A robust model of Stimulus-Specific Adaptation validated on neuromorphic hardware.

Stimulus-Specific Adaptation (SSA) to repetitive stimulation is a phenomenon that has been observed across many different species and in several brain sensory areas. It has been proposed as a computational mechanism, responsible for separating behaviorally relevant information from the continuous stream of sensory information. Although SSA can be induced and measured reliably in a wide variety of conditions, the network details and intracellular mechanisms giving rise to SSA still remain unclear. Recent computational studies proposed that SSA could be associated with a fast and synchronous neuronal firing phenomenon called Population Spikes (PS). Here, we test this hypothesis using a mean-field rate model and corroborate it using a neuromorphic hardware. As the neuromorphic circuits used in this study operate in real-time with biologically realistic time constants, they can reproduce the same dynamics observed in biological systems, together with the exploration of different connectivity schemes, with complete control of the system parameter settings. Besides, the hardware permits the iteration of multiple experiments over many trials, for extended amounts of time and without losing the networks and individual neural processes being studied. Following this "neuromorphic engineering" approach, we therefore study the PS hypothesis in a biophysically inspired recurrent networks of spiking neurons and evaluate the role of different linear and non-linear dynamic computational primitives such as spike-frequency adaptation or short-term depression (STD). We compare both the theoretical mean-field model of SSA and PS to previously obtained experimental results in the area of novelty detection and observe its behavior on its neuromorphic physical equivalent model. We show how the approach proposed can be extended to other computational neuroscience modelling efforts for understanding high-level phenomena in mechanistic models.

Clenbuterol activates the central IL-1 system via the ß2-adrenoceptor without provoking inflammatory response related behaviours in rats.

The long-acting, highly lipophilic, ß2-adrenoceptor agonist clenbuterol may represent a suitable therapeutic agent for the treatment of neuroinflammation as it drives an anti-inflammatory response within the CNS. However, clenbuterol is also known to increase the expression of IL-1ß in the brain, a potent neuromodulator that plays a role in provoking sickness related symptoms including anxiety and depression-related behaviours. Here we demonstrate that, compared to the immunological stimulus lipopolysaccharide (LPS, 250µg/kg), clenbuterol (0.5mg/kg) selectively up-regulates expression of the central IL-1 system resulting in a mild stress-like response which is accompanied by a reduction in locomotor activity and food consumption in rats. We provide further evidence that clenbuterol-induced activation of the central IL-1 system occurs in a controlled and selective manner in tandem with its negative regulators IL-1ra and IL-1RII. Furthermore, we demonstrate that peripheral ß2-adrenoceptors mediate the suppression of locomotor activity and food consumption induced by clenbuterol and that these effects are not linked to the central induction of IL-1ß. Moreover, despite increasing central IL-1ß expression, chronic administration of clenbuterol (0.03mg/kg; twice daily for 21days) fails to induce anxiety or depressive-like behaviour in rats in contrast to reports of the ability of exogenously administered IL-1 to induce these symptoms in rodents. Overall, our findings suggest that clenbuterol or other selective ß2-adrenoceptor agonists could have the potential to combat neuroinflammatory or neurodegenerative disorders without inducing unwanted symptoms of depression and anxiety.

Metabolic, hormonal and stress-related molecular changes in post-mortem pituitary glands from schizophrenia subjects.

OBJECTIVES: To identify a molecular profile for schizophrenia using post-mortem pituitaries from schizophrenia and control subjects. METHODS: Molecular profiling analysis of pituitaries from schizophrenia (n = 14) and control (n = 15) subjects was carried out using a combination of liquid chromatography tandem mass spectrometry (LC-MS(E)), multiplex analyte profiling (MAP), two-dimensional difference gel electrophoresis (2D-DIGE) and Western blot analysis. RESULTS: This led to identification of differentially expressed molecules in schizophrenia patients including hypothalamic-pituitary-adrenal axis-associated constituents such as cortisol, pro-adrenocorticotropic hormone, arginine vasopressin precursor, agouti-related protein, growth hormone, prolactin and secretagogin, as well as molecules associated with lipid transport and metabolism such as apolipoproteins A1, A2, C3 and H. Altered levels of secretagogin in serum from a cohort of living first onset schizophrenia patients were also detected, suggesting disease association and illustrating the potential for translating some components of this molecular profile to serum-based assays. CONCLUSIONS: Future studies on the molecules identified here may lead to new insights into schizophrenia pathophysiology and pave the way for translation of novel diagnostics for use in a clinical setting.

