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Prenatal infection increases the risk for neurodevelopmental disorders including autism spectrum disorder and schizophrenia. To better understand this link, a number of maternal immune activation (MIA) rodent models have been studied. However, the majority of these studies focus on adult behavioural outcomes that mirror adult symptoms related to neurodevelopmental disorders. There is little research reporting the effects of MIA on early postnatal development and even fewer using outbred mouse strains. Here, we use a modified version of the Fox scale to assess the effects of two MIA models, a bacterial model (LPS) and a viral model (PolyIC), on overall mouse pup sensorimotor development in CD-1 mice. Surprisingly, both bacterial and viral MIA models resulted in early reflex development when compared with control pups. To better characterize potential factors related to these changes, we examined indicators of sickness/inflammation in the immune-activated dams and in their pups. Sickness behaviour in the dams resulting from immune activation was assessed using a telemetry implant that allowed for continuous recording of temperature and activity in dams exposed to bacterial or viral immune activation. Although MIA dams showed reduced activity on the day immediately following MIA compared to controls, there was no evidence of fever. All dams showed elevated cytokines/chemokines associated with parturition, but this resolved by day 10 post-parturition and was unaffected by previous immune activation. Although circulating cytokines/chemokines in the dams were similar across MIA treatments, there were differences in the amount of interleukin-12p70 and interleukin-13 present in milk taken from milk bands in MIA pups, and interleukin-4 was overall decreased in LPS pup brain. These findings demonstrate that bacterial and viral models of MIA can result in similar precocious development in mice but differing long-term effects on inflammatory markers in both the milk provided to the pups and in their brains., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Despite frequent reports of mental health needs among older women with cancer, depressive symptoms often go unrecognized and untreated, particularly in socially vulnerable survivors. Here, we examined associations of sociodemographic factors and social limitations with depressive symptoms from pre-diagnosis to post-diagnosis in older women diagnosed with breast or gynecological cancer. Using the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey (SEER-MHOS) linked dataset, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between sociodemographic factors (race, ethnicity, marital status, rurality) and social limitations (i.e., health interfering with social activities) on depressive symptoms in women aged ≥65 years with breast or gynecologic cancer ( n  = 1,353). Most participants had breast cancer (82.0%), stage I-II cancer (85.8%), received surgery for their cancer (94.8%), and radiation treatment (50.6%). Prior to diagnosis, 11.8% reported depressive symptoms, which nearly doubled to 22.4% at follow-up. Participants were 2.7 times more likely of reporting depressive symptoms after cancer diagnosis compared with pre-cancer diagnosis (95%CI: 2.10-3.48). Race, ethnicity, rurality, marital status, and social interference were significantly associated with an increased risk of depressive symptoms after cancer diagnosis than before their cancer diagnosis ( p  < 0.05). In summary, depressive symptoms increased following a cancer diagnosis. Our results suggest potential avenues for intervention that could lead to reduced depressive symptoms among older female cancer survivors.

Mice naturally form social hierarchies, and their experiences as subordinate or dominant mice inform future behavioural strategies. To better understand the neural bases of social dominance, we investigated hippocampal gene and protein expression of histone deacetylase 2 (HDAC2), an epigenetic regulator that decreases expression of synaptic plasticity genes and reduces excitatory synaptic function. Hdac2 in hippocampus was associated with social status. The gene for a closely related histone deacetylase (Hdac1), and HDAC2 protein expression, were not associated with social rank in hippocampus. These findings suggest that Hdac2 expression in hippocampus is distinctly linked with social status., Competing Interests: Declaration of Competing Interest No conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Neuroimaging studies investigating the behavioral and psychological symptoms of dementia (BPSD)- such as apathy, anxiety, and depression- have linked some of these symptoms with altered neural activity. However, inconsistencies in operational definitions and rating scales, limited scope of assessments, and poor temporal resolution of imaging techniques have hampered human studies. Many transgenic (Tg) mouse models of Alzheimer's disease (AD) exhibit BPSD-like behaviors concomitant with AD-related neuropathology, allowing examination of how neural activity may relate to BPSD-like behaviors with high temporal and spatial resolution., Objective: To examine task-dependent neural activity in the medial prefrontal cortex (mPFC) of AD-model mice in response to social and non-social olfactory stimuli., Methods: We previously demonstrated age-related decreases in social investigation in Tg 5xFAD females, and this reduced social investigation is evident in Tg 5xFAD females and males by 6 months of age. In the present study, we examine local field potential (LFP) in the mPFC of awake, behaving 5xFAD females and males at 6 months of age during exposure to social and non-social odor stimuli in a novel olfactometer., Results: Our results indicate that Tg 5xFAD mice exhibit aberrant baseline and task-dependent LFP activity in the mPFC- including higher relative delta (1-4 Hz) band power and lower relative power in higher bands, and overall stronger phase-amplitude coupling- compared to wild-type controls., Conclusions: These results are consistent with previous human and animal studies examining emotional processing, anxiety, fear behaviors, and stress responses, and suggest that Tg 5xFAD mice may exhibit altered arousal or anxiety.

