Accurate ray-tracing optical model for coded aperture spectral snapshot imagers.

The image formation in coded aperture spectral imagers is key information for processing the acquired compress data, and the optical system design and calibration of these instruments require great care. We propose an analytical model for CASSI systems that builds upon ray-tracing equations of each optical component. The model takes into account optical distortions, sampling effects, and optical misalignments, and allows accurate modeling and fast calibration. Numerical comparisons with a simpler model usually exploited in the literature are provided, and an experimental validation is presented.

D1/5 dopamine receptors are necessary for learning a novel context.

Dopamine participates in encoding memories and could either encode rewarding/aversive value of unconditioned stimuli or act as a novelty signal triggering contextual learning. Here we show that intraperitoneal injection of the dopamine D1/5R antagonist SCH23390 impairs contextual fear conditioning and tone-shock association, while intrahippocampal injection only impairs contextual fear conditioning. By using the context pre-exposure facilitation effect test, we show that SCH23390 is able to block the encoding of the context during the pre-exposure phase. Thus, we provide additional evidence that dopamine is involved in encoding conjunctive representations of new contexts.

Sequential inhibitory plasticities in hippocampal area CA2 and social memory formation.

Area CA2 is a critical region for diverse hippocampal functions including social recognition memory. This region has unique properties and connectivity. Notably, intra-hippocampal excitatory inputs to CA2 lack canonical long-term plasticity, but inhibitory transmission expresses a long-term depression mediated by Delta-opioid receptors (DOR-iLTDs). Evidence indicates that DOR-iLTDs are insufficient to underlie social coding. Here, we report a novel inhibitory plasticity mediated by cannabinoid type 1 receptor activation (CB1R-iLTD). Surprisingly, CB1R-iLTD requires previous induction of DOR-iLTDs, indicating a permissive role for DOR plasticity. Blockade of CB1Rs in CA2 completely prevents social memory formation. Furthermore, the sequentiality of DOR- and CB1R-mediated plasticity occurs in vivo during successive social interactions. Finally, CB1R-iLTD is altered in a mouse model of schizophrenia with impaired social cognition but is rescued by a manipulation that also rescues social memory. Altogether, our data reveal a unique interplay between two inhibitory plasticities and a novel mechanism for social memory formation.

Altered inhibitory function in hippocampal CA2 contributes in social memory deficits in Alzheimer's mouse model.

Parvalbumin (PV)-expressing interneurons which are often associated with the specific extracellular matrix perineuronal net (PNN) play a critical role in the alteration of brain activity and memory performance in Alzheimer's disease (AD). The integrity of these neurons is crucial for normal functioning of the hippocampal subfield CA2, and hence, social memory formation. Here, we find that social memory deficits of mouse models of AD are associated with decreased presence of PNN around PV cells and long-term synaptic plasticity in area CA2. Furthermore, single local injection of the growth factor neuregulin-1 (NRG1) is sufficient to restore both PV/PNN levels and social memory performance of these mice. Thus, the PV/PNN disruption in area CA2 could play a causal role in social memory deficits of AD mice, and activating PV cell pro-maturation pathways may be sufficient to restore social memory.

Cardiac sensory afferents modulate susceptibility to anxio-depressive behaviour in a mouse model of chronic heart failure.

AIM: Impairments in cerebral structure and cognitive performance in chronic heart failure (CHF) are critical components of its comorbidity spectrum. Autonomic afferents that arise from cardiac sensory fibres show enhanced activity with CHF. Desensitization of these fibres by local application of resiniferatoxin (RTX) during myocardial infarction (MI) is known to prevent cardiac hypertrophy, sympathetic hyperactivity and CHF. Whether these afferents mediate cerebral allostasis is unknown. METHODS: CHF was induced by myocardial infarction. To evaluate if cardiac afferents contribute to cerebral allostasis, RTX was acutely applied to the pericardial space in controls (RTX) and in MI treated animals (MI/RTX). Subjects were then evaluated in a series of behavioural tests recapitulating different symptoms of depressive disorders. Proteomics of the frontal cortices (FC) was performed to identify contributing proteins and pathways responsible for behavioural allostasis. RESULTS: Desensitization of cardiac afferents relieves hallmarks of an anxio/depressive-like state in mice. Unique protein signatures and regulatory pathways in FCs isolated from each treatment reveal the degree of complexity inherent in the FC response to stresses originating in the heart. While cortices from the combined treatment (MI/RTX) did not retain protein signatures from the individual treatment groups, all three groups suffer dysregulation in circadian entrainment. CONCLUSION: CHF is comorbid with an anxio/depressive-like state and ablation of cardiac afferents relieves the despair phenotype. The strikingly different proteomic profiles observed in FCs suggest that MI and RTX lead to unique brain-signalling patterns and that the combined treatment, potentially through destructive interference mechanisms, most closely resembles controls.

Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism.

Developing nondopaminergic palliative treatments for Parkinson's disease represents a major challenge to avoid the debilitating side effects produced by L-DOPA therapy. Increasing interest is addressed to the selective targeting of group III metabotropic glutamate (mGlu) receptors that inhibit transmitter release at presumably overactive synapses in the basal ganglia. Here we characterize the functional action of a new orthosteric group III mGlu agonist, LSP1-2111, with a preferential affinity for mGlu4 receptor. In mouse brain slices, LSP1-2111 inhibits striatopallidal GABAergic transmission by selectively activating the mGlu4 receptor but has no effect at a synapse modulated solely by the mGlu7 and mGlu8 receptors. Intrapallidal LSP1-2111 infusion reverses the akinesia produced by nigrostriatal dopamine depletion in a reaction time task, whereas an mGlu8-receptor agonist has no effect. Finally, systemic administration of LSP1-2111 counteracts haloperidol-induced catalepsy, opening promising perspectives for the development of antiparkinsonian therapeutic strategies focused on orthosteric mGlu4-receptor agonists.

Joint effects of inbreeding and local adaptation on the evolution of genetic load after fragmentation.

Disruption of gene flow among demes after landscape fragmentation can facilitate local adaptation but increase the effect of genetic drift and inbreeding. The joint effects of these conflicting forces on the mean fitness of individuals in a population are unknown. Through simulations, we explored the effect of increased isolation on the evolution of genetic load over the short and long term when fitness depends in part on local adaptation. We ignored genetic effects on demography. We modeled complex genomes, where a subset of the loci were under divergent selection in different localities. When a fraction of the loci were under heterogeneous selection, isolation increased mean fitness in larger demes made up of hundreds of individuals because of improved local adaptation. In smaller demes of tens of individuals, increased isolation improved local adaptation very little and reduced overall fitness. Short-term improvement of mean fitness after fragmentation may not be indicative of the long-term evolution of fitness. Whatever the deme size and potential for local adaptation, migration of one or two individuals per generation minimized the genetic load in general. The slow dynamics of mean fitness following fragmentation suggests that conservation measures should be implemented before the consequences of isolation on the genetic load become of concern.

Targeting group III metabotropic glutamate receptors produces complex behavioral effects in rodent models of Parkinson's disease.

Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to L-DOPA (L-3,4-dihydroxyphenylalanine) for the treatment of Parkinson's disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/microl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after L-AP4 (1 nmol) or picrotoxin, a GABA(A) receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. L-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.

Functional interaction between adenosine A2A and group III metabotropic glutamate receptors to reduce parkinsonian symptoms in rats.

Non-dopaminergic drugs acting either on adenosine A2A or metabotropic glutamate (mGlu) receptors reduce motor impairment in animal models of Parkinson's disease (PD), suggesting a possible functional interaction between these receptors to regulate basal ganglia function. The present study therefore tested the behavioural effects of compounds acting selectively on A2A or on specific mGlu receptor subtypes, alone or in combination, in rodent models of PD. Acute administration of the adenosine A2A receptor antagonists CSC or MSX-3 at the highest doses tested (5 and 1.25mg/kg, respectively) significantly reduces haloperidol-induced catalepsy. Furthermore, the anticataleptic effect of MSX-3 was enhanced by a 3-week treatment. Acute administration of the selective group III mGlu agonist ACPT-I produces potent anticataleptic effects and prolongs time on rotarod of 6-OHDA-lesioned rats. In contrast, acute or chronic administration of MPEP (mGlu5 receptor antagonist) has no anticataleptic action. Furthermore, the acute co-administration of ACPT-I 1mg/kg, but not 5mg/kg, with CSC markedly reduces catalepsy. Opposite effects are observed after a 3-week co-administration. The co-administration of ACPT-I with MSX-3 has anticataleptic effects both after acute or chronic treatment. In contrast, acute combination of subthreshold doses of CSC and MPEP has no effect. After a 3-week treatment, however, the combination of CSC and MPEP was found to reduce haloperidol-induced catalepsy. Altogether, these results show for the first time that systemic activation of group III mGlu receptors with ACPT-I provides benefits in parkinsonian rats and underlie a possible interaction with A2A receptors to regulate basal ganglia motor function.

