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Second-generation antipsychotics are the drugs of choice for the treatment of neurodevelopmental-related mental diseases such as schizophrenia. Despite the effectiveness of these drugs to ameliorate some of the symptoms of schizophrenia, specifically the positive ones, the mechanisms beyond their antipsychotic effect are still poorly understood. Second-generation antipsychotics are reported to have anti-inflammatory, antioxidant and neuroplastic properties. Using the neonatal ventral hippocampus lesion (nVHL) in the rat, an accepted schizophrenia-related model, we evaluated the effect of the second-generation antipsychotic olanzapine (OLZ) in the behavioral, neuroplastic, and neuroinflammatory alterations exhibited in the nVHL animals. OLZ corrected the hyperlocomotion and impaired working memory of the nVHL rats but failed to enhance social behavior disturbances of these animals. In the prefrontal cortex (PFC), OLZ restored the pyramidal cell structural plasticity in the nVHL rats, enhancing the dendritic arbor length, the spinogenesis and the proportion of mature spines. Moreover, OLZ attenuated astrogliosis as well as some pro-inflammatory, oxidative stress, and apoptosis-related molecules in the PFC. These findings reinforce the evidence of anti-inflammatory, antioxidant, and neurotrophic mechanisms of second-generation antipsychotics in the nVHL schizophrenia-related model, which allows for the possibility of developing more specific drugs for this disorder and thus avoiding the side effects of current schizophrenia treatments.

It is known that continuous abuse of amphetamine (AMPH) results in alterations in neuronal structure and cognitive behaviors related to the reward system. However, the impact of AMPH abuse on the hippocampus remains unknown. The aim of this study was to determine the damage caused by AMPH in the hippocampus in an addiction model. We reproduced the AMPH sensitization model proposed by Robinson et al. in 1997 and performed the novel object recognition test (NORt) to evaluate learning and memory behaviors. After the NORt, we performed Golgi-Cox staining, a stereological cell count, immunohistochemistry to determine the presence of GFAP, CASP3, and MT-III, and evaluated oxidative stress in the hippocampus. We found that AMPH treatment generates impairment in short- and long-term memories and a decrease in neuronal density in the CA1 region of the hippocampus. The morphological test showed an increase in the total dendritic length, but a decrease in the number of mature spines in the CA1 region. GFAP labeling increased in the CA1 region and MT-III increased in the CA1 and CA3 regions. Finally, we found a decrease in Zn concentration in the hippocampus after AMPH treatment. An increase in the dopaminergic tone caused by AMPH sensitization generates oxidative stress, neuronal death, and morphological changes in the hippocampus that affect cognitive behaviors like short- and long-term memories.

Suicidal behavior is result of the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide). Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. We identified 153 differentially methylated sites between individuals with low and high-PRS. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment (CHD7, RFX4, KCNA1, PLCB1, PITX1, NUMBL) and ATP binding (KIF7, NUBP2, KIF6, ATP8B1, ATP11A, CLCN7, MYLK, MAP2K5). Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Increased dopaminergic activity in the striatum underlies the neurobiology of psychotic symptoms in schizophrenia (SZ). Beyond the impaired connectivity among the limbic system, the excess of dopamine could lead to inflammation and oxidative/nitrosative stress. It has been suggested that atypical antipsychotic drugs attenuate psychosis not only due to their modulatory activity on the dopaminergic/serotonergic neurotransmission but also due to their anti-inflammatory/antioxidant effects. In such a manner, we assessed the effects of the atypical antipsychotic risperidone (RISP) on the structural neuroplasticity and biochemistry of the striatum in adult rats with neonatal ventral hippocampus lesion (NVHL), which is a developmental SZ-related model. RISP administration (0.25 mg/kg, i.p.) ameliorated the neuronal atrophy and the impairments in the morphology of the dendritic spines in the spiny projection neurons (SPNs) of the ventral striatum (nucleus accumbens: NAcc) in the NVHL rats. Also, RISP treatment normalized the pro-inflammatory pathways and induced the antioxidant activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this model. Our results point to the neurotrophic, anti-inflammatory, and antioxidant effects of RISP, together with its canonical antipsychotic mechanism, to enhance striatum function in animals with NVHL.

Genetic factors have been implicated in suicidal behavior. It has been suggested that one of the roles of genetic factors in suicide could be represented by the effect of genetic variants on gene expression regulation. Alteration in the expression of genes participating in multiple biological systems in the suicidal brain has been demonstrated, so it is imperative to identify genetic variants that could influence gene expression or its regulatory mechanisms. In this study, we integrated DNA methylation, gene expression, and genotype data from the prefrontal cortex of suicides to identify genetic variants that could be factors in the regulation of gene expression, generally called quantitative trait locus (xQTLs). We identify 6,224 methylation quantitative trait loci and 2,239 expression quantitative trait loci (eQTLs) in the prefrontal cortex of suicide completers. The xQTLs identified influence the expression of genes involved in neurodevelopment and cell organization. Two of the eQTLs identified (rs8065311 and rs1019238) were previously associated with cannabis dependence, highlighting a candidate genetic variant for the increased suicide risk in subjects with substance use disorders. Our findings suggest that genetic variants may regulate gene expression in the prefrontal cortex of suicides through the modulation of promoter and enhancer activity, and to a lesser extent, binding transcription factors.

Cadmium (Cd) is a toxic metal and classified as a carcinogen whose exposure could affect the function of the central nervous system. There are studies that suggest that Cd promotes neurodegeneration in different regions of the brain, particularly in the hippocampus. It is proposed that its mechanism of toxicity maybe by an oxidative stress pathway, which modifies neuronal morphology and causes the death of neurons and consequently affecting cognitive tasks. However, this mechanism is not yet clear. The aim of the present work was to study the effect of Cd administration on recognition memory for 2, 3 and 4 months, neuronal morphology and immunoreactivity for caspase-3 and 9 in rat hippocampi. The results show that the administration of Cd decreased recognition memory. Likewise, it caused the dendritic morphology of the CA1, CA3 and dentate gyrus regions of the hippocampus to decrease with respect to the time of administration of this heavy metal. In addition, we observed a reduction in the density of dendritic spines as well as an increase in the immunoreactivity of caspase-3 and 9 in the same hippocampal regions of the animals treated with Cd. These results suggest that Cd affects the structure and function of the neurons of the hippocampus, which contribute to the deterioration of recognition memory. Our results suggest that the exposure to Cd represents a critical health problem, which if not addressed quickly, could cause much more serious problems in the quality of life of the human population, as well as in the environment in which they develop.