Adolescence is a period of transition during which there is extensive development of the brain and the hypothalamic-pituitary-adrenal axis. However, the term adolescence is broad and covers a number of important developmental periods ranging from pre-pubescence to sexual maturity. Using a predator stress model, we investigated the effects of chronic psychological stress on anxiety-like, depression-like, and social behaviours in male and female mice during early adolescence, when mice are pre-pubertal, and late adolescence, when mice are sexually mature. All stressed mice showed hyperactivity and increased anxiety-like behaviours. The anxiogenic effects were generally more pronounced in mice exposed to late, rather than early adolescent stress, but were clearly evident when stress was experienced at either timepoint. Risk assessment behaviours were also affected by the stress treatments, but the direction of these changes were sometimes sex- and age-specific. Surprisingly, mice stressed during adolescence showed no depressive-like behaviours as adults. This study provides evidence that adolescent psychological stress has pronounced long-term anxiogenic effects but that the precise behavioural phenotype differs based on sex and the sub-stage of adolescence during which the individual is exposed., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Exposures to stress at all stages of development can lead to long-term behavioural effects, in part through changes in the epigenome. This review describes rodent research suggesting that stress in prenatal, postnatal, adolescent and adult stages leads to long-term changes in epigenetic regulation in the brain which have causal impacts on rodent behaviour. We focus on stress-induced epigenetic changes that have been linked to behavioural deficits including poor learning and memory, and increased anxiety-like and depressive-like behaviours. Interestingly, aspects of these stress-induced behavioural changes can be transmitted to offspring across several generations, a phenomenon that has been proposed to result via epigenetic mechanisms in the germline. Here, we also discuss evidence for the differential impact of stress on the epigenome in males and females, conscious of the fact that the majority of published studies have only investigated males. This has led to a limited picture of the epigenetic impact of stress, highlighting the need for future studies to investigate females as well as males., Competing Interests: None to declare., (© 2022 The Authors.)

Purpose: The study aimed to evaluate the quality of life patterns and the effects of AC and AC-T chemotherapy's toxicities on QoL among Ethiopian women with breast cancer., Methods: QoL was measured at baseline and at every end of two cycles, for the median of 8 cycles among 146 breast cancer women on AC and AC-T chemotherapy, using EORTC QLQ-C30 and BR23 instruments. The effect of QoL score, socio-demographic, and clinical variables at baseline were adjusted for the effect of chemotherapy's toxicities on QoL., Results: Overall QoL, all functional scales (except cognitive functioning, body image, future perspectives, and sexual functioning) and symptom scales (except dyspnea, insomnia, pain score, arm, and breast symptoms) of EORTC QLQ-C30 and BR23 deteriorated significantly both clinically and statistically, in particular, during the first two cycles of chemotherapy. After the end of cycle 2 or 4, except for cognitive, social functioning, and financial difficulties of the patients, almost all other QoL dimensions were improved towards pretreatment score by the end of cycle 8. In addition to age, educational status, and tumor stage, the Global Health Status (-10.55≤B≤-7.71, P≤0.013), and the functional scales (-25.320≤B≤-6.351, P≤0.033) of EORTC QLQ-C30 and BR23 were significantly affected at least by one of the AC and AC-T chemotherapy's toxicity such as grade≥2 fatigue, dysgeusia, constipation, dry mouth, vomiting, oral mucositis, skin hyperpigmentation and/or peripheral neuropathy than their lower grade. Grade≥2 fatigue, dysgeusia, oral mucositis, constipation, peripheral neuropathy, anemia arthralgia/myalgia, dry mouth, diarrhea, constipation, and/or skin hyperpigmentation were positively predicted for the deterioration of symptoms scale of EORTC QLQ-C30 and BR23 (4.819≤B≤26.451, P≤0.043)., Conclusion: Quality of life among Ethiopian breast cancer patients on AC and AC-T regimens significantly deteriorated particularly during the first two cycles of chemotherapy. In addition to the age, tumor stage and educational status of the patients, grade≥2 fatigue, dysgeusia, constipation, oral mucositis, dry mouth, peripheral neuropathy, and skin hyperpigmentation due to AC and AC-T chemotherapy were frequently associated with deterioration of different scales/items QoL. Hence, devising different strategies to improve the deteriorated QoL due to chemotherapy's toxicities particularly during the first two cycles has paramount importance., Competing Interests: The authors declare that they have no conflicts of interest., (© 2021 Gadisa et al.)