Synthesis and biological evaluation of 1-amino-2-phosphonomethylcyclopropanecarboxylic acids, new group III metabotropic glutamate receptor agonists.

Stereoisomers of 1-amino-2-phosphonomethylcyclopropanecarboxylic acid (APCPr), conformationally restricted analogues of L-AP4 (2-amino-4-phosphonobutyric acid), have been prepared and evaluated at recombinant group III metabotropic glutamate receptors. They activate these receptors over a broad range of potencies. The most potent isomer (1S,2R)-APCPr displays a similar pharmacological profile as that of L-AP4 (EC50 0.72, 1.95, >500, 0.34 microM at mGlu4, 6, 7, 8 receptors, respectively, and no effect at group I/II mGluRs). It was characterized on native receptors located in the basal ganglia (BG) where it induced a robust and reversible inhibition of synaptic transmission. It was tested in vivo in haloperidol-induced catalepsy, a model of Parkinsonian akinesia, by direct infusion in the globus pallidus of the BG. At a dose of 0.5 nmol/microL, catalepsy was significantly antagonized. This study reveals that (1S,2R)-APCPr is a potent group III mGluR agonist and confirms that these receptors may be considered as a therapeutic target in the Parkinson's disease.

Spatial deficits in a mouse model of Parkinson disease.

RATIONALE: Accumulating evidence in humans demonstrated that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson disease (PD). These deficits have been generally attributed to cortical dopamine degeneration. However, more recent evidence suggests that dopamine loss in the striatum is responsible for the visuo-spatial abnormalities in PD. Studies based on animal models of PD did not specifically address this question. OBJECTIVES: Thus, the first goal of this study was to analyze the role of dopamine within the dorsal striatum in spatial memory. We tested bilateral 6-OHDA striatal lesioned CD1 mice in an object-place association spatial task. Furthermore, to see whether the effects were selective for spatial information, we measured how the 6-OHDA-lesioned animals responded to a non-spatial change and learned in the one-trial inhibitory avoidance task. RESULTS: The results demonstrated that bilateral (approximately 75%) dopamine depletion of the striatum impaired spatial change discrimination. On the contrary, no effect of the lesion was observed on non-spatial novelty detection or on passive avoidance learning. CONCLUSIONS: These results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.

Interaction between the mGlu receptors 5 antagonist, MPEP, and amphetamine on memory and motor functions in mice.

RATIONALE: Metabotropic glutamate mGlu receptors 5 (mGluR5) receptors are abundant in corticolimbic circuitry where they modulate glutamate and dopamine signal transduction. OBJECTIVES: In this study, we explored the hypothesis that mGluR5 antagonist, (2-methyl-6-(phenylethynyl)pyridine hydrochloride) (MPEP), facilitates dopamine-dependent effects on memory and motor functions. METHODS: To this aim, we examined the effects of different doses (from 0 to 24 mg/kg) of the mGluR5 antagonist, MPEP, on the modulation of amphetamine-dependent behaviors, namely passive avoidance, locomotor activity, and rotation behavior in intact and dopamine-depleted CD1 male mice. RESULTS: We demonstrated that a low dose (3 mg/kg) of MPEP, which is void of behavioral effects on its own, facilitates amphetamine-induced effects independently on the behavior measured both in naïve and in dopamine-lesioned mice; this synergistic effect is lost when higher doses of MPEP are used. CONCLUSION: The results are discussed in terms of possible balance between dopamine and glutamate activity in regulating the proper fine tuning of information processing.

