1,927 research outputs found
Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression
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Structural Plasticity Induced by Ketamine in Human Dopaminergic Neurons as Mechanism Relevant for Treatment-Resistant Depression
No full textThe mechanisms underlying the antidepressant effects of ketamine in treatment-resistant depression are only partially understood. Reactivation of neural plasticity in prefrontal cortex has been considered critical in mediating the effects of standard antidepressants, but in treatment-resistant depression patients with severe anhedonia, other components of the affected brain circuits, for example, the dopamine system, could be involved. In a recent article in Molecular Psychiatry , we showed that ketamine induces neural plasticity in human and mouse dopaminergic neurons. Human dopaminergic neurons were differentiated from inducible pluripotent stem cells for over 60 days. Mimicking the pharmacokinetic exposures occurring in treatment-resistant depression subjects, cultures were incubated with either ketamine at 0.1 and 1 µM for 1 h or with its active metabolite (2R,6R)-hydroxynorketamine at 0.1 and 0.5 µM for up to 6 h. Three days after dosing, we observed a concentration-dependent increase in dendritic arborization and soma size. These effects were mediated by the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor that triggered the pathways of mammalian target of rapamycin and extracellular signal-regulated kinase via the engagement of brain-derived neurotrophic factor signaling, as previously described in rodent prefrontal cortex. Interestingly, we found that neural plasticity induced by ketamine requires functionally intact dopamine D3 receptors. These data are in keeping with our recent observation that plasticity can be induced in human dopaminergic neurons by the D3 receptor-preferential agonist pramipexole, whose effect as augmentation treatment in treatment-resistant depression has been reported. Overall, the evidence of pharmacologic response in human inducible pluripotent stem cell-derived neurons could provide complementary information to those provided by circuit-based imaging when assessing the potential response to a given augmentation treatment
Simulation of the response properties of inferior area 6 neurons related to goal-directed motor acts: preliminary results using a neural network trained with backpropagation algorithm
No full textKetamine increases the expression of GluR1 and GluR2 α-amino-3-hydroxy-5-methy-4-isoxazole propionate receptor subunits in human dopaminergic neurons differentiated from induced pluripotent stem cells
No full textThe mechanisms underlying the prolonged antidepressant effects after a single exposure to ketamine are only partially understood. Converging findings indicate a critical role of structural neuroplasticity, recently also proposed for dopaminergic (DA) neurons known to be involved in a depression core symptom, anhedonia. We recently showed that ketamine induces dendritic outgrowth in human DA neurons differentiated in vitro from iPSC of healthy donors, a phenomenon blocked by the AMPA receptor antagonist NBQX. Since changes of expression of AMPA receptor subunits GluR1 and GluR2 were observed in neuroplasticity of rodent DA neurons, we aimed to explore this phenomenon in human DA neurons. Using specific antibodies against GluR1 and GluR2 AMPA receptor subunits, we demonstrated that GluR1 levels were significantly higher in soma than in dendrites, while for GluR2 levels were significantly higher in dendrites than in soma. One hr exposure to 1 μM ketamine increased the signal of both subunits in dendrites, but only of GluR2 in soma, at 24, 48 and 72 hrs. Non-linear polynomial fitting of dendritic expression indicated that the two curves were significantly different, with a stronger and more sustained effects on GluR2 expression. Both curves showed a relatively rapid building towards higher values when compared with the slow progression of structural plasticity parameters, whose maximal effects were observed at 72 hrs. Overall, these data support a role for GluR1 and GluR2 dendritic upregulation in driving structural plasticity in human DA neurons depending upon ketamine transient exposure, indicating translationally relevant downstream mechanism possibly involved in antidepressant effects
(2 R,6 R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans
No full textThe mechanisms underlying the prolonged antidepressant effects after a single infusion of ketamine are only partially understood. Ketamine half-life of about 2 hours cannot explain antidepressant effects that last for one week, suggesting the triggering of long lasting neuroplasticity. Recent human pharmacokinetics (PK) data indicate that a ketamine metabolite, (2R,6R)-hydroxynorketamine (HNK), persists in the high submicromolar range for additional 6-12 hours. Since in rodents HNK can induce dendrite outgrowth via AMPA receptor-mediated mechanisms, in this work we aimed to show that HNK produces similar effects in human neurons at concentrations and exposure-time compatible with human PK after ketamine infusion. Human dopaminergic neurons were differentiated in vitro from iPSCs obtained from healthy donors. Exposure to submicromolar HNK for 6 hours produced dendritic outgrowth when measured 3 days after exposure. These neuroplasticity effects were similar to those obtained with exposure to micromolar concentrations of ketamine for 1 or 6 hours and were blocked by pretreatment with the AMPA receptor antagonists NBQX and GYKI 52466, as well as by the mTOR pathway blocker rapamycin. It is reasonable to conclude that the mechanistic similarity of the effects produced by ketamine and HNK and their diachronic brain exposure due to their different plasma PK observed after single therapeutic infusion can contribute to the final sustained antidepressant action
Involvement of DA D3 Receptors in Structural Neuroplasticity of Selected Limbic Brain Circuits: Possible Role in Treatment-Resistant Depression
