seems to be a crucial factor in determining the direction of the effects. Although current approaches consider the first post-stress hour a uniform period, the dynamic pattern of activation of the physiological stress systems (i.e., the sympathetic nervous system and hypothalamic-pituitary-adrenal axis) suggests that its neurobehavioural impact might be heterogeneous. Here, we evaluate economic risk preferences on the gain domain (i.e., risk aversion) at three time points following exposure to psychosocial stress (immediately after, and 20 and 45 min from onset). Using lottery games, we examine decisions at both the individual and social levels. We find that risk aversion shows a time-dependent change across the first post-stress hour, evolving from less risk aversion shortly after stress to more risk averse behaviour at the last testing time. When risk implied an antisocial outcome to a third party, stressed individuals showed less regard for this person in their decisions. Participants' cortisol levels explained their behaviour in the risk, but not the antisocial, game. Our findings reveal differential stress effects in self- and other-regarding decision-making and highlight the multidimensional nature of the immediate aftermath of stress for cognition.

Incidence, risk factors and estimates of a woman's risk of developing secondary lower limb lymphedema and lymphedema-specific supportive care needs in women treated for endometrial cancer.

OBJECTIVES: Few studies have assessed the risk and impact of lymphedema among women treated for endometrial cancer. We aimed to quantify cumulative incidence of, and risk factors for developing lymphedema following treatment for endometrial cancer and estimate absolute risk for individuals. Further, we report unmet needs for help with lymphedema-specific issues. METHODS: Women treated for endometrial cancer (n = 1243) were followed-up 3-5 years after diagnosis; a subset of 643 completed a follow-up survey that asked about lymphedema and lymphedema-related support needs. We identified a diagnosis of secondary lymphedema from medical records or self-report. Multivariable logistic regression was used to evaluate risk factors and estimates. RESULTS: Overall, 13% of women developed lymphedema. Risk varied markedly with the number of lymph nodes removed and, to a lesser extent, receipt of adjuvant radiation or chemotherapy treatment, and use of nonsteroidal anti-inflammatory drugs (pre-diagnosis). The absolute risk of developing lymphedema was >50% for women with 15+ nodes removed and 2-3 additional risk factors, 30-41% for those with 15+ nodes removed plus 0-1 risk factors or 6-14 nodes removed plus 3 risk factors, but ≤ 8% for women with no nodes removed or 1-5 nodes but no additional risk factors. Over half (55%) of those who developed lymphedema reported unmet need(s), particularly with lymphedema-related costs and pain. CONCLUSION: Lymphedema is common; experienced by one in eight women following endometrial cancer. Women who have undergone lymphadenectomy have very high risks of lymphedema and should be informed how to self-monitor for symptoms. Affected women need greater levels of support.

Screening for obstructive sleep apnea in children with Down syndrome.

OBJECTIVE: To compare symptoms of obstructive sleep apnea (OSA) and polysomnography (PSG) results in children with Down syndrome and typically developing children. STUDY DESIGN: A total of 49 children with Down syndrome referred for PSG between 2008 and 2012 were matched with typically developing children of the same sex, age, and OSA severity who had undergone PSG in the same year. A parent completed a sleep symptom questionnaire for each child. Sleep quality and measures of gas exchange were compared between the matched groups. RESULTS: The 98 children (46 females, 52 males) had mean age of 6.2 years (range, 0.3-16.9 years). Fourteen children had primary snoring, and 34 had OSA (9 mild, 7 moderate, and 19 severe). Children with Down syndrome had more severe OSA compared with 278 typically developing children referred in 2012. Symptom scores were not different between the matched groups. Those with Down syndrome had a higher average pCO2 during sleep (P = .03) and worse McGill oximetry scores. CONCLUSION: Compared with closely matched typically developing children with OSA of comparable severity, children with Down syndrome had a similar symptom profile and slightly worse gas exchange. Referred children with Down syndrome had more severe OSA than referred typically developing children, suggesting a relative reluctance by parents or doctors to investigate symptoms of OSA in children with Down syndrome. These findings highlight the need for formal screening tools for OSA in children with Down syndrome to improve detection of the condition in this high-risk group.

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors.

Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

Safety, feasibility and effects of an individualised walking intervention for women undergoing chemotherapy for ovarian cancer: a pilot study.

