Neuroscience
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The centrally-projecting Edinger-Westphal nucleus (EWcp) has been shown to contribute to regulation of multiple functions, including responses to stress and fear, attention, food consumption, addiction, body temperature and maternal behaviors. However, receptors involved in regulation of these behaviors through EWcp remain poorly characterized. On the other hand, the oxytocin peptide (OXT) is also known to regulate a substantial number of physiological responses and behaviors. ⋯ A follow up study showed that injection of OXT (2.3 or 7.7 mg/kg, IP) is accompanied by a decrease in body temperature. Since EWcp is known to be involved in regulation of body temperature, we hypothesize that OXT's effects on body temperature could be mediated through the EWcp. The contribution of OXTR in EWcp to regulation of various functions of EWcp and OXT needs to be deciphered.
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Endocytosis of GluA2-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in CA1 of the hippocampus regulates forgetting; deficits in forgetting nociceptive memory can induce serious stress disorders. As a transporter of GluA2-containing AMPAR, the functions of glutamate receptor interacting protein 1 (GRIP1) in forgetting and possible stress responses remain unclear. Lentivirus-mediated interference of GRIP1 expression or function in the dorsal CA1 of the hippocampus in mice indicated that GRIP1 overexpression enhanced spatial memory, impaired forgetting in a Barnes maze, and induced anxiety-like behavior in the open field and elevated plus-maze test. ⋯ In vitro experiments showed that GRIP1-ov and -dn, inhibition of PDZ2 and PDZ4/5 domains of GRIP1, and GluA2-dn decreased glycine-induced GluA1 and GluA2 exocytosis; meanwhile, GRIP1-ov and -dn, and interference of PDZ2 and PDZ4/5 domains of GRIP1 blocked AMPA- and NMDA-induced GluA1 and GluA2 endocytosis. Overall, these results suggest that GRIP1 drives AMPA receptor endocytosis and exocytosis bidirectionally; furthermore, GRIP1-induced stabilization of anchoring postsynaptic GluA1 and GluA2 impairs forgetting and induces anxiety-like behavior. GRIP1 may provide a potential therapeutic target in posttraumatic syndromes and anxiety disorders.
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Comparative Study
Comparison of Golgi-Cox and intracellular loading of Lucifer yellow for dendritic spine density and morphology analysis in the mouse brain.
Dendritic spines are small protrusions on dendrites that serve as the postsynaptic site of the majority of excitatory synapses. These structures are important for normal synaptic transmission, and alterations in their density and morphology have been documented in various disease states. Over 130 years ago, Ramón y Cajal used Golgi-stained tissue sections to study dendritic morphology. ⋯ In the mPFC, head diameter was similar for Golgi staining and LY microinjection. However, in CA1, head diameter was approximately 50% smaller on LY-filled dendrites compared to Golgi staining. These results indicate that Golgi staining and LY microinjection yield different spine density and morphology measurements, with Golgi staining failing to detect dendritic spines and overestimating spine size.
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Here, neuromodulatory effects of selective angiotensin-converting enzyme 2 (ACE2) inhibitors were investigated. Two different types of small molecule ligands for ACE2 inhibition were selected using chemical genetic approach, they were synthesized using developed chemical method and tested using presynaptic rat brain nerve terminals (synaptosomes). EBC-36032 (1 µM) increased in a dose-dependent manner spontaneous and stimulated ROS generation in nerve terminals that was of non-mitochondrial origin. ⋯ Therefore, synthesized selective ACE2 inhibitors decreased uptake of glutamate and GABA as well as exocytosis of GABA at the presynaptic level. The initial rate of glutamate uptake was the only parameter that was mitigated by both ACE2 inhibitors despite stereochemistry issues. In terms of ACE2-targeted antiviral/anti-SARS-CoV-2 and other therapies, novel ACE2 inhibitors should be checked on the subject of possible renin-angiotensin system (RAS)-independent neurological side effects.
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Parkinson's disease (PD) is a complex and multifactorial neurodegenerative disease. The main pathological feature of PD is the loss or apoptosis of dopaminergic neurons in the substantia nigra (SN). This study aimed to investigate the protective effect of cannabidiol (CBD) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuronal dopamine injury by inhibiting neuroinflammation, which was one of the factors that cause neuronal apoptosis. ⋯ Mechanistically, CBD up-regulated the expression of Bcl-2, down-regulated the levels of Bax and Caspase-3, and repressed the expression of NLRP3/caspase-1/IL-1β inflammasome pathway. In summary, CBD has a therapeutic effect on MPTP-induced PD mice by inhibiting the apoptosis of dopaminergic neurons and neuroinflammation. Therefore, CBD is a potential candidate for PD therapy.