Aging and neurodegeneration: From molecular mechanisms to therapeutic interventions.

Protein aggregation is a common age-associated process and can be a pathological hallmark of various neurodegenerative conditions, possibly because of an age-associated decline in the activity of components of the proteostasis network. The specific molecular drivers of protein aggregation in certain cell types are not well understood, posing tremendous challenges to current research aimed at devising strategies to treat neurodegenerative diseases. This preface introduces the special issue "Aging and Neurodegeneration: from molecular mechanisms to therapeutic interventions," featuring articles that assess the drivers of pathology in the aging cell, including oxidative stress, protein glycation/aggregation, and mitochondrial impairment.

Altered hippocampal doublecortin expression in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Motor symptoms include bradykinesia, resting tremors, muscular rigidity, and postural instability, while non-motor symptoms include cognitive impairments, mood disturbances, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Some of these symptoms may be influenced by the proper hippocampus functioning, including adult neurogenesis. Doublecortin (DCX) is a microtubule-associated protein that plays a pivotal role in the development and differentiation of migrating neurons. This study utilized postmortem human brain tissue of PD and age-matched control individuals to investigate DCX expression in the context of adult hippocampal neurogenesis. Our findings demonstrate a significant reduction in the number of DCX-expressing cells within the subgranular zone (SGZ), as well as a decrease in the nuclear area of these DCX-positive cells in postmortem brain tissue obtained from PD cases, suggesting an impairment in the adult hippocampal neurogenesis. Additionally, we found that the nuclear area of DCX-positive cells correlates with pH levels. In summary, we provide evidence supporting that the process of hippocampal adult neurogenesis is likely to be compromised in PD patients before cognitive dysfunction, shedding light on potential mechanisms contributing to the neuropsychiatric symptoms observed in affected individuals. Understanding these mechanisms may offer novel insights into the pathophysiology of PD and possible therapeutic avenues.

Beyond Motor Deficits: Environmental Enrichment Mitigates Huntington's Disease Effects in YAC128 Mice.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by motor, psychiatric, cognitive, and peripheral symptoms without effective therapy. Evidence suggests that lifestyle factors can modulate disease onset and progression, and environmental enrichment (EE) has emerged as a potential approach to mitigate the progression and severity of neurodegenerative processes. Wild-type (WT) and yeast artificial chromosome (YAC) 128 mice were exposed to different EE conditions. Animals from cohort 1 were exposed to EE between postnatal days 21 and 60, and animals from cohort 2 were exposed to EE between postnatal days 60 and 120. Motor and non-motor behavioral tests were employed to evaluate the effects of EE on HD progression. Monoamine levels, hippocampal cell proliferation, neuronal differentiation, and dendritic arborization were also assessed. Here we show that EE had an antidepressant-like effect and slowed the progression of motor deficits in HD mice. It also reduced monoamine levels, which correlated with better motor performance, particularly in the striatum. EE also modulated neuronal differentiation in the YAC128 hippocampus. These results confirm that EE can impact behavior, hippocampal neuroplasticity, and monoamine levels in YAC128 mice, suggesting this could be a therapeutic strategy to modulate neuroplasticity deficits in HD. However, further research is needed to fully understand EE's mechanisms and long-term effects as an adjuvant therapy for this debilitating condition.

Ketamine, but not fluoxetine, rapidly rescues corticosterone-induced impairments on glucocorticoid receptor and dendritic branching in the hippocampus of mice.