Schizophrenia is a neurodevelopmental disorder identified by psychotic episodes, as well as cognitive deficits. There are reports of multiple alterations in the brain in schizophrenia, such as fewer dendritic spines with shape abnormalities in cortical and subcortical areas. A correlation has been established between shape and function in dendritic spines; and as the main site of excitatory synapses, the dendritic spine pathology represents a potential target for novel therapeutic tools in schizophrenia. Neonatal ventral hippocampus lesion (nVHL) in the rat has been extensively used to examine some of the pathophysiological mechanisms of schizophrenia since it mimics several behaviors, as well as abnormalities in morphological corticolimbic neurons. Thus, in this report, we determined the effects of the nVHL on locomotor behavior and memory in postpubertal rats. Also, we explored the density and the dynamics of the dendritic spines in the pyramidal neurons of layers 3 and 5 of the prefrontal cortex (PFC) and basolateral amygdala (BLA), and also in the nucleus accumbens (NAcc) medium spiny neurons (MSN). We found that nVHL rats have exhibited both hyperlocomotion and memory deficits. nVHL also reduced the number of dendritic spines and decreased the proportion of mature spines in these neurons. In conclusion, nVHL triggers behavioral abnormalities in postpubertal rats that can be associated not only with the lack of dendritic spines but also with distortion of these structures in corticolimbic neurons. Hence, the nVHL can be useful to explore the mechanisms of the dendritic spine pathology and its implications for schizophrenia.

Patients with substance use disorders (SUD) are at high risk to die by suicide. So far, the neurobiology of the suicide-SUD association has not been elucidated. This study aimed to identify potential pharmacological targets among hub genes from brain gene co-expression networks of individuals with SUD in a suicidal and non-suicidal context. Post-mortem samples from the prefrontal cortex of 79 individuals were analyzed. Individuals were classified into the following groups: suicides with SUD (n = 28), suicides without SUD (n = 23), nonsuicides with SUD (n = 9), nonsuicides without SUD (n = 19). Gene expression profiles were evaluated with the Illumina HumanHT-12 v4 array. Co-expression networks were constructed in WGCNA using the differentially expressed genes found in the comparisons: (a) suicides with and without SUD and (b) nonsuicides with and without SUD. Hub genes were selected for drug-gene interaction testing in the DGIdb database. Among drugs interacting with hub genes in suicides we found MAOA inhibitors and dextromethorphan. In the nonsuicide individuals, we found interactions with eglumegad and antipsychotics (olanzapine, clozapine, loxapine). Modafinil was found to interact with genes in both suicides and nonsuicides. These drugs represent possible candidate treatments for patients with SUD with and without suicidal behavior and their study in each context is encouraged.

In the aging process, the brain presents biochemical and morphological alterations. The neurons of the limbic system show reduced size dendrites, in addition to the loss of dendritic spines. These disturbances trigger a decrease in motor and cognitive function. Likewise, it is reported that during aging, in the brain, there is a significant decrease in neurotrophic factors, which are essential in promoting the survival and plasticity of neurons. The carboxyl-terminal fragment of the heavy chain of the tetanus toxin (Hc-TeTx) acts similarly to neurotrophic factors, inducing neuroprotection in different models of neuronal damage. The aim here, was to evaluate the effect of Hc-TeTx on the motor processes of elderly mice (18 months old), and its impact on the dendritic morphology and density of dendritic spines of neurons in the limbic system. The morphological analysis in the dendrites was evaluated employing Golgi-Cox staining. Hc-TeTx was administered (0.5 mg/kg) intraperitoneally for three days in 18-month-old mice. Locomotor activity was evaluated in a novel environment 30 days after the last administration of Hc-TeTx. Mice treated with Hc-TeTx showed significant changes in their motor behavior, and an increased dendritic spine density of pyramidal neurons in layers 3 and 5 of the prefrontal cortex in the hippocampus, and medium spiny neurons of the nucleus accumbens (NAcc). In conclusion, the Hc-TeTx improves the plasticity of the brain regions of the limbic system of aged mice. Therefore, it is proposed as a pharmacological alternative to prevent or delay brain damage during aging.

Background Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. Objective The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Methods Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. Results We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. Conclusions The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms.

The consumption of foods rich in carbohydrates, saturated fat, and sodium, accompanied by a sedentary routine, are factors that contribute to the progress of metabolic syndrome (MS). In this way, they cause the accumulation of body fat, hypertension, dyslipidemia, and hyperglycemia. Additionally, MS has been shown to cause oxidative stress, inflammation, and death of neurons in the hippocampus. Consequently, spatial and recognition memory is affected. It has recently been proposed that metformin decavanadate (MetfDeca) exerts insulin mimetic effects that enhance metabolism in MS animals; however, what effects it can cause on the hippocampal neurons of rats with MS are unknown. The objective of the work was to evaluate the effect of MetfDeca on hippocampal neurodegeneration and recognition memory in rats with MS. Administration of MetfDeca for 60 days in MS rats improved object recognition memory (NORt). In addition, MetfDeca reduced markers of oxidative stress and hippocampal neuroinflammation. Accompanied by an increase in the density and length of the dendritic spines of the hippocampus of rats with MS. We conclude that MetfDeca represents an important therapeutic agent to treat MS and induce neuronal and cognitive restoration mechanisms.

