Neuroscience
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Acetylcholine (ACh) acts through nicotinic and muscarinic ACh receptors in the ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson's disease, and schizophrenia. α6-Containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. ⋯ To complement these behavioral studies, we studied the ability of in vivo α6(∗) nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch-clamp electrophysiology, we show that activating α6(∗) nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in ventral tegmental area (VTA) DA neurons. Together, these results from in vivo studies strongly suggest that α6(∗) nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine.
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Comparative Study
Electron tomographic structure and protein composition of isolated rat cerebellar, hippocampal and cortical postsynaptic densities.
Electron tomography and immunogold labeling were used to analyze similarities and differences in the morphology and protein composition of postsynaptic densities (PSDs) isolated from adult rat cerebella, hippocampi, and cortices. There were similarities in physical dimensions and gross morphology between cortical, hippocampal and most cerebellar PSDs, although the morphology among cerebellar PSDs could be categorized into three distinct groups. The majority of cerebellar PSDs were composed of dense regions of protein, similar to cortical and hippocampal PSDs, while others were either composed of granular or lattice-like protein regions. ⋯ The scaffold molecule PSD-95, a major component of cortical PSDs, was found absent in a fraction of cerebellar PSDs and when present was clustered in its distribution. In contrast, immunogold labeling for the proteasome was significantly more abundant in cerebellar and hippocampal PSDs than cortical PSDs. Together, these results indicate that PSDs exhibit remarkable diversity in their composition and morphology, presumably as a reflection of the unique functional demands placed on different synapses.
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Sensory events in the space around us trigger specific motor patterns directed toward or away from the spatial location of the sensory source. Spatially-defined sensorimotor associations are well-known in the visual domain but less so for the auditory modality. In particular no spatially-directed audio-motor association has been described for the upper limb. ⋯ We show the presence in the upper limb motor system of auditory spatial tuning. Sound information accesses the motor system at very short latency, potentially compatible with both a subcortical and a cortical origin of the response. The use of TMS-evoked accelerations allowed us to disclose a strict directional tuning in audio-motor associations.
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Sulfuretin, one of the major flavonoid glycosides found in the stem bark of Albizzia julibrissin and heartwood of Rhus verniciflua, is a known anti-oxidant. We previously demonstrated that sulfuretin inhibits neuronal death via reactive oxygen species (ROS)-dependent mechanisms in human SH-SY5Y cells, although other relevant mechanisms of action of this compound remain largely uncharacterized. As part of our ongoing exploration of the pharmacological actions of sulfuretin, we studied the neuroprotective effects of sulfuretin against amyloid beta (Aβ)-induced neurotoxicity in human SH-SY5Y and primary hippocampal neuron cells and investigated the possible mechanisms involved. ⋯ Notably, we found that the neuroprotective effects of sulfuretin were diminished by an Nrf2 small interfering RNA (siRNA), the HO-1 inhibitor zinc protoporphyrin IX (ZnPP), as well as the PI3K/Akt inhibitor LY294002. Taken together, these results indicated that sulfuretin protects neuronal cells from Aβ25-35-induced neurotoxicity through activation of Nrf/HO-1 and PI3K/Akt signaling pathways. Our results also indicate that sulfuretin-induced induction of Nrf2-dependent HO-1 expression via the PI3K/Akt signaling pathway has preventive and/or therapeutic potential for the management of Alzheimer's disease.
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Alcohol hangover (AH) is defined as the temporary state after alcohol binge-like drinking, starting when ethanol (EtOH) is absent in plasma. Previous data indicate that AH induces mitochondrial dysfunction and free radical production in mouse brain cortex. The aim of this work was to study mitochondrial function and reactive oxygen species production in mouse cerebellum at the onset of AH. ⋯ Related to nitric oxide (NO) metabolism, neuronal nitric oxide synthase (nNOS) protein expression was 52% decreased by the hangover condition compared with control group. No differences were found in cerebellum NO production between control and treated mice. The present work demonstrates that the physiopathological state of AH involves mitochondrial dysfunction in mouse cerebellum showing the long-lasting effects of acute EtOH exposure in the central nervous system.