Social withdrawal and agitation/aggression are common behavioral and psychological symptoms of dementia presented by Alzheimer's disease (AD) patients, with males exhibiting more aggressive behaviors than females. Some transgenic mouse models of AD also exhibit social withdrawal and aggression, but many of these models only recapitulate the early stages of the disease. By comparison, the 5xFAD mouse model of AD exhibits rapid, progressive neurodegeneration, and is suitable for modeling cognitive and behavioral deficits at early, mid-, and late-stage disease progression. Anecdotal reports suggest that transgenic 5xFAD males exhibit high levels of aggression compared to wild-type controls, but to date, indirect genetic effects in this strain have not been studied. We measured home-cage behaviors in 5xFAD males housed in three different group-housing conditions (transgenic-only, wild-type only, and mixed-genotype) and social approach behaviors when exposed to a novel free-roaming or restrained, wild-type or transgenic conspecific. Transgenic-only home cages required earlier separation due to injuries arising from aggression compared to wild-type-only or mixed-genotype cages, despite no obvious increase in the frequency of aggressive behaviors. Transgenic 5xFAD males and females also spent less time investigating free-roaming conspecifics compared to wild-type controls, but they showed normal investigation of restrained conspecifics; the genotype of the conspecific did not affect approach behavior, and there was no aggression observed in transgenic males. These findings provide evidence in an animal model that amyloid pathology ultimately leads to avoidance of novel social stimuli, and that frequent interactions between individuals exhibiting an AD phenotype further exacerbates aggressive behaviors., (© 2020 Wiley Periodicals, Inc.)

Background: Management of patients with breast cancer undergoing chemotherapy is complicated by a very high rate of adverse drug reactions which is even more challenging in developing countries like Ethiopia where the toxicity profile of chemotherapy is lacking. The present study aimed at evaluating the toxicity profile of Doxorubicin-Cyclophosphamide (AC) and Doxorubicin-Cyclophosphamide→Paclitaxel (AC→T) regimens among 146 patients with breast cancer in Ethiopia., Methods: This prospective cohort study, with the median of six months' follow-up, was conducted from January 1 to September 30, 2017 GC at the only nationwide oncology center, Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia. Seventy-one patients received AC, while 75 received AC-T regimen. The toxicity with the highest grade during any cycle was considered as the toxicity grade for that patient. SPSS version 22 was used for analysis., Results: The overall frequent non-hematological adverse drug reactions reported for both regimens were fatigue 144 (98.7%), dysgeusia 142 (97.3%), skin hyperpigmentation 141 (96.6%), nausea 136 (93.2%), vomiting 129 (88.4%), gastritis 122 (83.6%), peripheral neuropathy 108 (74%), and myalgia/arthralgia 110 (75.3%). Neutropenia 107 (73.3%), leukopenia 102 (69.9%), and anemia 51 (34.9%) were the most frequent overall grade hematological toxicities reported. However, those received AC regimen suffered more from grade 2 and above leukopenia (35.2% vs. 17.3%, P = 0.014), anemia (16.9% vs. 2.7%, P = 0.004), and alkaline phosphatase increment (11.3% vs. 2.7%, P = 0.039) than AC-T regimen. On the contrary, those received AC-T regimen suffered more from severe arthralgia/myalgia (2.8% vs. 2%, P = 0.001), peripheral neuropathy (1.4% vs. 36%, P = 0.000), and gastritis (14.1% vs. 29.3%, P = 0.026) than AC regimen. Pretreatment blood cell counts, having stage IV breast tumor, older age, and lower body surface area were significant predictors of grade 2 to above hematological toxicities. Older age, arthralgia/myalgia, and skin hyperpigmentation occurred during the cohort were significant predictors of grade 2 to above oral mucositis, peripheral neuropathy, and fatigue, respectively., Conclusion: Patients who received the AC regimen suffered more from hematological abnormalities, while those on the AC-T regimen experienced more of non-hematological toxicities. Overall, we report high incidences of AC and AC-T regimens-induced toxicities in Ethiopian women with breast cancer, and they may require prior support based on pretreatment blood counts, age and body surface area, and close follow-up during chemotherapy.

