Awake perception is associated with dedicated neuronal assemblies in the cerebral cortex.

Neural activity in the sensory cortex combines stimulus responses and ongoing activity, but it remains unclear whether these reflect the same underlying dynamics or separate processes. In the present study, we show in mice that, during wakefulness, the neuronal assemblies evoked by sounds in the auditory cortex and thalamus are specific to the stimulus and distinct from the assemblies observed in ongoing activity. By contrast, under three different anesthetics, evoked assemblies are indistinguishable from ongoing assemblies in the cortex. However, they remain distinct in the thalamus. A strong remapping of sensory responses accompanies this dynamic state change produced by anesthesia. Together, these results show that the awake cortex engages dedicated neuronal assemblies in response to sensory inputs, which we suggest is a network correlate of sensory perception.

Deep imaging in the brainstem reveals functional heterogeneity in V2a neurons controlling locomotion.

V2a neurons are a genetically defined cell class that forms a major excitatory descending pathway from the brainstem reticular formation to the spinal cord. Their activation has been linked to the termination of locomotor activity based on broad optogenetic manipulations. However, because of the difficulties involved in accessing brainstem structures for in vivo cell type-specific recordings, V2a neuron function has never been directly observed during natural behaviors. Here, we imaged the activity of V2a neurons using micro-endoscopy in freely moving mice. We find that as many as half of the V2a neurons are excited at locomotion arrest and with low reliability. Other V2a neurons are inhibited at locomotor arrests and/or activated during other behaviors such as locomotion initiation or stationary grooming. Our results establish that V2a neurons not only drive stops as suggested by bulk optogenetics but also are stratified into subpopulations that likely contribute to diverse motor patterns.

The phosphodiesterase inhibitor, ibudilast, attenuates neuroinflammation in the MPTP model of Parkinson's disease.

BACKGROUND/AIMS: Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson's disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. METHODS: IBD [0, 20, 30, 40, or 50 mg/kg] was injected b.i.d. subcutaneously for nine days to three-month-old male C57Bl/10Tar mice, beginning two days prior to MPTP (60 mg/kg) intoxication. High-pressure liquid chromatography, Western blot analysis, and real time RT-PCR methods were applied. RESULTS: Our study demonstrated that chronic administration of IBD attenuated astroglial reactivity and increased glial cell-derived neurotrophic factor (GDNF) production in the striatum. Moreover, IBD reduced TNF-α, IL-6, and IL-1ß expression. CONCLUSION: IBD had a well-defined effect on astroglial activation in the mouse model of PD; however, there was no protective effect in the acute phase of injury. Diminished inflammation and an increased level of GDNF may provide a better outcome in the later stages of neurodegeneration.

Ibudilast: a non­selective phosphodiesterase inhibitor in brain disorders.

Ibudilast (IBD) is a non­selective (3, 4, 10, 11) phosphodiesterase (PDE) inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response) by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro­inflammatory cytokines (IL­6, IL­1ß, TNF­α), toll­like receptor 4 blockade (TLR­4), inhibition of a macrophage migration inhibitory factor (MIF), up­regulation the anti­inflammatory cytokine (IL­10), and promotion of neurotrophic factors (GDNF, NGF, NT­4). Recent data indicate that the efficacy of IBD appears to be independent from PDE inhibition activity and rather linked to glial activity attenuation. Additional advantages of IBD, such as crossing the blood-brain barrier, good tolerance and activity by oral administration, makes it a promising therapeutic candidate for treating neuroinflammatory conditions, where the currently available treatment remains unsatisfying due to poor tolerability and/or sub­optimal efficacy. IBD has no direct receptor affinity with exemption of some undefined effect on adenosine receptors that makes the drug devoid of its receptors­mediated adverse effects. Current article provides an overview of the pharmacology of IBD with a focus on preclinical and clinical data supporting its potential neuroprotective benefits for neurological conditions, including multiple sclerosis, neuropathic pain, medication overuse headache, stroke, opioid, alcohol and methamphetamine abuse.