Metabolic syndrome (MS) results from excessive consumption of high-calorie foods and sedentary lifestyles. Clinically, insulin resistance, abdominal obesity, hyperglycemia, dyslipidemia, and hypertension are observed. MS has been considered a risk factor in the development of dementia. In the brain, a metabolically impaired environment generates oxidative stress and excessive production of pro-inflammatory cytokines that deteriorate the morphology and neuronal function in the hippocampus, leading to cognitive impairment. Therapeutic alternatives suggest that phenolic compounds can be part of the treatment for neuropathies and metabolic diseases. In recent years, the use of Gallic Acid (GA) has demonstrated antioxidant and anti-inflammatory effects that contribute to neuroprotection and memory improvement in animal models. However, the effect of GA on hippocampal neurodegeneration and memory impairment under MS conditions is still unclear. In this work, we administered GA (20 mg/kg) for 60 days to rats with MS. The results show that GA treatment improved zoometric and biochemical parameters, as well as the recognition memory, in animals with MS. Additionally, GA administration increased hippocampal dendritic spines and decreased oxidative stress and inflammation. Our results show that GA treatment improves metabolism: reducing the oxidative and inflammatory environment that facilitates the recovery of the neuronal morphology in the hippocampus of rats with MS. Consequently, the recognition of objects by these animals, suggesting that GA could be used therapeutically in metabolic disorders that cause dementia.

Metabolic syndrome (MS) is a health problem that is characterized by body fat accumulation, hypertension, dyslipidemia, and hyperglycemia; recently, it has been demonstrated that MS also damages memory processes. The first-line drug in the treatment of MS and type 2 diabetes mellitus is metformin, which is an antihyperglycemic agent. This drug has been shown to produce neuroprotection and to improve memory processes. However, the mechanism involved in this neuroprotection is unknown. A 90-day administration of metformin improved the cognitive processes of rats with MS as evaluated by the novel object recognition test, and this finding could be explained by an increase in the neuronal spine density and spine length. We also found that metformin increased the immunoreactivity of synaptophysin, sirtuin-1, AMP-activated protein kinase, and brain-derived neuronal factor, which are important plasticity markers. We conclude that metformin is an important therapeutic agent that increases neural plasticity and protects cognitive processes. The use of this drug is important in the minimization of the damage caused by MS.

Attention deficit hyperactivity disorder (ADHAD) is a neurobehavioral disorder that affects children and adolescents with a high prevalence. Despite its prevalence and an unclear etiology, previous reports suggest that it is closely related to homocysteine metabolism. Male Sprague Dawley rats were administered with homocysteine from postnatal day (PD) 2 to PD 16. Locomotor activity was evaluated at 35 PD (prepuberal age) and 60 PD (adult age) before and after amphetamine administration. In rats evaluated at both ages, homocysteine induced hyperactivity, and the amphetamine administration reduced hyperactivity significantly at 35 PD, but not at 60 PD. In the social interaction test, homocysteine reduced the number of contacts and increased the latency to the first contact only in rats at 35 PD. Homocysteine also had an effect on short term memory at 35D and 60 PD and long-term memory at 60 PD. Morphological changes were found mainly in the shape of dendritic spines in the prefrontal cortex (PFC-3), dorsal hippocampus (CA1), dentate gyrus (DG) and nucleus accumbens (NAcc), in rats administered neonatally with homocysteine at both ages studied. In prepuberal and adult rats, there was an increase in dendritic length in DG and NAcc, respectively. The dendritic spine morphology also was altered at both ages, mainly decreasing the number of mushroom spines in NAcc and CA1 at 30 PD and in all the areas studied at 60 PD rats. Those areas are associated with the processes of attention, learning and memory that were studied, and those alterations are possibly related to changes observed in the behavioral tests. These behavioral and morphological changes in rats at 35 PD administered with homocysteine could be similar to changes found in children diagnosed with ADHD. Moreover, half to two thirds of children diagnosed with ADHD reach adulthood with this disorder. In this study we found similarities with ADHD, finding alterations in both rats at 35 PD and 60 PD. So, this may be proposed as an animal model to study this disorder present in children, adolescents and adults.

Objective: Dual diagnosis (DD) is the co-occurrence of at least one substance use disorder and one or more mental disorders in a given individual. Despite this comorbidity being highly prevalent an...

It is known that continuous abuse of amphetamine (AMPH) results in alterations in neuronal structure and cognitive behaviors related to the reward system. However, the impact of AMPH abuse on the hippocampus remains unknown. The aim of this study was to determine the damage caused by AMPH in the hippocampus in an addiction model. We reproduced the AMPH sensitization model proposed by Robinson et al. in 1997 and performed the novel object recognition test (NORt) to evaluate learning and memory behaviors. After the NORt, we performed Golgi-Cox staining, a stereological cell count, immunohistochemistry to determine the presence of GFAP, CASP3, and MT-III, and evaluated oxidative stress in the hippocampus. We found that AMPH treatment generates impairment in short- and long-term memories and a decrease in neuronal density in the CA1 region of the hippocampus. The morphological test showed an increase in the total dendritic length, but a decrease in the number of mature spines in the CA1 region. GFAP labeling increased in the CA1 region and MT-III increased in the CA1 and CA3 regions. Finally, we found a decrease in Zn concentration in the hippocampus after AMPH treatment. An increase in the dopaminergic tone caused by AMPH sensitization generates oxidative stress, neuronal death, and morphological changes in the hippocampus that affect cognitive behaviors like short- and long-term memories.

Schizophrenia is a debilitating disorder that may have a neurodevelopmental origin. For this reason, animal models based on neonatal insults or manipulations have been extensively used to demonstrate schizophrenia-related behaviors. Among those, the neonatal ventral hippocampus lesion (nVHL) is largely used as a model of schizophrenia-related behavior as it mimics behavioral and neurochemical abnormalities often seen in schizophrenic patients including hyperlocomotion in a novel environment. To investigate the neuroanatomical basis of coding novelty in the nVHL rat, we assessed the behavioral locomotor activity paradigm in a novel environment and measured expression of c-Fos, a marker of neural activation, in brain regions involved in the process of coding novelty or locomotion. Upon reaching adulthood, nVHL rats showed hyperlocomotion in the novel environment paradigm. Moreover, in nVHL rats the expression of c-Fos was greater in the prefrontal cortex (PFC) and CA1 region of the dorsal hippocampus compared to sham rats. Whereas similar expression of c-Fos was observed in the basolateral amygdala, nucleus accumbens and dentate gyrus region of hippocampus of nVHL and sham rats. These results suggest that the nVHL disrupts the neural activity in the PFC and CA1 region of hippocampus in the process of coding novelty in the rat.