Transgenic mouse models have been used extensively to model the cognitive impairments arising from Alzheimer's disease (AD)-related pathology. However, less is known about the relationship between AD-related pathology and the behavioural and psychological symptoms of dementia (BPSD) commonly presented by patients. This review discusses the BPSD-like behaviours recapitulated by several mouse models of AD-related pathology, including the APP/PS1, Tg2576, 3xTg-AD, 5xFAD, and APP23 models. Current evidence suggests that social withdrawal and depressive-like behaviours increase with progressive neuropathology, and increased aggression and sleep-wake disturbances are present even at early stages; however, there is no clear evidence to support increased anxiety-like behaviours, agitation (hyperactivity), or general apathy. Overall, transgenic mouse models of AD-related pathology recapitulate some of the BPSD-like behaviours associated with AD, but these behaviours vary by model. This reflects the patient population, where AD patients typically exhibit one or more BPSD, but rarely all symptoms at once. As a result, we suggest that transgenic mouse models are an important tool to investigate the pathology underlying BPSD in human AD patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Recent advances in neural circuitry techniques, like optogenetics and chemogenetics, have allowed for a greater understanding of the periaqueductal gray (PAG) and its importance in predator and prey behaviors. These studies in rodents have highlighted the role of the rostrolateral PAG in hunting behaviors, and have demonstrated functional differences across the dorsal-ventral/rostral-caudal axes of the PAG associated with defensive behaviors. Human imaging studies have further demonstrated that the PAG is active during situations involving imminent threat suggesting that the function of the PAG is likely largely conserved across species. This mini-review article highlights some of the recent advancements towards our understanding of the functional neuroanatomy of the PAG and its importance in the predator and prey behaviors that are critical for survival.

In addition to memory impairments, patients with Alzheimer's disease (AD) exhibit a number of behavioural and psychological symptoms that can affect social interactions over the course of the disease. While altered social interactions have been demonstrated in a number of mouse models of AD, many models only recapitulate the initial stages of the disease, and these behavioural changes have yet to be examined over the course of disease progression. By performing a longitudinal study using the 5xFAD mouse model, we have demonstrated that transgenic females exhibit progressive alterations in social investigation compared to wild-type controls. Transgenic females exhibited an age-related reduction in interest for social odours, as well as reduced investigative behaviours towards novel conspecifics in a novel environment. However, transgenic mice exhibited no obvious olfactory deficits, nor any changes in scent-marking behaviour compared to wild-type controls, indicating that changes in investigative behaviour were due to motivation to engage with a social stimulus. This evidence suggests that transgenic 5xFAD females exhibit increased social anxiety in novel environments compared to wild-type controls. Overall, transgenic 5xFAD female mice mimic some features of social withdrawal observed in human AD patients suggesting this strain may be suitable for modelling aspects of the social dysfunction observed in human patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In the past decades, evidence supporting the transmission of acquired traits across generations has reshaped the field of genetics and the understanding of disease susceptibility. In humans, pioneer studies showed that exposure to famine, endocrine disruptors or trauma can affect descendants, and has led to a paradigm shift in thinking about heredity. Studies in humans have however been limited by the low number of successive generations, the different conditions that can be examined, and the lack of mechanistic insight they can provide. Animal models have been instrumental to circumvent these limitations and allowed studies on the mechanisms of inheritance of environmentally induced traits across generations in controlled and reproducible settings. However, most models available today are only intergenerational and do not demonstrate transmission beyond the direct offspring of exposed individuals. Here, we report transgenerational transmission of behavioral and metabolic phenotypes up to the 4th generation in a mouse model of paternal postnatal trauma (MSUS). Based on large animal numbers (up to 124 per group) from several independent breedings conducted 10 years apart by different experimenters, we show that depressive-like behaviors are transmitted to the offspring until the third generation, and risk-taking and glucose dysregulation until the fourth generation via males. The symptoms are consistent and reproducible, and persist with similar severity across generations. These results provide strong evidence that adverse conditions in early postnatal life can have transgenerational effects, and highlight the validity of MSUS as a solid model of transgenerational epigenetic inheritance.

