Social enrichment reverses the isolation-induced deficits of neuronal plasticity in the hippocampus of male rats

Environmental enrichment is known to improve brain plasticity and protect synaptic function from negative insults. In the present study we used the exposure to social enrichment to ameliorate the negative effect observed in post weaning isolated male rats in which neurotrophic factors, neurogenesis, neuronal dendritic trees and spines were altered markedly in the hippocampus. After the 4 weeks of post-weaning social isolation followed by 4 weeks of reunion, different neuronal growth markers as well as neuronal morphology were evaluated using different experimental approaches. Social enrichment restored the reduction of BDNF, NGF and Arc gene expression in the whole hippocampus of social isolated rats. This effect was paralleled by an increase in density and morphology of dendritic spines, as well as in neuronal tree arborisation in granule cells of the dentate gyrus. These changes were associated with a marked increase in neuronal proliferation and neurogenesis in the same hippocampal subregion that were reduced by social isolation stress. These results further suggest that the exposure to social enrichment, by abolishing the negative effect of social isolation stress on hippocampal plasticity, may improve neuronal resilience with a beneficial effect on cognitive function

Mucuna pruriens (Velvet bean) Rescues Motor, Olfactory, Mitochondrial and Synaptic Impairment in PINK1(B9) Drosophila melanogaster Genetic Model of Parkinson's Disease

The fruit fly Drosophila melanogaster (Dm) mutant for PTEN-induced putative kinase 1 (PINK1B9) gene is a powerful tool to investigate physiopathology of Parkinson's disease (PD). Using PINK1B9 mutant Dm we sought to explore the effects of Mucuna pruriens methanolic extract (Mpe), a L-Dopa-containing herbal remedy of PD. The effects of Mpe on PINK1B9 mutants, supplied with standard diet to larvae and adults, were assayed on 3–6 (I), 10–15 (II) and 20–25 (III) days old flies. Mpe 0.1% significantly extended lifespan of PINK1B9 and fully rescued olfactory response to 1-hexanol and improved climbing behavior of PINK1B9 of all ages; in contrast, L-Dopa (0.01%, percentage at which it is present in Mpe 0.1%) ameliorated climbing of only PINK1B9 flies of age step II. Transmission electron microscopy analysis of antennal lobes and thoracic ganglia of PINK1B9 revealed that Mpe restored to wild type (WT) levels both T-bars and damaged mitochondria. Western blot analysis of whole brain showed that Mpe, but not L-Dopa on its own, restored bruchpilot (BRP) and tyrosine hydroxylase (TH) expression to age-matched WT control levels. These results highlight multiple sites of action of Mpe, suggesting that its effects cannot only depend upon its L-Dopa content and support the clinical observation of Mpe as an effective medication with intrinsic ability of delaying the onset of chronic L-Dopa-induced long-term motor complications. Overall, this study strengthens the relevance of using PINK1B9 Dm as a translational model to study the properties of Mucuna pruriens for PD treatment

Social isolation stress and neuroactive steroids

Social isolation of rats immediately after weaning is associated to a reduction in the cerebrocortical and plasma concentrations of progesterone and its metabolites 3,5-TH PROG and 3,5-THDOC. Although we found that the basal plasma concentration of adrenocorticotropic hormone in isolated rats was slightly decreased compared with that in group-housed animals no other significant changes were found in the steroidogenic machinery (peripheral benzodiazepine receptors, steroidogenic regulatory protein (StAR)). However, the functional response of the hypothalamic-pituitary-adrenal axis HPA axis to an acute stressful stimulus (foot shock), or to an acute injection of ethanol or isoniazid is markedly increased in isolated rats. Behavioral studies have also indicated that the ability of ethanol to inhibit isoniazid-induced convulsions is greater in isolated rats than in group-housed animals and this effect of isolation is prevented by treatment with the 5α-reductase inhibitor finasteride. Social isolation modified the effects of ethanol on the amounts of StAR mRNA and protein in the brain suggesting an alteration in the mechanism of cholesterol transport in mithocondria. Moreover, the amounts of the α4 and δ subunits of the GABAA receptor in the hippocampus were increased in isolated rats, and these effects were accompanied by an increase in GABAA receptor–mediated tonic inhibitory currents in granule cells of the dentate gyrus. Ethanol also increased the amplitude of GABAA receptor–mediated miniature inhibitory postsynaptic currents ( mIPSC) recorded from CA1 pyramidal neurons with a greater potency in hippocampal slices prepared from socially isolated rats than in those from group-housed, an effect inhibited by finasteride

Changes on neuronal plasticity in physiological (pregnancy and postpartum) and stressed conditions

Neural plasticity, also known as neuroplasticity is the capability of neurons to changes the structure, function and organization of neurons in response to new experiences. It specifically refers to strengthening or weakening nerve connections or adding new nerve cells based on environmental stimuli. These processes are responsible for physiological changes, learning and the formation of appropriate responses to external event. Neural plasticity is among the most important aspects of the field of modern neuroscience and its study is leading to a better understanding of brain development. In this work the neuroplasticity, in particularly the BDNF and Arc proteins levels, density of dendritic spines and neurogenesis, was studied after different conditions, such as during pregnancy and after delivery or after a prolonged stress, such as maternal separation and social isolation. Our studies have shown an increase in BDNF and Arc proteins levels, density of dendritic spines and neurogenesis during pregnancy and after delivery, in constrast was observed a reduction of BDNF and Arc proteins levels, density of dendritic spines and neurogenesis after a prolonged stress. These results demonstrate that physiological changes or social environments can have significant effects on neuronal plasticity

Three weeks of maternal separation induced a long lasting changes in the palsticity of hippocampal neurons of offspring and mothers