Background Suicidal behavior may be divided into completed suicide, suicide attempts, and suicidal ideation. It has been suggested that these behaviors represent a continuum and result from the interaction of several contributors, including genetic and environmental factors. The integration of approaches considering the polygenic component of suicidal behavior, such as polygenic risk scores (PRS) and DNA methylation is promising for improving our understanding of the complex interplay between genetic and environmental factors in this behavior. The aim of this study was the evaluation of DNA methylation differences between individuals with high and low genetic burden for suicidality. Methods The present study was divided into two phases. In the first phase, genotyping with the Psycharray chip was performed in a discovery sample of 568 Mexican individuals, of which 149 had suicidal behavior (64 individuals with suicidal ideation, 50 with suicide attempt and 35 with completed suicide) and 419 non-suicide controls. Then, a PRS analysis based on summary statistics from the Psychiatric Genomic Consortium was performed in the discovery sample. In a second phase, we evaluated DNA methylation differences between individuals with high and low genetic burden for suicidality in a sub-sample of the discovery sample (target sample) of 94 subjects. Methylation profile from individuals in the target sample was assessed with the Illumina Infinium Human Methylation EPIC BeadChip. Results We identified 153 differentially methylated sites between individuals with low and high-PRS. From these, 91 sites were hypermethylated and 62 hypomethylated in the high PRS group relative to low PRS group. Among genes mapped to differentially methylated sites, we found genes involved in neurodevelopment and ATP binding. Discussion To our knowledge, this is the first study integrating polygenic risk scores and DNA methylation in suicidality. Our results suggest that genetic variants might increase the predisposition to epigenetic variations in genes involved in neurodevelopment. This study highlights the possible implication of polygenic burden in the alteration of epigenetic changes in suicidal behavior.

Background Suicide rates vary substantially by sex. Suicides committed by males significantly outnumber female suicides. Disparities in community and social factors provide a partial explanation for this phenomenon. Thus, the evaluation of sex differences at a biological level might contribute to the elucidation of the factors involved in this imbalance. The aim of the present study was to evaluate sex-specific gene expression patterns in the suicidal brain. Methods postmortem samples from the dorsolateral prefrontal cortex (DLPFC) of 75 Latino individuals were analyzed. We considered the following groups: i) male suicides (n = 38), ii) female suicides (n = 10), iii) male controls (n = 20), and iv) female controls (n = 7). Gene expression profiles were evaluated by microarrays. Differentially expressed genes among the groups were identified with a linear model. Similarities and differences in the gene sets between the sexes were identified. Results Differentially expressed genes were identified between suicides and controls of each sex: 1,729 genes in females and 1,997 genes in males. Female-exclusive suicide genes were related to cell proliferation and immune response. Meanwhile, male-exclusive suicide genes were associated to DNA binding and ribonucleic protein complex. Sex-independent suicide genes showed enrichment in mitochondrial and vesicular functions. Limitations Relatively small sample size. Our diagnosis approach was limited to information found on coroner's records. The analysis was limited to a single brain area (DLPFC) and we used microarrays. Conclusion Previously unexplored sex differences in the brain gene expression of suicide completers were identified, providing valuable foundation for the evaluation of sex-specific factors in suicide.

The main characteristic of brain aging is an exacerbated inflammatory and oxidative response that affects dendritic morphology and the function of the neurons of the prefrontal cortex (PFC) and the hippocampus. This consequently causes memory loss. Recently, the use of the Goji berry (Lycium barbarum) as an antioxidant extract has provided neuroprotection and neuroplasticity, however, its therapeutic potential has not been demonstrated in aging conditions. The objective of this study was to evaluate the effect of Goji administration on memory recognition, as well as the changes in the dendritic morphology of the PFC and Hippocampus pyramidal neurons in old rats. Goji (3 g/kg) was administrated for 60 days in 18-month-old rats. After the treatment, recognition memory was evaluated using the new object recognition task (NORt). The changes in the neuron morphology of the PFC and hippocampus pyramidal neurons in old rats were evaluated by Golgi-cox stain and immunoreactivity for synaptophysin, glial fibrillary acidic protein (GFAP), caspase-3, 3-nitrotyrosine (3-NT) and nuclear factor erythroid 2-related factor 2 (Nrf2). The rats treated with Goji showed a significant increase in dendritic morphology in the PFC and hippocampus neurons, a greater immunoreactivity to synaptophysin and a decrease in reactive astrogliosis and also in caspase-3, in 3-NT and in Nrf2 in these brain regions was also observed. Goji administration promotes the plasticity processes in the PFC and in the hippocampus of old rats, critical structures in the brain aging process.

Reduction of the dendritic arbor length and the lack of dendritic spines in the pyramidal cells of the prefrontal cortex (PFC) are prevalent pathological features in schizophrenia (SZ). Neonatal ventral hippocampus lesion (NVHL) in male rats reproduces these neuronal characteristics and here we describe how this is a consequence of BDNF/TrkB pathway disruption. Moreover, COX-2 proinflammatory state, as well as Nrf-2 antioxidant impairment, triggers oxidative/nitrosative stress, which also contributes to dendritic spine impairments in the PFC. Interestingly, oxidative/nitrosative stress was also detected in the periphery of NVHL animals. Furthermore, risperidone treatment had a neurotrophic effect on the PFC and antioxidant effects on the brain and periphery of NVHL animals; these cellular effects were related to behavioral improvement. Our data highlight the link between brain development and immune response, as well as several other factors to understand mechanisms related to the pathophysiology of SZ.SIGNIFICANCE STATEMENTPrefrontal cortex dysfunction in schizophrenia can be a consequence of morphological abnormalities and oxidative/nitrosative stress, among others. Here, we detailed how impaired plasticity-related pathways and oxidative/nitrosative stress are part of the dendritic spine pathology and their modulation by atypical antipsychotic risperidone treatment in rats with neonatal ventral hippocampus lesion. Moreover, we found that animals with neonatal ventral hippocampus lesion had oxidative/nitrosative stress in the brain as well as in the peripheral blood, an important issue for the translational approaches of this model. Then, risperidone restored plasticity and reduced oxidative/nitrosative stress of prefrontal cortex pyramidal cells, and ultimately improved the behavior of lesioned animals. Moreover, risperidone had differential effects than the brain on peripheral blood oxidative/nitrosative stress.