The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.

Traumatic experiences in childhood can alter behavioural responses and increase the risk for psychopathologies across life, not only in the exposed individuals but also in their progeny. In some conditions, such experiences can however be beneficial and facilitate the appraisal of adverse environments later in life. Here we expose newborn mice to unpredictable maternal separation combined with unpredictable maternal stress (MSUS) for 2 weeks and assess the impact on behaviour in the offspring when adult. We show that MSUS in male mice favours goal-directed behaviours and behavioural flexibility in the adult offspring. This effect is accompanied by epigenetic changes involving histone post-translational modifications at the mineralocorticoid receptor (MR) gene and decreased MR expression in the hippocampus. Mimicking these changes pharmacologically in vivo reproduces the behavioural phenotype. These findings highlight the beneficial impact that early adverse experiences can have in adulthood, and the implication of epigenetic modes of gene regulation.

Exposure to stressful events can be differently perceived by individuals and can have persistent sequelae depending on the level of stress resilience or vulnerability of each person. The neural processes that underlie such clinically and socially important differences reside in the anatomical, functional, and molecular connectivity of the brain. Recent work has provided novel insight into some of the involved biological mechanisms that promises to help prevent and treat stress-related disorders. In this review, we focus on causal and mechanistic evidence implicating altered functions and connectivity of the neuroendocrine system, and of hippocampal, cortical, reward, and serotonergic circuits in the establishment and the maintenance of stress resilience and vulnerability. We also touch upon recent findings suggesting a role for epigenetic mechanisms and neurogenesis in these processes and briefly discuss promising avenues of future investigation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Mental retardation is a group of cognitive disorders with a significant worldwide prevalence rate. This high rate, together with the considerable familial and societal burden resulting from these disorders, makes it an important focus for prevention and intervention. While the diseases associated with mental retardation are diverse, a significant number are linked with disruptions in epigenetic mechanisms, mainly due to loss-of-function mutations in genes that are key components of the epigenetic machinery. Additionally, several disorders classed as imprinting syndromes are associated with mental retardation. This review will discuss the epigenetic abnormalities associated with mental retardation, and will highlight their importance for diagnosis, treatment, and prevention of these disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Visualization of brain activity in humans and animals using functional magnetic resonance imaging (fMRI) is an established method for translational neuropsychopharmacology. It is useful to study the activity of defined brain structures, however it requires further refinement to allow more specific cellular analyses, like for instance, the activity of selected pools of brain cells. Here, we investigated brain activity in serotonergic pathways in the adult mouse brain by using acute pharmacological challenge of 5-hydroxytryptamine (5-HT) 1A receptors. We show that administration of the 5-HT(1A) receptor agonist 8-OH-DPAT prompts a dose-dependent reduction in local cerebral blood volume (CBV) in brain areas rich in neurons expressing post-synaptic 5-HT(1A) receptor, including the prefrontal cortex, hippocampus and amygdalar nuclei. Region-specific inhibition of the response by co-injection of 8-OH-DPAT with the selective 5-HT(1A) receptor antagonist WAY-100635, or in 5-HT(1A) knock-out mice, suggests that 5-HT(1A) receptors are the primary targets of the agonist. Overall, the data demonstrate the feasibility of mapping region-specific serotonergic transmission in the adult mouse brain in vivo by non-invasive fMRI. The method opens novel perspectives for investigating 5-HT(1A) receptor functions in mouse models of human pathologies resulting from a dysfunction of the 5-HT(1A) receptor or the serotonergic system, including depression and anxiety., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)