Phosphoproteomic differences in major depressive disorder postmortem brains indicate effects on synaptic function.

There is still a lack in the molecular comprehension of major depressive disorder (MDD) although this condition affects approximately 10% of the world population. Protein phosphorylation is a posttranslational modification that regulates approximately one-third of the human proteins involved in a range of cellular and biological processes such as cellular signaling. Whereas phosphoproteome studies have been carried out extensively in cancer research, few such investigations have been carried out in studies of psychiatric disorders. Here, we present a comparative phosphoproteome analysis of postmortem dorsolateral prefrontal cortex tissues from 24 MDD patients and 12 control donors. Tissue extracts were analyzed using liquid chromatography mass spectrometry in a data-independent manner (LC-MS(E)). Our analyses resulted in the identification of 5,195 phosphopeptides, corresponding to 802 non-redundant proteins. Ninety of these proteins showed differential levels of phosphorylation in tissues from MDD subjects compared to controls, being 20 differentially phosphorylated in at least 2 peptides. The majority of these phosphorylated proteins were associated with synaptic transmission and cellular architecture not only pointing out potential biomarker candidates but mainly shedding light to the comprehension of MDD pathobiology.

Dopamine D1 receptor-mediated intracellular responses in the hypothalamus after co-administration of caffeine with MDMA.

Markers of dopamine D(1) receptor activation were determined to elucidate intracellular mechanisms associated with the combined effects of caffeine and 3,4 methylenedioxymethamphetamine (MDMA), reported previously to produce increased toxicity, when compared with either drug alone. Caffeine (10 mg/kg) and MDMA (15 mg/kg) were administered to male Sprague Dawley rats alone and in combination. One hour after drug administration, core body temperature and phosphorylation of the dopamine D(1) -related intracellular markers, cAMP response element binding protein (CREB), the dopamine and c-AMP-regulated phosphoprotein of 32 kDa (DARPP-32) and expression of the immediate early gene and cellular activation marker c-fos were determined in the hypothalamus. Co-administration of caffeine with MDMA increased core body temperature when compared with MDMA or caffeine treatment alone. Pre-treatment with the dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg, i.p.), 30 min. prior to caffeine and MDMA administration, produced a hypothermic response to MDMA that was unaffected by caffeine. Co-administration of caffeine with MDMA increased p-CREB, p-DARPP-32 and c-fos expression when compared with either treatment alone. Pre-treatment with SCH-23390 attenuated the changes in p-CREB, p-DARPP and c-fos. The results show an enhanced intracellular response when caffeine is combined with MDMA but not with either agent alone suggestive of synergistic intracellular actions convergent on a dopamine D(1) receptor signalling pathway. A dopamine-related synergy associated with the combined administration of caffeine and MDMA may have important use and safety implications for recreational drug users.

Proteomic technologies for biomarker studies in psychiatry: advances and needs.

In the postgenome era, proteomics has arisen as a promising tool for more complete comprehension of diseases and for biomarker discovery. Some of these objectives have already been partly achieved for illnesses such as cancer. In the case of psychiatric conditions, however, proteomic advances have had a less profound impact. Here, we outline the necessity of improving and applying proteomic methods for biomarker discovery and validation in the field of psychiatric disorders. While proteomic-based applications in neurosciences have increased in accuracy and sensitivity over the past 10 years, the development of orthogonal validation technologies has fallen behind. These issues are discussed along with the importance of integrating systems biology approaches and combining proteomics with other research approaches. The future development of such technologies may put proteomics closer to clinical applications in psychiatry.

Abnormalities in metabolism and hypothalamic-pituitary-adrenal axis function in schizophrenia.