Brain aging is a widely studied process, but due to its complexity, much of its progress is unknown. There are many studies linking memory loss and reduced interneuronal communication with brain aging. However, only a few studies compare young and old animals. In the present study, in male rats aged 3, 6, and 18 months, we analyzed the locomotor activity and also short and long-term memory using the novel object recognition test (NORT), in addition to evaluating the dendritic length and the number of dendritic spines in the prefrontal cortex (PFC) and in the CA1, CA3 and DG regions of the dorsal hippocampus using Golgi-Cox staining. We also analyzed the types of dendritic spines in the aforementioned regions. 6- and 18-month old animals showed a reduction in locomotor activity, while long-term memory deficit was observed in 18-month old rats. At 18 months old, the dendritic length was reduced in all the studied regions. The dendritic spine number was also reduced in layer 5 of the PFC, and the CA1 and CA3 of the hippocampus. The dynamics of dendritic spines changed with age, with a reduction of the mushroom spines in all the studied regions, with an increase of the stubby spines in all the studied regions except from the CA3 region, that showed a reduction. Our data suggest that age causes changes in behavior, which may be the result of morphological changes at the dendrite level, both in their length and in the dynamics of their spines.

The spontaneously hypertensive (SH) rat has been used as an animal model of vascular dementia (VD). Our previous report showed that, SH rats exhibited dendritic atrophy of pyramidal neurons of the CA1 dorsal hippocampus and layers 3 and 5 of the prefrontal cortex (PFC) at 8 months of age. In addition, we showed that cerebrolysin (Cbl), a neurotrophic peptide mixture, reduces the dendritic atrophy in aged animal models. This study aimed to determine whether Cbl was capable of reducing behavioral and neuronal alterations, in old female SH rats. The level of diastolic and systolic pressure was measured every month for the 6 first months and only animals with more than 160 mm Hg of systolic pressure were used. Female SH rats (6 months old) received 6 months of Cbl treatment. Immediately after the Cbl treatment, two behavioral tests were applied, the Morris water maze test for memory and learning and locomotor activity in novel environments. Immediately after the last behavioral test, dendritic morphology was studied with the Golgi-Cox stain procedure followed by a Sholl analysis. Clearly, SH rats with Cbl showed an increase in the dendritic length and dendritic spine density of pyramidal neurons in the CA1 in the dorsal hippocampus and layers 3 and 5 of the PFC. Interestingly, Cbl improved memory of the old SH rats. Our results support the possibility that Cbl may have beneficial effects on the management of brain alterations in an animal model with VD. Synapse 70:378-389, 2016. © 2016 Wiley Periodicals, Inc.

Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimer's disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1- and CA3-dorsal hippocampus (DH) as well as CA1-ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18-month-old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi-Cox stain procedure, followed by Sholl analysis on 20-month-old rats. In all resveratrol-treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimer's disease.

Background Dual diagnosis is the co-occurrence of at least one substance use disorder (SUD) and one or more mental disorders in a given individual. Despite this comorbidity is highly prevalent and associated with adverse clinical outcomes, its neurobiology remains unclear. Furthermore, patients with dual diagnosis are at higher risk for suicidal behavior in comparison with single disorder patients. Our objective was to evaluate brain gene expression patterns in individuals with dual diagnosis who died by suicide. Methods We compared the gene expression profile in the dorsolateral prefrontal cortex of suicides with DD (n= 10) to the transcriptome of suicides with SUD alone (n=10), suicides with mood disorders alone (n=13), and suicides without mental comorbidities (n=5). Gene expression profiles were assessed by microarrays. Microarray data quality control was performed. Then, microarray data were background corrected and quantile normalized. Differentially expressed genes among the conditions were identified by a linear model implemented in the limma package. Results When comparing the transcriptome of suicides with dual diagnosis to suicides with SUD alone and suicides with mood disorders alone, we identified 255 and 172 differentially expressed genes, respectively. When comparing suicides with DD to suicides without mental comorbidities, we identified 330 differentially expressed genes, mainly enriched in neurogenesis. Discussion Our results suggest that suicides with dual diagnosis present a gene expression profile distinct from that of suicides with a single disorder and suicides without mental disorders. Also, suicides with dual diagnosis, SUD and mood disorders exhibited alterations in the expression of synaptic genes. However, suicides with each condition (dual diagnosis, SUD or mood disorders) exhibited unique gene expression changes at different levels within synaptic signaling. These gene expression differences might contribute to the phenotypical and clinical discrepancies observed in patients with dual diagnosis and patients with a single disorder

Suicidal behavior is a complex human behavior and current data suggests that suicide is an increasing cause of death among young people. The neurobiology of suicide is unknown and data investigating the role of the pituitary in suicidal behavior is scarce. Imaging data suggests that this gland increases in size in patients with major depression and recent data implicates hyperactivity of the hypothalamus-pituitary-adrenal axis in suicidal behavior. In this study, we evaluate the size and number of cells as well as markers related to oxidative stress and lipid peroxidation of the anterior and posterior sections of the pituitary gland of male suicide completers. Stereological analysis is used to quantify the total cell number in anterior- and posterior-pituitary regions. We examined nitric oxide (NO) levels, Zinc (Zn) levels, superoxide dismutase (SOD) activity, 4-hydroxy-alkenals (4-HDA), malondialdehyde (MDA) and metallothioneins (MTs). Our results indicate that the anterior-pituitary region of suicide completers exhibits increased weight, likely due to an enhanced number of cells compared to the control group. In addition, we found a reduction of NO levels with higher SOD activity in the anterior-pituitary region of suicide victims. No changes in Zn, MDA, MTs, 4-HDA or MDA were observed in tissue of suicide completers compared to the control group. This study demonstrates that there is an increased number of cells, with an imbalance in oxidative stress without a process of lipid peroxidation in the anterior-pituitary region of young male suicide completers.