The long-term impact of early stress on behavior and emotions is well documented in humans, and can be modeled in experimental animals. In mice, maternal separation during early postnatal development induces poor and disorganized maternal care, and results in behavioral deficits that persist through adulthood. Here, we examined the long-term effect of unpredictable maternal separation combined with maternal stress on behavior and its transmissibility. We report that unpredictable maternal separation from birth to postnatal day 14 in C57Bl/6J mice has mild behavioral effects in the animals when adult, but that its combination with maternal stress exacerbates this effect. Further, the behavioral deficits are transmitted to the following generation through females, an effect that is independent of maternal care and is not affected by cross-fostering. The combined manipulation does not alter basic components of the hypothalamic-pituitary-adrenal axis but decreases the expression of the corticotropin releasing factor receptor 2 (CRFR2) in several nuclei of the amygdala and the hypothalamus in the brain of maternal-separated females. These results suggest a non-genomic mode of transmission of the impact of early stress in mice.

Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.

Background: Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations., Methods: To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14., Results: We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression., Conclusions: These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A complex interplay between the pattern of DNA methylation and a large and growing number of post-translational modifications (PTMs) of histones contribute to the epigenetic regulation of gene transcription. This epigenetic regulation involves histone acetylation, phosphorylation and methylation, and is now known to be important for several forms and phases of long-term memory. Anomalies in the epigenome have also been demonstrated to be critical factors in a number of cognitive and behavioural disorders. The epigenetic mechanisms that contribute to these deficits include: first, the dysregulation of key components of the epigenetic machinery; second, alterations in the expression of genes important for cognition and behaviour by epigenetic mechanisms; third, instability at trinucleotide repeats; and fourth, the breakdown of major epigenetic processes like imprinting and X-chromosome inactivation. Thus, both pharmacological and environmental interventions that act on epigenetic mechanisms provide a promising tool for the treatment of a wide variety of cognitive and behavioural disorders., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The epigenome is the overall epigenetic state of a cell and represents the ensemble of chromatin modifications. It is an essential mechanism for the regulation of the genome that depends on modifications of DNA and histones but does not involve any change of the DNA sequence. It was previously assumed that in order for appropriate cellular development and differentiation to occur in mammals, the epigenome was fully erased and reestablished between generations. However, several examples of incomplete erasure at specific genes have been reported, and this is suggested to be associated with the epigenetic inheritance of gene profiles. Although the existence of such a mode of inheritance has been controversial, there is increasing evidence that it does occur in rodents and humans. In this review, we discuss the evidence that adverse environmental factors can affect not only the individuals directly exposed to these factors but also their offspring. Because the epigenome is sensitive to environmental influence and, in some cases, can, in part, be transmitted across generations, it provides a potential mechanism for the transgenerational transmission of the impact of environmental factors. Environmental factors examined include exposure to toxicants, diet, and postnatal care, and DNA methylation is the main mechanism discussed in this review., ((c) 2009 Elsevier Inc. All rights reserved.)

The epigenetic marking of chromatin in the brain has recently been recognized as an essential mechanism for brain functions such as learning and memory formation. It allows nerve cells not only to respond to environmental stimuli and modulate their profile of gene expression, but also to establish and maintain their own identity. The epigenetic code is conferred by a set of covalent modifications on the basic elements of chromatin, DNA and histone proteins. These changes are catalyzed by specific enzymes and mechanisms, which include DNA methylation, and post-translational modifications of histone proteins such as acetylation, phosphorylation, methylation and ubiquitination. They are both stable and highly dynamic, and are triggered during stimulation of neuronal circuits but can also persist thereafter. Their study in animal models has demonstrated their importance, and revealed some of their modes of function., (© Société de Biologie, 2010.)

Retinal ganglion cells (RGCs) undergo apoptotic death in predictable time-dependant manners during development and as a consequence of injury. Recently, synthetic neural cell adhesion molecule (NCAM) agonists have been shown to provide neuroprotective support. Within the adult mouse retina, NCAM has been localized on all neurons and glia; however, no functional role has been determined. Using adult NCAM-/- mice, we directly tested the potential influence of NCAM on neuron survival in vivo and observed that, in NCAM-/- retinas, RGC densities are greater, RGC loss after injury is earlier and target tissue significantly influences adult RGC survival, all in contrast to wild-type retinas. Collectively, our results indicate that NCAM may play a vital role in regulating the developmental change in the effectiveness of local versus target-derived RGC trophic support and that, in the adult, endogenous NCAM influences the total number of CNS neurons and their survival following injury.