Exogenous α-Synuclein Monomers Alter Dopamine Metabolism in Murine Brain.

Alpha-synuclein (ASN) is a small presynaptic protein which is the major component of Lewy bodies-the histological hallmark of Parkinson's disease. Among many functions, ASN plays an important role in regulation of dopaminergic system by controlling dopamine concentration at nerve terminals. An abnormal structure or excessive accumulation of ASN in the brain can induce neurotoxicity leading to the dopaminergic neurodegeneration. To date, several transgenic mouse lines overexpressing ASN have been generated and there are several studies using injections of ASN fibrils into the murine brain. However, still is little known about the effects of exogenously applied ASN monomers on dopaminergic neurotransmission. In this study we investigated the influence of cerebral injection of human ASN on dopaminergic system activity. We have demonstrated that a single injection of ASN monomers into the substantia nigra pars compacta or striatum is sufficient to affect dopaminergic neurotransmission in murine nigro-striatal system.

The influence of AAV2-mediated gene transfer of human IL-10 on neurodegeneration and immune response in a murine model of Parkinson's disease.

BACKGROUND: The aim of this study was to examine the effect of AAV2-hIL-10 (vector containing cDNA for human interleukin 10) on dopaminergic system activity (measured as DA levels and TH mRNA expression in mouse striata), and other monoamine and amino acid neurotransmitters concentration as well as development of inflammatory processes (measured as TGF-ß, IFN-γ and GFAP mRNA expression) in a murine MPTP neurotoxicant model of Parkinson's disease. METHODS: Male C57BL/6 mice 12 months-old were used in this study. AAV2-hIL-10 vector was bilaterally administered into striatum at 14, 21 or 28 days prior to MPTP intoxication. Animals were sacrificed at 7 days following MPTP injection. The expression of hIL-10 (human interleukin 10) was examined by ELISA. Striatal monoamine and amino acid neurotransmitters were measured by HPLC method. TH, TGF-ß, IFN-γ and GFAP mRNA expression was examined by RT-PCR method. RESULTS: MPTP treatment dramatically reduced DA levels and decreased TH mRNA expression in mouse striata, effects that were significantly impeded by AAV2-hIL-10 administration prior to MPTP intoxication. AAV2-hIL-10 infusion increased IFN-γ, TGF-ß and GFAP mRNA expression. CONCLUSIONS: Our data suggest that the transfer of AAV2-hIL-10 into the striatum may play a neuroprotective role in the mouse MPTP model of PD and these effects are mediated by the anti-inflammatory action of IL-10.

Effect of human interleukin-10 on the expression of nitric oxide synthases in the MPTP-based model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. The degeneration of the nigro-striatal pathway has been linked with the inflammatory process accompanied by the robust up-regulation of the nitric oxide synthase (NOS) and production of the neurotoxic level of nitric oxide (NO). One of the therapeutic strategies of PD is based on the reduction of the detrimental neuroinflammatory markers in the lesioned nigro-striatal pathway. In this study we have investigated the neuroprotective effect of the cerebral infusion of recombinant adeno-associated viral vector, expressing the gene for human interleukin-10 (AAV2-hIL-10) in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It is known that IL-10 is a potent anti-inflammatory cytokine that limits the inducible nitric oxide synthase (iNOS) gene expression. METHODS: The striatal iNOS, neuronal nitric oxide synthase (nNOS) and tyrosine hydroxylase (TH) protein expression was evaluated by immunoblot analysis. RESULTS: The intracerebral injection of the AAV2-hIL-10, before the lesion, induced the upregulation of the striatal TH protein, depleted by MPTP intoxication. This AAV2-hIL-10-induced increase of TH level was associated with the suppression of iNOS protein expression in the lesioned striatum. CONCLUSION: The results revealed protective properties of AAV2-hIL-10.