Although numerous studies have investigated the mechanisms underlying the fast and sustained antidepressant-like effects of ketamine, the contribution of the glucocorticoid receptor (GR) and dendritic branching remodeling to its responses remain to be fully established. This study investigated the ability of a single administration of ketamine to modulate the GR and dendritic branching remodeling and complexity in the hippocampus of mice subjected to chronic corticosterone (CORT) administration. CORT was administered for 21 days, followed by a single administration of ketamine (1 mg ∕kg, i.p.) or fluoxetine (10 mg ∕kg, p.o., conventional antidepressant) in mice. On 22nd, 24 h after the treatments, GR immunocontent in the hippocampus was analyzed by western blotting, while the dendritic arborization and dendrite length in the ventral and dorsal dentate gyrus (DG) of the hippocampus was analyzed by Sholl analysis. Chronic CORT administration downregulated hippocampal GR immunocontent, but this alteration was completely reversed by a single administration of ketamine, but not fluoxetine. Moreover, CORT administration significantly decreased dendritic branching in the dorsal and ventral DG areas and caused a mild decrease in dendrite length in both regions. Ketamine, but not fluoxetine, reversed CORT-induced dendritic branching loss in the ventral and dorsal DG areas, regions associated with mood regulation and cognitive functions, respectively. This study provides novel evidence that a single administration of ketamine, but not fluoxetine, rescued the impairments on GR and dendritic branching in the hippocampus of mice subjected to chronic CORT administration, effects that may be associated with its rapid antidepressant response.

In Pursuit of Healthy Aging: Effects of Nutrition on Brain Function.

Consuming a balanced, nutritious diet is important for maintaining health, especially as individuals age. Several studies suggest that consuming a diet rich in antioxidants and anti-inflammatory components such as those found in fruits, nuts, vegetables, and fish may reduce age-related cognitive decline and the risk of developing various neurodegenerative diseases. Numerous studies have been published over the last decade focusing on nutrition and how this impacts health. The main objective of the current article is to review the data linking the role of diet and nutrition with aging and age-related cognitive decline. Specifically, we discuss the roles of micronutrients and macronutrients and provide an overview of how the gut microbiota-gut-brain axis and nutrition impact brain function in general and cognitive processes in particular during aging. We propose that dietary interventions designed to optimize the levels of macro and micronutrients and maximize the functioning of the microbiota-gut-brain axis can be of therapeutic value for improving cognitive functioning, particularly during aging.

New Avenues for the Treatment of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.

Antidepressant-like and pro-neurogenic effects of physical exercise: the putative role of FNDC5/irisin pathway.

Physical exercise has been shown to exert antidepressant effects, but the mechanisms underlying this effect are not completely elucidated. Therefore, we aimed at investigating the antidepressant, pro-neurogenic, and neuroprotective effects of physical exercise and the possible role of FNDC5/irisin for this effect. Treadmill running was used as a protocol of physical exercise (45 min/day/5 days/week for 4 weeks) in female Swiss mice. Immobility time was registered in the tail suspension test (TST) and forced swim test (FST). Immunohistochemical analyses to evaluate hippocampal cell proliferation, neuronal survival, and neuronal commitment and maturation, as well as expression of FNDC5 C-terminal fragment were performed in the entire, dorsal, and ventral dentate gyrus (DG) of the hippocampus. Fluoro-Jade B staining was performed to evaluate degenerating neurons in DG. FNDC5 C-terminal and FNDC5/irisin immunocontents were analyzed by western blot. Exposure to physical exercise reduced the immobility time both in the TST and the FST. This antidepressant-like effect was accompanied by an increase in hippocampal cell proliferation, hippocampal neuronal differentiation, and neuronal survival in the dorsal and ventral DG. Fluoro-Jade B staining was reduced in entire and dorsal DG in exercised mice. Finally, physical exercise also resulted in increased number of FNDC5-positive cells in the hippocampal DG as well as elevated FNDC5 C-terminal and FNDC5/irisin immunocontent in the entire hippocampus. The results suggest that the FNDC5 C-terminal fragment/irisin pathway may be implicated in the antidepressant-like, pro-neurogenic, and neuroprotective effects of treadmill running.

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

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

The Effects of Ethanol Exposure During Distinct Periods of Brain Development on Oxidative Stress in the Adult Rat Brain.