The purpose of the present experiment was to characterize changes in TrkB signaling in the rat visual system resulting from exposure to enriched environment. Female Sprague-Dawley rats were placed in enriched or impoverished conditions for 1, 7 or 28 days. Levels of BDNF protein and its predominant receptor TrkB were examined in the retina, superior colliculus and visual cortex. In the retina, 1 day of enrichment increased full-length TrkB and after 28 days increased BDNF. In the superior colliculus, enrichment for 7 days reduced full-length TrkB and after 28 days increased BDNF and full-length TrkB. One day of enrichment significantly increased BDNF, reduced full-length TrkB and increased truncated TrkB in the visual cortex. Consequently, we further investigated whether exposure to enriched environment and the subsequent changes in BDNF and TrkB translates into a neuroprotective effect on retinal ganglion cells (RGCs) following transection of the optic nerve. Although exogenous intraocular application of BDNF provides neuroprotection to RGCs after axotomy, the endogenous increase in BDNF in the retina after 28 days of enrichment had no effect on RGC survival. While enriched housing conditions offer a model of non-invasive rehabilitation treatment for injury and modulates changes in BDNF and TrkB levels, these molecular changes did not translate into a neuroprotective effect on RGCs following transection of the optic nerve.

Abnormal levels of brain-derived neurotrophic factor (BDNF) are associated with major depression, a disorder with a higher incidence in women than men. Stress affects BDNF levels in various brain regions and thus, a heightened stress response in females could contribute to the development of depression. As well, ovarian hormones directly affect brain levels of BDNF mRNA and protein. Two experiments were performed to investigate the effects of stress and sex and gonadal hormones on BDNF protein levels in CA1, CA3, and dentate gyrus (DG) subregions of the hippocampus. In the first experiment, male and female Sprague-Dawley rats were subjected to one hour of restraint stress or control handling prior to sacrifice. In the second experiment, fifty-one female rats were ovariectomized and separated into stress and control conditions, as described for the first experiment. Stressed and handled groups received a single injection of estrogen (E; 53h prior to stress), estrogen and progesterone (EP; E given at 53h and P given 5h prior to stress), or vehicle (OVX). In both experiments BDNF protein was quantified using an enzyme-linked immunosorbent enzyme assay (ELISA) in micropunches of hippocampus. Gonadally intact females had significantly higher levels of BDNF in CA3, but significantly lower levels in DG, relative to males. In CA3, stress significantly decreased BDNF in both males and females. In DG of ovariectomized female rats, the effects of stress were significantly different following EP vs. vehicle treatment. Thus, stress increased BDNF levels in EP-treated rats but decreased BDNF levels in vehicle-treated rats. Reduced trophic support in DG in the presence of estrogen and progesterone could jeopardize neurogenesis and under certain conditions could be a contributing factor to the hippocampal atrophy associated with stress-induced affective disorders. These results emphasize the need to consider sex, gonadal steroids, and hippocampal subregion when examining the effects of stress on the brain.

Heat shock proteins (Hsps) are highly conserved and under physiological conditions act as molecular chaperones and/or have anti-apoptotic activities. Expression in the brain of two heat shock proteins, the70 kDa Hsp (Hsp70) and the 27 kDa Hsp (Hsp27), is notable because both proteins are highly inducible in glial cells and neurons following a wide range of noxious stimuli including ischemia, epileptic seizure and hyperthermia. In the central nervous system, constitutive expression of Hsp27 is limited to many (but not all) sensory and motor neurons of the brain stem and spinal cord, while there is little or no constitutive expression of Hsp70. However, inducible expression of both Hsp70 and Hsp27 is present in many areas of the brain and retina and is associated with cellular resistance to a variety of insults. The potential for manipulating the expression levels of Hsps for therapeutic advantage in neurodegenerative diseases such as Alzheimer's disease, stroke and glaucoma will be explored.