BACKGROUND: Exercise interventions during adjuvant cancer therapy have been shown to increase functional capacity, relieve fatigue and distress and may assist rates of chemotherapy completion. These studies have been limited to breast, gastric and mixed cancer groups and it is not yet known if a similar intervention is even feasible among women with ovarian cancer. We aimed to assess safety, feasibility and potential effect of a walking intervention in women undergoing chemotherapy for ovarian cancer. METHODS: Women newly diagnosed with ovarian cancer were recruited to participate in an individualised walking intervention throughout chemotherapy and were assessed pre- and post-intervention. Feasibility measures included session adherence, compliance with exercise physiologist prescribed walking targets and self-reported program acceptability. Changes in objective physical functioning (6-minute walk test), self-reported distress (Hospital Anxiety and Depression Scale), symptoms (Memorial Symptom Assessment Scale - Physical) and quality of life (Functional Assessment of Cancer Therapy - Ovarian) were calculated, and chemotherapy completion and adverse intervention effects recorded. RESULTS: Seventeen women were enrolled (63% recruitment rate). Mean age was 60 years (SD = 8 years), 88% were diagnosed with FIGO stage III or IV disease, 14 women underwent adjuvant and three neo-adjuvant chemotherapy. On average, women adhered to > 80% of their intervention sessions and complied with 76% of their walking targets, with the majority walking four days a week at moderate intensity for 30 minutes per session. Meaningful improvements were found in physical functioning, physical symptoms, physical well-being and ovarian cancer-specific quality of life. Most women (76%) completed ≥85% of their planned chemotherapy dose. There were no withdrawals or serious adverse events and all women reported the program as being helpful. CONCLUSIONS: These positive preliminary results suggest that this walking intervention for women receiving chemotherapy for ovarian cancer is safe, feasible and acceptable and could be used in development of future work. TRIAL REGISTRATION: ACTRN12609000252213.

Does quality of life among breast cancer survivors one year after diagnosis differ depending on urban and non-urban residence? A comparative study.

BACKGROUND: This study examined the quality of life (QOL), measured by the Functional Assessment of Cancer Therapy (FACT) questionnaire, among urban (n = 277) and non-urban (n = 323) breast cancer survivors and women from the general population (n = 1140) in Queensland, Australia. METHODS: Population-based samples of breast cancer survivors aged < 75 years who were 12 months post-diagnosis and similarly-aged women from the general population were recruited between 2002 and 2007. RESULTS: Age-adjusted QOL among urban and non-urban breast cancer survivors was similar, although QOL related to breast cancer concerns was the weakest domain and was lower among non-urban survivors than their urban counterparts (36.8 versus 40.4, P < 0.01). Irrespective of residence, breast cancer survivors, on average, reported comparable scores on most QOL scales as their general population peers, although physical well-being was significantly lower among non-urban survivors (versus the general population, P < 0.01). Overall, around 20%-33% of survivors experienced lower QOL than peers without the disease. The odds of reporting QOL below normative levels were increased more than two-fold for those who experienced complications following surgery, reported upper-body problems, had higher perceived stress levels and/or a poor perception of handling stress (P < 0.01 for all). CONCLUSIONS: Results can be used to identify subgroups of women at risk of low QOL and to inform components of tailored recovery interventions to optimize QOL for these women following cancer treatment.

Programming effects of peripubertal stress on spatial learning.

Exposure to adversity during early life can have profound influences on brain function and behavior later in life. The peripubertal period is emerging as an important time-window of susceptibility to stress, with substantial evidence documenting long-term consequences in the emotional and social domains. However, little is known about how stress during this period impacts subsequent cognitive functioning. Here, we assessed potential long-term effects of peripubertal stress on spatial learning and memory using the water maze task. In addition, we interrogated whether individual differences in stress-induced behavioral and endocrine changes are related to the degree of adaptation of the corticosterone response to repeated stressor exposure during the peripubertal period. We found that, when tested at adulthood, peripubertally stressed animals displayed a slower learning rate. Strikingly, the level of spatial orientation in the water maze completed on the last training day was predicted by the degree of adaptation of the recovery -and not the peak-of the corticosterone response to stressor exposure (i.e., plasma levels at 60 min post-stressor) across the peripubertal stress period. In addition, peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. Importantly, by assessing the same endpoints in another peripubertally stressed cohort tested during adolescence, we show that the observed effects at adulthood are the result of a delayed programming manifested at adulthood and not protracted effects of stress. Altogether, our results support the view that the degree of stress-induced adaptation of the hypothalamus-pituitary-adrenal axis responsiveness at the important transitional period of puberty relates to the long-term programming of cognition, behavior and endocrine reactivity.

LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance.

The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1-receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour.

Neuropharmacology of the mesolimbic system and associated circuits on social hierarchies.

Most socially living species are organized hierarchically, primarily based on individual differences in social dominance. Dominant individuals typically gain privileged access to important resources, such as food, mating partners and territories, whereas submissive conspecifics are often devoid of such benefits. The benefits associated with a high social status provide a strong incentive to become dominant. Importantly, motivational- and reward-related processes are regulated, to a large extent, by the mesolimbic system. Consequently, several studies point to a key role for the mesolimbic system in social hierarchy formation. This review summarizes the growing body of literature that implicates the mesolimbic system, and associated neural circuits, on social hierarchies. In particular, we discuss the neurochemical and pharmacological studies that have highlighted the contributions of the mesolimbic system and associated circuits including dopamine signaling through the D1 or D2 receptors, GABAergic neurotransmission, the androgen receptor system, and mitochondria and bioenergetics. Given that low social status has been linked to the emergence of anxiety- and depressive-like disorders, a greater understanding of the neurochemistry underlying social dominance could be of tremendous benefit for the development of pharmacological treatments to dysfunctions in social behaviors. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood.

The neural cell adhesion molecule (NCAM) has been implicated in regulating synaptic plasticity mechanisms as well as memory consolidation processes. Attachment of polysialic acid to NCAM (PSA-NCAM) has been reported to down-regulate its adhesive forces, a process hypothesized to be implicated in synapse selection after learning experiences. PSA-NCAM has been critically implicated in hippocampus-related synaptic plasticity and memory storage, but information about its functional role in other brain areas remains scarce. Here, we studied mice deficient for polysialyltransferase-1 (ST8SialV/PST-1), an enzyme which attaches PSA to NCAM during postnatal development and adulthood, and whose deficiency results in a drastic reduction of PSA-NCAM expression throughout the brain in adulthood. Mice were tested for their performance in the water maze and auditory fear conditioning (AFC). We report that ST8SiaIV knockout mice were impaired in spatial as well as reversal learning in the water maze. On the other hand, AFC was intact and ST8SiaIV mice exhibited no impairments in the acquisition or retention of cued fear memories. Spatial orientation learning and reversal learning require complex integration of spatial information and response selection involving the hippocampus and prefrontal cortex, whereas cued fear conditioning is an associative type of emotional memory that highly depends on amygdala function. Therefore, our results indicate that PSA-NCAM contributes differentially to learning processes that differ in the nature of the neural computations involved, which probably reflects a differential role of this molecule in different brain regions.

Effects of P2, a peptide derived from a homophilic binding site in the neural cell adhesion molecule on learning and memory in rats.

The neural cell adhesion molecule (NCAM) plays a pivotal role in neural development, regeneration, synaptic plasticity, and memory processes. P2 is a 12-amino-acid peptide derived from the second immunoglobulin-like (Ig) module of NCAM mediating cis-homophilic interactions between NCAM molecules present on the same cell. P2 is a potent NCAM agonist, capable of promoting neuronal differentiation and survival in vitro. The aim of this study was to assess the effect of P2 on learning and memory. Rats treated with P2 intracerebroventricularly (1 h prior to test) performed significantly better than controls in the reinforced T-maze, a test of spatial working memory. Further, rats treated with P2 exhibited decreased anxiety-like behavior while learning the T-maze task. In the social recognition test, both intracerebroventricular (1 h prior to test) and systemic (1 and 24 h prior to test) P2 treatment enhanced short-term social memory and counteracted (administration 24 h prior test) scopolamine-induced social memory impairment. In contrast, P2 (1 h prior to test) did not significantly improve long-term (24 h) retention of social memory, nor did it have any significant effects on long-term memory evaluated by the Morris water maze (administration between 2 days before training and 5.5 h posttraining). In the open field test, P2 (1 h prior to test) decreased general locomotion and rearing, but did not influence any other anxiety-related behaviors, indicating only a minimal influence on baseline anxiety levels. Taken together, these data indicate that in vivo P2 enhances short-term memory and protects against the amnestic effects of scopolamine, while modulating emotional behavior in a learning or novelty-related task.

Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study.

Chronic restraint stress is known to affect the morphology and synaptic organization of the hippocampus, predominantly within CA3 but also in CA1 and dentate gyrus. In this study, we provide the first evidence for specific ultrastructural alterations affecting asymmetric axo-spinous synapses in CA1 stratum lacunosum-moleculare following chronic restraint stress (6 h/day, 21 days) in the rat. The structure of asymmetric axo-spinous post-synaptic densities was investigated using serial section three-dimensional reconstruction procedures in control (n=4) and chronic restraint stress (n=3) animals. Dendritic spine profiles (spine head+neck) associated with the sampled synaptic contacts (30 per animal) were also reconstructed in three-dimensions. Morphometric analyses revealed a significant increase in post-synaptic density surface area (+36%; P=0.03) and a highly significant increase in post-synaptic density volume (+79%; P=0.003) in the chronic restraint stress group. These changes were directly associated with 'non-macular' (perforated, complex and segmented) post-synaptic densities. A highly significant overall increase in the 'post-synaptic density surface area/spine surface area' ratio was also detected in the chronic restraint stress group (+27%; P=0.002). In contrast, no quantitative changes in spine parameters were found between groups. The Cavalieri method was used to assess the effects of chronic restraint stress exposure upon CA1 hippocampal volume. The mean volume of total dorsal anterior CA1 hippocampus was significantly lower in the chronic restraint stress group (-16%; P=0.036). However, when corrected for volume changes, no significant alteration in a relative estimate of the mean number of asymmetric axo-spinous synapses was detected in CA1 stratum lacunosum-moleculare between control and chronic restraint stress groups. The data indicate a structural remodeling of excitatory axo-spinous synaptic connectivity in rat CA1 stratum lacunosum-moleculare as a result of chronic restraint stress.

Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum.

Early-life stress and biological predispositions are linked to mood and personality disorders related to aggressive behavior. We previously showed that exposure to peripubertal stress leads to increased anxiety-like behaviors and aggression against males and females, as well as increased aggression against females in their male offspring. Here, we investigated whether paternal (pS) and individual (iS) exposure to peripubertal stress may exert additive effects on the long-term programming of anxiety-like and aggressive behaviors in rats. Given the key role of the lateral septum (LS) in the regulation of anxiety and aggressive behaviors and the hypothesized alterations in balance between neural excitation and inhibition in aggression-related disorders, markers for these processes were examined in the LS. Peripubertal stress was applied both in naïve male rats and in the offspring of peripubertally stressed males, and anxiety-like and aggressive behaviors were assessed at adulthood. Proton magnetic resonance spectroscopy at 6-months, and post-mortem analysis of glutamic acid decarboxylase 67 (GAD67) at 12-months were conducted in LS. We confirmed that aggressive behavior was increased by pS and iS, while only iS increased anxiety-like behavior. Individual stress led to reduced GABA, confirmed by reduced GAD67 immunolabelling, and increased glutamate, N-acetyl-aspartate, phosphocholine and creatine; while pS specifically led to reduced phosphocreatine. pS and iS do not interact and exert a differential impact on the analyzed aspects of brain function and anxiety-like behaviors. These data support the view that early-life stress can affect the behavioral and neurodevelopmental trajectories of individuals and their offspring, which may involve different neurobiological mechanisms.

'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.

Chronic restraint stress down-regulates amygdaloid expression of polysialylated neural cell adhesion molecule.