For decades, evidence has been emerging that the pathogenesis of schizophrenia can involve perturbations in metabolic and hypothalamic-pituitary-adrenal (HPA) axis pathways. Variations in manifestation of these effects could be related to the differences in clinical symptoms between affected individuals as well as to differences in treatment response, including the finding that a high proportion of subjects fail to respond to current antipsychotic medications. Here, we review the evidence for abnormalities in metabolism and HPA axis regulation in schizophrenia. Such studies may prove critical for increasing our understanding of the multidimensional nature of psychiatric illnesses and for improving the timeliness and accuracy of diagnosis. Stratification of subjects according to molecular phenotype reflecting the disease state or trait could help to improve existing treatments through application of novel personalized medicine strategies and by the development of much-needed novel antipsychotic agents.

A role for adenosine A(1) receptor blockade in the ability of caffeine to promote MDMA "Ecstasy"-induced striatal dopamine release.

Co-administration of caffeine profoundly enhances the acute toxicity of 3,4 methylenedioxymethamphetamine (MDMA) in rats. The aim of this study was to determine the ability of caffeine to impact upon MDMA-induced dopamine release in superfused brain tissue slices as a contributing factor to this drug interaction. MDMA (100 and 300µM) induced a dose-dependent increase in dopamine release in striatal and hypothalamic tissue slices preloaded with [(3)H] dopamine (1µM). Caffeine (100µM) also induced dopamine release in the striatum and hypothalamus, albeit to a much lesser extent than MDMA. When striatal tissue slices were superfused with MDMA (30µM) in combination with caffeine (30µM), caffeine enhanced MDMA-induced dopamine release, provoking a greater response than that obtained following either caffeine or MDMA applications alone. The synergistic effects in the striatum were not observed in hypothalamic slices. As adenosine A(1) receptors are, one of the main pharmacological targets of caffeine, which are known to play an important role in the regulation of dopamine release, their role in the modulation of MDMA-induced dopamine release was investigated. 1µM 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a specific A(1) antagonist, like caffeine, enhanced MDMA-induced dopamine release from striatal slices while 1µM 2,chloro-N(6)-cyclopentyladenosine (CCPA), a selective adenosine A(1) receptor agonist, attenuated this. Treatment with either SCH 58261, a selective A(2A) receptor antagonist, or rolipram, a selective PDE-4 inhibitor, failed to reproduce a caffeine-like effect on MDMA-induced dopamine release. These results suggest that caffeine regulates MDMA-induced dopamine release in striatal tissue slices, via inhibition of adenosine A(1) receptors.

Caffeine promotes dopamine D1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA ('ecstasy').

RATIONALE: Caffeine exacerbates the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') in rats characterised by hyperthermia, tachycardia and lethality. Depletion of central catecholamine stores and dopamine D(1) receptor blockade have been reported to attenuate the ability of caffeine to exacerbate MDMA-induced hyperthermia. OBJECTIVES: Here, we investigate whether dopamine D(1) and D(2) receptors mediate the effects of caffeine on MDMA-induced changes in body temperature, heart rate and locomotor activity. METHODS: All parameters were recorded continuously in individually housed rats using bioradiotelemetry from 1 h prior to 4 h following caffeine (10 mg/kg, s.c.) and/or MDMA (10 mg/kg, s.c.) administration. RESULTS: Co-administration of caffeine with MDMA provoked a switch from MDMA-induced hypothermia and bradycardia to hyperthermia and tachycardia without influencing MDMA-induced hyperlocomotion. Pre-treatment with a specific dopamine D(1/5) antagonist SCH 23390 (1 mg/kg) enhanced MDMA-induced hypothermia and blocked the ability of caffeine to provoke a switch from MDMA-induced hypothermia to hyperthermia. Furthermore, SCH 23390 blocked MDMA-induced hyperactivity and the ability of caffeine to promote a tachycardic response to MDMA. By contrast, pre-treatment with the selective D(2) antagonist, sulpiride (100 mg/kg) blocked MDMA-induced hypothermia, failed to influence the ability of caffeine to promote tachycardia whilst enhancing MDMA-induced hyperactivity. CONCLUSIONS: Our results highlight the importance of dopamine D(1) and D(2) receptors in shaping the behavioural and physiological response to MDMA and suggest that the ability of caffeine to provoke MDMA-induced toxicity is associated with the promotion of dopamine D(1) over D(2) receptor-related responses.