Activation of metabotropic glutamate 4 receptors decreases L-DOPA-induced dyskinesia in a mouse model of Parkinson's disease.

Group III metabotropic glutamate (mGlu) receptors modulate glutamatergic and GABAergic transmission in the basal ganglia. In this study, we examined a novel orthosteric agonist at the mGlu4 receptor, LSP1-2111, for its ability to affect L-DOPA-induced dyskinesia (LID), in a mouse model. In 6-OHDA-lesioned mice treated with L-DOPA, chronic co-administration of LSP1-2111 significantly attenuated the development of abnormal involuntary movements, which are regarded as a marker of dyskinesia. In contrast, a single injection of LSP1-2111 did not modify the expression of LID, once this condition had been established by previous administration of L-DOPA. LSP1-2111 did not affect L-DOPA-induced cAMP and extracellular signal-regulated protein kinase signaling, which have been previoulsy implicated in dyskinesia. These results indicate that co-administration of LSP1-2111 may improve the efficacy of standard L-DOPA therapy by attenuating its liability for dyskinesia.

Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32.

Administration of typical antipsychotic drugs, such as haloperidol, promotes cAMP-dependent signaling in the medium spiny neurons (MSNs) of the striatum. In this study, we have examined the effect of haloperidol on the state of phosphorylation of the ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. We found that haloperidol increases the phosphorylation of rpS6 at the dual site Ser235/236, which is involved in the regulation of mRNA translation. This effect was exerted in the MSNs of the indirect pathway, which express specifically dopamine D2 receptors (D2Rs) and adenosine A2 receptors (A2ARs). The effect of haloperidol was decreased by blockade of A2ARs or by genetic attenuation of the Gα(olf) protein, which couples A2ARs to activation of adenylyl cyclase. Moreover, stimulation of cAMP-dependent protein kinase A (PKA) increased Ser235/236 phosphorylation in cultured striatal neurons. The ability of haloperidol to promote rpS6 phosphorylation was abolished in knock-in mice deficient for PKA activation of the protein phosphatase-1 inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa. In contrast, pharmacological or genetic inactivation of p70 rpS6 kinase 1, or extracellular signal-regulated kinases did not affect haloperidol-induced rpS6 phosphorylation. These results identify PKA as a major rpS6 kinase in neuronal cells and suggest that regulation of protein synthesis through rpS6 may be a potential target of antipsychotic drugs.

Metabotropic glutamate receptors 5 blockade reverses spatial memory deficits in a mouse model of Parkinson's disease.

Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudate-putamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.

Identification in Saccharomyces cerevisiae of a new stable variant of alkyl hydroperoxide reductase 1 (Ahp1) induced by oxidative stress.

Yeasts lacking cytoplasmic superoxide dismutase (Cu,Zn-SOD) activity are permanently subjected to oxidative stress. We used two-dimensional PAGE to examine the proteome pattern of Saccharomyces cerevisiae strains lacking Cu,Zn-SOD. We found a new stable form of alkyl hydroperoxide reductase 1 (Ahp1) with a lower isoelectric point. This form was also present in wild type strains after treatment with tert-butyl hydroperoxide. In vitro enzyme assays showed that Ahp1p had lower specific activity in strains lacking Cu,Zn-SOD. We studied three mutants presenting a reduced production of the low pI variant under oxidative stress conditions. Two of the mutants (C62S and S59D) were totally inactive, thus suggesting that the acidic form of Ahp1p may only appear when the enzyme is functional. The other mutant (S59A) was active in vitro and was more resistant to inactivation by tert-butyl hydroperoxide than the wild type enzyme. Furthermore, the inactivation of Ahp1p in vitro is correlated with its conversion to the low pI form. These results suggest that in vivo during some particular oxidative stress (alkyl hydroperoxide treatment or lack of Cu,Zn-SOD activity but not hydrogen peroxide treatment), the catalytic cysteine of Ahp1p is more oxidized than cysteine-sulfenic acid (a natural occurring intermediate of the enzymatic reaction) and that cysteine-sulfinic acid or cysteine-sulfonic acid variant may be inactive.