The amygdala is a brain area which plays a decisive role in fear and anxiety. Since exposure to chronic stress can induce profound effects in emotion and cognition, plasticity in specific amygdaloid nuclei in response to prior stress has been hypothesized to account for stress-induced emotional alterations. In order to identify amygdala nuclei which may be affected under chronic stress conditions we evaluated the effects of 21-days chronic restraint stress on the expression of a molecule implicated crucially in alterations in structural plasticity: the polysialylated neural cell adhesion molecule. We found that polysialylated neural cell adhesion molecule-immunoreactivity within the amygdala, present in somata and neuronal processes, has a regional gradient with the central medial and medial amygdaloid nuclei showing the highest levels. Our results demonstrate that chronic restraint stress induced an overall reduction in polysialylated neural cell adhesion molecule-immunoreactivity in the amygdaloid complex, mainly due to a significant decrease in the central medial amygdaloid and medial amygdaloid nuclei. Our data suggest that polysialylated neural cell adhesion molecule in these nuclei may play a prominent role in functional and structural remodeling induced by stress, being a potential mechanism for cognitive and emotional modulation. Furthermore, these finding provide the first clear evidence that life experiences can regulate the expression of polysialylated neural cell adhesion molecule in the amygdaloid complex.

Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities.

Chronic stress and spatial training have been proposed to affect hippocampal structure and function in opposite ways. Previous morphological studies that addressed structural changes after chronic restraint stress and spatial training were based on two-dimensional morphometry which does not allow a complete morphometric characterisation of synaptic features. Here, for the first time in such studies, we examined these issues by using three-dimensional (3-D) reconstructions of electron microscope images taken from thorny excrescences of hippocampal CA3 pyramidal cells. Ultrastructural alterations in postsynaptic densities (PSDs) of thorny excrescences receiving input from mossy fibre boutons were also determined, as were changes in numbers of multivesicular bodies (endosome-like structures) within thorny excrescences and dendrites. Quantitative 3-D data demonstrated retraction of thorny excrescences after chronic restraint stress which was reversed after water maze training, whilst water maze training alone increased thorny excrescence volume and number of thorns per thorny excrescence. PSD surface area was unaffected by restraint stress but water maze training increased both number and area of PSDs per thorny excrescence. In restrained rats that were water maze trained PSD volume and surface area increased significantly. The proportion of perforated PSDs almost doubled after water maze training and restraint stress. Numbers of endosome-like structures in thorny excrescences decreased after restraint stress and increased after water maze training. These findings demonstrate that circuits involving contacts between mossy fibre terminals and CA3 pyramidal cells at stratum lucidum level are affected conversely by water maze training and chronic stress, confirming the remarkable plasticity of CA3 dendrites. They provide a clear illustration of the structural modifications that occur after life experiences noted for their different impact on hippocampal function.

The effects of stress during early postnatal periods on behavior and hippocampal neuroplasticity markers in adult male mice.

Infancy is a critical period for brain development. Emerging evidence indicates that stress experienced during that period can have long-term programming effects on the brain and behavior. However, whether different time periods represent different vulnerabilities to the programming of different neurobehavioral domains is not yet known. Disrupted maternal care is known to interfere with neurodevelopmental processes and may lead to the manifestation of behavioral abnormalities in adulthood. Mouse dams confronted with insufficient bedding/nesting material have been shown to provide fragmented maternal care to their offspring. Here, we compared the impact of this model of early-life stress (ELS) during different developmental periods comprising either postnatal days (PNDs) 2-9 (ELS-early) or PND 10-17 (ELS-late) on behavior and hippocampal cell adhesion molecules in male mice in adulthood. ELS-early treatment caused a permanent reduction in bodyweight, whereas this reduction only occurred transiently during juvenility in ELS-late mice. Anxiety was only affected in ELS-late mice, while cognition and sociability were equally impaired in both ELS-treated groups. We analyzed hippocampal gene expression of the γ2 subunit of the GABAa receptor (Gabrg2) and of genes encoding cell adhesion molecules. Gabrg2 expression was increased in the ventral hippocampus in ELS-late-treated animals and was correlated with anxiety-like behavior in the open-field (OF) test. ELS-early-treated animals exhibited an increase in nectin-1 expression in the dorsal hippocampus, and this increase was associated with the social deficits seen in these animals. Our findings highlight the relevance of developmental age on stress-induced long-term behavioral alterations. They also suggest potential links between early stress-induced alterations in hippocampal Gabrg2 expression and the developmental programming of anxiety and between changes in hippocampal nectin-1 expression and stress-induced social impairments.