BACKGROUND: The consumption of alcohol during pregnancy can result in abnormal fetal development and impaired brain function in humans and experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol (EtOH), a variety of structural and functional brain deficits can be observed. METHODS: This study compared the effects of EtOH exposure during distinct periods of brain development on oxidative damage and endogenous antioxidant status in various brain regions of adult female and male Sprague Dawley rats. Pregnant dams and neonatal rats were exposed to EtOH during one of the following time windows: between gestational days (GDs) 1 and 10 (first trimester equivalent); between GDs 11 and 21 (second trimester equivalent); or between postnatal days (PNDs) 4 and 10 (third trimester equivalent). RESULTS: EtOH exposure during any of the 3 trimester equivalents significantly increased lipid peroxidation in both the cornus ammonis (CA) and dentate gyrus (DG) subregions of the hippocampus, while also decreasing the levels of the endogenous antioxidant glutathione in the hippocampal CA and DG subregions as well as the prefrontal cortex of young adult animals (PND 60). CONCLUSIONS: These results indicate that EtOH exposure during restricted periods of brain development can have long-term consequences in the adult brain by dysregulating its redox status. This dysfunction may underlie, at least in part, the long-term alterations in brain function associated with fetal alcohol spectrum disorders.

The antidepressant-like effect of chronic guanosine treatment is associated with increased hippocampal neuronal differentiation.

Guanosine is a purine nucleoside that occurs naturally in the central nervous system, exerting trophic effects. Given its neuroprotective properties, the potential of guanosine as an antidepressant has been recently examined. Within this context, the present study sought to investigate the effects of chronic treatment with guanosine on the tail suspension test (TST), open field test and adult hippocampal neurogenesis. Swiss mice were administered guanosine for 21 days (5 mg/kg/day, p.o.) and subsequently submitted to the TST and open-field test. Following behavioural testing, animals were killed and the brains were processed for immunohistochemical analyses of hippocampal cell proliferation and neuronal differentiation. Animals treated with guanosine showed a reduction in immobility time in the TST without alterations in locomotor activity, confirming the antidepressant-like effect of this compound. Quantitative microscopic analysis did not reveal significant alterations in the numbers of Ki-67- and proliferating cell nuclear antigen (PCNA)-positive cells in the hippocampal dentate gyrus (DG) of guanosine-treated mice. However, guanosine treatment resulted in a significant increase in the number of immature neurons, as assessed by immunohistochemistry for the neurogenic differentiation protein. Interestingly, this effect was localized to the ventral hippocampal DG, a functionally distinct region of this structure known to regulate emotional and motivational behaviours. Taken together, our results suggest that the antidepressant-like effect of chronic guanosine treatment is associated with an increase in neuronal differentiation, reinforcing the notion that this nucleoside may be an endogenous mood modulator.

GluN2A-/- Mice Lack Bidirectional Synaptic Plasticity in the Dentate Gyrus and Perform Poorly on Spatial Pattern Separation Tasks.

The different secondary subunits of the N-methyl-d-aspartate (NMDA) receptor each convey unique biophysical properties to the receptor complex, and may be key in determining the functional role played by NMDA receptors. In the hippocampus, the GluN2A and GluN2B subunits are particularly abundant; however, their exact roles in synaptic plasticity and behavior remain controversial. Here, we show that mice carrying a deletion for the GluN2A subunit (GluN2A(-/-)) demonstrate a severely compromised NMDA to AMPA receptor current ratio in granule cells from the dentate gyrus (DG), while granule cell morphology is unaltered. This deficit is accompanied by significant impairments in both LTP and LTD in the DG, whereas only minor impairments are observed in the CA1. In accordance with these hippocampal region-specific deficits, GluN2A(-/-) mice show impaired performance on the DG-associated task of spatial pattern separation. In contrast, GluN2A(-/-) mice show no deficit in temporal pattern separation, a process associated with CA1 functioning. Thus, our results establish the GluN2A subunit as a significant contributor to both bidirectional synaptic plasticity and spatial pattern separation in the DG.

VEGF can protect against blood brain barrier dysfunction, dendritic spine loss and spatial memory impairment in an experimental model of diabetes.