Apomorphine is a dopamine receptor agonist that activates D1-D5 dopamine receptors and that is used to treat Parkinson's disease (PD). However, the effect of apomorphine on non-motor activity has been poorly studied, and likewise, the effects of dopaminergic activation in brain areas that do not fulfill motor functions are unclear. The aim of this study was to determine how dopamine receptor activation affects behavior, as well as plasticity, morphology, and oxidative stress in the hippocampus. Adult mice were chronically administered apomorphine (1 mg/kg for 15 days), and the effects on memory and learning, synaptic plasticity, dendritic length, inflammatory responses, and oxidative stress were evaluated. Apomorphine impaired learning and long-term memory in mice, as evaluated in the Morris water maze test. In addition, electrophysiological recording of field excitatory postsynaptic potentials (fEPSP) indicated that the long-term potentiation (LTP) of synaptic transmission in the CA1 region of the hippocampus was fully impaired by apomorphine. In addition, a Sholl analysis of Golgi-Cox stained neurons showed that apomorphine reduced the total length of dendrites in the CA1 region of the hippocampus. Finally, there were more reactive astrocytes and oxidative stress biomarkers in mice administered apomorphine, as measured by GFAP immunohistochemistry and markers of redox balance, respectively. Hence, the non-selective activation of dopaminergic receptors in the hippocampus by apomorphine triggers deficiencies in learning and memory, it prevents LTP, reduces dendritic length, and provokes neuronal damage.

Experimental evidence has revealed the role of mitochondria in various aspects of neuronal physiology. Mitochondrial failure results in alterations that underlie the pathogeneses of many neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD) and amyotrophic lateral sclerosis. The mitochondrial toxin 3-nitropropionic acid (3-NP) has been used to model failure; for example, systemic administration of 3-NP imitates the striatal degeneration that is exhibited in the postmortem tissue of patients afflicted with HD. We have demonstrated that low, sub-chronic doses of 3-NP are sufficient to initiate the damage to striatal neurons that is associated with changes in neurotrophin expression levels. However, the mechanisms underlying the alterations in neuronal activity and neurotransmission due to 3-NP-induced mitochondrial dysfunction remain to be elucidated. In this paper, we focus on how corticostriatal transmission and its modulation by neurotrophins are altered in vivo after 5 days of mitochondrial inhibition with 3-NP. Recordings of population spikes and a paired pulse (PP) stimulation protocol were used to document changes in corticostriatal synapses in 3-NP-treated brain slices. The corticostriatal synapses were modulated by neurotrophins but displayed differential amplitude increases in the presence of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) under control conditions. Neurotrophin-mediated synaptic modulation was decreased in slices from 3-NP-treated mice. The protein and mRNA levels of neurotrophins and their receptors were also modified in the 3-NP-treated tissue. Neuronal structural evaluation demonstrated that synaptic length and density were reduced in the 3-NP-treated mice, which partially explained the changes in the amplitudes of the synaptic field responses. Our results demonstrate that corticostriatal synapses are differentially modulated by neurotrophins and that this modulation is altered by mitochondrial failure. Mitochondrial dysfunction also affects neurotransmitter release in corticostriatal synapses, neurotrophin availability, dendritic arborization and the lengths of the striatal medium spiny neurons (MSNs).

The neonatal ventral hippocampal lesion (NVHL) is an established neurodevelopmental rat model of schizophrenia. Rats with NVHL exhibit several behavioral, molecular and physiological abnormalities that are similar to those found in schizophrenics. Schizophrenia is a severe psychiatric illness characterized by profound disturbances of mental functions including neurophysiological deficits in brain information processing. These deficits can be assessed by auditory evoked potentials (AEPs), where schizophrenics exhibit abnormalities in amplitude, duration and latency of such AEPs. The aim of the present study was to compare the density of cells in the temporal cerebral cortex and the N40-AEP of adult NVHL rats versus adult sham rats. We found that rats with NVHL exhibit significant lower amplitude of the N40-AEP and a significant lower number of cells in bilateral regions of the temporal cerebral cortex compared to sham rats. Because the AEP recordings were obtained from anesthetized rats, we suggest that NVHL leads to inappropriate innervation in thalamic-cortical pathways in the adult rat, leading to altered function of cortical networks involved in processing of primary auditory information.

Here we investigated the effects of chronic treated with resveratrol, a polyphenol (3,4’,5-trihydroxystilbene) found in more than 70 plant species and food products such as red grapes, berries and peanuts, or N-PEP-12, a mix of peptides, on arteries in aging rats. Aging rats have shown endothelial dysfunction. Aged Sprague-Dawley rats (18 months old) were treated with resveratrol (20 mg/kg/day by gavage) or N-PEP-12 (60 mg/kg/day by gavage) for 10 weeks. 24 hours after the last administration of resveratrol or N-PEP-12, the animals were weighed and diastolic and systolic blood pressure was measured by tail-cuff plethysmography. Thoracic and abdominal aorta artery segments were obtained from resveratrol-, N-PEP-12-and vehicle-treated rats and were mounted in isometric tension for isolated vessels. We found that resveratrol and N-PEP-12 improved acetylcholine-induced relaxation in the old animals. These results suggest that chronic administration of resveratrol or N-PEP-12 may in part reduce endothelial dysfunction in the aging.

