Neuroscience
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Clinical trials of new drugs for Alzheimer's disease (AD) have ended with disappointing results, with tremendous resources and time. Repositioning of existing anti-cancer epidermal growth factor receptors (EGFR) inhibitors in various preclinical AD models has gained growing attention in recent years because hyperactivation of EGFR has been implicated in many neurodegenerative disorders, including AD. Many recent studies have established that EGFR inhibition suppresses reactive astrocytes, enhances autophagy, ameliorates Aβ toxicity, neuroinflammation, and regenerates axonal degradation. ⋯ In this perspective article, we recap recent studies to merge data on the neuroprotective effects of EGFR inhibition. By consequent analysis of previous data, we notably find the under-investigated neuroprotective pathways that highlight the importance of additional research of EGFR inhibitors in attempts to be repurposed as burgeoning therapeutic strategies for AD. Finally, we will discuss future prospective challenges in the repositioning of EGFR inhibitors in AD.
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Alcohol use disorder is one of the most prevalent addictions, strongly influenced by environmental factors. Voluntary physical activity (VPA) has proven to be intrinsically reinforcing and we hypothesized that, as a non-drug reinforcer, VPA could mitigate ethanol-induced rewarding effects. The transcriptional factor cAMP response element binding protein (CREB), and deacetylases isozymes sirtuins 1 and 2 (SIRT-1 and SIRT-2) have a complex interplay and both play a role in the rewarding effects of ethanol. ⋯ Both VPA groups presented lower SIRT-1 levels in the NAc compared to the Sedentary groups. Thus, exposure to running wheels prevented ethanol-rewarding effects and ethanol-induced increases in CREB in the NAc. The molecular alterations underlying CPP prevention may be related to a lower expression of CREB in the NAc of Ethanol-VPA compared to the respective Sedentary group, given the positive correlation between CPP and CREB levels in the Ethanol-Sedentary group.
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The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. ⋯ We interpret these findings as evidence for an altered cognitive appraisal of the potential threatening stimulus. Consequently, the orexin system seems to bias the perception of stimuli towards danger or threat via OX1R and OX2R in the PL.
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Bipolar I disorder (BD-I) is associated with high-risk behaviors, such as suicide attempts and addictive substance abuse. Understanding brain activity exposure to risk decision making provides evidence for the treatment of BD-I patients. This study aimed to investigate the temporal dynamics of brain connectivity underlying risk decision making in patients with BD-I. ⋯ Moreover, the dEC of left supramarginal gyrus (SMG) influenced those of left orbital frontal and right cuneus (CUN), as well as the affective symptoms and BART behaviors in patients with BD-I. Our results suggested that the altered temporal dynamics of brain connectivity might contribute to the impulsivity of BD-I during resting and task states. More importantly, the left SMG might be a therapeutic target to reduce the risk behavior in BD-I patients.
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Circadian rhythms are regulated by a set of brain structures, one of which is the Intergeniculate Leaflet of the Thalamus (IGL). The most recognised role of the IGL is the integration of a variety of stimuli affecting rhythmicity, such as lighting conditions, received by the eye, or light-independent (non-photic) cues, the information about which is delivered via the activation of the non-specific projections. One of them is the norepinephrinergic system originating in the brainstem Locus Coeruleus (LC). ⋯ Using both agonists and antagonists of specific NE receptor subtypes, we confirmed the presence of functional α1-, α2- and β-adrenergic receptors within the investigated structure, allowing NE to exert multiple types of effects on different IGL neurons, mainly depolarisation of the neurons projecting to the Suprachiasmatic Nuclei - the master circadian pacemaker, and various responses exhibited by the cells creating the connection with the contralateral IGL. Moreover, NE was shown to affect IGL cells both directly and via modulation of the synaptic network, in particular the miniature inhibitory postsynaptic currents. To the best of our knowledge, these are the first studies to confirm the effects of NE on the activity of the IGL network.