Neural plasticity is the capability of neurons to changes the structure, function and organization of neurons in response to new experiences. It specifically refers to strengthening or weakening nerve connections or adding new nerve cells based on environmental stimuli. These processes are responsible for physiological changes, learning and the formation of appropriate responses to external events. Neural plasticity is among the most important aspects of the field of modern neuroscience and its study is leading to a better understanding of brain development. In this study the expression levels of BDNF and Arc protein, the density of dendritic spines and the neurogenesis, were studied after a long-lasting stress, due to maternal separation Neuroplasticity was evaluated in controls (mother and offspring not exposed to maternal separation) and after the stress induced by maternal separation (3h at day from the 3rd to the 21st day after birth). The mothers were sacrificed 21 days after the birth and pups in three different age groups: 21, 30 and 60 days. In the hippocampus of non-stressed we found an increase in the expression levels of the protein BDNF and Arc, in the dendritic spines density and in the neurogenesis, a phenomenon still present at weaning (21 days postpartum). In contrast, opposite effect (decrease) was observed on all the neurogenesis parameters in the mothers separated of their pups for 3 h per day for 20 days. Similarly to the mothers, also in hippocampus of the pups separated from their mothers was present a reduction of BDNF, Arc, dendritic spines density and neurogenesis in all three ages studied (21, 30 and 60). These results demonstrate that stress due to separation in the postnatal period results in adverse effects on neuronal plasticity in the hippocampus of both mothers and offspring

Maternal separation alters neuronal spine density and neurogenesis in the hippocampus of pups and mother

The vulnerability of the hippocampus to the negative effects of stress, particularly when experienced early in life, is one of the key translational neuroscience discoveries of the 20th century. Indeed, the quality of perinatal environment and postnatal experience has been shown to predict vulnerability to psychopathologies and cognitive function in the adult. The proposed study aims to improve the knowledge of the adaptive allostatic changes elicited by adverse experiences during lifetime. We focus on adverse experiences that involve mother-infant relationship disruption. In the present study the mothers was separated for three hours a day from their pups after delivery. The amount of BDNF, Activity–Regulated Cytoskeletal protein (Arc), dendritic spines and neurogenesis was measured in hippocampus of female rats at the weaning and in the hippocampus of pups at 21, 30 and 60 days after birth. All these parameters were markedly decreased in the in hippocampus of mother or pups, respect to the amount found in the mother or pups bred in normal conditions. The motherhood-induced increase the neuronal plasticity as well as the reversal by pups separation suggest a crucial role of these proteins in the regulation of rat maternal care

Ethanol exposure and withdrawal differentially affect the GABA - A receptor plasticity and function in two different neuronal populations

Gamma-Aminobutyric acid type A (GABA-A) receptors have been implicated as major target sites for the acute and chronic ac- tions of ethanol (EtOH). Prolonged exposure to and withdrawal from EtOH are associated with alterations in GABA-A receptor subunit gene expression as well as in receptor function and phar- macological sensitivity in different in vivo and in vitro experi- mental models. Here, we focus on the effects of chronic EtOH ex- posure and withdrawal on the expression of the delta subunit of the GABA-A receptor in cultured rat hippocampal neurons (HP) and cerebellar granule (CG) neurons. GABA-A receptors contain- ing the delta subunit are preferentially extrasynaptic, are respon- sible for the tonic inhibition, and possess an enhanced sensitivity to the agonist THIP, to the neurosteroid allopregnanolone as well as to low concentrations of EtOH. Immunocytochemical and con- focal microscopy studies showed that delta subunit is preferen- tially expressed on the soma of CG cells, whereas it is mainly den- dritic in HP neurons. Long-term EtOH exposure increased delta subunit mRNA and peptide levels in HP neurons, while it did not significantly modify its expression in CG cells. EtOH withdrawal was associated to a rapid (6 h) marked reduction of delta subunit expression in CG cells, and to a persistent enhancement in HP neurons during the first 6h from withdrawal compared to un- treated control. Patch clamp recordings revealed that these EtOH induced changes in delta subunit expression are associated, in HP and CG cells, to an opposite effect, increase and decrease, respec- tively, of the efficacy of THIP and allopregnanolone to potentiate the chloride currents. Our data demonstrate that the changes in gene expression and function of GABA-A receptor containing the delta subunit induced by long-term EtOH exposure and with- drawal are opposite in HP and CG cells, suggesting a putative dif- ferent role of these extrasynaptic receptors in controlling tonic in- hibition in these two different cell types. The results indicate also a strict association existing between the GABA-A receptors sub- unit diversity and their differential sensitivity to drugs and en- dogenous modulators. This evidence together with the different cellular localization of GABA-A receptors may explain the differ- ent threshold of excitability of selective neuronal populations in specific brain areas. It is well established that ethanol increases plasma and brain levels of GABA-A receptor active neurosteroids by activating the HPA axis. We now show that, in isolated rat hip- pocampal slices, EtOH dose dependently increased the concentra- tion of allopregnanolone as well as the amplitude of GABA-A re- ceptor-mediated inhibitory postsynaptic currents recorded from CA1 pyramidal neurons. This latter effect appears biphasic, con- sisting of a rapid, direct modulatory effect, insensitive to the 5 alfa reductase blocker finasteride, and a delayed, allopregnanolone- mediated action reversed by finasteride. These observations sug- gest that EtOH may modulate GABA-A receptor function through an increase in de novo neurosteroid synthesis in brain that is in- dependent from the HPA axis. Given that neurosteroids play a major role in the physiological modulation of GABA-A receptor plasticity and function this novel mechanism may be important in mediating some effects of ethanol in physiological and pathologi- cal conditions (menstrual cycle, pregnancy, menopause, premen- strual symdrome) and a variety of psychiatric and neurological disorders in which the steroidogenesis undergoes dramatic func- tional changes