No full textStructural neuroplasticity in the adult brain is a process involving quantitative changes of the number and size of neurons and of their dendritic arborization, axon branching, spines, and synapses. These changes can occur in specific neural circuits as adaptive response to environmental challenges, exposure to stressors, tissue damage or degeneration. Converging studies point to evidence of structural plasticity in circuits operated by glutamate, GABA, dopamine, and serotonin neurotransmitters, in concert with neurotrophic factors such as Brain Derived Neurotrophic Factor (BDNF) or Insulin Growth Factor 1 (IGF1) and a series of modulators that include circulating hormones. Intriguingly, most of these endogenous agents trigger the activation of the PI3K/Akt/mTOR and ERK1/2 intracellular pathways that, in turn, lead to the production of growth-related structural changes, enhancing protein synthesis, metabolic enzyme functions, mitogenesis for energy, and new lipid-bilayer membrane apposition. The dopamine (DA) D3 receptor has been shown to play a specific role by inducing structural plasticity of the DAergic neurons of the nigrostriatal and mesocorticolimbic circuit, where they are expressed in rodents and humans, via activation of the mTORC1 and ERK1/2 pathways. These effects are BDNF-dependent and require the recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to allow the structural changes. Since in mood disorders, depression and anhedonia have been proposed to be associated with impaired neuroplasticity and reduced DAergic tone in brain circuits connecting prefrontal cortex, ventral striatum, amygdala, and ventral mesencephalon, activation of D3 receptors could provide a therapeutic benefit. Sustained improvements of mood and anhedonia were observed in subjects with an unsatisfactory response to serotonin uptake inhibitors (SSRI) when treated with D3-preferential D2/D3 agonists such as pramipexole and ropinirole. The recent evidence that downstream mTOR pathway activation in human mesencephalic DA neurons is also produced by ketamine, probably the most effective antidepressant currently used in subjects with treatment-resistant depression, further supports the rationale for a D3 receptor activation in mood disorders
Emilio Ghione and the Mask of Za La Mort
No full textThis study aims to examine the cultural impact of Emilio Ghione's Za La Mort films (1914-1924) on Italian culture. These films constitute a significant Italian combination of several early cinema genres and sub-genres, such as the apache film, the traces of which have almost entirely disappeared. More broadly, the changing interpretations of Za La Mort figure allow us to understand wider shifts in Italian and European popular culture.
The first chapter of the study considers the wealth of influences from European popular culture that Emilio Ghione merged into the apache films, such as the apache sub-culture in Paris. The second chapter of the study then reconstructs the Za La Mort filmography, most of which has now been lost, from film viewings and archival documents. The third chapter considers Emilio Ghione's Za La Mort novels and theatrical productions in the years 1922-1930, and Ghione's attempts to make Za La Mort a more Fascist and nationalistic figure. The fourth chapter considers the enduring figure of Za La Mort in Italian popular culture, especially in Raffaele Matarazzo's Fumeria D'Oppio and a 1940's fumetti series. The fifth chapter considers the audience reception of the Za La Mort films from the limited remaining evidence and, positioning the series between the Cinema of Attractions of the 1900s and the Classical Cinema of the mid-1920's, analyses how the Za La Mort films were constructed to please a predominantly working class audience that valued spectacular thrills and great acting performances over narrative consistency and stable characterisation.
This research re-establishes the importance of one of Italian cinema's most important film-makers of the silent period, and his enduring importance as a popular cultural figure in Italy
Postnatal maternal separation during the stress hyporesponsive period enhances the adrenocortical response to novelty in adult rats by affecting feedback regulation in the CA1 hippocampal field
No full textThe aim of the present experiment was to study the effects of early postnatal maternal separation on behavioural and adrenocortical responses to novelty in rats tested as adults. Sprague-Dawley rat pups were exposed to daily maternal separation (5 h/day) from postnatal day 2 to 6, during the stress hyporesponsive period. Since this procedure requires physical contact with the animals, a first control group of daily handled pups was introduced. A second control group, consisting of pups never handled or separated from the mother, was also considered. At postnatal day 45, the rats were tested in a two-compartment exploratory apparatus: the maternally separated and the non-handled rats, whose behavioural performance did not differ, showed higher emotional behaviour when compared with the handled rats (P < 0.05), suggesting that the handling procedure hut not maternal separation improved the capacity to cope with novelty. Corticosterone plasma levels were found to be higher in the maternally separated rats than in the other two groups (P < 0.05), either at resting conditions or at 30 min after novelty exposure (P < 0.05). Levels of nuclear glucocorticoid receptor immunoreactivity in the CA1 hippocampal field were shown to be regulated by novelty exposure, as expected, in both the handled and the non-handled rats but not in the maternally separated rats. In conclusion, repeated maternal separation periods of 5 h/day during the first week of life produced long-lasting effects on the hippocampal regulation of the hypothalamic-pituitary-adrenocortical axis, which appear to be associated with increased responsiveness to stress stimuli in adulthood
Transient forebrain ischemia produces multiple deficits in dopamine D1 transmission in the lateral neostriatum of the rat.
No full textStriatal dopamine D1 transmission was studied in rats 7 days after transient (30 min) forebrain ischemia using the 4-vessel occlusion model. The striatal distribution of dopamine D1 ([3H]SCH 23390 binding sites) and D2 ([3H]sulpiride binding sites) receptors as well as the distribution of adenylate cyclase ( [3H]forskolin binding sites) and of the intracytoplasmic dopamine and cAMP-regulated phosphoprotein DARPP-32 related to D1 transmission were analyzed. While the distribution of D2 receptors was unaffected 7 days after the ischemic insult, all the other markers showed a patchy disappearance in the dorsolateral part of the neostriatum. These findings underline the existence of selective multiple deficits in D1 transmission after transient forebrain ischemia in rat striatum
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