The aging brain shows biochemical and morphological changes in the dendrites of pyramidal neurons from the limbic system associated with memory loss. Prolame (N-(3-hydroxy-1,3,5 (10)-estratrien-17β-yl)-3-hydroxypropylamine) is a non-feminizing aminoestrogen with antithrombotic activity that prevents neuronal deterioration, oxidative stress, and neuroinflammation. Our aim was to evaluate the effect of prolame on motor and cognitive processes, as well as its influence on the dendritic morphology of neurons at the CA1, CA3, and granule cells of the dentate gyrus (DG) regions of hippocampus (HP), and medium spiny neurons of the nucleus accumbens (NAcc) of aged mice. Dendritic morphology was assessed with the Golgi-Cox stain procedure followed by Sholl analysis. Prolame (60 µg/kg) was subcutaneously injected daily for 60 days in 18-month-old mice. Immediately after treatment, locomotor activity in a new environment and recognition memory using the Novel Object Recognition Task (NORT) were evaluated. Prolame-treated mice showed a significant increase in the long-term exploration quotient, but locomotor activity was not modified in comparison to control animals. Prolame-treated mice showed a significant increase in dendritic spines density and dendritic length in neurons of the CA1, CA3, and DG regions of the HP, whereas dendrites of neurons in the NAcc remained unmodified. In conclusion, prolame administration promotes hippocampal plasticity processes but not in the NAcc neurons of aged mice, thus improving long-term recognition memory. Prolame could become a pharmacological alternative to prevent or delay the brain aging process, and thus the emergence of neurodegenerative diseases that affect memory.

The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (Cbl), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats. We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether Cbl treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated Cbl treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that Cbl may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders.

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75NTR immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons. © 2012 Wiley Periodicals, Inc.

Metabolic syndrome (MS) is a serious public health problem, which can promote neuronal alterations in cognitive regions related to learning and memory processes, such as the hippocampus. However, up to now there has been information of a regional segregation of this damage. In this study, we evaluate the MS effect on the neuronal morphology of the hippocampus. Our results demonstrate that 90days of a high-calorie diet alters the metabolic energy markers causing the MS and causes memory impairments, evaluated by the recognition of novel objects test (NORT). In addition, MS animals showed significant differences in dendritic order, total dendritic length and density of dendritic spines in CA1, CA3 and the dentate gyrus (DG) of the hippocampal area, compared with rats fed with a normocaloric diet (vehicle group). Furthermore, the immunoreactivity to synaptophysin (Syp) decreased in the hippocampus of the MS animals compared to the vehicle group. These results indicate that metabolic alterations induced by the MS affect hippocampal plasticity and hippocampal dependent memory processes.

Neonatal basolateral amygdala (nBLA) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Recently, we reported that nBLA lesions result in significant decreases in the dendritic spine number of layer 3 prefrontal cortex (PFC) pyramidal cells and medium spiny neurons of the nucleus accumbens (NAcc), which all changes after puberty. At present, we aimed to evaluate the effect of this lesion in pyramidal neurons of CA1 of the ventral hippocampus (VH) and layer 5 of the PFC. In order to assess the effects of nBLA lesions on the dendritic morphology of the PFC and VH neurons, we carried out nBLA lesions in rats on postnatal day (PD) 7, and then we studied the dendritic morphology of these two limbic subregions at prepubertal (PD35) and postpubertal (PD60) ages. Dendritic characteristics were measured by Golgi-Cox procedure followed by Sholl analysis. We also evaluated the effects of nBLA lesions on the prepulse inhibition (PPI) and acoustic startle responses. The nBLA lesion induced a significant increase in dendritic length of layer 5 pyramidal neurons of the PFC at both ages, with a decrease in the dendritic spines density after puberty. The spine density of CA1 VH pyramidal neurons showed significant decreases at both ages. PPI was decreased in adulthood in the animals with an nBLA lesion. These results show that an nBLA lesion alters the dendritic morphology at the level of the PFC and VH in distinct ways before puberty, suggesting a disconnection between these limbic structures at an early age, and increasing our understanding of the implications of the VH in early amygdala dysfunction in schizophrenia.

Aging is a stage of life where cognitive and motor functions are impaired. This is because oxidative and inflammatory processes exacerbate neurodegeneration, which affects dendritic morphology and neuronal communication of limbic regions with memory loss. Recently, the use of trophic substances has been proposed to prevent neuronal deterioration. The neuropeptide-12 (N-PEP-12) has been evaluated in elderly patients with dementia, showing improvements in cognitive tasks due to acts as a neurotrophic factor. In the present work, we evaluated the effect of N-PEP-12 on motor activity and recognition memory, as well as its effects on dendritic morphology and the immunoreactivity of GFAP, Synaptophysin (SYP), and BDNF in neurons of the prefrontal cortex (PFC), dorsal hippocampus (DH) and nucleus accumbens (NAcc) of aged rats. The results show that N-PEP-12 improved the recognition memory, but the motor activity was not modified compared to the control animals. N-PEP-12 increases the density of dendritic spines and the total dendritic length in neurons of the PFC (layers 3 and 5) and in DH (CA1 and CA3). Interestingly NAcc neurons showed a reduction in the number of dendritic spines. In the N-PEP-12 animals, when evaluating the immunoreactivity for SYP and BDNF, there was an increase in the three brain regions, while the mark for GFAP decreased significantly. Our results suggest that N-PEP-12 promotes neuronal plasticity in the limbic system of aged animals, which contributes to improving recognition memory. In this sense, N-PEP-12 can be considered as a pharmacological alternative to prevent or delay brain aging and control senile dementias.

The original version of this article unfortunately contained a mistake. The spelling of the author Tommaso Ianniti was incorrect and has been corrected as Tommaso Iannitti. The original article has been corrected.

A neonatal basolateral-amygdala (nBLA) lesion in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morpho- logical alterations in pyramidal neurons from the prefrontal cortex (PFC) have been observed in postmortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nBLA-lesion on the dendritic mor- phology of neurons from the PFC and the nucleus accumbens (NAcc) in rats. nBLA lesions were made on postnatal day 7 (PD7), and later, the dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at PD35 (prepu- bertal) and PD60 (adult) ages. We also evaluated the effects of the nBLA-lesion on loco- motor activity caused by a novel environment, apomorphine, and amphetamine. Adult animals with nBLA lesions showed a decreased spine density in pyramidal neurons from the PFC and in medium spiny cells from the NAcc. An increased locomotion in a novel environment and in amphetamine-treated adult animals with an nBLA-lesion was observed. Our results indicate that nBLA-lesion alters the neuronal dendrite morphology of the NAcc and PFC, suggesting a disconnection between these limbic structures. The locomotion paradigms support the idea that dopaminergic transmission is altered in the nBLA lesion model. This could help to understand the consequences of an earlier amyg- dala dysfunction in schizophrenia. Synapse 63:1143-1153, 2009. V C 2009 Wiley-Liss, Inc.

Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimer's disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1- and CA3-dorsal hippocampus (DH) as well as CA1-ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18-month-old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi-Cox stain procedure, followed by Sholl analysis on 20-month-old rats. In all resveratrol-treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimer's disease.

Aging has been considered a natural process of any living being. The rate of aging depends on many factors, including genetic and environmental factors. For this reason, many researchers in this field suggest that aging is an epigenetic process.

Curcuma is a natural compound that has shown neuroprotective properties, and has been reported to prevent aging and improve memory. While the mechanism(s) underlying these effects are unclear, they may be related to increases in neural plasticity. Morphological changes have been reported in neuronal dendrites in the limbic system in animals and elderly humans with cognitive impairment. In this regard, there is a need to use alternative therapies that delay the onset of morphologies and behavioral characteristics of aging. Therefore, the objective of this study was to evaluate the effect of curcuma on cognitive processes and dendritic morphology of neurons in the prefrontal cortex (PFC), the CA1 and CA3 regions of the dorsal hippocampus, the dentate gyrus, and the basolateral amygdala (BLA) of aged rats. 18-month-old rats were administered curcuma (100 mg/kg) daily for 60 days. After treatment, recognition memory was assessed using the novel object recognition test. Curcuma-treated rats showed a significant increase in the exploration quotient. Dendritic morphology was assessed by Golgi-Cox staining and followed by Sholl analysis. Curcuma-treated rats showed a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC, the CA1 and CA3, and the BLA. The preservation of dendritic morphology was positively correlated with cognitive improvements. Our results suggest that curcuma induces modification of dendritic morphology in the aforementioned regions. These changes may explain how curcuma slows the aging process that has already begun in these animals, preventing deterioration in neuronal morphology of the limbic system and recognition memory.

The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (Cbl), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats. We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether Cbl treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated Cbl treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that Cbl may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders.

Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.

Haloperidol is a potent dopamine receptor antagonist and used to treat psychotic disorders, such as schizophrenia. Recent clinical and preclinical studies demonstrated the overactivity of the nitric oxide (NO) system in schizophrenia. Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Here, we investigate first whether the nVH lesion causes changes in NO levels in different limbic brain regions in young adults, postnatal day (PD) 81, and second, whether haloperidol treatment from PD60 to PD81 reverses these changes, by determining the accumulation of nitrites. The results show that NO levels at the level of the prefrontal cortex, occipital cortex, and cerebellum are higher in the nVH lesion animals, and that the haloperidol, in part, attenuates these altered NO levels. The NO levels observed in the nVH lesion animals with and without haloperidol treatment may be relevant to behaviors observed in schizophrenia. Synapse 64:941–947, 2010. © 2010 Wiley-Liss, Inc.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Abnormal accumulation and aggregation of alpha-synuclein (a-syn) within neurons, and mutations in the a-syn and UCH-L1 genes have been shown to play a role in the pathogenesis of PD. In light of recent reports suggesting an interaction between a-synuclein and UCH-L1, we investigated the effects of UCH-L1 inhibition on a-syn distribution and expression levels in primary neurons and hippocampal tissues derived from non transgenic (non tg) and a-syn over expressing tg mice. We show that suppression of UCH-L1 activity increased a-syn levels in control, non tg neurons, and resulted in a concomitant accumulation of presynaptic a-syn in these neurons. In contrast, blocking UCH-L1 activity in a-syn over expressing neurons decreased a-syn levels, and enhanced its synaptic clearance. In vitro studies verified the LDN-induced inhibition of UCH-L1 had minimal effect on LC3 (a marker of autophagy) in control cells, in cells over expressing a-syn UCH-L1 inhibition resulted in increased LC3 activity. These findings suggest a possible differential role of UCH-L1 function under normal and pathological conditions. Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain.

Dear Dr. Flores: In a recent Letter to the Editor published in this journal, Bernstein and coworkers performed a valuable integration of results obtained in his laboratory (Bernstein et al., 1999), our laboratory (Negrete-Diaz et al., 2010) and others about the role of nitric oxide (NO) in the pathophysiology of schizophrenia, and summarized them in a very comprehensive review (Bernstein et al., 2005). Using the same animal model of schizophrenia, adult rats with a neonatal ventral hippocampus (nVH) lesion, Bernstein and coworkers and our group found an alteration of the nitrergic system (an increase in the number of cortical neurons expressing neuronal nitric oxide synthase (nNOS) and NADPH diaphorase and increased production of NO respectively, in the prefrontal cortex of adult animals with nVH-lesions). Therefore, both works are complementary to each other and reinforce our view of the role of the nitrergic system in the pathophysiology of schizophrenia. The results are also consistent with postmortem studies in humans with schizophrenia, because the chronic treatment with haloperidol may produce a decrease in the expression of nNOS (see Bernstein et al., 2005 for review), and our results show that subchronic doses of the typical neuroleptic haloperidol (0.5 mg /kg) administrated to nVH-lesion animals result in a decrease of higher NO activity (NegreteDiaz et al., 2010). This suggests that haloperidol exerts in part its therapeutic effect through its action on the activity of NO. It is interesting to note that compared to other models, the animal model of the nVH lesion is one of the best characterized, having been published to date in around a hundred works (see Tseng et al., 2009 for review). This is a neurodevelopmental model in which the behavioral changes mimic some of the symptoms of schizophrenia and are clearly observable after puberty. In summary, we believe that our findings support the integration of the results of previous works and facilitate our understanding of the role of NO in the pathophysiology of schizophrenia, as described by Bernstein and coworkers quite clearly in his letter to the editor of this journal (Bernstein et al., 2010).