Clinical and experimental studies have shown a clear link between diabetes, vascular dysfunction and cognitive impairment. However, the molecular underpinnings of this association remain unclear. Since vascular endothelial growth factor (VEGF) signaling is important for maintaining vascular integrity and function, we hypothesized that vascular and cognitive impairment in the diabetic brain could be related to a deficiency in VEGF signaling. Here we show that chronic hyperglycemia (~8weeks) in a mouse model of type 1 diabetes leads to a selective reduction in the expression of VEGF and its cognate receptor (VEGF-R2) in the hippocampus. Correlating with this, diabetic mice showed selective deficits in spatial memory in the Morris water maze, increased vessel area, width and permeability in the dentate gyrus/CA1 region of the hippocampus and reduced spine densities in CA1 neurons. Chronic low dose infusion of VEGF in diabetic mice was sufficient to restore VEGF signaling, protect them from memory deficits, as well as vascular and synaptic abnormalities in the hippocampus. These findings suggest that a hippocampal specific reduction in VEGF signaling and resultant vascular/neuronal defects may underlie early manifestations of cognitive impairment commonly associated with diabetes. Furthermore, restoring VEGF signaling may be a useful strategy for preserving hippocampal-related brain circuitry in degenerative vascular diseases.

Impairments in hippocampal synaptic plasticity following prenatal ethanol exposure are dependent on glutathione levels.

Previous studies from our laboratory have shown that prenatal ethanol exposure (PNEE) causes a significant deficit in synaptic plasticity, namely long-term potentiation (LTP), in the dentate gyrus (DG) region of the hippocampus of male rats. PNEE has also been shown to induce an increase in oxidative stress and a reduction in antioxidant capacity in the brains of both male and female animals. In this study the interaction between LTP and the major antioxidant in the brain, glutathione (GSH), is examined. We show that depletion of the intracellular reserves of GSH with diethyl maleate (DEM) reduces LTP in control male, but not female animals, mirroring the effects of PNEE. Furthermore, treatment of PNEE animals with N-acetyl cysteine (NAC), a cysteine donor for the synthesis of GSH, increases GSH levels in the hippocampus and completely restores the deficits in LTP in PNEE males. These results indicate that in males GSH plays a major role in regulating LTP, and that PNEE may cause reductions in LTP by reducing the intracellular pool of this endogenous antioxidant.

Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration.

Neuroplasticity refers to the ability of the brain to reorganize and modify its neural connections in response to environmental stimuli, experience, learning, injury, and disease processes. It encompasses a range of mechanisms, including changes in synaptic strength and connectivity, the formation of new synapses, alterations in the structure and function of neurons, and the generation of new neurons. Neuroplasticity plays a crucial role in developing and maintaining brain function, including learning and memory, as well as in recovery from brain injury and adaptation to environmental changes. In this review, we explore the vast potential of neuroplasticity in various aspects of brain function across the lifespan and in the context of disease. Changes in the aging brain and the significance of neuroplasticity in maintaining cognitive function later in life will also be reviewed. Finally, we will discuss common mechanisms associated with age-related neurodegenerative processes (including protein aggregation and accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation) and how these processes can be mitigated, at least partially, by non-invasive and non-pharmacologic lifestyle interventions aimed at promoting and harnessing neuroplasticity.

SUMO-modifying Huntington's disease.

Small ubiquitin-like modifiers, SUMOs, are proteins that are conjugated to target substrates and regulate their functions in a post-translational modification called SUMOylation. In addition to its physiological roles, SUMOylation has been implicated in several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases (HD). HD is a neurodegenerative monogenetic autosomal dominant disorder caused by a mutation in the CAG repeat of the huntingtin (htt) gene, which expresses a mutant Htt protein more susceptible to aggregation and toxicity. Besides Htt, other SUMO ligases, enzymes, mitochondrial and autophagic components are also important for the progression of the disease. Here we review the main aspects of Htt SUMOylation and its role in cellular processes involved in the pathogenesis of HD.

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

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

Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway.

The mTORC1-dependent dendritic spines formation represents a key mechanism for fast and long-lasting antidepressant responses, but it remains to be determined whether this mechanism may account for the ability of guanosine in potentiating ketamine's actions. Here, we investigated the ability of ketamine plus guanosine to elicit fast and sustained antidepressant-like and pro-synaptogenic effects in mice and the role of mTORC1 signaling in these responses. The combined administration of subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) caused a fast (1 h - 24 h), but not long-lasting (7 days) reduction in the immobility time in the tail suspension test. This behavioral effect was paralleled by a rapid (started in 1 h) and transient (back to baseline in 24 h) increase on BDNF, p-Akt (Ser473), p-GSK-3ß (Ser9), p-mTORC1 (Ser2448), p-p70S6K (Thr389) immunocontent in the hippocampus, but not in the prefrontal cortex. Conversely, ketamine plus guanosine increased PSD-95 and GluA1 immunocontent in the prefrontal cortex, but not the hippocampus after 1 h, whereas increased levels of these proteins in both brain structures were observed after 24 h, but these effects did not persist after 7 days. The combined administration of ketamine plus guanosine raised the dendritic spines density in the ventral hippocampal DG and prefrontal cortex after 24 h Rapamycin (0.2 nmol/site, i.c.v.) abrogated the antidepressant-like effect and pro-synaptogenic responses triggered by ketamine plus guanosine. These results indicate that guanosine may boost the antidepressant-like effect of ketamine for up to 24 h by a mTORC1-dependent mechanism.

Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders.

Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder.

Changes in Affective Behavior and Oxidative Stress after Binge Alcohol in Male and Female Rats.

Binge alcohol consumption and alcohol use disorders (AUD) are prevalent, and there is comorbidity with depression and anxiety. Potential underlying mechanisms include neurophysiological, genetic, and metabolic changes resulting from alcohol exposure. Mood and anxiety disorders are more common among women, but whether females are more susceptible to binge-induced oxidative stress and co-occurring anxiety and depression-like behaviors remains unknown. Here, we used a repeated, weekly binge alcohol paradigm in male and female rats to investigate sex differences in despair and anxiety-like behaviors and brain oxidative stress parameters. A single binge alcohol exposure significantly elevated glutathione (GSH) levels in prefrontal cortex (PFC) of both male and female animals. This was accompanied by increased lipid peroxidation in PFC of both sexes. Repeated (once weekly) binge exposure induced changes in anxiety- and depression-like behaviors in both males and females and increased GSH level in the PFC without detectable oxidative damage. Our findings suggest that repeated binge alcohol exposure influences affect regardless of sex and in the absence of membrane damage.

Effects of postnatal ethanol exposure and maternal separation on mood, cognition and hippocampal arborization in adolescent rats.

Ethanol exposure and early life stress during brain development are associated with an increased risk of developing psychiatric disorders. We used a third-trimester equivalent model of fetal alcohol spectrum disorders combined with a maternal separation (MS) protocol to evaluate whether these stressors cause sexually dimorphic behavioral and hippocampal dendritic arborization responses in adolescent rats. Wistar rat pups were divided into four experimental groups: 1) Control; 2) MS (MS, for 3 h/day from postnatal (PND) 2 to PND14); 3) EtOH (EtOH, 5 g/kg/day, i.p., PND2, 4, 6, 8, and 10); 4) EtOH + MS. All animals were divided into two cohorts and subjected to a battery of behavioral tests when they reached adolescence (PND37-44). Animals from cohort 1 were submitted to: 1) the open field test; 2) self-cleaning behavior (PND38); and 3) the motivation test (PND39-41). Animals from cohort 2 were submitted to: 1) the novel object recognition (PND37-39); 2) social investigation test (PND40); and 3) Morris water maze test (PND41-44). At PND45, the animals were euthanized, and the brains were collected for subsequent dendritic analysis. Postnatal ethanol exposure (PEE) caused anxiety-like behavior in females and reduced motivation, and increased hippocampal dendritic arborization in both sexes. MS reduced body weight, increased locomotor activity in females, and increased motivation, and hippocampal dendritic arborization in both sexes. We found that males from the EtOH + MS groups are more socially engaged than females, who were more interested in sweets than males. Altogether, these data suggest that early life adverse conditions may alter behavior in a sex-dependent manner in adolescent rats.